The lOth Congress of the International Pediatric Nephrology Association August 27 - September 1,1995 Santiago, Chile

Abstracts

Springer

FOREWORD Welcome to Santiago, Chile and to the Tenth Congress of the International Pediatric Nephrology Association. We are deeply grateful to the IPNA Council for allowing us to host this important event, and hope that the meeting and your visit to our country are rewarding and pleasant. The Organizing Committee would like to thank all of those, both within and outside of Chile, who have helped us to prepare the Scientific Program. This Congress would not have been possible without their counsel and support. Special recognition is due to those who have accepted to share with us the results of their research endeavors. In the selection of the topics we have been guided by the desire to highlight the progress made in pediatric nephrology since our last international encounter. Emphasis was placed on those areas of medical science that profoundly affected our understanding of the mechanisms that promote normal kidney development or interfere with this process. Prominent among those are the control of renal growth and differentiation, the role of adhesion molecules in health and disease, the application of molecular biologic techniques to the diagnosis of inherited renal diseases, the role of free radicals and nitric oxide in renal injury, the mechanism of immunologically induced kidney damage, and the development of new drugs designed to prevent or suppress allograft rejection. This book provides, in abstract form, a preview of our debates. It should help the participants to select the sessions they want to attend, and serve as a reminder of the things they learned. Above all, however, it represents a symbol of the efforts made by international community for pediatric nephrologists to improve the condition of children affected by renal disease.

Dr. Carlos Saieh-Andonie President

Dr. Edda Lagomarsino Chairman Scientific Committee

TABLE OF CONTENTS

STATE OF THE ART LECTURES SA.2 Cell Biology of Kidney Development SA.3 Hormonal Disturbances in Chronic Renal Failure SA.5 Mechanisms of Glomerular Injury SYMPOSIA

S.1 S.2 S.3 S.4 S.5 S.6 S.7 S.8 S.9 S.11 S.12 S.15 S.16 S.17 S.18 S.19 S.20 S.21 S.22 S.23 S.24 S.25 S.26 S.27 S.28

Control of Growth and Differentiation Diseases due to Disturbances in Renal Development Adhesion Molecules Health and Disease Acute Renal Failure Fetal and Neonatal Renal Physiology Intracellular Mediators of Cell Function Prevention for Progression of Renal Disease Genetics and Pathophysiology of Cystic Renal Disease Clinical Aspects of Inherited Renal Disease Toxic Nephropathies Mechanism of Allograft Rejection and new Immunosuppressive Drugs IgA Nephropathy and Henoch-Sch6nlein Purpura Late Consequences of Renal Transplantation Adequacy of Dialysis Urinary Tract Infection, Pyelonephritls and Vesicoureteric Reflux Ion and Water Channels in Health and Disease Autocrine and Paracrine Factors in the Regulation Renal Function Clinical Disorders of Electrolyte Transport Mineral Metabolism HUS: Epidemiology and Prognosis Clinical Trials and Multicenter Studies Mediators of Renal Injury (Free Radicals, C Oxide) Post-Infectious Glomerulonephritis Urolithiasis and Nephrocalcinosis Treatment of Glomerular Diseases

FREE

COMMUNICATIONS

FC001 - F C 0 0 6

E x p e r i m e n t a l and D e v e l o p m e n t a l Renal P h y s i o l o g y

FC007 - F C 0 1 2

Glomerulonephritis

FC013 - FC018

Chronic Renal Failure

FC019 - F C 0 2 4

H e r e d i t a r y Renal Failure

FC025 - F C 0 3 0

N e o n a t a l Renal P h y s i o l o g y

FC031 - F C 0 3 6

Nephrotic Syndrome

FC037 - FC041

Dialysis

F C 0 4 2 - FC047

U r i n a r y Tract Infections

FC048 - FC053

A c u t e R e n a l Failure

F C 0 5 4 - FC059 F C 0 6 0 - FC065 FC066 - FC070

Transplantation

POSTER

Mineral Metabolism Hypertension

SESSIONS

P001 - P024

Renal P h y s i o l o g y

P025 - P058

Glomerulonephritis

P059 - P89.1 P090 - P 1 0 8 P109 - P l 1 8

C h r o n i c Renal Failure H e r e d i t a r y Renal Disease N e o n a t a l Renal P h y s i o l o g y

Pl19 - P150 P151 - P175.1

Nephrotic Syndrome

P176 - P208

U r i n a r y Tract Infections

P209 - P230

A c u t e Renal Failure

P231 - P257

Transplantation

P258 - P274 P275 - P281

Mineral Metabolism Hypertension

Dialysis

C12 STATE

OF THE

ART

LECTURES

(SA)

SA - 002

THE CELL BIOLOGY OF KIDNEY DEVELOPMENT Sanjay K. Nigam*

SA - 003

HORMONAL DISTURBANCES IN CHRONIC RENAL FAILURE O. Mehls, B. T6nshoff, D. Haffner, E. W~hl, F. Schaefer

...............................................................

Development of the metanephric or adult kidney begins with a mutual induction between epithelial cells of the ureteric bud and surrounding mesenchymal cells. Through a process of branching tubulogenesis, the ureteric bud gives rise to the collecting system. With the exception of the glomerular basement membrane, the rest of the nephron derives from cells of the metanephric mesenchyme after they have undergone a mesenchymal to epithelial transition. Thus, the process which results in formation of the nephron requires coordinated interaction of many cell types of different embryonic derivation, all in various stages of differentiation. In order to better understand this complex orchestration, many investigators have resorted to the use of model systems, including: 1) organ culture of the embryonic kidney, 2) cell culture systems to understand cell differentiation, as well as the biogenesis of intercellular junctions and apical-basolateral polarity in developing tubules, 3) cell culture systems for the study of branching morphogenesis such as occurs in the developing collecting system, and 4) genetically engineered (transgenic and knockout) mice. Using these model systems, growth factors, receptor tyrosine kinases, intracellular signalling molecules and transcription factors have been strongly implicated in nephrogenesis. In most cases, however, precise molecular and cellular mechanisms remain to be worked out. Since a substantial fraction of pediatric renal disease has a developmental component, it is likely that, as the molecular and cellular understanding of nephrogenesis improves, so will our understanding of the pathogenesis of these diseases. *Renal Division, Dept. of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115

SA - 005

MECHANISMS OF GLOMERULAR INJURY RJ. Johnson, University of W a s h i n g t o n , Seattle, W A , USA

Studies in experimental and human glomerular disease have demonstrated that endogenous glomerular cells, and particularly the mesangial cell, respond to injury with several characteristic responses. For example, in the rat model of mesangial proliferative nephritis (Thy 1 model), the mesangial cell proliferates, undergoes a phenotypic change in which it acquires characteristics ofa myofibroblast, and secretes excess mesangial matrix. The cell proliferation is partially mediated by platelets (which are rich in growth factors), basic fibroblast growth factor (bFGF) (released from injured mesangial cells) and platelet-derived growth factor (PDGF) (released from platelets and mesangial cells). Distinct from the proliferative response, the mesangial cell acquires smooth muscle and fibroblast-like properties similar to myofibroblasts in healing wounds. This response, as well as the marked increase in extracellular matrix production, appears to be mediated by transforming growth factor-[3 (TGF-I]). These proliferative, phenotypic, and sclerosing changes in mesangial cells can also be documented in progressive glomemlar diseases in both animals and man. Reparative processes are also operative within glomemli to counter these processes. This includes release of factors that terminate the proliferation (such as the protein SPARC), resolve the hypercellularity (by programmed cell death or apoptosis) and resorb excess matrix (via the release of proteases, especially the 72 Kd gelatinase). Capillaries can also be repaired by the process of angiogenesis. This involves a proliferative response of the glomerular endothelial cell and is associated with increased expression of vascular endothelial growth factor (VEGF) and VEGF receptors. The balance between the reparative and destructive processes may ultimately determine whether the glomerulus recovers or progresses to end stage. The use of new therapies to aid recovery (gene therapy) will also be discussed.

Whereas decreased hormonal levels in uremia point to a decreased production rate, increased levels are either due to increased production rate, decreased extrarenal metabolic clearance, or decreased renal metabolic clearance. The growth hormone (GH) production rate in chronic renal failure (CRF) is slightly reduced (mainly in late pubertal children) but may be increased in individual patients with end-stage renal failure (ESRF). In patients with ESRF the metabolic clearance of GH is decreased by 50% as an effect of reduced renal clearance, whereas the extrarenal clearance does not show a compensatory increase. The interaction of GH with the target organ is disturbed in uremia: The GH binding protein (BP) is reduced and the GH receptor mRNA is less expressed. Insulin-like growth factor (IGF)-I production rate is reduced, whereas serum IGFBPs accumulate. This results in a low IGF-I bioactivity. The negative correlation between glomerular filtration rate .and serum concentration of IGFBPs points to an accumulation of IGFBPs following reduced renal filtration of low molecular weight fragments. In renal transplant patients, GHBP serum concentration is reduced, IGFBP-3 increased, and IGF-I bioactivity reduced. This seems to be a direct consequence of corticosteroid treatment. Treatment with rhGH normalizes IGF bioactivity and improves growth in short children with CRF and after renal transplantation. University Children's Hospital of Heidelberg, Germany

C13 SYMPOSIA

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$1. C o n t r o l o f G r o w t h a n d D i f f e r e n t i a t i o n

S1.1

CONTROL OF PROLIFERATION, POLARIZATION AND DIFFERENTIATION IN HUMAN NEPHROGENESIS Patdcia D. Wilson Mammalian renal development is characterized by reciprocal induction between the ingrowing, branching ureteric bud and the metanephric mesenchyme leading to conversion of undifferentiated nephroblasts into polarized epithelia with characteristics of different segments of the nephron. An in vitro cell culture model system has been developed in which undifferentiated human renal progenitor cells (12-17 weeks gestation) can be proliferated and subsequently induced to differentiate into epithelia (PNAS 90: 6066-6070, 1993). Control of renal progenitor cell number during nephrogenesis is dependent on an appropriate balance between proliferation and apoptosis. The in vitro system has shown that pfoliieration is dependent on a protein secreted by a Wilms' tumor cell line, G401, while other proteins appear to act as survival factors and may protect against apoptosis. Epithelial differentiation can be induced in vitro by treatment with media containing 10% serum. Different morphological characteristics of epithelial or fibroblast differentiation were induced by midkine, HGF or PDGF-BB, suggesting the possibility for roles of different growth factors in the control of differentiation of particluar cell lineages. Epithelial differentiation is characterized by acquisition of polarity. Immature epithelia express rudimentary apical microvilli and intercellular tight iunctions but many membrane proteins fail to express their mature polarized distribution patterns until late in gestation or until after birth. Mechanisms regulating the immature, apical localization of NaK-ATPase have been studied in detail and shown to be associated with the additional expression of the beta-2 isoform, not seen in normal adult kidneys. Abnormalities in the molecular control of renal cell proliferation, epithelial differentiation and polarization can lead to important real functions in adults, and may lead to cyst formation as in polycystic kidney diseases. * Divisionof Nephrology-TheJohnsHopkinsSchoolof Medicine-Baltimore- USA

S1.3 GROWTH FACTOR-RECEPTOR INTERACTIONS IN P R O L I F E R A T I O N AND D I F F E R E N T I A T I O N Emanuela Ferretti*, Elena Torban*, Cynthia Goodyer*, Jerry Pelletier** and Paul Goodyer* In response to signals from each branch of the ureteric bud, adjacent m e t a n e p h r i c cells are induced to cluster and take on an epithelial phenotype. The small cell mass must then undergo a rapid proliferative burst to form the final nephron; control of proliferation appears to be segment-specific. One of the important arbiters of local tubular cell proliferation is the EGF receptor (EGFR), expressed at especially high levels in fetal vs postnatal kidney. We have localized EGFR peptide of 17-week human fetal kidney to proximal and distal tubules at a m o d e r a t e l y advanced stage of differentiation; it was not detected in naive blastema, g l o m e r u l a r epithelial cells, S-shaped body or ureteric bud. In Vitro p r o l i f e r a t i o n of cultured human fetal k i d n e y cells is EGFR-dependent ; EGFR expression and cell division is specifically increased by thyroxine and retinoic acid. Conversely, we have shown that activity of human EGFR and retinoic acid receptor-~ promoters are inhibited by the Wilms' tumour gene product in t r a n s f e c t i o n assays. Thus, local regulation of EGFR expression may account for limited p~oliferation of glomerular epithelial cells at a~stage when other tubular segments are expanding rapidly.

S1.2 TRANSCRIPTIONAL REGULATION OF RENAL GROWTH AND DIFFERENTIATION. CHRISTOPHER R, BURROW* The recent identification of a large number of transcription factor genes of the homeobox , pax, zinc finger and POU classes offer the potential for establishing a molecular basis for the complex pattern of transcriptional control required for the determination of cellular differentiation during kidney otganogenesis. This work has led to the identification of a growing number of genetic mutations which result in renal developmental abnormalities and have established the critical importance of Pax-2, Liml, and Wt-1 in mammalian kidney organogenesis. Although familial disorders of renal development are uncommon, identification of the genetic basis for these mendelian traits can identify crucial regulatory pathways in the molecular control of nephrogenesis and provide important insights into potential mechanisms which form the basis for sporadic devlopmental disorders of the kidney. The newly-identified POU gene KDN- 1 is expressed in a temporally and spatially-restricted pattern during human embryogenesie where expression is restricted to the brain and kidney. Within the developing kidney, KDN- 1 expression is found in the tip and trunk of the ureteric bud as early as 12 weeks of gestation, and is subsequently expressed in the cortical and medullary collecting ducts at 24 weeks of gestational age. Our present data support the conclusion that KDN-1 encodes the developmentally-regulated octamer binding protein OctK and belongs to a restricted subfamily of brain-4 related genes of the POU Ill subclass. The expression of KDN- 1 precedes the differentiation of collecting duct cells into H+ translocating A TPase positive cells of the intercalated ceil lineage. Based on recent immunohistochemical analysis, the pattern of KDN- I protein expression matches that seen by in situ hybridization studies with the KDN- 1 specific probes. The developing ureteric bud epithelial cells express a large number of transcription factor/homeobox genes which have not been organized into a plausible genetic pathway for the regulation of the complex morphogenetic and differentiatlon events which must occur for the proper branching morphogenesis of the bud, induction of the metanephric blastemal cells to initiate nephrogenesis and cellular differentiation events necessary to give rise to the diverse cell types of the collecting duct. This challenge of defining such pathways will require tests of genetic epistasis in defined clonal cell culture systems. * The Johns Hopkins University School of Medicine, Baltimore, MD, U.S.A.

S1.4 CONTROL OF DIFFERENTIATION FUNCTIONS IN DEVELOPMENT ~THE RENIN-ANGIOTENSIN SYSTEM, Norwo0d'~ A. Tufro-MeReddie~ and R.A. Gomez. University of Virginia, Depamnent of Pediatrics, Charlottesville, Virginia, USA 22~08. Angiotemin It (AID, affects the growth of a variety of renal vas~-ular and epithelial cells by interactions with its r receptors, AT-I and AT-2. Inhibition of AT-1 in postnatal rats results in vascular thickening and truncation, tubular dilatation, and fewer, hypoplastig glomeruli suggesting that AT-1 is important for normal renal devel0ptuent. Similar postnatal inhibition of AT-2 does not lead to abnormalities leaving its importance poorly understood. T h e expression and cellular distribution of All receptors during early renal morphogenesis were defined using RT-PCR and in situ radioligand binding autoradiography and marked differcmes in temporal and spatial patterns were found. AT-I mRNA was minimal at El4, but ties highly expressed by E20 and persisted into adulthood. Conversely, AT-2 was most highly expressed during fetal life and was rapidly downsegttlated to tmdotectable levels by postnatal day 21. rmI-AIl binding showed a similar reciprocal pattern where the majority of receptors were AT-2 at El4 changing to equal prevalence of AT-I and AT-2 by E20. AT-2 was localized to the condens~ mesenchyme and differentiating structures while AT-I was found in the d~per, more mature ~phron segments. Metaaephrie organ culture in serum-free, defined media for six days has been used to localize and define the in vitro expression patterns of the components of the renin-angiotemin system. Following culture, RTPeR deteet~l mRNA for both AT-I and AT-2 in roughly equivalent proportions, mirroring the pattern of in rive deveiopmom. M~aumphric ALl contain incte..a,se~l during culture confirming that tissue All production is maintained in this model of renal differentiation. Blockade of the AT-2 receptor with PD123319 throughout the culture p ~ o d resulted m increased glomerulogen~is without alteration of overall explain growth. These results suggest that while AT-I acts as a stimulator of nephrovascular development, AT-2 acts as a sesmentspecific suppressor of nephron differentiation.

C14 SYMPOSIA - $2. Diseases due to Disturbances in Renal Development $2.1

$2.2

Dr. Adrian S. Woolf, Develc~mental Biology Unit, Institute of Child Health, London, WCIN 1EH, UK. " THE BIOLOGY OF KIENEY MALFORMATIONS" Various lines of evidence from animal studies suggest that kidney malformations can be generated in vivo by: i) the mutation of master genes expressed during nephrogenesis, including fonnins, ret, retinoic acid receptor, wnt-4 and wt-l; ii) the prenatal obstruction of the urinary tract; iii) and by the teratogens such as ethanol. Other work, using the metanephric organ culture model, has shown that cytokines, such as the insulin-like, hepatocyte and tranform/rig growth factors, may also have roles in enhancing or inhibiting renal morphogenesis. Little is understood regarding the pathogenesis of htm~n renal malformations. These disorders,which constitute the cc~monest causes of end-stage renal failure in the first years of life, include the total absence of renal tissue (aplasia) end organs which contain undifferentiated kidney cells (dysplasia). In the dysplasias, renal cells appear to be "frozen" in a dedifferentiated state and recent studies have shown that there is a major deregulation of pro-9 grammmed cell death in these organs. Although the majority of hunan renal malformations occur sporadically, sane are familial end would thus appear to have a genetic basis. These iclude the Kallmann S y n ~ when a cell adhesion gene expressed during normal nephrogenesis is mutated these patients have renal aplasia. An understanding of the biology of normal and abnon~al nephrogenesis will ult/mately lead to earlier diagnoses of renal malformations and will make it possible to conceive of therapeutic strategies which may enhance the differentiation and survival of metanephric precursor cells hence averting renal failure.

$2.3 Effect of fetal renal maldevelopment on pulmonary maturation Craig A. Peters, M.D., Children's Hospital, Boston, MA Normal pulmonary development is characterized by an orderly sequence of morphological changes; renal maldevelopment is reflected by specific alterations of lung development. These alterations are dependent upon the timing and severity of renal abnormality, and may be reversible to the extent of the reversibility of renal pathology. The mechanisms of interaction between the kidney a n d lung remain incompletely defined. Evidence exists to indicate humeral factors as well as factors mediated through the amniotic fluid. The latter may involve direct factors as well as the mechanico-hiologic effects of lung fluid and amniotic flui& Severe bladder outlet obstruction in the fetus produces a characteristic pattern of pulmonary hypoplasia with impaired lung growth and maturation. These elements may be differentially affected in various degrees of fetal bladder obstruction dependent upon the timing of oligohydramnios and the-pattern of renal maldevelopment, suggesting separate mechanisms of action. The influence of the kidney on lung development can be experimentally dissociated by in atero tracheal ligation. In fetal nephrectomy with an intact hing-arnniotic fluid connection, pulmonary hypoplasia results. When the trachea is ligated to prevent tung fluid drainage into the amniotic space, lung growth is not impaired, and may be accelerated. Maturation is also maintained. Further experiments have indicated the presence of growth factors in secreted lung fluid that may be acting in a paracrine or autoerine fashion to regulate lung growth. The specific influence of the kidney on lung development appears to be active early in gestation and this is supported by clinical data in fetal patients with late onset oligohydrarnnios in whom outcome was determined by the condition of the kidneys and not their lungs. If renal development is sufficient to maintain arnniotic fluid volume (through urine output) until the end of the second trimester, lung development is not significantly impaired from a renal cause. This has dear clinical impact in terms of management decisions of the fetal patients with late onset oligohydramnios.

THE ROLE OF THE RENAL ANGIOTENSIN SYSTEM IN ABNORMAL RENAL DEVELOPMENT. RA Gomcz*. PV Reddi. KF Hilgers, A TufreMcgeddie. and VF Norwood. University of Virginia School qf Medicine, Department of Pediatrics, Charlottesville, Virginia 22908 USA Kidney vaseularization oCCurS sinmltaneonsly with nephrogenesis. Microdisscction and immtmohistologieal studies indicate that the basic blueprint of arterial development is already present in the fetal rat. With postnatal maturation there is progressive arterial branching that continues after ncphrogenesis has ceased. The origin of the kidney vaseulatu~ has not been fully defined. Aa angiogen/r mechanism seems to be responsible. :However, the presence of endothelial precursors expressing VEGF receptors prior to 9 vessel invasion suggests that vaseulogenesis may br an additional mechanism for local vessel fermatiou in the embryonic kidney. Multiple mechanisms am likely to regulate kidney vessel development Wr have shown that endothelial cell differentiation occurs in the mctaneplh'ic,-blastema in response to relative hypoxemia and exposure to VEGF. Development of the kidney vasouhture is also tightly linked to expression of the t~imaagiolcnsi, system. Blockade of angiotensin r~eptor subtype I (ATl) in newborn rats induced an arrest in nephrogenesis and vascular development resulting in altered kidney anzhiteeture chareclorized by fewer, thicker and shorter afferent -arterioles, redu'c~adglomerular size and number, and tubular dilatation. Similarly, inhibition of angiotensin Ii generation in tadpoles undergoing metamorphosis induee.A even more marked alterations i, nephrogenesis and renal vascular development. These fmdhgs demonstrate the importance of angiotensin II in renal morphogenesis and vascular growth, a function that is conserved across the phylogenotio scale. The histological changes resulting from AT1 blockade resembl~ those found in congenltal hypoplasia-dysplasia in humans including those associatexl with the USeof ACE inhibitors during pregneney. The signaling pathways involved in the growth effects of angiotensin remain to be d~r g ~ t l y , using targeted differential display PCIL we identified a novel gone, the (repression of which is downregulated hy AT1 receptor inhibition. We anticipate that this germ, termed WeT.I, may play a role in angiotensin depend~at renal morphogonesisand vascular growth.

$2.4 GROWTH FACTORS AND APOPTOS~S ~N THE RENAL RESPONSE TO URETERAL

OBSTRUCTIQN IN THE NEONATE. Robert L. Chevaller. D e p a r t m e n t of P e d i a t r l c s t U n i v e r s i t y of Char10tteaville, Virginia, USA.

Virginia,

Renal insufficiency due to congenital obstructive nephropath~ is a c o n s e q u e n c e of a r r e s t e d or abnormal renal growth. unilateral ureteral obstruction (uUO) for 2 weeks in the neonatal rat impairs growth of the s kidney, whereas elmilar UUO in the adult does not. The renin-anglotensin system is highly activated in early development, end UUO increases further this activity, resulting in vasoconstriction and g l o m e r u l a r c o n t r a c t i o n . C h r o n i c U U O also c a u s e s p r o g r e s s i v e i n t e r s t i t i a l fibrosls~ w h i c h p r e s u m a b l y uontrlhutes to arrested growth of the kidney. This may result from excessive deposition of extracellular matrix stlmu~atsd by increased expression of transforming growth factor-hera 1 {TGF-B1). Enhanced production of TGF-B1 ale in turn largely m e d i a t e d by a n g i o t e n s l n II. N e o n a t a l U U O d e l a y s the expres,lon of epidermal growth factor (EGF) (which appears in the rat kidney after 3 days of aqe), and p r o 1 ~ n g e the expreeslon of peritubuler alpha smooth muscle actin (which normally disappears from the rat perltubuler capillaries by 2 weeks ef age). These fiNdlngs suggest that renal maturation is delayed by UUO. In addition, renal apoptosis (which is stimulated by increased TGF-BI and reduced EOF expression), is increased by ipailaterel UUO. Nowever, the increase is greater in the neonate than in the adult. Renal expression of c~ustsrln, a glyecprotsin a~soelated with cell adhesion and protection from spoptosis, is ale0 increased by Ipsilateral uuo. However, the increase is threefold greater in the adult than in the neonate. We conclude that compared to the adult, neonatal UOO induces greater apoptosis, whloh in turn leads tc reduced renal DNA content and renal growth arrest. Slnco inhibition of angiotensin II AT1 receptors stimulates the renal expression Of r the greater activation of the renin-anglotensln system by UUO in the neonate maycontrlbute to enhanced apoptoels through reduced elusterln expression.

C15 S Y M P O S I A - $3. A d h e s i o n Molecules in Health and D i s e a s e

S3.1 CELLULARINTERACTIONSMEDIATEDBY ADHESIONMOLECULESIN IMMUNEDISEASE Caroline O.S. Savage CCRIS, The Medical School, University of Birmingham, Birmingham, U.K. Circulating leukocytes require adhesive interactions with endothelial cells (EC) to initiate normal immune or inflammatory responses. Adhesion molecules of the immunoglobulin superfamily, integrin or selectin families, sialomucins or specialised carbohydrate ligands, mediate these interactions. SpecificitY is dependent partly on the EC site-specific expression o f / constitutive or cytokine-inducible molecules as well as on the type and avidity-state of molecules on different leukocyte subsets. Leukocytes destined for a particular immune or inflammatory site, use a sequence of receptor-ligand interactions to (a) halt their motion and (b) promote EC adhesion and guide extravascular migration; the former is selectin- and the latter iutegrin-dependent. The importance of EC-leukocyte interactions is highlighted by the development of severe bacterial infections in children who have an inherited lack of certain integrin molecules, preventing neutrophil migration into inflammatory foci. Similarly, autoimmune diseases are dependent on EC-leukocyte interactions for leukocyte accumulation in tissues. This may be tissue-specific as in lymphocyte homing to joints in rheumatoid arthritis, while in autoimmune vascutitis there is intense leukocyte accumulation within and around vessel walls themselves. The EC at vasculitic foci are activated, with enhanced expression of adhesion molecules; this phenomenon extends to glomerular capillary EC affected by focal segmental necrosis. Such EC activation is believed to encourage leukocyte recruitment, while the inappropriate intravascular activation of neutrophils by antineutrophil autoantibodies (ANCA) when neutrophils are adherent to EC, is believed to contribute to vascular damage in ANCA-positive vasculitis. Understanding the complexity of EC-leukocyte molecular interactions may permit targeted therapy to inhibit unwanted inflammatory or immune interactions.

$3.3 R O L E OF C E L L A D H E S I O N M O L E C U L E S IN R E N A L D E V E L O P M E N T AND M I N E R A L I Z A T I O N John R. Hoyer* Cell adhesion molecules have crucial roles in the interaction of cells with the extracellular matrix and with other cells during renal growth and development? Integrins on the surface of cells allow the attachment of cells to the extracellular matrix and may also influence cellular differentiation and migration by intracellular signalling that originates thru integrins. The stage specific e x p r e s s i o n of integrins in distinct n e p h r o n segments supports their role during differentiation. During the c o n v e r s i o n o f m e s e n c h y m e to e p i t h e l i u m , m e s e n c h y m a l adhesion proteins such as N C A M are replaced by epithelial cell-cell adhesion molecules such as E-cadherin which appear to play an important role in the development of cell polarity. Other cell adhesion proteins with RGD domains that mediate their binding to integrins appear to have multiple roles in mineralization. One role, the adhesion of cells to mineralized matrix via osteopontin in bone, is regulated by divalent cation concentrations. Other roles involving stereospecific interactions of osteopontin with crystal faces of hydroxyapatite in bone and of uropontin (the urinary form of osteopontin) with calcium oxalate in urine modulates the growth of these crystals. Such interactions with crystals may be important in the remodeling of bone and as a protective mechanism against urinary stone formation which counteracts supersaturation of calcium oxalate in urine by inhibiting crystallization. *Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, U.S.A.

S Y M P O S I A - $4. Acute Renal Failure

$3.4 CELL ADHESION MOLECULES MODULATE RENAL INFLAMMATION IN NEPHRITIS AND REJECTION J.D. Mahan* The families of cell surface proteins known as cell adhesion molecules [CAM], and their integrin and carbohydrate ligands, are involved in a variety of cell-cell and cellmatrix interactions. Since selectins, integrins and members of the immunoglobulin superfamily modulate leukocyteendothelial interactions and regulate local inflammatory responses in a number of different pathologic conditions, it is not surprising that a role for CAM in inflammatory renal diseases has been defined. In models of renal transplantation, CAM (intercellular adhesion molecule-i [ICAM-I] and vascular cell adhesion molecule-i [VCAM-I]) are expressed on tubular epithelial and endothelial cells in acute rejection; administration of antibodies against CAM can modify acute rejection. Similar findings in haman renal allograft biopsies support a role for CAM in mediation of local events in transplant rejection. Increased glomerular and tubule-interstitial ICAM-I and VCAM-I occurs in models of immune-complex and lupus GN. Increased ICAM-I has been demonstrated in several forms of human GN although increased ICAM-I tends to occur in areas of interstitial inflammation. Monoclonal antibodies against CAM and their ligands have been shown to modify glomerular inflammation in animal models of GN. Although increased glomerular E-selectin was noted in a primate model of septic shock, there is limited evidence for a role for cell surface seleetins in GN. The ability of cytokine-activated endothelial cells to shed soluble selectins may provide another mechanism to influence inflammatory cells and leukocyte adhesion in the kidney. Circulating levels of adhesion molecules may also provide a useful marker of vascular or interstitial inflammation. As more is understood about the protean functions of CAM, therapies directed against CAM or that modulate CAM expression by renal and/or circulating cells may become useful in treatment of renal inflammatory disorders. * - Dept of Pediatrics, The Ohio State University - Columbus, Ohio - USA

$4.2 IGF-I in Acute and Chronic Renal Failure. Jen-lar Lin, Riohard N. Fine, Frederick J. Kaskel, SU~Y at Stony Brook, Stony Brook, ~ , USA

Several mitogenic factors such as IGF-I, EGF, and hepatocyte growth factor have been shown to ac.r.deratcthe recoveayfrom acute renal failure (ARF) with a concomitant increase in DNA synthesis, suggesting interactions of these factors during the recovery fi'om ARF. We found that at one day al~or postisohemic injury IGF-I increa.~ the phosphotyrosine content of EGF receptor (EGF-R) in post-ischemiokidneys. This was a.~odated with increases in EGFR protein and receptor binding suggesting that the improved recovery and DNA synthesisduring ARF by IGF-I was at least partially due to an increased expression of EGF-R. Combinedgrowth hormone (GI-I)/IGF-Itherapy has been advocated to minimize the diabctogenic effect of GH with additive anabolir effect_ However, GH has been suggested to accelerate the development of glomerular sclerosis(GS) in experimental animals and IGF-I mediates the renal effect of GH, We therefore examined the effect of GH and/or IGF-I on mosangial matrix of 5/6 nephrectomized rats. GH induced proportional increases in masangial area (MA) and glomerular area (GA), whereas IGF-I induced a similarincrease in GA as did GH but without eorresponding changes in MA. Combined GH/IGF-I therapy induced a further increase in GA and a reduction in MA when compared with GH therapy alone. These results indicate opposite effects of exogenous GH and IGF-I/n v/re on mosanglal e~pansion which is one of the central mechanisms leading to GS. This suggests an additional beneficialeffect of combined GH/IGF-I therapy during chronic renal failure. Long-term studies are needed to verify this speculation.

C16 S Y M P O S I A - $5. F e t a l a n d N e o n a t a l R e n a l P h y s i o l o g y $5.1

$5.2

Regulation of proximal tubule NaC! reabsorption during the transition from fetus to newborn. E.N. Guillery & J.E. Robillard, Departments of Pediatrics, the University of Wisconsin, Madison, WI and the University of Iowa, Iowa City, IA, U.S.A.

Fetal Renin Angiotensin System: fluid volume.

The fetal kidney has high fractional excretions ofNa + and CI" and has a limited ability to conserve NaC1. Within days of birth, however, the newborn kidney maintains fractional excretions of these ions at adult levels of 1% or less. Brash border membrane vesicles (BBMV) from renal cortex were used to study the roles of proximal tubule apical membrane Na+/H + exchange (NHE) and Cl-/formate exchange (CFE) in this maturational process. BBMV from term fetal and 24 hour old newborn lambs were exposed to an outwardly directed proton gradient and a kinetic analysis o f n N a + uptake was performed. The Vmax of NHE in the newborns was 235% greater than that of the fetuses while the KM'S were not significantly different (newborn Vmax 3.32:~:0.37 nmol/sec/mg-protein, K~ 12.5• raM; fetal Vmax 1.41• nmol/sec/mgprotein, KM 14.9• mM). In subsequent experiments, intraperitoneal cortisol infusion in preterm sheep fetuses produced a 162% increase in NHE Vmax (treated 2.12• control 1.31• nmol/sec/mg-protein) and a 410% increase in NHE-3 mRNA levels, suggesting that circulating cortisol may play a role in the maturation of NHE in the newborn. CFE was studied in BBMV obtained from term fetal and 3-5 day old guinea pigs. An outwardly directed formate gradient and an inwardly directed proton gradient induced a significantly greater level of 36C1" uptake by the BBMV from newborns (following a 30 see. incubation, newborn BBMV accumulated 360- to 166• of equilibration levels, with fetal BBMV to 107• This maturation in CI- uptake could not be ascribed to CI-/OH-(HCO3-) exchange. Taken together, these results support the hypothesis that parallel upregulation of NHE and CFE in the newborn mediate increased renal NaCI reabsorption. Glucocorticoids may play a role in the induction of this maturation.

$5.4 ENDOTHELIN AND NITRIC OXIDE REGULATE THE RENAL MICROCIRCULATION DURING DEVELOPMENT J.-P. Guignard, L. Ball~vre and D. Semama Department of Paediatrics, CHUV, 1011 Lausanne, Switzerland The renal microcirculation is regulated by various vasoactive agents that tend to vasodilate or vasoconstrict the kidney. Some of these agents are active systematically while others are released and act locally. While angiotensin-II, adenosine and the prostaglandins play crucial roles in both physiological and pathological conditions, the contribution of two endothelium derived factors, endothelin and nitric oxide, remain more speculative. Endothelin : endothelin is a potent vasoconstrictor peptide in vitro. The administration of exogenous endothelin-1, 5 nmol/kg, to newborn rabbits increases mean blood pressure (MBP), the renal vascular resistance (RVR) and induces a fall in GFR and RBF. Surprisingly, the infusion of an endothelin-1 antiserum also induces an increase in RVR (by 34 • 5 %) associated with a fall in GFR (by 20 _+ 4 %) and RBF (by 25 • 4 %), while the filtration fraction and MBP remain unchanged. The occurrence of a vasoconstrictive response to the infusion of the endothelin-antiserum suggests that, in normal condition, endogenous endothelin is active at low levels that induce renal vasodilatation without affecting MBP. Nitric oxide : NO promotes vasorelaxation of renal vessels in vitro. In vivo, the administration of L-Name, a NO synthesis inhibitor (50 ~g/kg + 10 ~g/kg x min), does not modify MBP or pulse rate, but significantly increases the RVR (by 31 • 5 %), while progressively decreasing RBF (by 20 • 6 %) and at a later stage, GFR (by 13 S 5%). The renal vascular bed appears highly sensitive to the inhibition of NO. The changes in GFR and RBF induced by L-Name suggest that the renal vasoconstriction observed after inhibiting NO synthesis is related primarily to the afferent arteriole and to a lesser extent to the efferent arteriole. By decreasing the RVR in normal conditions, NO appears to play a significant role in maintaining the perfusion of the immature kidney. Conclusion : in normal conditions, both endogenous endothelin and NO appear to favour renal perfusion by vasodilating the developing renal vascular bed.

its role in maintenance of amniotic

E.R. Lumbers, K.M. Stevenson, K.J. Gibson, A.D. Stevens School of Physiology and Pharmacology, The University of New South Wales, Sydney, Australia, 2052 The ovine fetal kidney is perfused at a low arterial pressure relative to the adult (56/36 mmHg compared with 103/61 mmHg). As well, renal vascular resistance (RVR) is approximately i0 times higher than in the adult kidney (1.67 compared with 0.17 units) yet adult and fetal filtration fractions are similar. This high RVR is also evident in the isolated ovine fetal kidney. Maintenance of this high resistance in the post-glomerular vascular bed is important for the maintenance of normal fetal glomerular function. Blockade of the renin-angiotensin system (RAS) for 3-4 days in chronically catheterised fetal sheep by the angiotensin converting enzyme inhibitor, captopril, can cause oliguria or anuria because glomerular ultrafiltration ceases. The nonpeptide AT I angiotensin (All) antagonist, losartan, also causes a fall in fetal GFR. Intravenous All (6 ~g/kg/h) restored fetal GFR and urine flow in captopril treated fetuses. Arginine vasopressin (56 mUnits/kg/h) had similar effects to All. Intravenous All had no effect on tubular sodium reabsorption when infused for 1.5 h; when infused for 3-5 days it caused a fall in proximal fractional sodium reabsorption. Treatment of fetal sheep with either losartan or captopril either had no effect on proximal sodium reabsorption or caused an increase in proximal fractional sodium reabsorption. These findings suggest that in the fetus, in contrast to the adult, neither endogenous nor exogenous All stimulates proximal tubular sodium reabsorption, possibly because fetal tubular sodium reabsorption is directly influenced by actual oxygen levels. Thus in the fetus, the RAS maintains glomerular function by maintaining post-glomerular vascular resistance. Since this effect of All is not offset by a stimulatory effect of All on proximal tubular sodium reabsorption, the fetal RAS ensures the continuous production of urine and hence maintains amniotic fluid volume.

C17 S Y M P O S I A - $6. Intracellular Mediators o f Cell Function

$6.1

$6.4

M E C H A N I S M S BY W H I C H G L U C O C O R T I C O I D S REGULATE RENAL TUBULAR MATURATION Gianni Celsi

EXPRESSION OF A MUTANT REGULATORY SUBUNIT OF cAMPDEPENDENT PROTEIN KINASE IN MDCK CELLS PREVENTS cAMPMEDIATED MODULATION OF PROUNE TRANSPORT. Israel Zelikovic*, Stephanie Orellana*, James Miller*, Christopher Neff*, Benno Mohr*.

The adaptation of newborn mammals to extra uterine life is conditioned by a tissue-specific expression of proteins. Differentiation is therefore dependent on the presence of transcriptional factors that switch on and off specific genes according to a well-regulated time schedule. In the fetus and the early infant, glucocorticoids accelerate maturation of several organs. We have recently shown that Na,K-ATFase gene is a primary target for glucocorticoids in infancy. The hormones modulate Na,K-ATPase mRNA in a tissueand age-dependent manner, at the time when the organ function most rapidly matures. However, the mechanisms by which steroids regulate Na,K-ATPase gene transcription are still disputed. We suggest that the action of glucocorticoid receptor in infant cell might require the presence of an auxiliary factor, whose expression is ontogenically regulated.

cAMP-dependent protein kinase (cAK) regulates the activity of several membrane-bound ion channels and carriers. We have previously demonstrated that cAK inhibits proline transport across the proximal tubular luminal membrane. The role of cAK in regulating the transport of this osmoprotective amino acid in the distal tubule is unknown. We examined the regulation of proline transport in MDCK cells expressing a mutant murine regulatory subunit (RICtAB) of cAK. For this purpose, MDCK cells were transtected by lipofection with an expression vector encoding RIo~B driven by the metallothionein 1 promoter fo~ether with a neomycin-resistance t~tEO) gene. StabIe G418resistant colonies were isolated that expressed R[r as demonstrated by: 1) Northern hybridization analysis using a ~2P-labeled cDNA probe for RI(~ that identified a 1.7kb transcript corresponding to R[~^8, 2) cAK assay that showed decreased cAMP-dependent activity of the enzyme, A clone expressing constitutively high levels of RI~Aa (MAc) in a Zn-independent manner was selected. A clone transfected with the NEO gene alone (MNEo) served as a control. NaCI-dependent uptake of [3H] proline by confluent monolayers of MDCK cells was examined in the absence and presence of the cAMPstimulating agents forskolin (F) (10~M) and IBMX (0.5mM). While F/IBMXinduced mean inhibition of proline transport in MNEOcells was 48% and 45% at 5 rain and 15 rain, respectively, inhibition of proline uptake in MAa cells, was 9% (5 rain) and 0% (15 rain). These data demonstrate that the inhibition of proline transport in response to elevated cAMP is reversed in mutant MDCK clones and provide evidence that cAK mediates the modulatory action of cAMP on preline transport. cAK may play an important role in controlling transport of preline and other osmoprotective am/no acids in the renaPtubule.

Department of Woman's and Child's Health, Karolinska Institute, Stockholm, Sweden

* University of Washington, Department of Pediatrics, Seattle, Washington, U.S.A,

C18 SYMPOSIA - S7. Prevention of Progression of Renal Disease S7.1 FREE RADICAL RELEASE AND PROGRESSION OF RENAL D~ISEASES. J.C.M. Chan~"and P. Futrakul.~ Free radicals produced by activated leukocytes and renal mesangial cells have been implicated in renal injury. Glomerular macrophages induce experimental nephritis through oxidant release. Endogenous antioxidant enzymes, e.g. heme oxygenase, suppress this free radical release. These observations have wide therapeutic implications. For example, glueocorticoids by increasing glomerular antioxidant enzyme activity provide a renal protective effect against the heavy proteinuria induced by hydrogen peroxide (Kidney l n t 40:291, 1991).

In experimental IgA nephropathy (IgAN), reduced renal malondialdehyde contents, implyinga lower lipid peroxidation, have been demonstrated in vitamin E-treated rats (Trachtman etal: JASN5:956, 1994). In this study, we also demonstrated that vitamin E treatment reduced the incidence of hematuria and proteinuria. Vitamin E treatment produced a smaller glomerular planar area, implying reduced mesangial proliferation. In a recent study, we demonstrated that flee radical production in resident peritoneal macrophages of rats with IgAN is significantly suppressed by vitamin E (Yi e t a l : Pediatr R e s 1995). Fish oil supplementation and essential fatty acid deficiency down-regulate nitric oxide synthesis by peritoneal macrophages (Kidney l n t 46:1280, 1994). In a controlled clinical trial, fish oil has been shown to slow the rate of progression oflgAN (NEJA#331:1194, 1994), although three previous studies with similar doses offish oil fal!ed to demonstrate any benefits. Finally, with reference to progression of focal segmental glomerulosclerosis (FSGS) with severe vascular dysfunction, we have demonstrated that conventional treatment with prednisone, cyclophosphamide, reserpine and hydralazinc does not prevent progression over 5 years to end-stage renal disease (Futrakulet al: J A S N 5 : 3 2 9 , 1994). In contrast, treatment with vasodilators, heparin and prednisone showed renal functional improvement in children with FSGS followed for up to 7 years.

$7.2 INHIBITION OF MESANGIAL CELL ACTIVATION AND FREE RADICAL PRODUCTION BY THE NATURALPRODUCT OF CORDYCEPS SINENSIS Lin CY, Ku FM, ShiaoMS Cordyceps sinensis (CS) is a parasitic fungus which has been used as a Chinese medicine for a long time in the ireatment of nephritis. Today. the hypothesis about the pathogenesis of lgA nephropathy (lgAN) is that nephritogenic lgA-immune complexes (lgA-1C) go to the kidney to stimulate resting mesangial cells (MC) to release cytokines, growth factors (GFs) and free radicals. These cytokines and GFs cause MC proliferation & release matrix, chemical mediators which together with free radicals lead to the glomerular injury then disease progression. However, nephritogenic lgA-1C in humans is still unknown. To solve this problem previously, we established an in vitro model in which cultured human MC stimulated with 1L-1 plus 1[,-6 can cause MC proliferation, increasing production of chemical mediators and superoxide anion. In viva model also proved that the above culture medium may lead to renal injury with hematuria/proteinuria. Therefore, in order to fractionate the crude components which can be used in the treatment of lgAN, we cultured human MC, then a human MC activating model using human MC incubated with 1[,-1 and 1L-6 was established We fractionated the crude methanolic extracts from fruiting bodies of CS using this in vitro inhibition of human MC activation model as our assay method. Briefly, the fruiting bodies were extracted by silica gel column chromatography. One out of 18 column fractions significantly inhibited the human MC activation by IL-1 plus 1L-6. This fraction was then purified by HPLA and got a purified compound A. The acute toxicity test using male 1CR mice showed there was no liver toxicity and mutagenecity. Then we tested compound A using spontaneous lgAN mice model (DDY mice), DDY mice fed with 1% compound A in diet for 3 months dentonstrating significant reduction of hematuria and proteinuria together with histopathological improvement. These results give us a new regimen for the treatment of lgAN and prevent progression in the future. Departments of Pediatrics & Medical Research, Veterans General Hospital-Taipei, Taiwan, R.O.C.

#Virginia Commonwealth Universlty's Medical College o f Virginia, Richmond, VA, USA, and ,tChulalongkorn Medical School Hospital, Bangkok, Thailand.

S7,3 THE ROLE OF ACE INHIBITORB IN RETARDING RENAL DISEASE PROGRESSION P, Ruggenenti and G. Remuzzi. Institute for Pharmacological Research "Made Negri"- Via Gavazzeni, 11 - 24125 Bergamo, Italy When sclerosis of the glomenJlar tu/t affects a c~ical number of nephrons renal filtration decreases and the disease progress 1o renal failure. It has been suggested that reduction Of a critical number of nephrons causes structural and functional damage to the remaining due to the adaptive increase in the perfusion pressure and flow. Therapeutic maneuvers that attenuate the adaptive glomerular haemodynamies, reduce proteinuria limil glomerular structuraf iniury. Thus dietary protein restrielion, by normalizing glomerular capillary pressure limits of glomerulosclerosis in most models. Similarly, ANG I converting enzyme (ACE) inhibitors have proved beneficial in reducing proteinuria and retarding renal disease progression in experimental models of chronic renal failure, including extensive ablation of the renal mass and streptozotocin-induced diabetes. Recent studies in insulin~ependent diabetic patients with persistent proteinuria or mictoalbuminuda have suggested that ACE inhibitors reduced the albumin excretion rate and retard the progression of established renal disease. The renoprotective properties of ACE inhibitors were recently confirmed in non insulin-dependent diabetics and in proteinuriC non-diabetic renal diseases. Whether the effect of this class of compounds of retarding renal diseases progression is only a function of its antihypertensive properties or depends on a specific effect' on structure and function of th~ 91omerular network will be discussed in detail.

$7.4 ROLE OF DIET AND ANTILIPEMIC D R U G S A.-M.Wingen From animal studies and in vitro experiments it can be concluded, that low protein intake may slow down the progression of chronic renal failure (CRF). But, in humans recent results at studies in adults and children With adequate numbers of patients and proper study design did not show any reasonable effect of low protein intake on progression rates. It is unquestioned that low protein diet can postpone renal replacement therapy by ameliorating uremic symptoms. On the other hand limited studies in humans demonstrated a favourable influence of low protein intake on parathyroid hormone, insulin metabolism, derangements of lipids and proteinuria: . . . . Carbohydrates are not accused to be invowea in the progression or renal failure, but, simple sugars can add to the disturbance of lipid metabolism, while this adverse effect is not seen with complex carbohydrates. Children as adults with CRF demonstrate severe disturbances of lipid metabolism, which start early, in CRF. In the European Study of Nutritional lreatment of Children with CRF about 50% of patients have high triglyceride and LDL-C concentrations and the occurence of high cholesterol and low HDL-C is frequent. Other studies demonstrated-high lipoprotein (a) concentrations in CRF. This pattern of dyslipidemia is significantly correlated to atherosclerosis. In animal experiments diets high in cholesterol accelerate progression of CRF and in cell culture experiments overall oxidized LDL deranges the metabolism of mesangial and tubular cells mediating sclerosis. From theoretical aspect it is tempting to speculate, that hypenipioemia and nypenipiouria accelerate me progression of CRF. In humans high rates of progression of CRF are usually correlated to hyperlipidemia. But, protemuria and high blood pressure seem to be the primary determinants of progression of CRF, while hyperlipidemia develops as a consequence of low GFR andproteinuria only. Studies in adults with diets and exercise aiming to reduce hyperlipidemia in CRF, demonstrate moderate effects on hpid profiles, while lipid-lowering drugs, overall statins (e.g. simvastatin) and probucol proved to be highl7~effective with a moderate frequency of side effects. It can be concludedfrom animal experiments, that these drugs influence progression of CRF less probably by lowering serum liplds than by special actions, e.g. probucol as antioxidant Therefore, these drugs have highlypromising therapeutical aspects tar patients with CRF. But, up to now adequate studies in humans are missing, University Children's Hospital, 45122 Essen, F R G

C19 SYMPOSIA - $8. Genetics and Pathophysiology of Cystic Renal Disease S8.1

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STRUCTURE AND CLASSIFICATION OF RENAL CYSTIC DISEASE Jay Bernstein

FROM CELL BIOLOGY TO THE BEDSIDE: CLINICAL IMPLICATIONSOF THE CELLULAR PATHOPHYSIOLOGYOF POLYCYSTICKIDNEY DISEASE(PKD) Ellis D. Avner, M.D."

Renal cystic disease in children comprises princlpally autosomal recessive polycystie kidney disease (R-PKD), autosomal dominant polycystic kidney disease (D-PKD), giomerulocystic kidney disease (GCKD), and diffuse cystic dysplasia. Renal cystic disease occurs also in association with several malformation syndromes, e.g., tuberous sclerosis and oral-faclal-digital syndrome. R-PKD at all ages is characterized by collecting duct ectasia and is accompanied by intrahepatie biliary dysgenesis. Progressive renal cortical and hepatic portal fibrosis are probably responsible for the renal insufficiency and portal hypertension that develop with time. Congenital D-PKD is characterized by glomerular cysts, commonly admixed with tubular cysts, and the medullary pyramids are sometimes dysplastic. Neonatal D-PKD cannot be differentiated clinically, radiographieally, or morphologically from neonatal sporadic GCKD, and initially negative ultrasound studies in parents may with time turn positive. Apparently sporadic GCKD is conceivably a new mutation for D-PKD. Both GCKD and D-PKD may have asynchronous or asymmetrical onsets in children, the latter with a frequency as high as 10-20%. D-PKD with medullary dysplasia, which is often confused with diffuse cystic dysplasia, is recognized by its relativelynormal cortical development and glomerular cysts. All of these conditions have similar ultrasound imaging patterns, with large, diffusely hypereehoie kidneys of abnormal sonographic architecture. The family history is essential to diagnosis, and ultrasound evaluation of immediate family members may be necessary. All forms of renal cystic disease evolve morphologically as the kidney develops during gestation, and early fetal appearances are often different from those in the fully formed neonatal kidney. Recognition of fetal patterns of renal cystic disease is increasingly important in evaluating pregnancies terminated because of ultrasound abnormalities, but there are few systematic studies to provide morphologie criteria.

Studies at the whole kidney, kidney explant, and cellular level have determined that the three major factors contributing to renal cyst formation and progressive enlargement are: 1) tubular epithelial hyperplasia; 2) altered transtubular Solute transport (conversion of an absorptive to a secretory phe~otype); and 3) altered cell matrix-tubular cell interactions. Each of these areas represents a potential target of immune- ot specific pharmacotheraw.

William Beaumont Hospital Research Institute - Royal Oak, Dept. Pathology, Wa~rne State Univ. SCh. Mcd. - Detroit - Michigan - USA

$8.4 C l i n i c a l d i a g n o s i s and m a n a g e m e n t of p o l y c y s t i c k i d n e y d i s e a s e in c h i l d h o o d O.Koskimies, A-T.Lahdenkari, J.Jaaskel6inen, H.K~ari&inen A u t o s o m a l r e c e s s i v e p o l y c y s t i c kidney d i s e a s e (RPKD), the infantile f o r m , a n d a u t o s o m a l d o m i n a n t p o l y c y s t i c k i d n e y d i s e a s e (DPKD),the adult form are two completely d i f f e r e n t c o n d i t i o n s w i t h renal cysts in common. D P K D is u s u a l l y d e t e c t e d in adults but may m a n i f e s t d u r i n g n e w b o r n period. D i f f e r e n t i a l d i a g n o s i s b e t w e e n t h e s e d i s e a s e s and e x c l u s i o n of o t h e r cystic d i s e a s e s m a y thus be difficult. Our e x p e r i e n c e of p o l y c y s t i c d i s e a s e is b a s e d on 82 patients. T h e d i a g n o s i s cannot d e p e n d on c l i n i c a l findings o n l y . N e o n a t a l d e a t h was m o r e common in RPKD (84%) than w i t h DPKD (23%). Loss of u r i n e c o n c e n t r a t i n g c a p a c i t y and changes c a u s e d by h e p a t i c f i b r o s i s are typical f i n d i n g s in RPKD. In u l t r a s o n o g r a p h i c e x a m i n a t i o n e n l a r g e d d i f f u s e l y hyp e r e c h o g e n i c kidneys w i t h o u t c o r t i c o m e d u l l a r y d i f f e r e n t i a t i o n are seen in RPKD and in CT scan these kidneys are large w i t h a c c e n t u a t i o n of contrast m a t e r i a l in cortical layers. T y p i c a l findings for DPKD are m a c r o s c o p i c cysts and evenly d i s t r i b u t e d c o n t r a s t dye In m o r p h o l o g i c a l s t u d i e s of RPKD cyst e p i t h e l i u m was low cuboidal, g l o m e r u l a r cysts w e r e a b s e n t and diffuse b i l i a r y d y s g e n e s i s was always p r e s e n t in the liver In D P K D g l o m e r u l a r cysts w e r e present. The treatment of a n e w b o r n w i t h RPKD c o n s i s t s of c a r d i o r e s p i r a t o r y support, a n t i h y p e r t e n s i v e s , salt s u p p l e m e n t a t i o n and l a t e r treatment of steadily d e c r e a s i n g renal function p o r t a l h y p e r t e n s i o n and e v e n t u a l cholangitis. M a n y of o u r living p a t i e n t s will d e v e l o p t e r m i n a l renal failure at the age of appr.20 years. D P K D p a t i e n t n e e d follow-up, some are on a n t i h y p e r t e n s i v e medication, and p r o g r e s s i o n is m u c h s l o w e r than in RPKD. C h i l d r e n ' s Hospital, U n i v e r s i t y of H e l s i n k i and V&est01iitto, Finland

Tubular epithelial hyperplasta is a central feature of tubular cyst formation and prngress~ve enlargement. Recant studies suggest that altered epidermal growth factor (EGF)-receptor expression in cystic tubular epithelium coupled with the presence of bloreaotive EGF-I~e peptides in cyst fluid mediate an endocdneparaerins cycle of mitogenesis. In vitro data demonstrate that antibodies blocking ligand-receptor interaction inhibit experimental cyst formation. Further, specific pharmacotherapy targeted at inhibiting the tyreslne kinase activity of the EGFreceptor can reverse in vitro renal cyst development. Phase I trials of such agents in patients who have other disease states mediated by altered EGF/EGF-receptor interactions (Le., breast cancer) have shown premising results. Altered transtubular transport mediates the conversion of a normally absorptive tubular epithelium into a secretory epithelium in PKD. Progressive tubular cystic enlargement is a result of fluid movement across epithelial cyst walls rather than simple filling by glomerular filtrate. To date, attered polarized Sorting of Ion transporters, increased sodium transporter activity, and inoreesed oAMP-mediated chloride transport have all been irnplic~ed as mediating tubular cyst fluid secretion in human and experimental PKD. tn vitro studies suggest that a number of specific transport [nhibitors (ouabain, pmbensoid, bumetanide, chiodde channel inhibitors) or agents which interfere with the generation or effects of cAMP may have potential value in decreasing cyst formation and enlargement. Anatomical, bioohemical and immunohiatochemical study of cystic tubular extracelluiar matrix has revealed a number of abnormalities. Such changes likely alter matrix-ceU interactions which uan cent#outs to hyperpiasia, altered transtubular transport, and the formation of interstitial fibrosis which is common in late-stage PKD. Inhibition of altered matrix formation or processing, as well as specific inhibition of fibrosis may prove useful in decreasing cyst growth. Further delineation of the unique phenotype of cystic epithelium will permit the design of future therapies to decrease cyst formation and enlargement in PKO. "Professor of Pediatrics. University of Washington

C 20 S Y M P O S I A - $9. Clinical Aspects o f I n h e r i t e d R e n a l Disease $9.1 CLINICOPATHOLOGIC AND MOLECULAR ASPECTS OF ALPORT SYNDROME (ASL Clifford F...Kashtan, U. of Minnesota Medical School AS is an inherited cause of renal failure due to mutations affecting type IV collagen, the predominant collagen of basement membranes (BM). Type IV collagen consists of six distinct ct chains encoded by three pairs of genes. The 0ff(W) and ct2(IV) chains, which are encoded by the genes COL4A1 and COL4A2on chromosome13, occurin all basementmembranes and are not directly involved in AS. The O3(IV)and ct4(W) chains are products of the COL4A3 and COL4A4 genes on chromosome 2, respectively; they are found in GBM,distal TBM and Bowman's capsule (BC)as well as some BM of the cochlea and eye, and have been implicated in autosomai recessive AS (ALIAS). The orS(IV) chain, which is encoded by the X-chromosomal COL4A5 gene, occurs in GBM, distal TBM and BC, cochlear and ocular BM, and epidermal BM, and is mutated in X-linked dominant AS (XLAS). Patients with XLAS and diffuse leiomyomatosis of the esophagus, tracheobronchial tree and female genital tract have deletion mutations involving COL4A5 and the adjacent COL4A6, which encodes the ct6(IV) chain. Post-transpiant anti-GBM nephritis occurs in about 5% of those transplanted for AS; most of these are male patients, many of whom have deletions in COL4AS; females with past-transplant anti-GBM nephritis and COL4A3 mutations have been reported. Renal biopsy with electron microscopy remains the cornerstone of diagnosis of AS; immunohistologic analysis of expression of ~t3, ix4 and ot5(W) chains in BM and genomic analysis of the COIAA3, COL4A4 and COL4A5 genes are additional diagnostic tools. Males with XLAS typically lack expression of the ct3, ct4 and 0tS(IV)chains in GBM, distal TBM and BC, and of the otSflV)chain in epidermal BM, while females with XLAS exhibit mosaic expression of these chains. Patients with ALIASlack expression of the o3 and ct4(IV) chains in GBM, distal TBM, and BC, while the ct5(W) chain is absent from GBM but persists in distal TBM, BC and epidermal BM. The precise relationships of the o3, tx4 and orS(IV)chains to each other in normal and Alpert BM have yet to be determined. The mechanisms by which mutations in these chains result in ~omenflosclerosis and renal failure are poorly understood, and dfective interventions must still be identified. In viva studies of canine hereditary nephritis (which results from a COL4A5 mutation) and of transgenic animals, and in vitro studies using recombinant proteins and appropriate cell types may resolve these uncertainties and perhaps lead to therapies for AS other than renal transplantation.

$9.3 CYSTINURIA : CLINICAL ASPECTS G. Rizzoni* - L. Dello Strologo* Cystinuria is an autosomal-recessive disorder o f the kidneys and of small intestine affecting the luminal transport m e c h a n i s m o f cystine, omithine, arginine and lysine. Blood aminoacid levels are normal and the exclusive ctinical manifestation is lithiasis and its complications. The heterozygous state m a y reflect t r u e recessive or incompletely recessive inheritance. Treatment consists in reducing the concentration o f cystine in urine in different ways. The more relevant clinical aspects that will be discussed are: a The most appropriate treatment and its side-effects 9 The use o f new drugs in particularly difficult cases 9 The association between cystinuria and other genetical defects 9 N e w advances in the correlation between the types o f cystinuria and mutation in the rBAT gene in c h r o m o s o m e 2 *Division of Nephrology, Children's Research Hospital B a m b i n o Gesfl, Rome, Italy.

$9.2

NEPHROGENIC DIABETES INSIPIDUS: CLINICAL SYMPTOMS, GENETICS AND PATHOGENESIS. N. Knoers*, A. van Lieburg*', M. Veedijk*, P. Deen***, C. van Os***, B.A. van Oost*, L&.H. Monnens*'. Congenital nephrogenic diabetes insipidus (NDI) is characterized by insensitivity of the distal renal nephron to the antidiuretic effect of arginine vasopressin, resulting in an inability to concentrate urine. Patients present in their first year of life with aspecific symptom like vomiting, anorexia, growth retardation and vomiting. After infanthood, the clinical picture is dominated by the less alarming symptoms polyuria and polydlpsia. Without treatment, mental retardation may develop. In a psychological study of 17 NDI patients, we have found that the prevalence of mental retardation in NDI is considerably lower than suggested in the literature. In the last three years two different genetic defects causing hto NDI phenotype have been identified. The genes involved encode proteins that reside at both ends of the cellular vasopressln signalling cascade, namely the vasol~ressinV 2 receptor and the aqnaporin-2 water channel. In Xlinked recessive NDI, wifich is by far the most frequent form of the disease encountered, mutations in the ~r2 receptor gene have been identified. In autosomal recessive NDI, mutations in the aquaporin-2 gene have been found. The results of in vitro expression studies in COS cells orXenotTusoocytes have confirmed that most of the identified mutations in the V2 receptor gene and all the mutations found in the aquaporin-2 gene are indeed harmful mutations and not polymorphisms. In addition, these studies give insight in the structure-function relationship of beth the receptor and the water channel. As yet, there is no significant difference in the severity of clinical symptoms between patients with X-linked recessive NDI and those with the autosomal recessive form of the disease. On the basis of extrarenal responses to the administrationof the V2 analogue DDAVP, a differentiation between the two genetic forms can be made. Whether a third category of NDI patients exists remains to be seen. The identification of such patients should help to identify other proteins essential in the cellular pathway of vasopressin-induced antidiurasis. Departments of Human Genetics*, Pediatrics'*, and Cell Physiology***, University Hospital Nijmegen, The Netherlands

$9.4 PRIMARY HYPEROXALURIA TYPE 1 AND TRANSPLANTATION P Cochat*, M di Maio, A Mahmoud, M O Rolland, D Haffner * Unit6 de N6phrolo~ie P&liatrique, H6pital E Herriot, Lyon, France. Primary hyperoxaluria type 1 (PH1) is due to an autosomal recessively inherited deficiency of hepatic peroxisomal alanine: glyoxylate aminotransferase (Danpure 86) which always leads to urolithiasis, C R F and systemic oxalosis. Kidney transplantation (KTx) has been first proposed since it replaces the main target organ (Deodhar 69); liver (L) Tx has been subsequently performed since it is both gene and enzyme therapy (Watts 85). Before considering Tx in a patient, we need to focus on 1) early diagnosis procedure with enzymological confirmation, 2) aggressive conservative treatment, 3) pyridoxine responsiveness, 4) assessment of oxalate burden, 5) pre-emptive Tx. To date more than 100 KTx have been reported. In the EDTA experience the 3-yr allografts survival is 23% for LR and 17% for C A D donors (Broyer 90); the North American strategy favours LRD with intensive dialysis before and after Tx (Scheinman 94). 64 combined LKTx have b e e n registered in Europe; the actuarial graft and patient survival is 88% at I yr and patient survival is 80% at 5 yrs (Jamieson 94). Only 3 patients are k n o w n to have had (successful) isolated LTx. The major advantage of KTx is to preserve ethical bases and limit early mortality; however morbidity and quality of life are questionable and no available data are provided in this field. In most cases, the European experience favours combined LKTx especially in children with severe forms. A conservative treatment should be introduced as soon as possible since the risk of systemic oxalosis occurs when GFR (mL/min.1.73 m2) had dropped below 40; LKTx should be planned when GFR is between 30 and 20. Isolated KTx and LTx should be limited to selected patients.

C21 SYMPOSIA

S l l . Toxic Nephropathies

Sll.I

SH.2(1)

8-LACTAMANTIBIOTICS:ANTIBACTERIALANDNEPHROTOXlCMECHANISMS BM.Tune*

L.G. Fine and M. Kitamura, Oniversiti College London Medical School, Deparment of Medicine, London, UK.

8-1actam antibiotics acylate and inactivate a series of proteins important for bacterial replication. Several features allow a 19-1actamto exert this effect: resistance to bacterial 8-1actamases, ability to pass through cell-wall porins, affinity for target proteins, and lactam-ring reactivity (acylating potential). 8-1actam nephrotoxicity, a selective acute proximal tubular necrosis, develops in proportion to: 1) secretory uptake of the antibiotic by the tubular cell, 2a) acylation of mitochondrial substrate transporters, and/or 21)) in the case of cephaloridine, lipid peroxidation. Concentrative uptake and reactivity, two important elements in the production of tubular necrosis, are influenced by the B-lactam core and a series of side-group substituents. Reactivity is, in general, greatest in the newer 8-1actam classes: penems > cephaiosporins >> ponicillins. Certain side-groups have boon associated with cephalosporin nephrotoxicity, but no single or typical substituent has been involved. An R2 pyridinyl, which increases reactivity and bacterial cell-wall penetration, is also implicated in the unique tubular cell sequestration and the singular ability to cause lipid peroxidation that make cephaloridine so nephrotoxic. An R 1 phenylglycyl allows enteric absorption, but also favors tubular reabsorption and higher tubular cell concentrations. Two of the phenylglycylcephalosporins undergo nearly identical high tubular cell uptake, but have very different toxicologtc properties as a result of their R2 substituents: cephaloglycin (R2 =acetoxy) has high reactivity, mitochondrial succinate-carrier target affinity, and nephrotoxicity, while cephalexin (R2 = hydrogen) has low reactivity, affinity, and toxicity. Other cephalosporins with either limited cellular uptake or low reactivity also cause little or no nephrotoxicity. The development of betalactam antibiotics lacking the features that promote renal injury has historically occurred by chance. Recently, carbon-for-sulfur substitution has been used in cephalosporins to lower reactivity without loss of antibiotic effect. However, the first of these carbacephems to be studied in the kidney undergoes much greater tubular cell uptake and is no less toxic than its cephalosporin analogue. It is not known whether this pattem will be found with other carbacephems, or whether modification of the penems can minimize their nephrotoxicity without loss of antibacterial potency. Imiponem and panipenem are sufficiently toxic to require use with inhibitors of their tubular cell transport and renal toxicity. There is evidence, however, that associated inhibition of penem transport by the choroid plexus increases CNS concentrations and predisposes to neurotoxicity. * Division of Pediatric Nephrology - Stanford - California - USA

THE TRANSFER OF GENES INTO THE MAMMALIAN KIDNEY

$11.2(2) lation leads to selective entrapment within the glomerulus . mesangial cells transfected with Lac Z where transferred into the rat kidney via the renal artery, leading to selective entrapment within the glcmeruli. In the normal kidney, the reporter cells populated into 57 + - 13% of glcmeruli site spe-cifically, and the expression of B-galactosidase was sustained for four weeks and declined thereafter. Within the glcme rulus, s~me of the reporter cells remained in the glomerular capillaries, while others repopulated the mesangial area. When the cells were transferred into glcmeruli subjected to transient mesangiolisys induoed by monoclonal antibody 1-22-3, insitu expression of B-galactosidase was anplified 7-12 fold, a n d the enhanced level of expression continued for up to 8 weeks. The mesangial cell vector system thus achieves site-spe_ cifie delivery of an exogenous gene into the glcmerulus and is amenable to in situ amplication and sustained expression by pre conditionig of the garget site. Studies are now in progress in which single gone products are being introduced /]ate the glomeruli of deseased kidneys in an attempt to modify the inflammatory response.

The multifactorial nature of most i n f l ~ t o r y and pro-fibre tic processes in renal diseases is so cc~plex that identifying the roles of individual mediators in vivo is beccming in_ creasingly difficult. The simple expression of a gone pro duct does not necessarily imply functional relevance nor does it establish where such a molecule fits into the hierarchy of participating molecules. We have developed methods for transferring genes into selected subpopulations of cells or into especifie anatomical sites in the rat kidney. Initial studies have used the gene for bacterial B galactosidase (Lac Z) as a maker to identify site specificity an efficiency of gone expression. Our early experience with in rive gene transfer is as follows: a)

Gone Transfer into tubular cells

A replication-defective retroviral construct containing the B gal gene was targeted to tubular epithelial cells by direct intrarenal injection. Since replicating cells are necessary for integration of retroviral genes, short-lived acute tubular necrosis was induced by bolus injection of relie acid prior to injection of the vector. The vector was introduced sat 24 - 36 hours when DNA synthesis was maximal. Expression of Lac Z was detected by X gal reaction and was found to be confined to tubular cells an the site of injection. Nested PCR on tissue extracts revealed that ~hereas the viral DNA was detected after 2 weeks in virtually all animals, only a small percent expressed the gone product.

h)

Gone Transfer into the Glcmerulus

Because cultured mesangial cells are larger in diameter than glc~erular capillaries, their injection into the renal circu_

Sll.3 CYCLOSPORIN AND ENDOTHELIN ACT D I ~ F E R E N T ON INTERCELLULAR ADHESION MOLECULES (CADHERINSCATENINS) IN LLCPK-1 CELLS, M O D E L OF P R O X I M A L T U B U L E A ~ D M D C K CELLS, M O D E L O F COLLECTENG DUCT* L.B. Zimmerhackl and M.Brandis

The zonula adherens and tile desmosomes are framed by tile adhesion molecule E-cadherin. Its extramembrane part is Ca*+-depeodent. The iutracellular part is connected with the cytosceleton through c~-,!3-,y-catenins to the actin filaments. Cadherins are essential for differentiation, cell proliferation and cell fimction. We evaluated the effect of eyclosporin A (CyA) and endothelin-I (ET-I) iu cell culture models of the proximal tubule and collecting duct on the cadherin-cateuin complex. LLCPK-I and MDCK cells, respectively were grown on collagen coated filters (Costa~~) allowing access to the basolaterat and apical compartment. CyA (10< 104M) in DMSO was applied with and without ET-1 (1014-10eM) for 24 h in the apical or basolateral compartment. CyA is toxic to both cell lypes However proximal tubular cells are much more sensitive to CyA In addition, endothelin potentiates the effect of CyA in physiological concentrations (10 -24) particularly from the apical side. The mechanisms of aclion of CyA can be subdivided into a time dependent scheme. CyA first affects the brushb~rder, probably by increasing the intracellular Ca'*-coacentradou which can be augmented by ET-I. This causes a eonfonnational change in the villin moIecute resulting in actin severing and shedding of bmshbm-der. Persistent toxin causes disruption of the intracellulal compartments, decrease in eellproliferation and finally disruption of the cell-cell adhesion molecules cadherin-catenin. This may eventially lead to loss of polarity with complete loss in transpm~t ability. This effect could not be seen in MDCK cells. In eontrast, CyA caused an increase in transepithellal resistance and endothelin had no effect. Since H7 (inhibitor of protein kinase C), herbimycin or vanadate (inhibitors of tyrosine kinase) suppress the CyA effect, it seems likely, that CyA interacts with the regulatory mechanisms of the cell adhesion, the plmsphoJTlation of the catenins. In conclusion. CyA interferes with cell adhesion molecules in proximal tubule and collecting duct by different inechmfisnls. In proximal tubule CyA dislupl~ lhe e~osceleton and the cndhefin-catenin complex, in collecting ducts il seems to interfer with roll,cellular regulate O, lneehanisms. ~zupponed by the GeiTnan Research Fonndztion Dep,lt~.lne.t oi"Pediatrics. Albel't-Ludwigs-Uiiivetsite, t. D-7q 106 Iheiburg

C 22 SYMPOSIA - S12. Mechanism Allograft Rejection and New Immunosuppressive Drugs S12.1

$12.2

M E C H A N I S M S OF A L L O G R A F T REJECTION A. M. Krensky*

NEW IMMUNOSUPPRESStVEAGENTS: 1995 R. Etten.qer*

HLA molecules are the major target antigens recognized in t r a n s p l a n t rejection. CD4+ helper T l y m p h o c y t e s r e c o g n i z e HLA class II antigens, inciting an immune response. T h e s e T cells o r c h e s t r a t e the i m m u n e r e s p o n s e by releasing s o l u b l e m e d i a t o r s (cytokines, lymphokines) into the local environment. These factors and recognition of foreign antigens activate the various e f f e c t o r arms of the i m m u n e r e s p o n s e , including cytolytic T lymphocytes (CTL). CTL recognize HLA class I a n t i g e n s and d a m a g e the g r a f t directly. T cell activation occurs via the T cell receptor and involves a m y r i a d of b i o c h e m i c a l e v e n t s which result in the expression of new genes by the T cell. It is clear from a basic understanding of T lymphocyte biology that there are s e v e r a l levels at which to interrupt t r a n s p l a n t rejection. These include the HLA-peptide-T cell receptor (TCR) interaction, CD3-TCR c o m p l e x mediated signaling, cellular adhesion molecules, second messengers, transcription f a c t o r s and t h e i r b i n d i n g sites, a n d effector molecules (perforin, g r a n z y m e s ) . Laboratories throughout the world are in the process of evaluating each of t h e s e steps in T l y m p h o c y t e r e c o g n i t i o n , a c t i v a t i o n and differentiation as potential t a r g e t s for i m m u n o t h e r a p e u t i c intervention.

There are limited data in pediatricson two new immunosuppressive agents that may soon becomewidely available. MycophenolateMofetil (MMF) is an inhibitorof de novo pudne biosynthesisand Neoral is a microemulsicn formulation of cyclosporine(CsA). Data are available on 14 patients (pts.) treated with MMF as primary immunosuppression in combinationwith CsA and prednisone. Nine patients received MMF at a dose of 15 mg/kg bid and five received23 mg/kg bid. Of the nine pts. on 15 mg/kg bid, only three had biopsy-provedrejection episodesand a fourth receivedtreatmentfor a rejection episodenot documentedby biopsy; of the five on 23 mg/kg bid, none had a biopsy-provedrejectionepisodes,but one pt was treated for a rejectionepisodethat was not documentedby biopsy. Three patients had adverseevents which led to temporarydose reductionor interruption; these included leukopenia,vadcella and CMV gastritis. All patients were restartedand continueon MMF. Pharmacokineticstudies showed a lower mean area underthe curve (AUC)than that seen in adults. In young patients,the apparentclearanceof an oral dose of CsA is higher and bioavailabililyis reducedwhen comparedto adults. In adults Neoral is associatedwith a more predictableand enhancedpattern of CsA absorption. A six-weekdouble-blindcrossoverstudy has comparedCsA pharmacekineticsin 28 children receiving Neoral and the standard CsA formulation, Sandimmune, at the same dose. Preliminarydata in six of these pediatriclots.show that the AUG for CsA is markedlyenhancedwith Neoralwhen comparedto Sandimmune. In addition, AUCs are more uniform and there is a tighter correlation between trough levels and the AUC Thesedata reinforce the recentlypublishedstudies (BSkenkampet al. PediatrNeph: 196,1995)that Neoralmay improve the bidavailabilityof CsA in children. This may necessitateeither lowertarget trough CsA levels or lower Neoraldoses, relative to Sandimmune. Both of these studies will help establishthe role of MMF and Neoral in pediatric renal transplantation.

*Department of Pediatrics, Stanford University, USA

S12.4 HLA PEPTIDES AS NOVEL IMMUNOSUPPRESSIVES C. Clayberger*, J. Goldberg*, E. Noessner**, and A.M. Krensky** Synthetic peptides corresponding to regions of HLA class I molecules have been evaluated for effects on immune responses in vitro and in rive. A peptide corresponding to residues 75-84 (RENLRIALRY) of the ~1 alpha helix of some HLA class 1 molecules, including HLA-B2702, -B38, and -B58 was found to inhibit all in vitro assays tested. The inhibition was observed independent of the HLA type of the responder or stimulator cells. Studies to determine the mechanism of action of this peptide have been conducted. The class I peptide caused an increase in intraceliular calcium in cells that closely resembles that induced by anti-CD3 monoclonal antibodies. Both anti-CD3 and the class I peptide caused release of calcium from intracellular stores, but only anti-CD3 stimulated an increase in inositol phosphates, indicating that the peptide uses a different second messenger for release of internal calicum stores. Reporter gene assays were used to investigate the effect of this peptide on various promoters. The peptide blocked assays driven by NFAT (nuclear factor of activated T ceils), but not AP-1 or CMV. The peptide also caused a reduction in the amount of NFAT isolated from Jurkat cell nuctei after activation with PMA and ionomycin, as shown by gel shift analysis. Using a biotin-conjugate of the peptide, we have shown that it binds to members of the Hsp70 family, and in particular, to the constitutive 74 kD protein. These results define a new pathway by which peptides derived from structural regions of HLA molecules can modulate T cell function and reveal of pathway of potential therapeutic importance. Departments of *Cardiothoracic Surgery and ** Pediatrics, Stanford University, Stanford, CA USA

*Pediatric Nephroiogy- UCLA School of Medicine

C 23 S Y M P O S I A - S15. I g A Nephropathy and Henoch-Sch0nlein P u r p u r a S15.1 NEW INSIGHTS NEPHROPATHY R. Coppo

INTO

THE

PATHOGENESIS

OF

IgA

S15.2 PROGNOSTIC FACTORS FOR THE DEFINITION OF RISK GROUPS OF PRIMARY IgA NEPHROPATHY T. Linn6*

The pathogenesis of igA nephropathy does not follow a calculable model of balance between production of IgA, kinetics of formation and removal of IgA containing immune complexes (IgAIC) and complement activation. It is now accepted that the mesangial deposition of IgA and nephritogenesis are modulated by factors which affect the interaction of circulating immune material with mesangial cells and/or matrix. Beside increased antigenic exposure leading to high IgAIC levels, structural alterations of the IgA molecule may favour the formation of circulating nonimmune aggregates, including IgA-fibronectin aggregates, IgA/IgG rheumatoid factor complexes or IgA-lectin macromolecular aggregates. The localization of IgA to the mesangium is possibly enhanced by its peculiar physico-chemical and electrical characteristics, including altered glycosylation of carbohydrate side chain and highly negative electrical charge of IgA molecule, which can increase the affinity of IgAIC for the mesangial area. The O-linked carbohydrate chains of the IgA hinge region are possibly truncated, resulting in decreased galactosylation of the IgA molecule, which may be insufficiently cleared by the hepatic asiaioglycoprotein receptor and preferentially bound to mesangial cell receptors. An altered glycosylation of IgA may involve the N-terminal linked carbohydrate residues as well. Moreover. the immune deposits may be favoured by a particular affinity (lectin-like activity) of the antigenic component of the IgAIC for mesangial matrix constituents or mesangial cell receptors. Two synergistic elements seem a requisite for the development of IgAN: the presence of abnormal IgA in circulation must meet a receptive mesangial area. Following this hypothesis, genetically determined or acquired mesangial cells disreactivity "per se" further enhances IgAIC binding to mesangial cell receptors, cytokine local production, and glomerular hemodynamics disregulation. Among the others, PDGF, IL-1, IL-6 and TGF~3 as cytokines and endothetin, nitric oxide, thromboxane and angiotensin as hemodynamic factors have been demonstrated to play a crucial role in the pathogenesis and progression of IgA nephropathy leading to mesangial cell contraction and activation and to the following proliferative and sclerotic changes.

Primary IgA nephropathy (lgAN) was first considered to be a relatively benign disease in children. However, long-term follow-up studies have shown that a substantial number of children with IgAN run a significant risk for a deteriorating course, with development of hypertension and end-stage renal disease (ESRD). In most cases the course of IgAN is of a chronic character, with long duration between first glomerular symptom and renal failure, but sometimes there is a rapidly progressive course. Mild depression of the GFR in connection with episodes of macroscopic hematuria, is not uncommon. Steroid sensitive nephrotic syndrome may occasionally develop. With time, however, more and more patients also show apparent remission. Since the diagnosis o f l g A N has to be confirmed with a kidney biopsy, the biopsy indications will influence the apparent prognosis. Patients with more severe symptoms, and higher probability of severe biops~r changes, are probably more likely to be biopsied. The duration of the d~sease also has to be taken into consideration, since the correlation between biopsy findings and clinical symptoms are sometimes poor in early biopsies. IgAN has thus a very variable course, with risk of hypertension and renal failure, but also a good chance of complete clinical remission. It is therefore important to be able to define prognostic risk factors in order to select groups of patients who need treatment. It would also be of value to avoid treatment of patients with low risk of progressive disease. The following variables have been found to have a predictive value for development of ESRD: sclerotic changes and crescents in a high proportion of the glomeruli, moderate or severe tubulointerstitml changes, diffuse mesangial proliferation, hypertension at biopsy, heavy proteinuria at biopsy, male gender and black race. However, some patients with pronounced biopsy changes may also show complete clinical remission. Of the patients with mild biopsy changes, very few appear to develop ESRD.

Nephrology and Dialysis, Regina Margherita Children's Hospital - Torino , Italy

*Department o f Pediatrics - Karolinska Institute - Karolinska and St. G6ran's H o s p i t a l - S t o c k h o l m - S w e d e n

$15.3 PROGNOSIS OF THE NEPHRITIS OF SCHONLEIN-HENOCH PURPURA (SHP) K. Sch~rer 1, R.T. Krmar 1, R. Waldherr z, H. Ruder a U. Querfeld 4

Renal i n v o l v e m e n t is f o u n d in a b o u t 5 0 % o f patients with SHP. It usually presents with macroscopic haematuria and/or proteinuria and rarely with nephrotic s y n d r o m e or renal failure. 1 2 % o f patients w i t h SHP nephritis progress to ESRD (White: N e p h r o n 6 8 : 1 , 1 9 9 4 ) . Earlier investigations suggested t h a t the clinical p r e s e n t a t i o n largely predicts the o u t c o m e . M o r e recent studies d e m o n s t r a t e that no d i f f e r e n c e exists in the degree o f initial proteinuria or h y p e r t e n s i o n b e t w e e n patients progressing to ESRD c o m p a r e d to t h o s e w h o recover. Proteinuria and h y p e r t e n s i o n m a y r e a p p e a r and renal function deteriorate after many y e a r s o f a p p a r e n t l y normal renal findings. Prediction on the o u t c o m e is s o m e w h a t more reliable on the basis o f renal biopsy findings t h a n on clinical g r o u n d s although severe c r e s c e n t f o r m a t i o n and g l o m e r u l a r sclerosis may be associated with resolution. The c o m b i n a t i o n o f clinical and histological grading at o n s e t o f the disease p r o b a b l y yields the best prognostic indicator. In our report w e describe the initial and s u b s e q u e n t clinical findings in relation t o renal h i s t o l o g y in 7 0 pediatric patients with SHP nephritis f o l l o w e d up for 2 - 2 5 years. O u t c o m e indicators w e r e proteinuria, 2 4 - h r blood pressure and GFR. Emphasis is given to the o u t c o m e o f 8 patients w i t h nephrotic s y n d r o m e or l o w GFR and crescentic nephritis a f t e r repeated plasma e x c h a n g e w h i c h seems to d e l a y the progression. No f a v o r a b l e long-term results w e r e o b t a i n e d by the use o f c o r t i c o s t e r o i d s or c y c l o p h o s p h a m i d e . The t r e a t m e n t o f SHP nephritis remains a challenge requiring prospective multicenter studies. U n i v e r s i t y Children's Hospitals Heidelberg 1, Erlangen 3, C o l o g n e 4 and ZDepartment o f Pathology, University Heidelberg - G e r m a n y

$15.4 IgA AND HSP NEPHROPATHY: CHOICE OF TREATMENT. Ronald d Hogg* There have been numerous agents reported to be beneficial in patients '~'ithq~N~ In recent studies, cortlcosterofds, fish oils, and anglotensln converting enzyme (ACE) Inhlbitora have shown the moat encouraging results and will be the focus of this revtew. McEnery et aJ first described the beneficial use oforal prednlsone In IgAN In a small group of children. Some recent studies of steroids have also reported benefit, whereas others have not. Waldo et al reported that t3 children with IgAN treated with alternate-day prednlsone had better preservation of GFR than a hlstorfcal control group of 15 untreated patients (p=0.03). Kobayashi et al reported that a 2-year tapering course of dally prednisona (plus a non-sterolda{ anti-Inflammatory agent) resu{ted in better renal survival in patients with "moderately progressive" IgAN than in a control group-after 5 years (100% vs 83%) and 10 years (77% vs 42%) of follow-up. In rapidly progressive forms of both IgA and HSP nephropathy, Nlaudet et al have reported that pattents treated with IV pulse steroids fared better than historical controls. In contrast, preliminary results from three recent controlled clinical trials of oral steroids in IgAN (Nlcholls et el, Welch et al and Julian et el) have shown no statistically significant benefit. However, these were short term studies and Included small numbers of patients, some of whom may have had non-progreesNe disease. The use of fish oils In patients with IgA~l is based on the premtse that omega~ polyunsaturated fatty acids may limit the production or action of cytokinss and elcosanoids evoked by the initial Immunologic renal injury, Donadto et al recently puDlished a placebo.controlled study in which dietary flsh-olt supplements significantly slowed the rate of renal deterforation In adult patients with [gAN. The results of other studies evaluating fish oils in IgAN have been conflicting (Ramazaki at, Bennett et el, Petterseon at ai). The variable results In these studies may have resulted from differences in the rate of progression of disease in the different populations, variation in the composition of the fish oil used, or differences In the duration of treatment. The management of hypertension in }gAN Is also controversial Some reports Indicate that ACE inhibitors induce an improvement in protein excretion and maintenance of GFR not observed with other anti-hypertensive medications, whereas others report no difference between ACE Inhibltors and Beta btockers or calcium channel blockers. Further confirmation of the possible benefit of the therapies described above is clearly needed. One approach to this will be described; the Southwest Pediatric Nephrology Study Group trial of the efficacy of alternate-day prednisone or fish oll capsules In children and young adults with moderately severe IgAN. In addition, recommendations for treatment of 3 chUdren with IgAN of varying sevadty by an international pane~of nephrcicglsts (Pediatric and Internal Medicine) will be reviewed. *Center for Children, Medical City Dallas Hospital, Dallas, TX

C 24 SYMPOSIA - $16. Late Consequences of Renal Transplantation S16.1

S16.2

OF RENAL TRANSPLANTATION LATE CONSEQUENCES R.Fine* The late consequences of renal Rx to be discussed are the following: (1) Allograft Function; (2) De Novo Malignancy; (3) Final Adult Height; & (4) Psychosocial Adaptation. Despite the introduction of newer immunosuppressive drugs which have markedly reduced the incidence of acute rejection and

significantly

improved

the

short-term

survival rates, there continues deterioration of graft function

to

be

graft a

slow

with ultimate graft failure in the majority of allografts. Whether this phenomenon is immunologic or physiologic remains to be established; however, definitive treatment to curtail the continuous decline remains elusive. De Novo malignancy is increasing in frequency in the NAPRTCS registry. The type of tumors as well as the interval following transplantation will be presented. Final adult height in the pre-cyclosporin era was below a standard deviation score of -2.00 in a substantial number of patients. Data from the cyclosporin era is minimal, bu t substantial improvement has not been anticipated. The use of recombinant human growth hormone may be beneficial in improving this phenomenon. Sparse data are available regarding the psychosocial adaptation of long-term allograft recipients. At least one-third of recipients in one study who survived less than ten years have voiced dissatisfaction with short stature being a prominent etiology. The extent to which non-compliance accounts for late graft failures requires elucidation. *State University of New York at Stony Brook Stony Brook, New York - USA

$16.4 OUTCOME AND ETHICS OF KIDNEY TRANSPLANTATION IN CHILDREN Cyril Chantler*, Geraldine Ward* and Sue Rigden*

Many problems of chronic renal failure (CRF) in childhood, such as renal osteodystrophy, anaemia and poor growth can now be overcome. Others such as long term survival, rehabilitation and the ethics of treatment in some children with CRF remain. Patient survival after 20-25 years of treatment is about 70% though many will require more than one graft. Whilst full rehabilitation is common with a successful graft, survivors and their families often suffer problems related to stress, poor body image, inadequate personal relationships and educational attainment. Sometimes it is necessary to consider whether treatment should be started or withdrawn. The possibilities of long term success, the quality of life, the availability of resources and the wishes of the child and family must be considered. Other considerations include the rights of the child, including respect for autonomy, the general obligation to protect life and health, the need to deal justly between different individuals, the rights of the parents to consent and the concept of moral hazard. Information on the effects on parents and siblings of caring for infants with CRF is inadequate and more research is needed. We need to engage ethicists to discuss the balance of responsibility of paediatricians to the family and the child, bearing in mind that infants are not autonomous and can rarely be reared successfully outside the family . All the carers including the doctors should discuss openly together and with the families whether treatment should be started and whether it should be withdrawn. *Evelina Childrens Department, United Medical and Dental Schools o f G u y ' s and St Thomas' Hospitals, Guy's Hospital, London SEl 9RT, UK.

ETIOLOGY, MANIFESTATIONS A N D M O L E C U L A R P A T H O L O G Y OF CHRONIC A L L O G R A F T REJECTION Pekka H~yry, Transplantation Laboratory, University of Helsinki, Helsinki, Finland Among t he r i s k f a c t o r s p r e d i s p o s i n g t he r e c i p i e n t for c h r o n i c r e j e c t i o n a r e h i s t o i n c o m p a t i b i l i t y , d u r a t i o n of p e r i o p e r a t i v e p e r i o d , donor a g e , f r e q u e n c y a nd i n t e n s i t y of a c u t e r e j e c t i o n e p i s o d e s , i n f e c t i o n s ( p a r t i c u l a r l y CMV), an d p o s s i b l y l i pi d a b n o r m a l i t i e s . Additional p a r a m e t e r s , not s t u d i e d so f a r , may i n c l u d e h y p e r t e n s i o n a n d d i a b e t e s . C o n s i d e r i n g t he two most i m p o r t a n t m a n i f e s t a t i o n s in c h r o n i c r e j e c t i o n h i s t o l o g y , inflammation a n d a r t e r i o s c l e r o s i s , th e following w o r k i n g h y p o t h e s i s a r i s e s : immune r e s p o n s e c h a r a c t e r i z e d by p e r i v a s c u l a r inflammation i n d u c e s p e r s i s t e n t l o w - g r a d e damage to v a s c u l a r e n d o t h e l i u m , which in t u r n b e g i n s to s e c r e t e g r o w t h f a c t o r s to r e p a i r t h e damage. This r e s u l t s in smooth muscle cell r e p l i c a t i o n in th e v a s c u l a r wall a nd i n f l u x of m y o c y t e s from t he media into th e intima a nd g e n e r a t i o ~ of an a r t e r i o s c l e r o t i c l e s i o n . All i n t r a m u r a l a r t e r i e s of a t r a n s p l a n t a r e a f f e c t e d d u r i n g a l l o g r a f t a r t e r i o s c l e r o s i s , which is c o n c e n t r i c a n d g e n e r a l i z e d in c o n t r a s t to t h e t~_sually focal a nd e c c e n t r i c c l a s s i c a l atberosclerosis. A c ut e inflammation (re j e c t i on) is a p r e r e q u i s i t e for c h r o n i c c h a n g e s . T h e r e a r e s e v e r a l molecular c a s c a d e s p a r t i c i p a t i n g in t h e g e n e r a t i o n of c h r o n i c r e j e c tion. The final e f f e c t o r molecules a r e most l i k e l y g r o w t h f a c t o r s s y n t h e s i z e d as a r e s p o n s e of i n j u r y b y t h e p a r e n chyma] a nd e n d o t h e l i a l cells of t he t r a n s p l a n t . T h e r e will b e no s i n g l e t h e r a p y for t he p r o p h y l a x i s or t r e a t m e n t of c h r o n i c r e j e c t i o n , a nd s e v e r a l p a r a m e t e r s m u s t be e n c o u n t e r e d to c o u n t e r a c t t h e s e a l t e r a t i o n s . However, if th e c u r r e n t 7 - 8 - y e a r h a l f - l i f e of r e n a l t r a n s p l a n t s could be d o u b l e d, c h r o n i c r e j e c t i o n would f a c t u a l l y be ove rc ome.

C 25 SYMPOSIA - S17. Adequacy of Dyalisis $17.1(1) Claudio Roman, MD, Enrico Verrina, ~3, Dept. of Nephrology. St. Bortolo Hospital and Gaslini Institute, Vicenza and C~nova, Yta

ly. PPHIqCIPLES OF SOLLTfE KINETIC MODET.I.TNG The principles of solute kinetic modelling in dialysis are basi cally referring to a critical analysis of the solute transpot properties in the exchange system (,hemodialyzer or peritoneal membrane) and in the whole body of the patient. Hemodialysis is a therapy and therefore it must be a) correctly prescribed, b) precisely delivered, c) effective in producing the desired effects. This prooess includes the whole concept of of dialysis adequacy. Despite adequacy is a concept that includes not only urea kinetics, but also the manteinance of an acceptable level of hcn~os tasis in the body (electrolytes, fluid, acid base, etc.), we can specifically focus on the aspects relevant to blood purification, which drive all other aspects of the therapy. Taking Urea is a marker molecule of dietary protein intake and dialysis efficiency, dialysis is prescribed to achieve a fractional clearance of urea greater than i, in relation to the volume of distribution in the body. Asslmling that this is a correct methodology of prescription (which is under debate, since the adequate value of Kt/V is different for different treat ments) several factors may affect a certain discrepancy between prescription and delivery of the dialytic dose.

S17.1(2) and convection, access recirculation, t6mperature and dialyzer surface area represent critical factors. In peritoneal dialysis, dialysate cxmEoosition, peritoneal microcirculation and peritoneal m~nbrane condition, linphatic reabsorption and treatment schedule are the most important aspects. All this factors may present some problems with a negative impact on the expected efficiency of the system. Even though the wanted clearance is obtained, we must make sure that it is maintained cons rant over time and that it is applied for the exact n~aber of minutes prescribed for that dialysis session. Time is in fact the second factor in the calculation of Kt/V and frequently the time spent in dialysis by the patient may be shorter compared to the original duration prescribed. Finally, the determination of the volume of distribution of the molecule is a misleading parameter. The volume is ass~ned to be cotant and equal to the whole body content of water. This asstmiotion is absolutely incorrect; each single session has access to a diferent volume of distribution in the body due to several factors such a hypotension, cardiopulmonary recirculation, peripheral vasoconstric tion and fluid sequestration. This aspect makes Kt/V absulutely unstable in the same patient at the sane treatmentregimen and renders very inloortant the calculation of the postdialysis concentration rebound ( expression of the double pool kinetic of the molecule). For these reasons, Kt/V should be accc~Ipanied by a parallel measurement of the total amount of solute removal. The recent approach to oontinuous urea monitoring in dialysis, might further help in the future to establish a closer relation between prescription and delivery of the desired dialytic dose.

Considering Kt/V as a par~neter of efficiency, most of the factors affecting K (clearance) are related to the extracorporeal circuit. In particular, for extracorporeal treahrents, blood flow rate, dialyzer function~and membrane permeability, dialysa te flow rate, blood and dialysate distribution inside the dialy zer, rate of ultra filtration and interaction between diffusion

S17.3(1)

$17.3(2)

Edward C. Kohaut, MD, Pediatric University of Alabama at Bir mingh~n, Birminghan, Alabama, USA.

When changing a dialysis regimen it must be r ~ r e d that drain and fill times should be minimized since during these periods little or no dialysate is in the abdomen. Dialysis regimens in young infants should be changed with care and clearances should be mesured if there is any question of adequacy.

PRESCRIBING AND MC~qITORING ADEQUATE PERITClqEAL DIALYSIS FOR IN F A N T S AND YOUNG C~ILDREN. What is adequate dialysis for infants and young children has been difficult to detezmine. In adult patients treated with pe_ ritoneal dialysis it has been suggested that weekly Kt/V equal to 1.7 is adequate. However, should we as pediatric nephrologist accept this a s adequate for children. We are dealing with active growing individuals who are not only developing physical ly but mentally. Our patients are certainly different than the adults, therefore, our bias should be that these patients should be provided as much dialysis as we possibly can. Early in our experience with pediatric peritoneal dialysis, dwell volLraes were based on milliliters per kilogram extrapolated from the adult experience. Utilizing these relatively low dwell vol%~aes it was found that most of the young pediatrics p a tients fall into the category of "rapid equilibrators". How ever mass transfer area coefficients measured in children show ed no difference between adults values. Over the last decade-nL~nerous studies have now demostrated that peritoneal membrane of infants and young children is equivalent to the adult membra ne and the difference is that the surface area of the membrane-is greated when corrected for body weigth. Therefore, one me thod to provide dialysate vol~mes equivalent toperitoneal surfa c e area. This can be done by using dialysate voltm~es as high as 1200 ml/M2 rather than 30 ml/kg as suggested in the adult po_ pulation. Once dwell volt~nes are maximezed the anount of dialy sis provided by peritoneal dialysis in this patient population would be almost directly related to dialysate flow vol~nes. Because we as pediatric nephrologist tend to want to provide as much dialysis as possible for our patients most pediatric pa tients are treated with CCPD where multiples exchanges can be done at night and thus maximize dialysis flow rates.

If forced to give a n~nber for adequancy of dialysis in these young infants one would have to extrapolate from the adult popu lation a Kt/V of i. 7 or a total creatinine clearance of 40 liters per i. 73 m2/ week. Adequancy of dialysis and adequate nutritional suppl~nentation must be carefully balanced. When changes are made in protein intake it may be efficacious to make changes in total dialysis. When changes are made in the dialysis regimen changes, changes in dietary intake must also be cosidered. As pediatric nephrologist we do have same objective measurement of adequancy. The most inioortant is growth. In the era of rgGH, growth may not be as valid an indicator of dialysis ade quancy, however the response to rg6~ will be optimal only if -dialysis clearances and nutritional intake are max/mized.

C 26 SYMPOSIA - S18. Urinary Tract Infection, Pyelonephritis and Vesicoureteric Reflux S18.1 LONGTERM FOLLOW UP OF "MINIMAL" RENAL COLLECTING SYSTEM DILATATION DETECTED IN THE ANTENATAL PERIOD. Andrew R. Rosenberg 1, Gad Kainer 1, Tarak Srivastava ~, Christine Hughes ~, Diane Leighton 1, William Garrett z, Peter Warren 2. Prince of Wales Children's Hospital ~ and Royal Hospital for Women 2, Sydney, Australia. We prospectively investigated and followed the progress of 86 children (58M:28F) whose antenatal ultrasound (US) showed minimal (3-10mm) renal pelvic dilatation in the A-P diameter. Early US was defined as <20 wk gestation and late US as >~20wk. Voiding cystourethrography (VCU) and US was carried out on. all children. Those without vesicoureteric reflux (VUR) were followed with US. 6 children had only an early US, 45 had only a late US and the rest had both early and late US. Of 41 children studied early, 16 had no dilatation detected, 18 had bilateral and 7 had unilateral dilatation. In these 25 children (43 dilated renal units), only 4 pelves were not dilated on later US. 80 children had late US; 54 had bilateral dilatation and 26 unilateral dilatation. 15 of the 86 children had <3 mm dilatation on first postnatal US (range 3-16 wk, median 4 wk). None of the 15 pts had VUR on VCU performed at a median age $ weeks. At f o l l o w up postnatal US, (range 4-104 wk, median 25wk), 3 of these 15 patients had 3-5 mm dilatation and the others remained <3mm. 69 of 86 children showed dilatation 3-10mm at first postnatal US. 18 of these had VUR (10 bilateral, 8 unilateral) on their first postnatal VCU. VUR was detected in 3 further children at 12-64 wk of age, investigated for UTI or fluctuating dilatation. Thus 21 of 66 children had VUR (11 bilateral, 10 unilateral). 15/21 children had VUR grades 3-5 and 24/32 refluxing renal units were grade 3-5. There was no correlation between degree of pelvic dilatation on US and grade of VUR. DMSA studies were performed in 10 of these children and 5 were abnormal. 6 patients underwent reimplantation surgery for grade 4-5 VUR. Two children had postnatal US dilatation exceeding t0 mm at 2 and 5 wk. Both were subsequently shown to have UPJ obstruction and underwent pyeloplasty. Follow up US were performed for up to 2 yr on the 63 children without VUR or UPJ obstruction. None showed progresssive dilatation. We conclude that VUR occurs in 24% of children with minimal dilatation of the renal pelvic A-P diameter. Most of the VUR is of grades 3-5. Progression of dilatation in the absence of VUR is uncommon and is likely to be detected in the first 6 weeks postnatally.

S18.6 C O N T R O V E R S I E S IN U T I I. G O R D O N . G R E A T O R M O N D S T R E E T H O S P I T A L L O N D O N E N G L A N D All children with a UTI require investigation to detect an obstructive uropathy or a renal calculus, or the possibility o f the child ending up in renal failure or the possibility o f the child developing hypertension from a scarred kidney. With the introduction on n e w e r imaging techniques the strengths and weaknesses o f each technique m u s t be fully appreciated. W h i c h children should be investigated - should this require a pure growth o f > 1 0 0 0 0 0 organisms or is there a place for investigating the child with a "suspected" UTI? V~'hat is the definition o f u p p e r tract involvement in a UTI - is this a clinical diagnosis or is a D M S A scan required? W h a t is file role o f acute D M S A in the m a n a g e m e n t o f U T I - should an abnormal "acute" scan change m a n a g e m e n t ? W h a t is the long term importance o f a renal scar in respect to hypertension in later life'? The diagnosis o f V U R has required a M C U - is this technique an acceptable "reference method"? Is a catheter c y s t o g r a m always required or can an indirect isotope c y s t o g r a m suffice? Is the radiation burden from a M C U ever justified in a girl? W h a t is the importance o f V U R in the development o f renal scarring - are there clinical situations that VUR m a y be unimportant? Discussion o f these aspects o f UTI will highlighted.

S18.3 BLADDER DYSFUNCTION IN INFANTS WITH GROSS REFLUX. U. SiU~n, Children's Hospital, Dept of Pediatric Surgery, University of GOteborg, Sweden The gross reflux seen during infancy mainly in boys, has earlier been attributed only to a congenital malformation of the vesico-ureteral junction, and not to a bladder dysfunction. In children beyond infancy, on the other hand, bladder dysfynction is readily accepted as a contributor to reflux occurrence. Lately we have given some evidence for the exsistence of a congenital bladder dysfunction in some of the infant boys with gross reflux. The urodynamic pattern registered is characterized by hypercontractility with instability of the detrnsor, low bladder capacity, high voiding pressures and often EMG signs of dyscoordinated voiding.Videourodyunmic studies with simultaneously performed VCUG and cystometry in these infant boys have also shown pressure related refluxes in the majority of the cases with occurrence of reflux as a response to increase in bladder pressure, either as an unstable contraction during filling or at the voiding contraction. These urodynamic data in infants with reflux have evoked the need for an age-matched control group, since data regarding normal lower urinary tract urodynamics in this age group are sparse. We have therefore performed cystometric investigations simultaneously with the mandatory VCUG in infants after acute pyelonephritis and excluded those with reflux or other malformations. Unexpectedly we found that 5 ( ~ of the boys had a hypercontraetile pattern very similar to that seen in boys with reflux. However, in comparison between the complete groups of infant boys, those with pyelonephritis and those with gross refluxes, there is a significant difference in detrasor pressure levels. In conclusion thus it is still controversial whether a congenital bladder dysfunction contributes to gross infant reflux or not. It is however tempting to suggest that the hypercontractile urodynamic pattern seen in the infant boys with dilating reflux and in some of the infants with pyelonephritis have a similar congenital bladder dysfunction inducing both the refluxes and the pyelonephrifis, respectively.

C 27 SYMPOSIA - S19. Ion and Water Channels in Health and Disease S19.2

S19.1 CLONING

OF

A

CALCIUM-SENSZNG

RECEPTOR

AND

ITS

ROLE

IN THREE H U M A N DISORDERS. M.R. Pollak, S.C.Hebert, D.Riccardi, Y.-H.W.Chou, C.E.Seidman, J.G.Seidman, E.M.Brown, Brigham & Women's Hosp., Boston, US. Parathyroid cells possess a cell surface glycoprotein that detects changes in extracellular Ca 2§ concentration and regulates PTH secretion by altering phosphoinositide turnover and cytosolic Ca 2+. We have identified a cDNA clone encoding the bovine parathyroid Ca2+-sensing receptor (CAR) using an expression cloning approach in Xenopus oocytes. This cDNA predicts a 121 kD protein with seven membrane spanning domains characteristic of G-protein-coupled receptors. The expressed CaR is pharmacologically similar to the Ca2+-sensing activity of PT cells. Northern analysis shows strongest expression of the gene in parathyroid, thyroid, and kidney, with weaker expression in the brain. Southern blot and PCR analysis demonstrated the human homolog of the bovine CaR ("HuPCaR") was located on the proximal portion of the long arm of chromosome 3. Previously we had demonstrated that the human disorder FHH (familial hypocalciuric hypercalcemia) maps to this locus. We therefore screened a human genomic library to obtain clones containing HuPCaR coding sequence. Analysis of these clones demonstrated that the coding sequence was comprised of six exons. PCR amplified DNA from FHH and Neonatal Severe Hyperparathyroid (NSHPT) patients was used in RNase protection assays and as sequencing template to look for gene defects. In eight unrelated families with FHH and/or NSHPT, we found missense mutations predicting nonconservative amino acid changes segregating with disease. We investigated the possibility that defects in this gene could also cause a hypocalcemic phenotype. Similar analysis of DNA from members of a family with autosomal dominant hypocalcemia revealed a missense mutation in the extracellular domain of the receptor which was hyperactive upon expression in oocytes. In summary, the physiologic and genetic evidence together reveal a critical role for this receptor in calcium homeostasis by the parathyroid gland and kidney. The disease state resulting from homozygous mutant HuPCaR demonstrates that its function is critical and nonredundant.

S19.3 MOLECULAR CLONING, EXPRESSION, SELECTIVITY, RENAL REGULATION AND LOCALIZATION OF THE W A T E R C H A N N E L A Q U A P O R I N - 3 . G. Frindt t M. Echevarr~a, C.A. Ecelbarger, S. Nielsen, M.A. Knepper. Dept. of p h y s i o l o g y and B i o p h y s i c s , Cornell University Medical College, New York, N.Y., USA The aquaporin f a m i l y of w a t e r c h a n n e l s plays an i m p o r t a n t role in t r a n s e p i t h e l i a l w a t e r m o v e m e n t in the kidney. We have identified aquaporin-3 (AQP3) by homology cloning from a rat kidney library. The isolated cDNA has 1.9 kb, with an open reading frame of 876 bp encoding a deduced polypeptide of 292 amino acids (Mr, 31,431). As for other aquaporins, the h y d r o p a t h y analysis of the d e d u c e d AQP3 protein predicts six p u t a t i v e transmembrane domains separated by five connecting loops and both termini located intracellularly. AQP3 has the highest identity (37%) with the w a t e r - i m p e r m e a b l e glycerol facilitator p r o t e i n of E. coli. Only one N - g l y c o s y l a t i o n consensus site at residue Asn-141 is identified, supporting the extracellular location of this domain. Both cell-free tranlation and immunoblots of cell m e m b r a n e fractions of rat kidney c o r t e x or m e d u l l a u s i n g an affinity p u r i f i e d anti-AQP3 p o l y c l o n a l antibody i d e n t i f y a ~27 kDa band and a 33-40 k O a b a n d p r o b a b l y containing the glycosylated protein. Expression of AQP3 in Xenopus oocytes after injection of ~5ng c R N A / o o c y t e increases the oocyte osmotic water p e r m e a b i l i t y (Pf) ~15fold and, to a lesser extent, the permeability to formamide, glycerol and urea. Mercurial reagents abolish the expressed Pf but do not alter the glycerol permeability. In situ hybridization, immunocytochemistry and i m m u n o e l e c t r o n microscopy studies reveal that labeling is restricted to the principal cells of cortical and medullary collecting ducts; and, w i t h i n these cells, l a b e l i n g is c o n f i n e d to the b a s o l a t e r a l domain. N o r t h e r n analysis and i m m u n o b l o t t i n g studies demonstrated that t h i r s t i n g of rats for 48 h approximately doubles the amount of AQP3 I~RNA and of AQP3 protein in the kidney relative to well-hydrated rats. T h e s e studies are c o n s i s t e n t with a role for AQP3 in water t r a n s p o r t in the c o l l e c t i n g tubules and w i t h l o n g - t e r m regulation of the expression of this water channel. (Supported in part by NIH grant ROI DKI1489)

REGULATION OF fi-AMINO ACID TRANSPORTER IN RAT KIDNEY CORTEX AND CULTURED KIDNEY CELLS BY SUBSTRATE CONCENTRATION. R.W. Chesnev. X. Han. A. M. Budreau.D.P. Jones. University of Tennessee, Memphis, Department of Pediatrics, Memphis, TN, USA, 38103. g-amino acid (taurine, tau) transport is influenced by dietary tan content in rat kidney cortex and by the extracellular substrate ([tan]ex) concentration in two cultured renal tubular ceils LLC-PK1 and MDCK. Recent studies have determined that manipulation of dietary tau alters expression of mRNA for the tan transporter. Northern blot analysis of rat kidney cortex mRNA using both pNCT (MDCK tan transporter) and the rB16a (rat brain tan transporter) as probes detected a decrease in the expression of mRNA after high tan intake and an increase following low tan diet for 2 weeks. Using a polyclonal antibody directed against a highly conserved cytoplasmic domain of the cloned tau transporter (AbTBs), western blot analysis demonstrated the reciprocal expression of tan transporter depending upon the dietary intake. LLC-PKI cells express a similar adaptive response following changes in medium [tan]. Two mRNA bands were detected using pNCT probe (7.2 kb, 9.6 kb); the 7.2 kb increased within 12h exposure of ceils to tan-free medium, with no appreciable effect on expression of the 9.6 kb. In contrast, in cells bathed in high [tan]ex (500 gM), the expression of the 7.2 kb mRNA decreased after 12 h. The 9.6 kb remained stable up to 48h yet decreased by 72h, suggesting differential expression of these two mRNA products. MDCK cells express a single band of mRNA (7.2 kb) which increases following 12h in tan-free medium and decreases in high [tau]ex. Western blot analysis of pNCT injected oecytes using AbTBs yielded two protein bands of 70 and 30 kDa size. The abundance of both proteins was reduced after exposure of pNCT injected oocytes to high [tau]ex while only the 30kDa protein was increased by tan-free medium. [Tau]ex also modified the translation of tau transporter from mRNA: oocytes injected with comparable quantities of pNCT mRNA exhibited different levels oftau transport and tan transporter protein after manipulation of [tau]ex. We conclude that 1) substrate concentration regulates tau transporter activity by at least two mechanisms-transcriptional and translational, 2) that the [tau]ex displays divergent actions upon expression of mRNA and transporter proteins, and 3) that the mechanisms by which [tau]ex effects changes in transporter expression differ among cell types, possibly related to species or tubular site of origin.

$19.4 ONTOGENY OF K TRANSPORT IN THE CORTICAL COLLECTING DUCT (CCD). L.M. Satlin, A. Constantinescu, R.B. Silver, and L.G. Palmer. The process of growth is dependent on K retention. The final regulation of K homeostasis occurs in the CCD which, in the adult, secretes K at high rates. No net K secretion, however, was detected in CCDs isolated from newborn (NB) animals and perfused in vitro. The lack of net K secretion early in life may be due to a reduced secretory and/or enhanced absorptive capacity. K secretion by principal cells (PCs) results from active K uptake via the NaK pump and passive diffusion through apical K channels. To determine whether a scarcity of apical K channels limits K secretion early in life, we compared the apical K permeability of PCs in split-open CCDs isolated from NB and 5-wk-old rabbits using the patch-clamp technique. At 5 wks, with KCI in the pipette and Ringer's solution in the bath, inward currents with a conductance of 32+2 pS were observed in 6 out of 13 cell-attached patches. In contrast, in the NB, channels with this conductance were not identified in 23 patches. The lack of functional apical K secretory channels can account for the limited ability of the NB to secrete K. K absorption by intercalated cells (ICs), mediated by H-K-ATPase, may contribute to K retention in the NB. We therefore examined the Na-independent H+ extrusion pathways in NB CCD ICs using fluorescence microscopy and BCECF. Split-open CCDs were acutely acid-loaded (NH4 pulse), and Na-independent pHi recovery was monitored in the absence (to identify K-independent H + transport) and then in the presence (to identify K-dependent H§ transport) of K. In the absence of K, pH~partially recovered by a bafilomycin-sensitivepathway, suggesting that it was mediated by a H+-ATPase. Restoration of K to the bath led to a further increase in pHi at a rate of 0.06_+0.02 pHU/min; this recovery was inhibited by SCH 28080, a specific inhibitor of H-K-ATPase. To identify whether the H-K-ATPase was located at the apical or basolateral membrane, Na-independent pH~ recovery of acidloaded ICs was monitored in CCDs perfused in vitro. In the absence of Na and K in lumen and bath, pH~ recovery was not observed. Addition of K to the luminal perfusate led to a prompt increase in pH~ of 0.5_+0.1 pH U (n=4); restoration of K to the bath had little further effect on pI~. These results are consistent with an apical location of the H-K-ATPase. In summary, these data suggest that the absence of net K secretion in NB CCDs results from a limited K secretory flux due to the absence of apical K secretory channels in PCs and the presence of a reabsorptive flux, mediated by apical H-K-ATPase, in ICs. These two processes promote K retention, as required for growth. Albert Einstein Coll. of Med., Dept. of Pediatrics, Bronx, N.Y., 10461, USA, and Cornell U. Medical College, Dept. of Physiology, N.Y., N.Y., 10021, USA.

C 28 S Y M P O S I A - $20. A u t o c r i n e a n d P a r a c r i n e F a c t o r s in t h e R e g u l a t i o n o f R e n a l F u n c t i o n $20.1

S20.2

MOLBC~ A N D CELLULAR ASPECTS OF ~ KENINANGIOTENSIN SYSTEM. R.A. Gomez, E.A. Katsinnva.Universityof VirginiaSchool of Medicine,Charlottesville, Virginia. We have previously shown that expression of the main ggne is developmentallyregulated. During fetal life, renin-eontainingcells are found along large kidney vessels whereas in the adult animal renin expression is restrictedto thejextaglomemlar apparatus. These changesin renin expression are the result of transacting factors that regulate the activity of the renla promoter_ We have identifiedputative DNA sequencesand binding proteins that may be responsible for the high expression o f ' r ~ u during early development. In addition, we are studying the mechanismsthat regulate JG cell differentiation. JG cells maintained 2 days in culture have abundant levels o f ' ~ i n and its mRNA. However by 10 days in culture, the cells dedifferentiate, do not contain or release mnin ~mdthe level of renin mRNA, as determined by quantitative competitive PCP~ ~ reduced 500 fold. To detect genes involved in maintenance of the differentiated state, we compared RNAs from JG cells eulturad for 2 and 10 days using the diff~mtial display method. Selectedfragmentswere cloned, sequencedand used to probe Northern blots of mRNA from newborn and adult kidneys. One fragment, differentially expressed in the 2 day $G cell culture detected a 2.4kb mR.NAexpressedat higher levels in newbornthan adult kidney. This fragmen,t was used to probe a eDNA library we constructed from the 2 day JG cell edtare. The eDNA sequence has a region similar to a zinc finger protein from Xenopus laevis and domains eharaeterlstie of RNA binding proteins and splicing factors. Therefore this gene was termed Ziss(.~me finger,splicing, stability). Northern blots probed with Ziss eonfrrmed its developmental reg-ulation in the kidney and showed an additional [,Skb Iransoript in 2 day JG cell culture. In summary, we have identified a novel gene expressed in differentiated J~J cells and newborn kidney. The eDNA sequence suggests a possible role in the regulation of Irauscription and/or splicing, both important known steps for controlling developmentally expressed genes.

Jean E. Rohillard, Anne Monique Nuyt, Jeffrey L. Segar, David C. Merrill. Department of Pediatrics, College of Medicine, University of lows, lowa City IA Studies during renal development have suggested that renal nerves influence renal growth and play an important role in the regulation of fluid and electrolyte homeostasis and renin production during the transition from fetal to newborn life. THere is evidence that renal nerves influence fluid and electrolyte homeostasis during development. Studies in sheep at the time of parturition have shown that renal nerves play an important role in the regulation of sodium homeostasis during the transition from fetal to newborn life. Fetal lambs suhmitt~d to surgical renal denervation prior to birth and delivered by cesarean section had a greater diuresis and natriuresis than fetuses delivered with intact kidneys. Furthermore, renal denervation during fetal life suppressed the physiological rise in plasma renin activity and renal renin gene expression observed after birth. Factors modulating renal sympathetic nerve activity (RSNA) during the transition from fetal to newborn ls have also been studied. RSNA increased by =250% at birth. THis rise is not dependent on an increase in angiotensin II, but reflects changes at the level of the hypothalamus. Finally, studies designed to determine the influence of the eardiopulmonary reflex in modulating RSNA during hoth volume expansion and volume depletion have shown important adaptive changes in these mechanisms, during fetal and newborn periods.

$20.4

S20.3 THE ROLE OF PGE a IN TUBULAR FUNCTION IN PATIENTS WITH HYPERPROSTAGLANDIN E SYNDROME H.W. Seyberth, S. C. Reinalter, A. K0ckerling Children with hyperprestaglandin E syndrome (lIPS), a neonatal variant of Bartter syndrome with enhanced renal and systemic PGE 2 formation, have a olinical presentation which has many features in' common with chronic furosemide treatment in infancy, such as polyuda, hypercalciuda with nephrecalcinosis and hypokalemic alkalosis. This similarity might be to explain by furosemide is targeting the same transepithelial electrolyte transport at the ascending limb of the loop of Henle which is supposed to be the most proximal defect in patients with HPS. To test this hypothesis 9 children with HPS (age 6.7-11,6 y) were challenged with furesemide (2 mg/kg p.o.) after a 6-day indomethacin wash.out peded. The diuretic effects of furesemide in these polyuric and hyperprostaglandinudc patients were compared to those effects in agematched healthy controls (n=t4). in general there was a marked decrease in the furesemide-induced diuretic response in patients with HPS as compared with controls (p< 0.05): diuresis ( AVurine 4.5 • 1.0 versus 7.6 • 0,7 ml/kg/h), calciuda (A Ca**urin e 0.39 + 0.1 versus 0.56 + 0.07 mg/kg/h) and CI --excretion (A CI -urine 0.26 + 0.09 versus 0.88 • 0.09 mmollkgld). However, with respect to urinary PGE 2 excretion, furosemide triggered an additional rise of the elevated urinary PGE 2 levels in patients with HPS (from 49,3 + 15.9 to 97.0 • 26.8 ng/h/1.73m 2, p < 0.03), while in the controls no significant effect was observed on urinary PGE 2excretion dudng furesemide treatment (from 20.4 + 2.5 to 11.8 • 2.5 ng/h/1,73 m2). In summary patients with HPS display a partial furesemide resistance which is associated with a high reagibility in renal PGE 2 formation. Thus taking into constderation the beneficial response of indomethacin treatment in HPS together with these observations it appears that renal PGE 2 formation plays a very proximal role in:the pathomechanism of HPS. Universit~its-Kinderklinik,

INFLUENCE OF RENAL SYMPATHETIC INNERVATION ON RENAL FUNCTION DDRING RENAL DEVELOPMENT.

Deutschhausstr. 12, D-35033 Marburg, Germany

The E n d o t h e l i u m in Health and Disease G a b o r M. Rubanyi, M.D., Ph.D. Berlex Biosciences, R i c h m o n d , CA, USA Key discoveries in the past decade revealed that the vascular endothelium is an important regulatory organ that is involved in maintaining cardiovascular homeostasis in health and contributes in a significant way to the pathomechanism of several cardiovascular diseases. Occupying a strategically important location between circulating blood and tissues and having the ability to respond to changes in its physical, chemical and humeral environment by the production of a host of biologically active substances, the normal endothelium regulates the tone of underlying vascular smooth muscle, maintains a nonadhesive luminal surface and mediates -' hemostasis, cellular proliferation, inflammatory and immune mechanisms in the vascular wall. Modulation of smooth muscle tone is mediated by the synthesis release of endothelium-derived relaxing (PGI2, EDRF(NO), EDHF) and contracting factors (arachidonic acid metabolites, endothelin-1 and angiotensin II). Anticoagulant, fibrinolytic and antithrombotic properties contribute to the maintenance of the fluidity of blood. Injury or activation of endothelial cells disrupts these normal regulatory mechanisms and results in morphologic and functional alterations commonly defined as endothelial dysfunction. Clinically, the "syndrome" of endothelial cell dysfunction can be described as generalized or localized vasospasm, thrombosis and atherosclerosis. Further knowledge of the pathobiology of the impaired endothelium will contribute to better understanding of the pathomechanism of cardiovascular diseases and will enable to successfully design novel therapies to prevent and treat them.

C 29 SYMPOSIA - $22.

Mineral Metabolism

$22.1

S22.2

MOLECULARBASISOF THE HIGH RENALPHOSPHATE REABSORPTION RATE DURING GROWTH M. Barac-Nieto*, D. Silverstein* and A. Spitzer* The high fractionalreabsurptionof Pi observedin rapidly growingorganisms is associatedwith a high capacity (Vm,~)for Na+-Pi cotransportin renal microvilli. Because of the similaritiesbetween adaptation of the kidney to a high Pi demand (growth), and that to low Pi supply, we studied the levels of NaPi-2 protein and mRNA present in kidney cortex of 3- and > 12-wk-oldrats. Western blots revealed that a protein, between80-85 Kd, that reacts stronglywith antiserumdirectedagainst the N-terminal region of the NaPi-2 protein, is 2-3 times more abundant in renal brush-border membranes of 3- than of > 12-wk-oldanimals. Hybridizationsof the NaPi-2 eDNA probe with renal cortical RNA derived from 3-wk-old rats were of lower intensitythan those observedwith RNA from adult rats, even whennormalized by reprobing the blots with/3-actineDNA. Yet, Na+-Pi uptake was 2-fold higher in oocytesinjectedwith polyA RNA derived from 3- than from > 12-wk-oldrats. These data suggestthat mRNAtranscriptsuniqueto the growinganimalsare responsiblefor the high renal Na+-Pi cotransport observed in this age group. We next investigated whether inductionof Na+-Pi cotransportin oocytesis independentof the presenceof NaPi-2 mRNAtranscripts.Hybridizationof an antisenseNaPi-2 oligomerwith polyA RNA of adult rats and with NaPi-2 cRNAcompletelyabolishedtheir abilityto induce Na§ cotransport. By contrast, hybridizationof the antisenseoligomerwith polyA RNA of 3-wk-old rats had no effect on its ability to induce Na+-Pi cotransport in oocytes. In separate experiments,renal cortical polyA RNA from 3-wk-oldrats was hybridized with eDNA generated from renal cortex mRNA of adult rats. The effectivenessof the subtraction was assessedthrough PCR amplificationof residual /~-actin and NaPi-2 mRNA using appropriate primers. After three subtraction passages,/3-actinrnRNA was still detectable,while NaPi-2 mRNA was absent. Yet, inductionof Na+-dependentPi uptake was similar whetherthe oocyteswere injected with polyA RNA obtained prior to (444+157 dpm/oocyte.h) or after the third subtractive passage (5695:112 dpm/oocyte.h, P>0.2). Thus, polyA RNA from young rats depleted of NaPi-2 mRNA by antisense or subtractive hybridization preservedits abilityto encodefor Na+-Pitransportin oocytes. This stronglyindicates the presence of a renal Na+-Pi cotransporterspecificto the growing animal. *Departmentof Pediatrics,AlbertEinsteinCollegeof Medicine,Bronx, N.Y., USA

PHOSPHATE METABOLISM AND HYPOPHOSPHATEMIC RICKETS Uri S. Alon* The abnormalities in mineral metabolism in familial hypophosphatomic tickets (FHR) are low TP/GFR and inadequate serum concentration of 1,25(OH)2D3. The latter due to diminished production and enhanced degradation of the metabolite. Parabiosis and cross kidney-transplantation experiments between Hyp and normal mice indicated the existence of a humeral factor affecting TmP/GFR. A role for a circulating factor is supported by the reversible hypophosphatemia observed in patients with oncogenous osteomalacia following resection of the tumor. On the other hand, Hyp mice osteoblasts demonstrated an intrinsic defect uncorrected when cells were transplanted into normal mice. The conflicting evidence of circulating Vs. intrinsic factor may be combined to one theory; the intrinsic defect in the bone cells may release a humoral factor affecting the proximal tubule. Renal hypophosphatemic tickets with hypercalciuria is characterized by low TP/GFR and hypophesphatemia but serum 1,25(OH)2D3 is elevated causing hypercalciuria and urolithiasis. Apparently the metabolic abnormality within the proximal tubule is different than that of FHR and caused by another genetic defect. A mirror image of FHR in tumoral calcinosis characterized by elevated rP/GFR, serum P and 1,25(OH)2D3. The hallmark of all these diseases is an abnormal TP/GFR. It can be easily measured in the non-fasting child by the formula TP/GFR = Sp - Up:Ucr x Scr. Treatment of FHR is based on combination of oral phosphate and 1,25(OH)2D3 or 1 (OH)D3. With this treatment, when started early, rickets is expected to heal, bone deformities to be prevented and height improved. The latter may not be true for all FHR patients. These patients have normal GH secretion but they may still benefit from GH treatment. Treatment with P and 1,25(OH)2D3 should be accompanied by close follow-up of urine and serum biochemistries including PTH, and annual renal ultrasound. Optimal therapy should aim at a good balance between correction of hypophosphatemia and prevention of hypercalciuria, hypercalcemia and secondary hyperparathyroidism. *Children's Mercy Hosp., Univ. of Missouri at Kansas City, MO, USA

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$22.4

G E N E T I C H Y P E R C A L C I U R I A IN C H I L D R E N . Craig B. Langman, M.D." Epidemiologic studies in ethnically diverse populations of children have demonstrated similar age- and gender-independent values for urinary calcium excretion, thereby definin g a universally acceptable s t a n d a r d for the labeling of hypercalciuria. The differential diagnosis of hypercalciuria in the face of normecalcemia is limited in children, with the majority demonstrating idiopathic hypercalciuria (II-1). Genetic Hypercalcinria (GI-I) accounts for the majority of cases of IH. The pathogenesis of GH involves an abnormality of 1,25dihydroxyvitamln D, since either the level of the hormone or its paranuclear receptor, or both, are elevated in both h u m a n and experimental models of the disease. In addition to the association between GH and calcium oxalate (mono- and di-) hydrate nepbxolithiasis, GH is associated with a variety of renal-related complaints. Such disturbances include the frequency-urgency syndrome, enuresis, and the finding of sterile pyuria. Extra-renal disturbances in GH include cortical osteopenia. We p r e s e n t data on 50 patients with GH and cortical osteopenia to show t h a t relief of the hyperealciuria not only e]imin ates the likelihood of stone formation, but increases cortical bone mass towards normal. The exact roles of thiazide-like drug therapy and of calcium supplementation in this process will be discussed. The pathogenesis of the osteopenia will be described in terms of bone turnover to prove the hypothesis t h a t the majority of calcium in the urine in children with GH is derived from a bone source. Thus, peak bone mass in children may be altered in GH.

*Dept. of Pediatrics,Northwestern UniversityMedical School, Chicago IL.

N E P H R O C A L C I N O S I S (NP): CLINICAL A S P E C T S , ETIOLOGY A N D LONG-TERM FOLLOW-UP. L. Callis, E. Lara, A. Salvfi, G. Enriquez, ~ Villa." Over a M-year period prior to the advent of echography, our total number of cases of NP was 31:20 were diagnosed by radiography and in the other 11, all with vit. D intoxication, diagnosis was confirmed by renal biopsy. Since 1980 when renal echography study began at our Hospital, 76 cases of NP have been detected. Age at diagnosis ranged from 4 months to 18 years, with no sex predominance. A family history of hypercalciuria, oxalosis, kidney stones and Cachi-Ricci disease was present in 12.7%. Symptoms motivating the study were: hematuria in 63%, polyuria-polydipsia in 36.8%, and abdominal pain in 42%. Much less frequently were growth retardation, kidney stones, emesis, proteinuria and urinary infection. Echography was positive in 84.7%, showing the presence of NP, and was confirmed by radiographic study in 78.8%. NP was related to the following nephropathies in 35.8%: distal renal tubular acidosis, cystinosis, calcium-losing syndrome, Cachi-Ricci disease, and oxalosis; in the majority of cases (57.8%), only hypercalciuria, classified as hyper-absorptive, was found. After a mean follow-up of 10.4%, renal function worsened in 20.6%, and renal insufficiency appeared in 18%, probably due more to the causal nephropathy t h a n to NP. Since renal echography study became a reality, NP has proven to be more common t h a n prior to its use. Its prognostic significance remains unclear.

*Ped. Nephmlogy Unit, Hospital Materno-infantil Vail d'Hebron, BarceLonaSpain.

C 30 SYMPOSIA - $23. HUS: Epidemiology and Prognosis S23.2(1)

$23.1 Symposium t i t l e ,

: HUS : Epidemiology and Prognosis

INTRODUCTION AND REVIEWOF LONG-TERMOUTCOME Dr. Carlos A.Gianantonio The acute mortal.ity of the classical Hemolytic-ureMic syndrome (HUS) has been substantially reduced with the present management. The late consequences of the disease especially chronic f a i l u r e (CRF) are areas of rapiddly growing interest. This presentation describes t h e incidence of terminal kidney function f a i l u r e in classic HUS; its relation to the acute phase (severity,duration of o l i g u r i a , a r t e r i a l hypertension,etc.)~ age of the patients, time of presentation; rate of progression and prognosis. I t is based on Lhe present experience of the Hospital Italiano and on the results of a m u l t i ~ n t e r prospective follow up of 383 patients. The patterns of the renal histologic abnormalities ,observed in kidney biopsies of 30 patients with an excellent folIow up, are described and i t s possible 9athogenesis are discussed. In the author experience in Argentina, HUS was the primary diagnosis of the children and adolescents included in the dialysis and transplantation program ,in 28 per cent of the. cases (4.2 per cent in the H,American PediatFic Renal Transplant Cooperative Study). Recurrence of the syndrome ~as not observed in the transplanted patients . Departamento de PediatrTa Hospital Italiano -Buenos Aires ,Argentina

$23.2(2) HUS/hemolytic anemia (HA) in children with suspected or proven VTEC; 2) To estimate the therapeutic effect of SynsorbPk in the amelioration of early HUS; 3)To measure the efficacy of Synsorb-Pk in reducing the levels of free stool veretoxin in VTEC gastroenteritis; 4) To measure the inmunologic response to verotoxin after VTEC infection treated with Synsorb-Pk; and 5) To measure the adverse effects of Synsorb-Pk in children with VI~C gastroenteritis. Twelve participating sites from across Canada are involved in this two year study. The eligibility criteria are: A) age 6 months to 6 years; B) diarrhea defined as 2 or more loose stools in the 24 hour period prior to enrollment AND ONE OF THE FOLLOWING, C) Bloody diarrhea; D) Non-bloody diarrhea with severe abdominal cra~os; E) Rectal prolapse; F) Evidence of E. Coli 0157 or other VTEC sere%q~s frc~ stool culture; G) Diarrhea in someone who was in close contact with an individual with HUS or proven VTEC infection. At the end of the first year of study, 135 patients were enrolled. Twuenty-five had uncomplicated VTEC infection; 2 had HA; 41 had suspected VTEC gastroenteritis (serology still pending); 7 had }{US but did not require dialysis or P intensive care and all survived; 4 had severe HUS of which one died, 48 had an alternate pathogen and 8 patients were nonccmpliant. An update of the outcc~e including information frcm the second year of this study will be presented at the Symposi~n.

Peter N. McLaine, MD FRCPC THE USE OF SYNSORB PK FOR PREVENTING HEMOLYTIC URKMIC SYNDROME (HUS) Armstrong, et al, previously demonstrated that veretoxin 1 (VTI) ,also known as Shiga-like toxin (SLT-I)and Vt2 (SLT-II) bound with high affinity to synthetic alpha Gal (1-4) beta Gal (1-4) beta Glc (Pk trisaccharide receptors covalently coupled through and 8 carbon linker to Chrcmosorb, a silicon dioxide sand-like material produced from diatomaceous earth and related to a common anticl~ping agent in many constlner food products. This suggested a potential use for this novel agent, called Synsorb - Pk, in preventing the hemolytic uremic syndrcr~e (HUS), a cc~plication in 8-10 % of patients with VT- producing Escherichia Coli (VTEC) gastroenteritis. Before conducting a clincial trial to test this hypothesis, we first wanted to establish how well Synsorb-PK was tolerated by healthy adults end if it ~ u l d neutralize VT activity in VT positive stools from children with VTEC infections. A double blind placebo controlled study was conducted to doc~lent possible side effects associated with oral cons~nption of Synsorb -Pk by healthy adult volunteers. No participant reported any Synsorb-Pk related adverse rections and no clinically important transient laboratory data were evident. Synsorb-Pk recovered from stools retained its ability to absorb VT. These results encouraged us to further test Synsorb-Pk in children with VTEC gastroenteritis. On June i, 1994, a two year prospective clinical trial was therefore initiated in Canadian children with suspected VTEC infection. The objectives of the study are: i) To estimate the therapeutic effect of Synsorb-Pk in the prevention of

$23.3 THE CELLULAR

TG.Obrig* ,

BIOLOGY

CB.Louise*,

O F HUS

CA.Lingwood** ,

B.Boyd

**

The pathology of HUS suggests that glomerular endothelial cells represent the major site of d a m a g e w i t h i n t h e kidney. Studies conducted with human endothelial cells in v i t r o support this concept. It now seems plausible t h a t E. c o l i Ol57:H7-associated HUS may result from combined action of bacterial factors, Shiga-like toxins (SLTs) a n d l i p o p o l y s a c c h a r i d e (LPS), p l u s h o s t factors tumor necrosis factor (TNF-alpha) and interleukin-i ( I L - I b e t a ) a c t i n g on g l o m e r u l a r endothelial cells. Recently, it has been demonstrated that human renal microvascular endothelial c e l l s (HRMEC) a r e v e r y s e n s i t i v e to low concentrations (< 0 . i nM) of the SLTs, particularly S L T - 2 w h i c h is t h e p r e d o m i n a n t f o r m of S L T p r o d u c e d by E. coli O 1 5 7 : H 7 o b t a i n e d from HUS patients. It is n o w k n o w n that, i n d i v i d u a l l y , SLTs, LPS, T N F a n d IL-I i n t e r a c t w i t h e n d o t h e l i a l cells, most resulting in a p r o c o a g u l a n t state. Thus, in d e v e l o p i n g HUS, c i r c u l a t i n g LPS m a y c a u s e a l o c a l i z e d i n c r e a s e in T N F and IL-I w h i c h a d d s a further burden on the renal endothelium. In addition to their procoagulant a c t i o n s , LPS, T N F and IL-I have been shown to upregulate the SLT receptors on human endothelial cells. Together, these multiple forces create a unique situation t h a t a p p e a r s to r e s u l t in t h e p a t h o p h y s i o l o g y of t y p i c a l HUS. :~icrobiol./Immunol., U. of R o c h e s t e r , NY, USA. M i c r o b i o l . , Hosp. S i c k C h i l d r e n , T o r o n t o , CAN.

C 31 $23.4

Renal Transplantation in Hemolytic Uremic Syndrome. r ~ e r , , e r a S . ~ a p l e n T h e r i s k of a r e c u r r e n c e and the p o t e n t i a l hazards of c y c l o s p o r i n e (CSA), e n c u m b e r t r a n s p l a n t (TX) d e c i s i o n s in HUS. T h e f o l l o w i n g g u i d e l i n e s a r e b a s e d o n a c a r e f u l a n a l y s i s of t h i s d i f f i c u l t problem. C S A a n d flus : There is no convincing evidence that CSA triggers HUS. Post-TX HUS occurs with and without CSA. D+HUS: Verocytotoxin induces D+HUS and anti-VT a n t i b o d i e s develop. T h e r e are no d o c u m e n t e d cases of post-TX D+HUS. Autosomal recessive flUS: T h e r e is a hiqh l i k e l i h o o d of p o s t - T X r e c u r r e n c e of HUS in ARHUS. T h i s is n o t i n f l u e n c e d by s o u r c e of a l l o g r a f t , length of time between HUS and TX, use of CSA, or a previous recurrence. L i v i n g - r e l a t e d donors must be u s e d w i t h c a u t i o n b e c a u s e of the l i k e l i h o o d of recurrence. Autosomal dominant H U S : P o s t - T X r e c u r r e n c e is e x t r e m e l y u n c o m m o n u n l e s s t h e HUS w a s a s s o c i a t e d with a low serum C3 level. Atypical D-HUS: In t h e a b s e n c e of a p o s i t i v e family history of HUS, sporadic cases of D-HUS pose a m a j o r d i l e m m a . In t h e a b s e n c e of e v i d e n c e of exposure to verocytotoxin, these should be considered to be inherited,

Division of Nephroiogy, The C h i l d r e n ' s H o s p i t a l of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104

S Y M P O S I A - $24. Clinical Trials and M u l t i c e n t e r Studies $24.2 THE IMPACT OF THE PAEDIATRIC EDTA REGISTRY REPORTS ON CLINICAL PRACTICE IN THE LAST 20 YEARS M. Broyer* Evaluation of the impact of registry data on clinical practice is extremely difficult if not impossible. The aim of the present paper is only to suggest that some studies performed in the EDTA Pediatric Registry may have had some impact. In most of european countries before 1980 a very few number of children less than 2 years of age were accepted on a dialysis transplant programme, but it was not the case in other countries. After showing that this was possible, there was a regular increase in the acceptance rate for this age group from 3.6% in the period 1978-1982 to 11.6% in 1991 of new patients under 15 year of age. Analysis of causes of death was certainly useful showing for example that death rate was significantly related to overweight between dialysis and also the high proportion of children dying from hyperkaliemia in the years 1980-1985. Special studies were specially useful, for example the poor results of isolated kidney transplantation (KT) in oxalosis reported in a large number of patients was certainly an incentive for stimulating combined liver kidney graft in this primary renal disease. The pediatric group of the EDTA registry worked especially on pregnancy after KT and reported the first large series of 490 pregnancies, showing that babies born from such mothers had no more malformations and had a normal development except for an increased risk of prematurity, with a birth weight in accordance with their gestional age, while the mothers had no more degradation of renal function than a control group. These results certainly contributed to change the general attitude of doctors who previously discouraged or even interrupted pregnancy in transplanted patients. The data from the paediatric EDTA registry were also very useful for supporting the concept of treating children apart from adults and in specialized area. The pediatric unit was rigorously defined by the active participation of different specialists including pediatric nephrologist, dietetian, social worker, child psychologist, school facilities, a children ward and a combined dialysis transplant programme. Only 11% of dialysis units treating children corresponded to the definition in 1979, they were 83% in 1992. Many other examples might have been also given of the possible impact of registry data. *HOpital Necker-Enfants Malades, Paris - France

C 32 S Y M P O S I A - $25. Mediators of Renal Injury (Free Radicals, C Oxide) S25.1(1)

Sharon P. Andreoli, Indiena University Medical Center, Departraent of Pediatrics, Indianapolis, Indiana , USA. MECHANISMS OF OXIDANT MEDIATED c~.r.L INJURY Rective oxygen molecules may participate in the pathogenesis of several different renal diseases including inflarmatory lesions such as glomerulonephritis end 5anterstitial nephritis, ischemic reperfusion injury, toxic nephropathies, and possibly in the progression of chronic renal failure.Reactive oxygen molecules including superoxide anion, hydrogen peroxide, hydroxyl radical, hypochlorous acid end peroxynitrite (which is derived from superoxide anion end nitric oxide)may be generated by activated neutropholis, monocytes and mesangial cells, during metaholi~a of drugs and toxins, during reperfusion following ischemia, end during normal end abnox~aal metabolic processes. When oxidant generation increases, or when antioxidant defense mechaniszns are decreased, oxidant injury results frcra the shift in the oxidant/entioxidant balence. Each class of biological molecules including anino acids end proteins, lipids and membrenes, EIqA, end extracellular basement membranes are molecular targets of oxidant injury. Qxidant stress may induce injury to proteins by oxidation of critical amino acids resulting in loss of enzymatic activity or structural integrity. Oxidant induced lipid peroxidation may result in loss of m~mbrene stability end integrity. Early responses of cells to oxidant stress include activation of glutathione redox cycle, elevation of intercellular calciu~n, NAD depletion, ATP depletion with loss of ATP metabolites from the cell, and DNA damage. In addition, cell-cell and cellsubstrat~n contacts are disrupted leading to increased transepithelial permeability and detachment of epithelial cells frcm the underlyng basement membrene. Specialized functions of proximal renal tubular epithelial cells including sedi~m dependent uptake of glucose end phosphate are substentially decreased following oxidant stress. The mechanism of such

$25.2 REGULATION OF ANTIOXIDANT ENZYME GENE EXPRESSIONS IN GLOMERULAR CELLS. T. Yoshioka* A n t i o x i d a n t e n z y m e s a r e o n e o f the p r i m a r y m e c h a n i s m s for d e f e n d i n g c e l l s f r o m o x i d a n t stress. T h e e x p r e s s i o n o f antioxidant e n z y m e s is u p - o r d o w n - r e g u l a t e d in v a r i o u s p h y s i o l o g i c a l and pathophysiological conditions. G l o m e r u l a r e x p r e s s i o n s o f M n - s u p e r o x i d e d i s m u t a s e ( S O D ) are r e d u c e d in an e a r l y p h a s e o f p u r o m y c i n a m i n o n u c l e o s i d e n e p h r o s i s and i s c h e m i c renal i n j u r y in rats, as w e l l as in h u m a n p r i m a r y nephrotic s y n d r o m e at relapse. T h e e x p r e s s i o n is e n h a n c e d b y glucecorticoids, c y t o k i n e s , a n d oxidant stress. T h e m e c h a n i s m for these c h a n g e s in the g l o m e r u l a r e n z y m e e x p r e s s i o n s includes transcriptional regulation, a m a j o r regulatory step o f gene expressions. T h e M n - S O D gene contains r e s p o n s e e l e m e n t s ( b i n d i n g sites f o r transcriptional f a c t o r s ) f o r glucocorficoid receptor, and intracellular factors r e s p o n s i v e to s e r u m e l e m e n t s and oxidant stress. W h e n g l o m e r u l a r antioxidant e n z y m e s are e n h a n c e d b y oxidant stress or by glucocorticoids, these tissues o r ceils confer resistance against s u b s e q u e n t o x i d a n t stress. H o w e v e r , w h e n M n - S O D is e n h a n c e d selectively b y an o v e r e x p r e s s i o n o f the transfected gene, results are not a l w a y s p r o t e c t i v e to o x i d a n t stress. T h i s i m p l i e s that c o o r d i n a t i o n o f s e v e r a l antioxidants are r e q u i r e d for an efficient handling o f oxidants in pathophysiological condil/ons, O x i d a n t s a r e m e d i a t o r s o f glomerulonephritis, n e p h r o t i c s y n d r o m e , a c u t e and c h r o n i c renal failure, and renal allograft rejection. T h u s , gene r e g u l a t i o n o f antioxidant e n z y m e s in s u c h pathophysiological conditions m a y be crucial in d e v e l o p m e n t and/or p r o g r e s s i o n o f renal diseases. *Dept. o f Pediatric N e p h r o l o g y , T o k y o W o m e n ' s Medical College, T o k y o , Japan.

$25.1(2) injury is related to inactivation of Na + K + kTPase end inhibition of the sodi~n pump resulting in increased intracellular sodit~a content, decreased intracellular potassitrn content end disruption of the normal sodi~a gradient needed to drive transport. Depressed glucose transport is also a result of intrinsic alteratios of trensporter activity within the membrane. Many, but not all,of the deleterious cellular responses to oxidant stress can be inhibited by membrane pezmeable iron chalators but are little effected b~( m~br.~ne inioermeable iron chelators suggesting that injury is mediated by the intracellu lar generation of an iron dependent radical. The mecanism of -oxidant mediated DNA damage is ccraplex. Oxidant stress results in single strand breaks in endothelial cells end in proximal end distal renal tubular epithelial cells. In addition, oxidant stress results in base modification and activation of I/qA repair enzymes. The role of apoptosis in oxidant induced DNA damage is variable and may be cell dependent. We have not found the ENA fragmentation ladder pattern characteristic of apoptosis in h t ~ n endothelial cells or in LLC-PKI cells exposed to oxidant stress while the ENA ladder fragmentation pattern characteristic of apoptosis was seen in MDCK cells exposed to oxidant stress. In s~anary, the mechanisms of cell injury that ultimately leads to cell death following oxidant stress are ccr~lex and multifactorial and may differ according to cell type. The mechenisms of recovery following oxidant stress in cells that survive an oxidant insult are unknown end a topic for future investigation.

$25.4 ROLE OF OXIDANT INJURY IN PROGRESSIVE RENAL DISEASES S. Turi Following an overview of the current status of research in this field the author present his data on the glutathione redox system, haemoglobin (Hb) oxidation, the activity of antioxidant enzymes and the lipid peroxidatinn products malonyl dialdehl~e (MDA) m red bloodcells (RBC) in progressive renal diseases. Children with nephrotie syndrome (ns) (in relapse and in remission), postatrepteeoeeal glomerulonephritis (PSGN), and adults with lgA nephropathy (IGAN) and the corresponding controls were investigated. All patients with relapsing glomerular diseases had signifieanfly higher level of oxidized glutathinne (GSSG) than in remission and in the eentrels (i0 <0.01). Reduced glutathione (GSH) concentration was elevated in minimal change ns (MCNS) with relapse, but not in SLE or in IGAN. GSH produetlon is a compensatory reaetinn of the cellular defense mechanism, which is better in MCNS than in mote progressive glomerelopathies. The oxidized products of Hb, metHb and heminhrome as well as MDA eoneentratlnn were increased in all patients either in relapse or in remission. Superoxide dismutase (SOD) and catalase (Cat) activity were reduced. But in MCNS the patients had higher activity in remission than in relapse. The release of free oxygen radicals plays an important role in the pathogenesis of leucocyte dependent and independent forms of glomerelar diseases. Children with haemolytin uremic syndrome (HUS) had a higher level of GSSG (26.3+12.6 vs 10.9+1.8 nM/gHb), MDA concentration, and med-lb than the controls. The in vitro oxidative stress (GSH instability test) induced a profound decrease in GSH concentration (p<0.01) and a significant elevation in metHb. Activities of SOD, Cat and glutathione porexldase (GP-ase) were low. Oxidative stress, utilization of GSH and ant/oxidant enzymes lead to an increased Hb oxidation and oxidative haemolysis in HUS. The effect of chronic uremia, erythropoietin (EPO) treatment and free radical seavanger vitamin E were investigated respectively in children with haemodialysis (HD). A significantly increased level of MDA, GSSG, metHb and hemichrome and reduced activities of SOD, Cat and GP-ase were demonstrated in all patients. GSH instability test was positive demonstrating a decreased GSH regeneration. 4 week EPO treatment induced a 4x increase in GSSG concentration, and GSH instability became more expressed (p<0.00l). MetHb and heminhrome level were increased (< 0.001). Following the 5th weeks the signs of the oxidative stress rapidly diminished which was fo~/owed by a significant increase in the level of haematoerit (Hte) and Hb. When vitamin E was added to EPO GSH and Hb oxidation was markedly reduced, and a more rapid elevation in Hte andHb was achieved. These results are compatible with oxidative damage of RBC-s in the early period of EPO treatment. Department of Paediatries, University of Szeged, Hungary

C 33 S Y M P O S I A - $26. Post-Infectious G l o m e r u l o n e p h r i t i s

S26.2 MECHANISMS

S26.3 OF

INJURY

AND

REPAIR

~N

OLOMERULAR

DISEASES. Jes~s Egido. Renal Unit. Fundaci6n Jim6nez Dfaz. OAM. Madrid. Spain. Proliferation of resident glomerular cells and accumulation of extracellular matrix proteins are central features of various human glomerular diseases. Cytokines,lipid mediators and vasoactive hormones have been implicated in the mediation of glomerular and tubulointerstitial damage, Many of snch mediators are released in the injured glomeruli by leucocytes and intrinsic glomerular cells, Those lediators recruit inflammatory cells in the kidney and also induce a variety of responses on glomerular, cellsr that range from a direct toxic effect to proliferation and the synthesis of extracellular matrix and further inflammatory mediators. TNF~, PDGF: and TGF~ are probably the most representative ms~era of the proinflammatory and flbrogenic cytokines.Their overexpression has been identified as a ~ j o r pathogenic factor in the progression of several experimental renal_diseasea.-Anti~cyzokine strategies have proved to be effective therapeutical alternatives in such situations.A new mechanism of glomerular injury has been recently identified. The ~interaCtion of kidney deposited immune complexes with mesangial cells through the Fc receptors triggers a series of responses, initiating and, probably perpetuating renal injury.Apoptosis has been considered a key factor in controlling the cell ~umber in the inflamed glomerulus. The inhibition of anglotensin IE generation and endothelin receptor antagonists has proved to be useful and the treatment of several experimental models,and may be a general approach to the therapy of a series of human glomerular diseases. The advances in the pathogenesis ~f glomerular injury will indeed provide new tools for the treatn~nt of such diseases.

$26.4 PHYSIOPATHOLOGY OF THE CLINICAL SYNDROMES ASSOCIATED WITH POSTINFECTIOUS GLOMERULONEPHIRITS

B. Rodriguez-lturbe* Postinfectious glomerulonephdtis may present with the acute nephritic syndrome (ANS), the nephrotic syndrome (NS) and a rapidly progressive course of increasing azotemia. This discussion will deal with the comparative physiopathology of the ANS and NS. The ANS (edema, hematuda, oliguria and hypertension) is characterized by overexpansion of the intravascular compartment, due to a renal lesion inducing primary sodium and water retention. There is no correlation between the fall in the glomerular filtration rate and the degree of extracellular expansion. The site of the defect is not the proximal tubule which shows a compensatory fall in reabsorption; instead, the defect is located at a distal level where reabsorption is maintained (or increased) despite delivery of a reduced volume of filtrate. Hemodynamic measurements show increased plasma volume, cardiac output and peripheral vascular resistance. Volume-sensitive hormones are responding appropriately: plasma renin activity (PRA) and aldosterone are supressed and Atrial Natduretic factor (ANF) is stimulated. The degree of reduction of PRA and the increment of ANF are correlated with the amount of fluid retention (increased above dry weight). The NS (edema, massive proteinuria, hypoalbuminemia and hyperlipidemia) is also characterized by water and sodium retention. The accumulated evidence indicates that in NS there is also a primary distal renal defect, which exists in association with normal, increased or decreased glomerular filtration rate. However, the existence of hypoalbuminemia lessens the hemodynamic repercussion of the fluid retention, facilitating its escape to the interstitial compartment. As a consequence, the levels of PRA, aldosterone and ANF, as well as the hemodynamic values are not consistently modified. *Seevicio de Nefrologia, Hospital Universitafio de Maracaibo.

HIV-NEPHROPATHY (HIVN) IN CHILDREN: PATHOGENESIS, CLINICAL PRESENTATION, AND THERAPEUTIC OPTIONS Gaston Zilleruelo*, Carolyn Abitbol* and Joss Strauss* Infants and children with perinatally acquired IMV infection may develop HIVN even before development of the Acquired Immune Deficiency Syndrome (AIDS). HIVN typically presents with persistent abnormal proteinuria, a broad spectrum of histopathologic changes, and slow progression to chronic renal insufficiency. Mechanisms proposed to explain HIVN include direct viral infection, toxic effect of viral proteins, immune complex renal disease and cytokine-induced renal damage. Over a 12-year period at our Medical Center, we have studied a total of 568 HIV + pediatric patients. Of these, 84 (14.8%) were diagnosed as having HIVN; 85 % were Blacks. Mean age at onset of HIVN was 30 months. Nephrotic Syndrome developed in 47 children (56%), and 16 (19%) progressed to chronic renal insufficiency. Renal histopathology showed Focal Glomerulosclerosis in half of these patients; the rest showed Mesangial Proliferative GN, minimal change lesions, segmental necrotizing GN (SLE-like lesions), IgA Nephropathy, and Hemolytic Uremic Syndrome. Five children (6%) required dialytic therapy due to End Stage Renal Disease. HIVN was associated with high mortality (50%), but from non-renal causes. PCP prophylaxis, a combination ofantiretroviral therapy with Zidovudine (AZT) and Didanosine (ddI), aggressive nutritional support, and correction of anemia seemed to improve the outcome and quality of life of these patients. Screening for proteinuria and early diagnosis of HIVN appear essential if the safety and efficacy of specific modalities of therapy (e.g., prednisone) are to be evaluated. *Pediatric Nephrology, University of Miami/Jackson Memorial Medical Center, Miami, Florida, USA

C 34 SYMPOSIA

-

S27. Urolithiasis and Nephrocalcinosis S27.2

S27.1 INTERACTION OF PROSTAGLANDIN E2 and PTH IN CALCIUM METABOLISM IN PATIENTS WITH HYPERPROSTAGLANDIN E :SYNDROME H. W. Seyberth, S. C. Reinalter, A. Leonhardt There is abundant experimental and clinical evidence that prostaglandins and padicularly PGE 2 are involved in calcium and bone metabolism. However, apparently PGE 2 works in concod with a variety of other endocrine and paracrine systems. To elucidate in pad these complex interactions we investigated the relationship between PGE 2 and PTH in patients with hyperprostaglandin E syndrome, a neonatal variant of Badter syndrome with high systemic PGE2 formation, hypercalciuria, nephrocalcinosis and osteopenia. During the long-term follow-up with suppressed PGE 2 formation (indomethacin treatment, mean dose: 3.1 + 1.6 mg/kg/d) urinary Ca++-excretion remained elevated associated with high plasma concentration of intact PTH. Nevertheless there was some decrease in nephrocatcinosis and increase in renal function. In 1988 (age: 6.2 y; 5.2-6.5) and in 1994 (age 10.2 y, 7.7-11.7) indomethacin treatment was discontinued for 6 days in nine patients with hyperprostaglandin E syndrome. Median

PGE-M

PTH

Ca++mmm

(mmollB trio/IV1.73 m2~ Ino/ml~ 2.4 89 103 1988 (2.1-2.6) (32-253) (634-113) n=9 (#) 2.4* 490* 64* (2.3-2.8) (123-1403) (29-92) 2.5 313 96 1994 Indo + (2.4-2.6) (39,9-491) (22-301) n=9 2.6" 1293" 64* (2.3-2.6) (482-2090) (24-94) 2.2-2.6 normal range 62-482 15-70 ~) Leonhardt et al (1992) J Pediatr 120: 546-554; *p < 0.05 compared with data during indomethacin treatment. /Ranoel Indo +

Ca+%a~ [mo/knldl 6.3 (5.3-14.0) 9.0" (4.4-38.0) 5.4 (2:8-13.8) 10.9" (2.8-13.7) < 4.0

HYPERCALCIURIA: R O L E IN UROLITHIASIS AND BONE METABOLISM.

H.C.Perrune* Idiopathic hypercalciuria (IH) is the most common abnormality in children with nephrolithiasis, occurring in approximately 70-80% of children with calcium stone formation. While overt bone disease with pain and fracture is extremely rare in IH patients, the frequent observation of increased bone turnover and decrease in bone density is consistent with the hypothesis that an increase in bone resorption contributes to some cases of IH. Pyridinoline (Pyr) and deoxypyndinoline (dPyr) are the two nonreducible pyridinium crosslinks present in the natural form of collagen. Pyr and dPyr are likely to be released from bone matrix during its degradation by the osteoclasts. A recent study observed a decrease in bone mineral density in young male calcium stone formers, suggesting that probably the bone would be affected in this disease. We studied the effect of hydrochlorothiazide (HCT), chronic oral calcium load (OCL) and indometaein (1ND) on bone metabolism markers. Nine children aged 8 to 16 yrs with bematuria and/or nephrolithiasis due to IH after a basal period (BAS) were submitted to 3 twenty day periods with a 20 day rest period. Serum levels of calcium, phosphorus, PTH, 1,25 dihydroxyvitamin D3 and osteocalcin were determined as well as urinary excretion of Pyr and dPyr. Results (X+SD; p<0.05): Pea Pp PTH 1,25D3 OC dPyr BAS 9.44-0.2 4.8• 27• 7 71• 23• 794-41 HCT 9.44-0.3 5.04-0.6 1 8 4 - 1 0 554-36 25• 644-41 OCL 9.54-0.3 4.54-0.7 184- 8 664-24 214- 8 554-25 IND 9.14-0.4 4.94-0.8 26• 8 764-15 204-19 91• When results of bone mineral density (BMD) were examined during a follow-up of 5 years we observed that the dPyr urinary excretion was significantly decreased during HCT, in those children who presented normal BMD values compared with the group who presented less BMD development (p=0.048). * Pediatric/Nephrology Department of Santa Casa SP-Brazil

In summary there is a consistent inverse relationship between PGE 2 and PTH activity. This hormonal interaction leading to increased bone resorbing activity could explain the persistent hypercalciuda with and without indomethacin treatment. Apparently there is some kind of pathological up-regulation at the Ca ++sensor level in these patients. Univemit~lts-Kinderklinik. Deutschhausstr. 12, D 35033 Marburg, Germany

S27.3 INHIBITION OF URINARY CRYSTALLIZATION BY URINARY PROTEINS John R. Hoyer* Since normal urine is frequently supersaturated with respect to calcium oxalate, inhibition of crystallization by urinary proteins such as uropontin, nephrocalcin and Tamm-Horsfall protein appears to have an important role in preventing urinary stone formation. We initially isolated the urinary form of osteopontin (uropontin) by monoclonal antibody immunoaffinity chromatography and showed that it has the same N-terminal sequence as osteopontin from bone. Since uropontin is a potent inhibitor of calcium oxalate monohydrate (COM) crystal growth and nucleation, we investigated its potential role in urinary stone formation. Studies of urinary excretion showed that concentrations of uropontin that are inhibitory for COM crystallization (-0.1gM) prevail in normal human urine. Evidence for a specific in v i v o interaction with COM was shown by analysis of EDTA extracts of calcium stones. The mean content of uropontin in COM stones (~8mg/gram of stone) is much higher than in calcium oxalate dihydrate stones (<0.2mg/gram) or hydroxyapatite stones (<0.1mg/gram). While uropontin and other urinary proteins are inhibitory in the fluid phase, their precise role is uncertain since they could also promote stone formation by serving as nucleation sites after binding to the surface of damaged urinary epithelium. *Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, U.S.A.

$27.4 IATROGENIC NEPHROCALCINOSIS Uri S. Alon* The most common wpe of iatrogenically-induced nephrocalcinosis (NC) is that associated with furosemide therapy in the premature infant. Recently it has been reported also in older infants receiving the diuretic for congestive heart failure. Pathophysiology was first thought to be related to hypercalciuria but later studies indicated multi-factorial etiology. Stones are mainly composed of Ca oxalate whereas NC is caused mostly by Ca phosphate. Morbidity. includes hem~m~a~ UT!, pain and obst~etion. Long-term studies showed that discontinuation of the diuretic often results in ultrasonographic resolution of the NC but glomerular and tubular perturbations may persist. The latter often characterized by abnormal (U-B) pCO2. Studies on rats showed that 12 weeks after stopping fitrosemide only partial resolution of NC is observed. It is unclear whether the addition of thiazides to furosemide protects the kidneys from developing NC. Studies in rats showed that the addition of amiloride results in partial protection. Other studies showed that increase in dietary. Mg intake provides a complete protection against furosemide-induced NC. Another commonly seen iatrogenically-induced NC is that observed in children with familial hydrophosphatemic rickets treated with vitamin-D and phosphate. Both agents can cause NC bat it seems that in recent years it is more commonly associated with the latter. A few patients developed severe N C with diminished GFR. They usually also had secondary hyperparathyroidism and hypercalcemia. Surgical or medicat correction of the hyperparathyroidism protected the patients from fixrther damage to the kidneys. However, the NC itself seems to be irreversible. Studies in animals show that parathyroidectomy protects from phosphate-induced NC. Prevention of nephrocalcinosis can be achieved by judgmental use of vitamin-D and phosphate and careful observation of the patients urine and serum biochemistry including PTH. *Children's Mercy Hosp., Univ. of Missouri at Kansas City, M e , USA

C 35 S Y M P O S I A - $28. T r e a t m e n t o f G l o m e r u l a r Diseases $28.1 TREATMENT OF SCHONLEIN-HENOCH PURPURA NEPHRITIS P. Niaudet I T. Hoang and R. Habib

Clinico-pathologic studies have shown that renal symptoms in patients with ScOnlein-Henoch purpura (SHP) nephritis are well correlated w i t h the severity of glomerular involvement and that the long term prognosis is closely related to the proportion of glomeruli affected with crescents. Among the 64 patients (pts) followed in our unit for more than one year and who presented with a nephrotic syndrome, 18 had a poor outcome including 8 who progressed to end stage renal failure (ESRF). Similarly, among the 60 pts whose initial renal biopsy h a d shown more than 50% crescents, 33 had a poor outcome including 22 who progressed to ESRF. These data prompted us to undertake a prospective study to evaluate the effects of three methylprednisolone pulses (1 g/1,73 m 2 each) followed by oral prednisone for 3.5 months in 39 patients who presented with a nephrotic syndrome and/or mere than 50% crescents on renal biopsy. Eight pts received in addition oral cyclophosphamide, 2,5 m g / k g / d , for 8 weeks and 2 pts p l a s m a exchanges. Focal and segmental glomerulonephritis (GN) was present in 6 pts, diffuse proliferative GN in 2, endo and extra capillary GN with less than 50% crescents in 10 and with more than 50% crescents in 21. At latest follow-up, 25 pts h a d clinically recovered, 7 had minimal urinary abnormalities, 4 h a d persistent nephropathy and 3 h a d progressed to ESRF. Five of the 7 patients with poor outcome either had recurrent episodes of macroscopic hematuria or were treated late in the course of the disease. The 3 pts who progressed to ESRF h a d mere than 50% crescents an initial renal biopsy. A second renal biopsy performed 6 months to 2.5 years after t h e treatment in 30 pts showed an improvement in 23 pts with a disapearance of hypercellularity and a decrease in the size of the involved segments. In 4 pts, the proportion of affected glomeruli was similar but the lesions consisted of global or segmental sclerosis. In the remaining 3 pts, the second biopsy performed because of recurrent macroscopic hematuria and increase of proteinuria showed endo and extra GN with the same proportion of crescents than on initial biopsy and these patients received a second course of MP pulses. Although uncontrolled, our results show that MP pulse therapy m a y be beneficial clinically and histologically in severe forms of SHP nephritis. Hopital Necker-Enfants Malades, Paris, France

C 36 FREE COMMUNICATION (FC) - Experimental and Developmental Renal Physiology FC001 N I T R I C O X I D E (NO) I N T H E D E V E L O P I N G R A T A . l a i n a , Y W o l l m a n , T C h e r n i h o v s k y , G P e e r , M Blum, E Kaplan,DS Silverberg,T Weinstein. D e p a r t of N e p h r o l , I c h i l o v H o s p , T e l A v i v M e d Ctr, ISRAEL. N i t r i t e (NO2) a n d N i t r a t e (NO3), s t a b l e m e t a b o l i t e s o f N O w e r e m e a s u r e d in the p l a s m a and urine in the o n e day, 6 days, 3 weeks, 6 w e e k s a n d a d u l t r a t s (12 w e e k s ) . U r i n a r y p r o t e i n (Uprot) was d e t e r m i n e d . F r o m the s a m e age g r o u p s m e s a n g i a l c e l l s (MC) w e r e c u l t u r e d ( p a s s a g e 3, no o l d e r t h e n 5 weeks). The basal and LPS stimulated mesangial c e l l s N O 2 + N O 3 w e r e m e a s u r e d a f t e r 24 h o u r s incubation. P NO U NO MC NO Uprot basal +LPS id 94.8_+5.6* 730 62* 9.4• 14• 8.4_+0.2* 6d 39.5_+2.3* 352 40* 7.2_+1.2 31_+1.1" 5.4• 3w 46.6_+7.1" 198 16" 12.1_+1.3 28• 0.4• 6w 18.6_+0.9 157 15" 9_+1.2 61_+11 0.5• 12w 17.3• 108 12 9.7_+2.1 58_+9 0.2• P l a s m a N O BM, U r i n e N O n M o l e s / m g c r e a t i n i n e , MC NO nMoles/25000 cells/24 h incubation, LPS s t i m u l a t e d M C % f r o m b a s a l NO. Mean-+SD * < 0 . 0 1 at l e a s t vs a d u l t (12 w e e k s ) rats. T h e n e w b o r n r a t s h a v e v e r y h i g h N O p r o d u c t i o n . It d e c r e a s e s w i t h age a n d at 6 w e e k s is s t i l l h i g h e r t h a n in a d u l t rats. T h e h i g h e s t N O v a l u e s w e r e f o u n d d u r i n g the f i r s t w e e k o f life a n d t h i s w a s associated with very high urine protein excretion. T h e m e s a n g i a l c e l l s b a s a l N O p r o d u c t i o n d o e s not c h a n g e w i t h age b u t the s t i m u l a t e d N O p r o d u c t i o n is i m p a i r e d in the f i r s t t h r e e w e e k s p o s t - d e l i v e r y . It is s u g g e s t e d t h a t t h e p o s t - n a t a l N O - p a t h w a y d e v e l o p m e n t is a c c o m p a n i e d w i t h c h a n g e s in r e n a l glomerular protein transport and mesangial cells function.

FCO03 HUMAN GLOMERULAR ENDOTHELIAL CELLS IN CULTUREFORM CAPILLARY VESSEL-LIKE STRUCTURES IN RESPONSE TO MATRIGEL J.D. Mahan*, C. MeAllister* Human glomerular capillary endothelial cells (GCEC) isolated from normal kidneys require an extracellular matrix (ECM) protein such as fibronectin for propagation in vitro. On such substrates the cells grow in monolayers and are usually studied in this condition. The use of more complex ECM proteins in culture with large vessel endothelial cells promotes more complex cellular organization and growth. Moreover, endothelial cell behavior is often different than when the cells are grown in monolayers. We examined whether human GCEC organization and growth is influenced by specific ECM in vitro. Human GCEC, obtained from normal kidneys, were isolated and propagated on wells coated with either fibronectin (FN), laminin (LN), collagen type IV (COL IV) or Matrigel (Collaborative Research), a complex ECM product of EHS mouse tumor cells which contains all basement membrane components. Human GCEC grew as polygonal cells in flat monolayers on FN, LN and COL IV while they arranged in impressive tubular fragments resembling capillary vessels in Matrigel. Vessellike formation was seen within 24 hr in Matrigel but never seen with FN, LN or COL IV alone. Human GCEC growth was greater on FN than on LN or COL IV. Human GCEC growth was minimal in Matrigel. Conclusion: Human GCEC growth in vitro is influenced by the ECM environment. Studies of GCEC behavior in vitro should be explored in GCEC grown in complex ECM proteins like Matrigel since it is likely that cellular responses (eg., to eytokines) will be different and may better mimic that seen in vivo. * - Dept of Pediatrics, The Ohio State University - Columbus, Ohio - USA

FC002 REGULATION OF RENAL HEMODYNAMICS IN THE DEVELOPING KIDNEY BY NITRIC OXIDE AND THE RENIN ANGIOTENSIN SYSTEM. Solhaug MJ, Wallace MR, Adelman RA, Granger JP. Depts of Pediatries and Physiology, Eastem Virginia Medical School, Norfolk, VA 23501 and Dept of Physiology, Univ. of Mississippi Med. Ctr, Jackson, MS 39219. Intrarenal nitric oxide, NO, synthesis inhibition with N-Nitro-L-Arginine methylester, L-NAME, produces greater renal hemodynamic responses in the developing piglet than the adult pig ( Solhaug, et al, Pediatr Res 34:750-754, 1993). To determine the interaction between intrarenal NO and the renin angiotensin system, these experiments measured in developing piglets (3 wks) and adult pigs: 1. the functional and renal hemodynamic responses to intrarenal L-NAME alone (UNtreated), or following the preinfusion of the non-peptide specific angiotensin II (AID AT1 receptor antagonist, A-81988 (ATX-treated), and 2. plasma renin activity (PRA) following intrarenal L-NAME alone. The UNtreated piglet responses of decreased renal blood flow, RBF, 29%, increased renal vascular resistance, RVR, 47% were greater than the adult pig, RBF, 9%, RVR, 13%. Intrarenal L-NAME altered glomerular filtration rate, GFR, only in the UNtreated piglet, decreasing 50%. ATX produced greater renal hemodynamic responses in the piglet than the adult pig. ATX preinfusion significantly attenuated the responses to L-NAME in both age groups. In ATX-treated adult pigs, the RBF response to LNAME decreased to 5%, but RVR response was not altered. In the ATX-treated piglets, both responses were changed, RBF to a 14% decrease, and RVR to a 29% increase. However, both RBF and RVR responses in the ATX-treated piglet were still significant, and remained greater than the adult. ATX preinfusion abolished the L-NAME decrease in GFR in the piglet. L-NAME alone did not alter PRA in the adult pig, however, PRA increased 51% in the piglet with L-NAME. Summary: 1. Intrarenal L-NAME produces greater responses in the developing piglet than the adult pig, 2. The developing piglet demonstrates greater responses to ATX than the adult pig, 3. The piglet renal hemodynamic responses to L-NAME, although attenuated by ATX pretreatment, remain greater than the adult pig, 4. The LNAME decrease of GFR in the piglet is abolished with ATX preinfusion, 5. Only the piglet increases PRA with L-NAME. Conclusion: 1. AII is a more important vasoconstrictor in the developing kidney than in the adult, 2. NO is a more important vasodilator in the developing kidney than the adult, counter-balancing the vasoconstriction and functional effect of AII.

FC004 HISTOLOGIC LONG-TERM OUTCOME OF FUROSEMIDE-INDUCED NEPHROCALCINOSIS IN THE YOUNG RAT. U. S. Alon*, R. Kaplan*, L. Gratny*, M. Nichols*, R. Garola* The long-term prognosis of furosemide-associated nephrocalcinosis in the infant is still unclear. Although discontinuation of the diuretic often results in radiologic resolution of the calcifications, functional abnormalities may persist. The natural history of the renal histopathology of these patients is yet unknown. In the present study we investigated the histologic long-term outcome of furosemide-induced nephrocalcinosis in the young rat. Thirty-six weanling male Sprague-Dawley rats were divided into 3 groups (A) controls (B) furosemide given for 8 weeks (C) furosemide given for 2 weeks followed by 6 weeks of observation. Metabolic studies at the end of the experiment demonstrated a significant diuretic and natriuretic effect in group B. Kidney histology showed nephrocalcinosis scores (mean + SD) in (A) 0.0 + 0.0 (B) 2.6 + 1.5 and (C) 0.8 + 0.6, when (B) significantly higher than (A) and (C), and (C) greater than (A). Kidney calcium content (ggm/gm dry tissue) in (B) 3421.9_+2558.7 was significantly greater than in (A) 310.4+21.3 and (C) 1470.1_+932.2. Another group of 6 rats receiving 2 weeks treatment of furosemide showed a nephrocalcinosis score of 2.2 _+ 1.5, not different from group B, and an additional group of 6 rats treated with furosemide for 2 weeks and observed for another 12 weeks showed a score of 1.3 + 0.4, not different from group C. We conclude that most of the renal calcifications induced by furosemide occur during the early days of treatment and that up to 12 weeks after discontinuation of the diuretic the resolution of the calcifications is only partial. If applied to the human this observation may explain the discrepancy between radiologic resolution of the calcification and persistency of some functional perturbation in kidney functions. * Children's Mercy Hosp., Univ. of Missouri at Kansas City, MO, USA

C 37 FC006

FC005 ROLE OF RENAL KALLIKREIN 1N THE REGULATION OF ACID BASE BALANCE. Vall~s,P.; Manaeha, W.; Maria Grez, M~* I~stitutode Fisiopatologia-U.N_C.Mendoza, Argentina and *Physiologisehes/nstitukMunchen, Germany-. Renal kallLkreinis localized in the eonnceting tubule cells and secreted into the tubular find at late distalnephron segments.This quite specific localization suggest that enzyme acts on the lamina membrane of cells downstreamfrom the site of secretion. We have previouslyreportedthatbiea_dxmateexcretionrate is inverselyrelated to urinarykallikreui activity. The experiments reporter here were performed to demonstrate that renal kallikmmis involvedin the regulationof acid base balance, by acting on renal bicarbonate handling. a)- Intra-lnmlnal admini~xafion of kalllkxein (lp.g/ml and 3gg/ml) increased renal kaUikrerin activity (Fr:Ff kk/Fr:Ff Polyfi'u~t) in the second fraefion (1251d) of urine collected two minates after ureter oeclnsion: 1.19-L-O.1versus 0.73i-0.05 (i)<0.05), 1.34a:0.1 versus 0.80-~-0.07 (p<0.01) respectively. Bicarbonate secretion (Fr:Ff HCOf /Fr:Ff polyfmet) was detected in the second fraction (that coming from the collecting ducts)of bothcontrol groups which received only the vehicle, comparedto experimental group to which kallikrein had been administrated (lp_g/ml (p
FREE

COMMUNICATION

P O S T N A T A L C H A N G E S IN W A T E R C O N T E N T AND P R O T O N M A G N E T I C R E S O N A N C E R E L A X A T I O N H I - N M R T I M E S IN NEWBORN RABBIT TISSUE Sulyok E J, Berdnyi E. 2 Szendr6 Zs.2, and R6zsahegyi p.2

H1-NMR was used to determine water mobility in the skin, skeletal muscle and liver tissues of N e w Zeland white rabbit pups. Serial studies were carried out at the age of 0-1, 24, 48 and 72 hours in pups suckling ad libitum (group I) and in those completely withheld from suckling (group II). Tissue water co'atent (desiccation) and TI, and T2 relaxation times (H1-NMK) were measured, the free (FW), loosely bound (LBW) and tightly bound water (q BW) fractions were calulated by applying multicomponent fits of the T2 relaxation curves. It was demonstrated that skin water content and T1 and T2 decreased with age (p
(FC) - Giomerulonephritis

FC007

FC008

EFFECT OF GROWTH HORMONE ON GLOMERULAR TGF-[3 AND IGF-1 mRNA EXPRESSION IN THE RAT MODEL OF CHRONIC CATIONIC BOVINE ALBUMIN (cBSA) NEPHRITIS WITH GLOMERULOSCLEROSIS IlK.Yap*, E.Firzli**, ES.Kamil**, AH. Cohen**, M.Toyoda**, SC.Jordan**

PLATELET-ACTIVATING FACTOR INDUCES CELL GROWTH THROUGH TYROSINE-PHOSPHORYLATION PATHWAY IN CULTURED RAT MESANGIAL CELLS H. Komatsu, K. Ishiwari, A. S h i k a t a , M. Nishida, H. Kawakatsu,T. S a w a d a

We have previously shown that growth hormone (GH) enhanced the development of glomemloselerosis (GS) in the rat model of chronic cBSA nephritis. This study aimed at determining if the GH effect was mediated through the growth factors TGF-13s and IGF-1. Male Sprague Dawley rats were preimmunized with either complete Freund's adjuvant (CFA) or 1 mg of cBSA (pI 8-9) in CFA, following which the cBSA rats were injected with cBSA daily for 6 weeks. At 8 wks, a group of cBSA nephritis rats and CFA rats were treated with recombinant human GH (rhGH) (Nutropin | Genentech, Inc.) (0.05 mg/kg/d) for 2 wks. All the rats were sacrificed at 10 wks immediately on completion of rhGH injections (n=3/group). Glomeruli were isolated from renal cortices by sieving and RNA was extracted. TGF-131, 132, 133, IGF-1 and IGF-1 receptor (IGF-1R) mRNA expression were studied after RT-PCR. A cytokine index was derived from the densitometric readings: CI = [x{~plo)/y(~#) ] + [x{st~a~d/yot~d) ] where x=cytokine and ~yclophilin. Mean CI (SEM) are shown. ~ytokine Ctrl (CFA) CtrI+GH IcBSA IeBSA+GH ITGF-I~1 [1.11 (0.07) 1.02 (0.20) /1.04 (0.14) 11.oo (0.25) ITGFq32 0.97 (0.05) 1.16 (0.10) [0.84 (0.15) [1.15 (0.21) [TGF-!33 [0.73 (0.25) 0.93 (0.12) 10.74 (0.15) [0.90 (0.30) [IGF-1 [ 1.90 (0.70) 2.27 (0.33) [2.58 (0.79) 2.62 (0.45) IIGF-1R 10.59 (0.27) 1.14 (0.20) 10.66 (0.29) 0.73 (0.30) At l0 wks, % GS was as follows: CFA 0%, CtrI+GH 1.26%, cBSA 14%, cBSA+GH 32%. No significant difference in cytokine gene expression was found between CFA and Ctr+GH rats or cBSA and cBSA+GH rats. In conclusion, the accelerated GS associated with GH treatment in chronic cBSA nephritis was not directly due to an increase in glomemlar mRNA expression of TGF-13s or IGF-I. Moreover, glomemlar IGF-IR express!on was not raised following GH administeration in eBSA rats, consistent with reports that mice transgenic for IGF-1 do not develop GS, unlike GH transgenic mice. Instead, GS may be due to the effect of GH on hyperfiltration, mediated via enhanced local IGF-t action on the renal collecting ducts. * Dept. of Pediatrics, National University of Singapore, Singapore. ** Depts. of Pediatrics and Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Accumulating evidence suggests that platelet-activating factor (PAF) may play a role in renal pathophysiology. Therefore, the effects of PAF on cell growth and tyrosine phosphorylation were analyzed in cultured rat mesangial cells by 3H-thymidine incorporation and ImmunoblotSng with antiphosphotyrosine antibody, respectively. PAF was found to enhance a time- and concentration-dependent increase in phosphotyrosine in several proteins and stimulate SH-thymidine incorporation. Tyrosine phosphorylation was also enhanced by PAF in Protein kinase C fPKC)-depleted cells, whereas a tyrosine kinase inhibitor, geinstein, inhibited tyrosine phosphorylation of these proteins at the concentration of l~g/ml. PAF stimulated sH-thymidine incorporation at concentrations below 10" M, but exerted progressive inhibition at concentrations above 10"s M. Phorbol 12-myristate 13-acetate (PMA) pre-treatment did not affect PAF-en]mnced incerporation at lower concentrations of PAF, and reversed the inhibitory effects of PAF at higher concentrations Finally, genistein pretreatment completely inhibited PAF-induced cell growth at the concentration of 1/lg/ml. Both tyrosine phosphorylation and 3H-thymidine incorporation induced by PAF were completely inhibited by pre-treatment of PAF-recepter antagonist, CV-6209, at the concentration of 10-SM. These results suggest that PAF enhancement oftyrosine phosphorylation occurred in a PKC independent manner and that a tyrosine kinase was associated with PAF-induced tyrosine phosphorylation. Moreover, it was suggested that the phosphoinositide hydrolysis-PKC pathway is not essential for PAF-induced celt proliferation, and that PKC activation may play an inhibitory rather than stimniatery role in mitegenesis in response to PAF. Our results indicate that the tyrosine phosphorylation pathway induced by PAF could critically participate in downstream mitegenic signaling through the PAF receptor. Department of Pediatrics, Kyoto Prefectural University of Medicine - Kyoto Japan,

C 38 FC009

SERUM IgA REACTING WITH NEUTROPHIL CYTOPLASMIC ANTIGENS (ANCA) IN HENOCH-SCHOENLEIN NEPHRITIS: EVIDENCES OF A NON-IMMUNE BINDING BASED ON CARBOHYDRATE INTERACTIONS R Coppo Since IgG or IgM ANCA are associated with several systemic vasculitis and Henoch-Schoenlein nephritis (HSP) is a vasculitis characterized by IgA deposits, many researches have been devoted to employ igA-ANCA as a new serum marker of HSP. Increased levels of IgA directed to PMN acid extracts have been found but without a clear specificity. A reactivity of IgA for fibronectin or a membrane-associated yet unidentifiable 51-KD protein have been reported. A role for capsular bacterial lypopolysaccharides in inducing renal and systemic lesions of HSP has been recently hypothesized. Moreover, an altered glycosilation of the IgA molecule has been demonstrated in Berger's disease which shares several features with HSP. Based on these considerations we tested sera from 76 HSP patients and biopsy proved renal involvement (43 adults and 33 children) enrolled in a retrospective multicenter study of the Italian Group of Immunopathology. These sera with 25 healthy controls were investigated for an altered IgA glycosylation by the binding to the lectin jacalin (which shows affinity for the D*Gal residues of the IgA1 molecule). In parallel the sera were tested for the binding to ANCA antigens alpha granules (rich in serine protease) and myeloperoxidase (MP) in basal conditions and after addition of 1 M D-Galactose(Gal) and 1M NAc Glucosamine (NAc-GIc). The binding of IgA to jacalin was significantly reduced in children with HSP (p100% of the values found in controls. Both Gal and NAc-GIc significalty reduced this binding in HSP in comparison to controls (29+18% vs 13.2+13% p
FC010 Predictors of Glomerular Disease in Children with Sickle Cell Anemia.

Delbcrt R. Wigfall, Russell Ware, Peg Burchinal, Roaald J. Falk, John W. Foreman, Thomas R. Kirmcy. Duke/UNC Comprehensive Sickle Cell Center. Glomerulopathy and renal failure are frequently observed sequelae of Sickle Cell Disease in adult patients homozygous for hemoglobin S, and less frequently in patients with hemoglobin SC. Given improved survival and life expectancy, there is renewed interest in the pathophysiology of organ damage in Sickle Cell Disease, and the prevalenea of organ involvement. The predictors and prevalence of renal involvement in children have not yet been defined. The present study was designed to ascertain whether there was a relationship between anemia, decline in renal function, proteinuria, hypertension, and age in children with SS or SC. There were 496 children identified, 342 children with SS and 154 children with SC. There were no SS, nor SC affected children with advanced renal insufficiency. None of the children with SS or SC had abnormal blood pressures. Urinary protein excretion was elevated (greater than 1+) in 60 of 337 children with SS in whom data was available. No children with SS under age 6 had proteinuria. In contrast, 30% of children with SS over age 13 had significant proteinuria. None oftbe children with SC had significant proteinuria. Creatiulna determinations were normal in children studied, and their estimates of ghimerular filtration rate were elevated. There was an age related increase in ereatinine clearance estimates in children with SS in the first decade of life, with a decline toward normal in the second decade. There were no association between hemoglobin concentration, and proteinuria in children with SS. No children with SC had significant anemia, proteinuria, hypertension, or an abnormal creatinine clearance. There was no association between the onset of proteinuria and clinical correlates of aseptic necrosis, gallstones, stroke, or chest ss,ndrome in children with SS. There is a correlation between proteinuria and hospitalizations for pain crises in the subset of children with SS between the ages of 7-12 years. We conclude that the renal involvement of SS Disease presents in childhood accompanied by proteinuria and hyperfiltration, but is net associated with severity of anemia. Renal involvement in children occurs independent of other organ involvement, and as a result, suggests the need for close surveillancr and appropriate intervention.

For the Italian Group of Renal Immunopathology

FC011

FC012

iDNC~TERM COURSE OF RENAL TRANSPLANTS (RT) IN HI~MOLYTIC-UR~MIC SYNDROME (HUS) L.Rodriguez-Rilo , M.Brandi , H.A.Repetto, G.Palti, L.A.Vazquez This study reports the findings of a retrospective analysis of the presence of recurrence(R), the long term survival of the graft,the incidence of acute rejection(AR) and the prevalence of proteinuria(P) and hypertension(H) in children who received RT for HUS, as compared with a randcmly selected group(C) of 19 children transplanted (16 LRD, 3 CD) for diseases other than HUS. 23 RT were performed in 20 children who had had HUS (19 LRD, 4 CD). The HUS had been diarrhea associated(D+) in 16 children. The only R was observed in one patient with a familial HUS Dwho lost the graft 1 month after RT. No evidence of thrombotic mycroangiopathy was seen in the 3 transplantectmmiea or in the 6 graft biopsies performed for othr diagnostic purposes. Mean follow-up was 4.7 ys(HUS) vs. 5.0 ys(C)(r=l to ii ys}. There were 14 AR in the HUS D+ vs. 8 in the C (p'NS). Actuarial survival of the grafts was:ist y 88.6% vs. 88.2%, 5th y 68.9% vs. 74.1%, 8th y 57.4% vs. 74.1% (HUS D+ vs. C, log-rank test: p 0.73). Mean survival of the graft was 7.16 ys (HUS D+) vs. 8.53 ys (C)(pNS). Actuarial survival of RT with normal SCr was: ist y 61.1% vs 47.1%, 5th y 32.6% vs 23.6% (HUS D+ vs. C, log-rank test: p 0.27). mean survival with normal SCr was 2.07 (HUS D+ vs. 2.71 ys (C) (p NS). Concl.: i- There were no differences in survival and evolution of function of the grafts between HUS D+ and C, in a follow-up of ii ys. 2- Prevalence of P and H at 1 and 5 ys post RT was similar in both groups. 3- No R was found in the 19 RT in patients with diarrhea associated HUS. 4- The use of cyclosporin A (12 of 19 RT} w a s not associated with R in HUS D+.

I'POST STREPTOCOCCAL ACUTE GLONERULONEPHRITIS IN CHILE: 10 YEARS OF OBSERVATION, 1980 1989." • ~, E, LAGONARSINO**,6.GUZMAN*, I,RIEDEL*~ With the aim o f c h a r a c t e r i z e the c l i n i c and eDidemiology o f PSAGN, a prospective study was designed, registering a]! admissions t o the Gener'a] H o s p i t a l of a Locai Health Service i n C h i l e . Metnob c o n s i s t e d i n a p p l y i n g a c l i n i c a l or'otocol investigating: previous streptococcal i n f e c t i o n (SI), throat and skin swabs for' the isolation of group A beta nemo!itic s t r e p t o c o c c i (GABttS), sequential d e t e r m i n a t i o n s o f serum ASO, antiDNase6, and C3 and socioeconomic s i t u a t i o n (SES), 773 cases were admitted during the study p e r i o d : 53.5 % males, 92% under' l& years o l d , Incidence snowed an epidemic outbreak (EO) d u r i n g 9984 t o I987. For" t h i s , the a n a l y s i s i s done comparing EO and the endemic per'iod(EP), Average r'isR d u r i n g EP was 37.5 and 115.5 during EO , w i t h a range from 3.8 t o 16,9 , assessed in r a t e s per' 100o000 poD. The highest s p e c i f i c age r a t e , was i n the 5-9 age group i n both p e r i o d . . SES was homogeneous w i t h 80 % o f the p o p u l a t i o n on low and middle ]ow c a t e g o r i e s ; the average size o f the f a m i ] v i s 6.2 versus &.5 in genera] p o o u ] a t i o n . Pyo~er'ma was more f r e a u e n t than phar'vngeal i n f e c t i o n , and more fr'e~uent d u r i n g the EO. Isolation r a t e o f GABHS f r ' o f a p h a r y n x was 20% versus 61% fr'om s k i n swab. Most p r e v a l e n t serotvpes were Tla-Mo and T1 - M1 from pharynx and Timp19 - No from skin d u r i n g EP. TI9 - No (30~) was more p r ' e v a | e n t d u r i n g EO. 82% o f the s t r a i n s were positive to T protein and 18% to M protein agg)utination tests. Significant titer's for ASO and for' antiDNase B wer'e found on admission: 53.1 and 73.~% respectively. Both test were able to identify 100% of previous SI. Clinical picture did not showed any difference in both periods. We conclude: {noidence has an uneven trend during the observed period: EO is mainly due to skin infection and predominance of I serotvpe is observed. Clinical picture does not show significant differences during the observed periods.

Instituto de Nefrologla- Buenos Aires- Argentina.

Dept. o f Public Hea]th* and Dept. o f U n i v e r s i t y o f C h i ) e , Santiago, C h i l e ,

-

Pediatr, i c * ~ C a t h o l i c

C 39 FREE COMMUNICATION

(FC) - Chronic Renal Failure

FC013 LONG-TERM ANTIPROTEINURIC EFFECT OF ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS IN CHILDREN WITH RENAL SEQUELAE FOLLOWING HEMOLITIC UREMIC SYNDROME (HUS). L.Briones,A.Turconi,J. Pefialoza,N.Delgado. Proteinuria has been shown to be a prognostic factor for the progression of chronic renal failure. ACE inhibitors have been considered usefull in reduction of proteinuria in human renal diseases. We evaluated the longterm effect ( ~=48,5 months,r =17-94 months) of ACE inhibitors in 25 normotensive patients with persistent proteinuria.All of them had had a previous episode of classic HUS with severe acute renal failure in early chilhood. All patients received a controlled protein intake for RDA,sodium dietary restriction and enalapril therapy,dose 0.19 4- 0.02 mg/kg/day (Mean $ SEM,r = 0.07-0.4mg/kg/day.). Renal sonography performed in 21 children showed abnormal parenchimal ecogenicity and or decreased renal size in 16 of them. Protein~ia dropped from x=63.55 u mg/m2/hour(Mcan $SEM) to 9.84 + 2.42 mg/m2/hour (p=<0.001) Creatinine clearances was 82.12 + 6.89 ml/'/l.73m2(Mean +SEM) before and 84.78 $ 5.64 ml/'/l.73m2 (p=NS) after medication.No colateral effects were observed. Enalapril significantly lowered proteinuria in sustained fashion without impairing renal function. Prospective controlled trials will be carried to show that the progressive renal disease may be arrested by longterm administration of Ace inhibitors.

Service of Nephrology. Hospital J.P. Garrahan.Bs A ires. Argentina.

FC015 THE PROTEIN-INDUCED PROGRESSION OF CHRONIC RENAL FAILURE (CRF) IS RELATED TO THE AMOUNT OF INGESTED SULFUR AMINO ACIDS (SAA) D. V. Michalk, R. Leitz and J. Rauch The progression of CRF is accelerated with a high protein intake, but the mechanism and the causal protein-components are still unknown. One factor might be protein-induced hypercalciuria with calcification of the residual renal tissue. Since calcium (Ca) excretion is related to the Saa-eontent of the ingested protein and the corresponding sulfate (Si) production we investigated the influence of diets with different protein and Saa-content on growth, renal tissue Ca-concentration and GFR (Ccr) in growing rats with CRF (7/8 nephrectomy). Methods. The animals were fed for 4 weeks with either: 1. high protein (HP: 32%, Saa 1,45%) 2. low protein (LP: 8%, Saa 0,46%) 3. LP + 0,89% methionine (LP Saa: 8%, Saa 1,45) or 4. LP (soja 10%) supplemented with 0,22% of taurine (LP Tau, Saa 0,24%). Control animals received either LPSaa or LPTau. Energy, Ca and phosphate (Pi) were equal in all diets. Growth, GFR and BUN we measured before and after, plasma Ca, Pi, Si and renal Cacontent (RCa) after the feeding period. Results. Growth and renal function (1,14 ml/min/kg body weight) were best in the animals fed the LP diet. The feeding of HP or LP enriched with Saa were likewise associated with a decrease of growth and GFR (0,90 ml/min/kg) and with an increased renal Ca concentration (47,2 vs 9,3 pM/g dry weight). RCa was positively correlated with the amount of ingested Saa (r = 0,9, p<0,01) and the plasma ion product of Ca, Si and Pi (r = 0,67, p<0,05), and inversely with the GFR (r = -0,80, p<0,0t). Conclusion: The negative effect of a high protein diet on renal function in CRF might be partially due the the high Saa-content of these diets resulting in an increased .production and excretion of Si and a concomitant hypercalciuria and calcification of renal tissue. University Children's Hospital, Cologne, FRG

FC014 ENAMEL HYPOPLASIA OF PRIMARY TEETH IN CHRONIC RENAL FAILURE (CRF) M~J. Koch 1, R. Bfhrer t, T. Pioch 1, K. Sch~rer z Different defects o f enamel (EN) formation have been reported in a high proportion o f permanent teeth in children w i t h CRF (Bublitz et al, Proc. EDTA 1 8 : 5 1 7 , 1981). They may become manifest as dental hypoplasia, as a result of impaired enamel f o r m a t i o n , or as opacities by delayed enamel maturation in prenatal or early postnatal life. The time of formation of these defects can be determined by their localization in the primary or secondary dentition. In order to define the time sequence of dental damage in CRF more precisely w e examined the primary or mixed dentition in 33 children w i t h preterminal CRF or end-stage renal disease due to congenital (n = 24) or acquired (n = 9) kidney diseases by clinical inspection. From 10 o f these 33 patients exfoliated primary t e e t h w e r e embedded and sectioned for microscopic examination using polarized light. Primary teeth of 10 additional children w i t h CRF w e r e similarly examined by microscopy. Results: By inspection the primary canines of 4 patients w i t h congenital nephropathies s h o w e d localized enamel hypoplasia indicating an impaired enamel formation. No other cases o f hypoplasia or opacities w e r e observed in the primary teeth. Light m i c r o s c o p y s h o w e d no evidence of an impaired prenatal d e v e l o p m e n t of enamel. The l o w prevalence of enamel hypoplasia in primary teeth of CRF children suggests that prenatal enamel f o r m a t i o n is rarely affected. The localized enamel hypoplasias o f the primary canines described may be attributed to a fenestration o f the surrounding bone and subsequent disruption o f the ameloblast layer or deformation of developing enamel. The role o f surrounding bone on postnatal enamel development needs to be explored: Departments of 1Conservative Dentistry and 2pediatric Nephrology, University o f Heidelberg - Germany

FC016 CHANGE IN GLOMERULAR FILTRATION RATE~ (GFR) IN CHILDREN WITH ADVANCED CHRONIC RENAL FAILURE (CRF) DURINGTHERAPYWITH GROWTH HORMONE (GH). REPORT OF THE SOUTHWEST PEDIATRIC NEPHROLOGY STUDY GROUP. E Brewer~, C Ouw R Hogg +, S Watkins@, D Powellw J Frane#, D Brown#. GH therapy promotes statural growth in children with CRF. Whether GFR deteriorates more rapidly during therapy with GH, especially in children with advanced CRF, was studied by a multicenter trial in 27 centers. 69 children, 2-14 y.o. (mean 6.7) with baseline GFR 10-40 ml/min/1.73m 2 were studied for at least 24 mon. 46 were treated subcutaneously with GH, 0.05mg/kg/d, and 23 were untreated controls (C). GFR was assessed at 0,3,12 & 24 mon by clearance of non-radioactive iothalamate (io) using an IV infusate method (GFRio) for 5 hr (child >._3y.o.) or 8-12 hr (child 2-3 y.o.). Steady state samples collected by a research nurse during studies at each center were measured in a central lab by HPLC assay. Resultswere rejected if 8io wes._~>1.5 mg/dl or not at steady state. 24/267 (9%) GFRio studies at 14 centerswere rejected for technical reasons; 8 (3%) could not be repeated (NOR). Baseline GFRio (ml/min/1.73m2__+8D) did not differ between groups: 27.2 +_.8.9(C) v. 26.0__+7.8 (GH). Baseline GFRio was a predictor of time to _~>20%decline in GFR (2.20% Dec) or end-stage renal disease (ESRD) (p=0.0004). During 0-24 mon study. change in height SDS (AHtSD8) and growth rate (cm/yr) were significantly greater in GH v. C for each yr of study, but progression of CRF was similar in each group: No. Patients with Mon Gr~ AHtSDS cm/yr GFR Stable >20%Dec E S R D Exit/NoR 0-12 C 0.0__+0.3 5.6__+1.8 11 (48%) 5 (22%) 4 (17%) 3 (13%) GEl 0.8+0.5* 9.4+2.8* 25 (54%) 10 (22%) 8 (17%) 3 (7%) 0-24 C 0.1+0.4 5.6_.+2.2 8 (35%) 4 (17%) 5 (22%) 6 (26%) GH 1.3+0.9" 7.5+1.7"* 10 (22%) !5 (33%) 13(28%) 6 (17%) p:C v. GH *<0.0001 **<0.025 NS NS NS N8 During 0-24 mon study, 9/23 (39%) C v. 28/46 (61%) GH (p=0.21) progressed to _>20% Dec or ESRD. Survival analysis of time to __>20% Dec or ESRD was not significantly different between groups. We conclude that even in children with advanced CRF, growth improves with GH therapy; GFR declines, although not statistically significantly more than in controls.

Sponsored by # Genentech, Inc., South San Francisco CA. Dept Pediatrics w College Med, Houston TX; +Baylor Univ Med Ctr, Dallas TX; @Univ Washington, Seattle WA,

C 40 FC017

FCOl8

TREATMENT WITH GROWTH HORMONE INCREASES LIPOPROTEIN(A) SERUM LEVELS IN CHILDREN WITH CHRONIC RENAL INSUFFICIENCY. U. Queffeld 1, D. Haffner~, E. W~hl2, D.V. Michalk~, O. Mehls~ We have previously shown that children with chronic renal disease frequently have elevated blood levels of lipoprotein(a) [Lp(a)]. Lp(a) is an independent risk factor for atherosclerosis and thrombosis. Normally, Lp(a) levels a r e largely dependent on the inherited apolipoprotein(a) [apo(a)] phenotype and are not influenced by diet or drugs. We investigated whether treatment with recombinant human growth hormone (rhGH) in children with growth failure due to chronic renal insufficiency (CRF) has an effect on serum Lp(a) levels. Lp(a) was measured in 13 patients treated with nhGH (1 ]U/kg/week) for 6 to 9 months. All children were on consewative treatment; median age was 8.3 yearn (1.6-14.5), median Ccr was 24 ml/min/1.73m2 (8-45). Morning blood samples were obtained in 3 month intewals. Lp(a) was analyzed by a one-step immunoassay (Immune, Heidelberg) and the ape(a) phenotye was determined by Westem blot. All Lp(a) measurements were performed in tnplicate, Results: in 5 patients, no Lp(a) could be measured either before or after treatment ("0-phenotype"). In the other 8 patients, ape(a) phenotypes could be identified and the median Lp(a) serum level at baseline was 37 mg/dl; 6/8 patients had serum Lp(a) levels > 30mg/dl (3(>98 mg/dl) before the start of treatment. Although Lp(a) serum levels showed considerable variation dudng treatment, a net increase (14%-175%, median 47%) could be obsewed in all patients (last measurement compared to fimt) and the median Lp(a) levels at 3,6 and 9 months were 53, 60, and 61 mg/dl, respectively. These data indicate that treatment with GH in children with CRF leads to increases in serum Lp(a) concentrations. Lp(a) should be monitored in studies evaluating effects of ~nGH treatment. Further data are needed to determine the magnitude and duration of the effect of rhGH on Lp(a) and to establish therapeutic guidelines for (nGH treatment of children with CRF and high Lp(a) levels.

LOW DOSE S.C. RECOMBINANT ERYTHROPOIETIN CHILDREN WITH CHRONIC RENAL FAILURE.

Burke J * , Paediatric

Mizusawa Y, F a l k M, Nephrology Association.

Aust.

IN

& N,Z.

In a multicentre trial, low dose s.c. r e c o m b i n a n t human e r y t h r o p o i e t i n ( r - H u EPO) was e v a l u a t e d i n 22 c h i l d r e n aged 4 months t o 16 y e a r s w i t h anaemia o f c h r o n i c renal failure o v e r a 12 month p e r i o d . A commencing dosage o f 5 0 p / k g t w i c e w e e k l y was g i v e n u n t i l a t a r g e t Hb of 9-11g/dl was a c h i e v e d . The dosage was i n c r e a s e d by 5 0 u / k g p e r week, each f o u r weeks, if t h e Hb d i d n o t i n c r e a s e by l g / d l / m o n t h . When t h e t a r g e t Hb was a c h i e v e d t h e same w e e k l y dosage was g i v e n as s i n g l e i n j e c t i o n . If the Hb c o n c e n t r a t i o n exceeded 11g/dl or fell below 9 g / d l t h e dosage was d e c r e a s e d o r i n c r e a s e d by 50u/kg weekly. After treatment t h e mean Hb i n c r e a s e d from 6.7 • 0.7 to 9.6 • 1,9g/dl (P < 0 . 0 0 1 ) , and h a e m a t o c r i t from 19.8 • 2.4 to 29.3 • 6 . 3 (P < 0 , 0 0 1 ) . By f o u r months the target Hb was a c h i e v e d i n 19 p a t i e n t s on 5 0 u / k g t w i c e w e e k l y and one p a t i e n t on 7 5 u / k g twice weekly. Two c h i l d r e n with severe renal o s t e o d y s t r o p h y f a i l e d t o r e s p o n d t o 9 5 u / k g and 150u/kg t w i c e w e e k l y . The m a i n t e n a n c e w e e k l y dose o f r-Hu EPO in n i n e c h i l d r e n o v e r 4-12 months ranged between 4 5 - t 2 5 u / k g . WISC-R form I . Q . i n 11 c h i l d r e n i n c r e a s e d from 92 • 16 t o 97 • 17 o v e r t h e 12 month p e r i o d ( P = 0 . 0 0 7 ) . No a d v e r s e e f f e c t s were r e c o r d e d . A starting dose o f r-Hu EPO 5 0 u / k g s . c . l y twice weekly is recommended as an e f f e c t i v e and s a f e dosage. Princess Alexandra Hospital,

B r i s b a n e 4102

University Children's Hospitals of Cologne ~ and Heidelberg2, Germany.

FREE COMMUNICATION

(FC) - H e r e d i t a r y Renal Failure

FC019 L I N K A G E OF THE GENE F O R CYSTINOSIS TO M A R K E R S ON

THE SHORT ARM OF CHROMOSOME 17 W G van't Hoff 1, M M Town 2, M Farrall 3, CG Mathew 2 and GA McDowell 4, W A Gahl 4, L Stephenson 5, JA Schneider 6, J

Weissenbach 7, MH Polymeropoulos 5 Nephropathic cystinosis (MIM 219800) is an autosomal recessive disorder of lysosomai cyst• storage. Affected children present with poor growth and features of the renal Fanconi syndrome. Untreated patients develop endstage renal failure in the first decade. In an attempt to isolate the cystinosis gene, we determined its chromosomal location by screening 23 cystinosis families (including one family with a late-onset cystinosis patient) using 328 highly polymorphic microsatellite markers spanning all the human autosomes. Markers were typed either by conventional radiolabelling and autoradiography or by fluorescence analysis on an automated DNA sequencer. The cystinosis gene is linked to markers on chromosome 17p; Zmax = 10.89 at 0 = 0.03 for the marker AFMa061za9. Analysis of marker haplotypes in recombinant families suggests that the gene is located in the 4cM interval between markers AFMb307zg5 and AFMa061za9. The cystinosis gene is distinct from the cystinuria gene (SLC3A1) locaiised to 2pl2-2pter. These results also suggest that the classic (infantile-onset) and juvenile (late-onset) forms ofcystinosis are allelic. The Cystinosis Collaborative Research Group: 1 Institute of Child Health, 30 Guilford St, London ,LrK,2UMDS, Guy's Hospital, London, UK, 3 The Wellcome Trust for Human Genetics, Nuftield Orthopaedic Centre, Oxford , UK ,4 Human Genetic Branch NICI-IDand 5 Natl. Center for Human GenomeResearch ,NIH, Bethesda,USA, 6 Dept of Pediatrics, UCSD School of Medicine, La Jolla, USA, 7 Unite de Genetique MoleeulaireHumaine, Institut Pasteur, Paris, France.

FC020 IMPAIRED GLUCOSE TOLERANCE IN CHILDREN WITH CYSTINOSIS G. Filler*, U. Bade*, P. Amendt*, J H H . Ehrich*, and J. Brodehl** Glucose tolerance was studied by oral glucose tolerance test (OGTT) in 24 (I0 female and 14 male) children with cystinosis and in 20 children with chronic renal failure (CRF) due to other primary disease. Children with cystinosis had a mean age of 13 years (range 5-22 years). No patient was on cysteamine or phosphocysteamine nor did they receive insulin or ghbenclamid. 8 children were in CRF, 3 on HD and 13 were transplanted, no patient was tested on CAPD. Median serum treat• was 175 ~tmol/1. Mean HbAlc was 5.2 • 1.6% (range 3.8 - 99%, 4/24 > 6%). Before OGTT, blood glucose was 5.0 • 1.2 mmol/l in patients with cystinosis, after 60' it rose to 10.6 * 3.2 mmol/l and after 2 hours it dropped to 8.1 • 2.9 mmol/l. In 9/24 patients glucose after 2 h was less than 6.7 mmol/1, 9/24 patients showed impaired glucose tolerance and 6/24 patients showed diabetes according to WHO criteria. One patient had 6 OGTT between 1 t and 15 years o f age, starting with impaired glucose tolerance and developing diabetes after 4 years suggesting a slow progression. Insulin was 11.1 • 4.2/aE/ml before oral glucose load and rose to 47.1 • 24.8 p.E/ml after 30', 65.7 • 28 p.U/ml after 60' and 47.2 • 23/aU/ml after 2h. When compared to the control group, the 60', 120' and 180' blood glucose level were significantly higher in patients with cystinosis, and insulin production after 15 and 30' was less than in the control group. IVTT was performed in 5/24 patients with cystinosis, k-values were significantly lower than in controls with other renal disease and blood glucose levels from 30' post injection onwards were significantly higher in patients with .infantile cystinosis. The early insulin response in patients with cystinosis was significantly lower after 1 min (35 • 27 vs. 134 • 113 ~tU/ml) and 3 min (32 • 27 vs 90 • 90 ~tU/ml) post injection. We conclude that the early insulin secretion was insufficient, possibly due to increasing deterioration of beta-cell function following cyst• storage in the endocrine pancreas. * Department of Pediatric Nephrology - Humboldt University - Berlin - Germany **Department of Pediatric Nephrology - Medical School - Hannover - Germany

C 41 FC021 FAMILIAL MEDITERRANEAN FEVER. LOCALIZATION OF THE GENE AND ITS ORIGIN. M. Pras*, R. Sood**, X. Chen**, P. Langevitz*, A. Livneh*, I. Aksentijevitz**, E. Pras ~*, J. Balow Jr.**, D. Kastner**. Familial Mediterranean Fever (FMF) is an autosomal recessive disorder of unknown pathogenesis, characterized by recurrent selflimited attacks of fever with peritonitis synovitis or pleurisy. Many untreated FMF patients had developed systemic amyloidosis of the AA type presented clinically as nephrotic syndrome which led to end stage renal disease. In the last 20 years, since continuous colchicine treatment has been introduced, most febrile attacks as well as the development of amyloidosis have been controlled. Using DNA's from affected Israeli Sepharadi Jewish families, we have recently mapped the gene causing FMF to the short arm of chromosome 16, with two point lod scores in excess of 20. To map the FMF gene more precisely, we have now tested additional markers. Two-point and multipoint linkage analysis as well as a study of recombinant haplatypes, placed the FMF gene in a genetic interval of 160KB. FMF gene is prevalent among Sepharadi Jews and Armenians. Sepharadi Jews have l i v e d in Spain and North African countries since the era of king Solomon in the 9 century B.C. The highest gene frequency occur in Libyan Jews and in "New Christians" in Palms di Mallorca, descendants of Spanish Jews converted during the Inquisition. FMF seems to be relatively frequent among Anatolian Turks and less so in Arabs of the Middle East. The FMF gene which does not occur in non Semite population has probably a very low rate of mutation, originated at least 10,000 years ago at the cradle of civilization in Middle East where Jews Armenian Turks and Arabs came into existence. * Heller Institute of Medical Research, Tel-Hashomer Israel. **Arthritis and Rheumatism, Branch National Institutes of Health, Bethesda U.S.A.

FC023 In vitro cyst formation from rats: a model of polycystic

kidney disease R. Pey*, P. Schnorr**, N. Gretz***, M. Hafner ** In 1989, a rat model of autosomal dominant polycystic kidney disease (PKD) was described. These rats develop uremia, exhibit a gender-dependent disease expressivity and liver cysts in females. Renal histology resembles human PKD. Up to now attempts to establish cell cultures of rat renal cysts were not successful. We designed a procedure to obtain cysts in vitro. The polarity of the epithelial cells was determined as well as the distribution of cytoskeletal components (actin, tubulin, etc.). A semi-automatic method was developed to count the amount of cysts obtained in the cultures. Our preliminary results reveal that epidermal growth factor (EGF) increased significantly the number and size of the cysts. In contrast the addition of taxol to the culture medium decreased the number of cysts, even in the presence of EGF. Further substances and different culture conditions, like amiloride, verapamil, endothelin and some of its antagonists, CI- and pH, are currently under scrutiny. In conclusion: Since the PKD rat model closely resembles the human disease, we anticipate that the described in vitro system can be used for testing drugs potentially useful to prevent cyst growth. * Dpt. Biologia, Fac. Ciencias, Universidad de Chile ** Technical University Mannheim (FH-M), FRG *** Dpt. Nephrology, Klinikum Mannheim, University Heidelberg, FRG R. P. was recipient of a Fundacion Andes fellowship

FC022 ACTIVITY, SUBCELLULAR LOCALIZATION AND DNA ANALYSIS OF ALANINE: GLYOXYLATE AMINOTRANSFERASE (AGT) IN PRIMARY HYPEROXALURIA TYPE 1 (PH1) P Cochat, MO Rolland, C Dumontel, D Bozon, I Lepoutre Unit~ de NEphrologie P&liatrique, H6pital E Herriot, Lyon, France PH1 is an autosomal recessive inborn error of glyoxylate metabolism due to a deficiency of the liver specific peroxisomal enzyme AGT. We report on our preliminary experience of biological diagnosis in patients presenting with clinical picture of oxalosis. A liver biopsy was obtained from 20 patients. AGT activity was measured with a micro radiochemical method (Danpure 87); cytosolic glutamate: glyoxylate aminotransferase (GGT) was measured concomitantly to correct for interference. Subcellular localization of AGT was performed on liver sections by postembedding protein A-gold (20 nm) immunoelectron microscopy (Cooper 88). Two polymorphisms (duplication in intron 1 and P11L) and 4 mutations (G41R, G82Q, F151I, G170R) previously described were tested. In 10 patients (50%) AGT activity (corrected for GGT) was null; the residual activity was 6 to 50% in 7 patients (35%) and normal in 3 (15%). There was no correlation between AGT activity and the age at first symptoms nor the age at ESRF. Among 5 patients who had immunoelectron microscopy study, 1 had normal immunoreactive AGT protein and normal AGT activity, 4 had no or very low peroxisomal (less than 3 gold particlesAtm2) itnmunoreactive AGT protein (AGT activity 12% in 1 and 0% in 3). The mutation screening identified only 5 chromosomes out of the 28 studied. The minor haplotype (duplication in intron 1 and P11L) which is usually found in 15-20% of a normal caucasian population was present in 64% of the chromosomes of PH1 patients. In the presence of a clinical picture of oxalosis, the biological assessment of AGT is required. Moreover, the AGT assay and intracellular localization in association with DNA analysis should contribute to correlate genotype with clinical and/or biological phenotype. This work was supported by a national grant from the Programme Hospitalier de Recherche Clinique (PHRC 003).

FC024 IMMUNOHISTOCHEMICAL STUDY OF a 1 TO a 6 CHAINS OF TYPEIV COLLAGEN IN ALPORT SYNDROME(AS) M.Taki*, K.Sugihara,, H.Ohomori*, l.Naito**, Y.Sado**, M.Kagawa-*, Y.Ninomiya,-

The distribution of a 1 to a 6 chains of type

coi]agen in the glomerular basement

membrane(GBM), Bowman's capsular BM (BCBM),tubular BM (TBM) and epidermal BM(EBM) in 6 male patients with AS, in which the characteristic alterations of the GBM were observed on electron microscopy, was examined by indirect immanofluorescence using epitope-defined monoclonal antibodies. In glomeruli from normal control kidney tissues a 1 and a 2 were distributed in all BMs and mesangium, while a 3 & a 4 were confined to the GBM and a pan of TBM and a 5 was detected in BCBM and a part of TBM, while a 6 was

limited in BCB M and a part of TBM. In normal control skin tissues a 1, a 2 and a 5 were diffasely distributed in the EBM. Case 1(10yrs) & 2(8yrs) patients of X-linked AS (mild deafness and progressive nephritis) showed no reactivity of the GBM with anti- a 3, a 4, a 5 antibody, of the BCBM with anti- a 5 and a 6 and of the TBM with a 3 to a 6 antibody. Case ! patient presented the defect of a 5 and a 6-antigen in EBM and his mother showed the segmental staining of a 5 and a 6-antigen in EBM. Case 3(19yrs) patient in non X-linked AS who had no deafness and subnormal renal function, showed the segmental distribution of a 3 to a 6 antigen in GBM, BCBM and TBM. Case 4(9yr) patient who had family history of chronic renal failure with deafness, showed the defect of a 3 to a 5 in GBM, but the presence of a 5 and a 6 antigen in BCBM and TBM. In case 5(16yrs) & 6(19yrs) who were sibilings without deafness and progressed to end-stage renal failure, EBM staining of a 5 and a 6 was detected in skin tissues, but not done in GBM,BCBM and TBM. These cases might be non Xlinked patients as the abnormal expression of the a 5 antigen was always associated with abnormal expression of the a 3 and a 4 antigens in the GBM, but it was not clarified whether this relationship was defined in case 5 & 6. In conclusion, the hetrogeneity of hereditary nephritis reflects the variety of aberrant expression of a 3 to a 6 with GBM, BCBM, TBM and EBM. *Shigei Medical Research Hospital - Okayama -, Japan .*Shigei Medical Research Institute - Okayama -, Japan **.Okayama University Medical School - Okayama-, Japan

C 42 FREE COMMUNICATION

(FC) - N e o n a t a l R e n a l P h y s i o l o g y

FC025 F O L L O W - U P O F R E N A L F U N C T I O N IN C H I L D R E N W I T H N E O N A T A L SIGNS OF KIDNEY I M P A I R M E N T

H. Lindblad*, U. Berg**, A. Iveroth*, H. Hecht*, P. Hjort*** and B. Olsson**** The aim of the study was to describe the clinical outcome of children with signs of neonatal renal impairment. 24 children with gestational ages of 27.641.6 (median 34.7) weeks, with birth weights ranging from 818 to 4662 (median 2457) g and an elevated serum creatinine concentration during the first postnatal week, were investigated at a median age of 4.8 years. 4 patients died in the immediate neonatal period and 3 children declined participation. Renal function was determined by clearance of iohexol as well as by formula clearance based on serum creatinine concentration and height. Renal size was evaluated as kidney length and volume measured by sonography. A significant correlation was found between neonatal formula clearance and gestational age with a mean GFR of 8_+l in infants with gest.age <.35 weeks and 11+1 ml/min per 1.73 m 2 in infants with gest.age _>35 weeks. Mean (-+SE) clearance of iohexol at follow-up was 124_+14ml/rriin per 1.73 m 2 and mean GFR formula was 135+7 ml/min per 1.73 m 2. There was no correlation between neonatal GFR and GFR at follow-up and no correlation between GFR at follow-up and gestational age. Mean kidney volume ranged from 71-146 (median 94)% of that of normal for corresponding body weight. Significant correlations were found between total kidney volume in % and clearance of iohexol (r=0.837) and formula clearance (r=0.752). There was a significant correlation between kidney length and volume but not between kidney length and renal function. In conclusion: Despite neonatal renal impairment renal function and volume showed normal values at the age of about 4 years in patients surviving the neonatal period. *Deps of Pediatrics - Jrnk6ping and **Huddinge - Sweden. ***Dep. of Radiology and **** Dep. of Clinical Chemistry - Jrnk6ping - Sweden.

FC026 NEONATAL PHOSPHATE DEFICIT (PD): IS IT A MAJOR CULPRIT IN CAUSING LONG-TERM RENAL ACIDIFICATION DEFECT IN VERY LOW BIRTH WEIGHT INFANTS (VLBW)? M.Monge, V.Garcia-Nieto, P.Ruiz-Espiga, C.Le6n, G.Eizo, E.Dom~nech, R.Trujillo The dramatic improvement in the survival rate for VLBW infants in the last decades has led us to recognize peculiar new metabolic disturbances at this age as, for example PD. To our knowledge, there are no reported long term renal function studies in children who had neonatal PD. We performed an acidification test with furesemide stimulus (Img/Kg) to 16 VLBW children (11V,5M) at 6.73 • 1.63 years of age, whose birth weight was 1202 • 212.20 gr. They had not been treated with furosemide and they had phosphate metabolism data in their files. The results were compared with those of a control group (C) of 10 children at 8.2 • 2.4 years who were born term infants with adequate weight. Although we did not find differences in minimum pH, ammonium urinary excretion was lower in VLBW group in relation to C group (31.87 • 10.86 vs 57.69 • 25.51 ~Eq/min/1.73mZ; p<0.05), and it happened the same when we evaluated the H § total excretion (ammonium plus titrable acidity) (50.77 • 16.50 vs 86.23 • 35.45 ~Eq/min/1.73mZ; p<0.05). We found a direct correlation between H § total excretion and minimum neonatal phosphatemia (r=0.7; p=0.004). We defined neonatal PD when phosphatemia was lower than 5 mg/dl or when urinary ratio phosphate/creatinine was lower than 0.1 mg/mg with an urinary ratio calcium/creatinine higher than I mg/mg. VLBW children who had neonatal PD (n=5) showed lower ammonium urinary excretion than those VLBW who had not (n=11) ( 22.07 • 8.51 vs 36.32 • 8.84 ~Eq/min/1.73m2; p<0.05). Neonatal PD may be a major cause in the long term renal tubular disturbances reported in VLBW children (Pediatr Nephrol 6:C107,1992).The pathogenic mechanism may be related to hypercalciuria as it has been reported in children who were treated with furosemide in the neonatal age (J Pediatr 120:559604,1992). Hospital Nuestra Islands-Spain

FC027 PLASMA LEVELS AND RENAL HANDLING OF CARNITINE IN ILL PRETERM AND TERM NEONATES S. Zamora, N. Benador, G. Lacourt, E. Girerdin The ability of the neonate and especially the premature baby to synthesize camitine is inadequate to maintain normal plasma camitine levels and dietary intake constitute the main source of camitine in the neonatal period. In normal adults, plasma camitine is readily filtered by the renal glomerulus and almost completely reabsorbed in the proximal tubule. The aim of this study was to investigate the carnitine status and the renal handling of camitine in a group of 32 ill neonates during the first week of life. Twelve babies were born between 26 and 31 weeks of gestation, 15 between 32 and 36 and 5 between 36 and 42 weeks of gestation. Twenty eight babies received more than 90% of their caloric intake by i.v. glucose. None received camitine supplementation. Mean plasma levels were: total camitine 15.5 + 1.4, free carnitine 8.9 + 0.9 and acyl camitine 6.6:1:0.7 p.mol/I. The fractional tubular reabsorption (FTR) of free carnitine correlated with the FTR of phosphate(r = 0.61, p < 0.001), with the protein/creatinine ratio (r = 0.64, p < 0.001) and with the logarithm of the glucose/creatinine ratio (r = 0.56, p < 0.001). It also correlated with gestational age (r = 0.60, p < 0.001). The FTR of acyl carnitine was lower than the FTR of free camitine in all patients indicating a possible tubular secretion of acyl carnitine. FTR of acyl carnitine but not of free carnitine correlated with the plasma total carnitine (r = 0.53, p = 0.002). These data indicate that premature and term newborns have low plasma carnitine levels when parenterally fed. Although a low FTR of acyl carnitine may be partially responsible for decreased plasma levels, the FTR of free carnitine were within normal range and showed a maturation with gestational age comparable to the maturation of the other known indexes of the proximal tubular function. D~partement de pediatrie - HCUG - Gen~ve - Suisse

Sefiora

de

la

Candelaria-Tenerife-Canary

FC028

J.-P. Guignard 1, V. Matos I and P. Hohlfeld 2 Departments of paediatrics I a n d obstetrics 2, CHUV, 1011 Lausanne, Switzerland. E L E V A T E D P L A S M A C O N C E N T R A T I O N IN T H E N E W B O R N I N F A N T IS A C O N S E Q U E N C E OF C R E A T I N I N E T U B U L A R REABSORPTION According to c u r r e n t concept, the elevated p l a s m a creatinine concentrations observed in neonates are m a t e r n a l in origin. This concept was questioned in the p r e s e n t s t u d y involving human neonates (gestational age : 15-40 weeks), mother-foetus couples, and newborn rabbits. Newborn infants : on day 1-2, the plasma creatinine concentration was 66 + 3 ~mol/l in t e r m neonates (N = 30) a n d 91 + 4 [tmol/l in p r e m a t u r e neonates (N = 40). Creatinine was highest in the most p r e m a t u r e infants who also presented the slowest decline in plasma creatinine during the first postnatal weeks. Pregnancies : the maternal and fetal plasma creatinine concentrations were measured during 522 pregnancies followed from the 15th to the 41th week of gestation. The m e a n fetal/maternal creatinine ratio never significantly differed f r o m 1, the m e a n m o n t h l y plasma creatinine being always below 47 ~mol/I. These two h u m a n studies indicate that the elevated plasma creatinine concentrations present in the neonate do not reflect the maternal plasma creatinine. Newborn rabbits : in 20 newborn rabbits studied on day 4-8, the clearance of creatinine significantly underestimated the clearance ot inulin, with a m e a n fractional reabsorption rate of creatinine of 12.6 _+ 3.7 %. The significant net reabsorption of creatinine by the immature kidney was not observed in 8 adult animals. Conclusions : 1) elevated creatinine plasma levels in neonates are the consequence of net (passive) tubular reabsorption of ereatinine and are not maternal in origin ; 2) during intra-uterine life, the plasma fetal creatinine concentration is maintained at a low level thanks to transplacental diffusion from fetus to mother. Speculation : leaky tubules in neonates are responsible for the backdiffusion of creatinine.

C 43 FC029

FC030

NEONATAL BARTTER SYNDROME WITH HYPERMAGNESEMIA, HYPERPHOSPHATEMIA AND HYPERCALCEMIA IN TWO SISTERS M.Ohali*, H.Shalev**, D.Landau**

INFLUENCE OF DIFFERENT FEEDING CONDITIONS ON OXALATE AND CALCIUM TO CREATININE RATIO IN PRETERM AND TERM BORN INFANTS

Bartter syndrome is a clinical disorder characterized by hypokalemic alkalosis, renal potassium wasting, hyperreninentia and hyperaldosteronisnl in the presence of normal blood pressure. Since the first report of Bartter syndrome, ramay reports have appeared in the literature describing a wide spectrum of clinical and biochemical fcatares(hypomagnesemia, hypercalcemia, hypercalciuria). Hypermagnesemia together with hyperphosphatemia mad hypercalcemia have never been reported in Bartter syndrome. We hereby describe two siblings with the Neonatal Bartter Syndrome in whom llyponnagnesemia, hypercalccmia and hyperphosphatemia were observed in the neonatal period, which responded promptly to therapy with Indomethacin. Discharge of Indomethacin lead to the reappearance of the mineral imbalance.

Results: Patient 1-before IND. 1-with IND. 2-before IND 2-with 1ND

Mg m~/% 3.1 1.9 3.1 2.6

Ca

P

U/croat

CL

HCO3

12.0 10.8 11.4 10.0

7.5 4.6 6.4 4.7

37/0.4 35/0.3 69/0.5 44/0.5

89 93 93 98

31 26 29 25

FeMg % 99.9 93.0 99.9 98.6

Ca/croat 0.42 0.35 0.50 0.40

Conclusions: 1. This is the first report describing cases of Neonatal Bartter Syndrome with hypermagnesemia, reported. 2. The changes of Mg plasma levels were correlated to changes in Ca and P plasma levels. 3. We demonstrated that hypermagnesemia was corrected by Indomethacin treatment. 4. The FeMg increased as a result of Indomethacin treatment. * Departnlent of Pediatrics, Barzilai Medical Center, Asllkelon, Israel. ** Department of Pediatrics, Soroka Medical Center, Beer Sheva, Israel.

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COMMUNICATION

(FC) - Nephrotic

B. Hoppel, 2, T. Neuhaus 1, S. Fanconi 1, N. Blau 1, B. Roth 2, E. Leumann t Accurately timed urine collections in infants are difficult to obtain, data for oxalate (Ox) and calcium (Ca) are therefore related to urinary creatinine (Cr). Normal values for molar Cr ratios are not easily available for preterm and term born infants. Different feeding conditions may have an influence on these molar ratios. Therefore, we established normal values for preterm and term born infants either fed formula or breastmilk. Spot urines were collected in healthy infants (birth weight 1200-4100 g, age 1-60 days), without any other medications except Vit D-prophylaxis. Urine was collected in plastic bags and later directly acidified with HCL for conservation. Results (geometric mean [+/- SEMI, total number: n = 195):

Ox/Cr (mmol/mol)

Ca/Cr (mol/mol)

preterm infants form. breastm, 267 219 [14.6] [13.2] 0.28 [0.16]

0.38 [0.22]

term infants form. breastm. 191 175 [16.1] [15.3] 0.38 [0.091

0.13 [0.10]

Ox/Cr in preterm infants is higher than in term born infants, which supports our previous finding that the ratio is declining with age. The ratio is higher when formula is fed, in both term and preterm infants. No special difference is seen in Ca/Cr ratio, except a considerably lower value in term born infants fed breastmilk (n=23). IUniversity Children's Hospital - CH-8032 Zurich - Switzerland 2University Children's Hospital - D-50924 Cologne - Germany

Syndrome

FC031

FC032

INCREASED EXPRESSION OF VASCULAR PERMEABILITY FACTOR (VPF) DURING RELAPSE OF CHILDHOOD STEROID SENSITIVE

NEPHROTIC SYNDROME (SSNS) NJA Webb, MA Lewis, RJ Postlethwaite, PEC Brenchley1. Capillary permeability has been shown to be modulated in animal models by VPF, also known as vascular endothelial growth factor, which interacts with specific receptors on endothelium. Alternate splicing ofVPF mRNA, found in peripheral blood mononuclear cells (PBMC) and glomerular endothelial, mesangial and epithelial cells, allows expression of four protein variants, VPF 121 and VPF 165 be!ng secreted and freely soluble. The aim of this study was to identify the involvement of soluble VPF in the pathogenesis of acute proteinuria in S SNS. Plasma and urine samples were collected from children with SSNS in relapse prior to the commencement of steroid therapy (n=9), SSNS in remission (n=4), normal age and sex matched controls (n=9) and normal adult volunteers (n=8). We have developed an ELISA for VPF using a rabbit polyclonal antibody generated against the VPF C-terminal sequence for capture and monoclonal anti-VPF antibody (gift from Dr N Ferrara) for detection. The assay is calibrated against recombinant human VPF. Median (interquartile range) plasma VPF levels (pg/ml) are shown below. Relapse Remission Paediatric Adult

controls

controls

Plasma VPF

1041(321-1440) 78 (78-161) 234 (166-380) 78 (78-165) Relapses vs Paediatric controls p=0.038; Relapse vs Remission p=0.011; Relapses vs Adult controls p=0.002; Remission vs Paediatrie controls n/s (Mann Whitney U). There was no significant difference in urine VPF/creatinine ratios between the groups. These data suggest that a five to ten fold increase in expression of VPF in plasma is associated with the development of proteinuria in relapses of SSNS. We propose that VPF production by vascular endothelium or PBMC is dysregnlated in relapses, leading to enhanced capillary permeability and consequent proteinuria.

ABERRANT PROTEOGLYCAN COMPOSITION OF THE GLOMERULAR BASEMENT MEMBRANE IN A PATIENT WITH DENYS-DRASH SYNDROME LP. van den Heuvel, P.J. Westenend, J. van den Born, N. Knoers, K.J.M. Assmann, C.H. Schr6der and L.A.H. Monnens. A diagnosis of Denys-Drash syndrome (DDS) was made in our patient based on a congenital nephrotic syndrome, scrotal hypospadia and a mutated WT1 gene. The pathogenesis of nephrotic syndrome in DDS relative to the changes in the glomerular basement membrane (GBM) proteoglycan was investigated. Glomeruli, tubules and basement membranes were prepared according to established procedures. The glycosaminoglycan (GAG) content and composition of renal basement membranes was determined. We analyzed the GAG content and composition of the GBM and tubular basement membrane ('IBM) from the DDS patient and age-matched control infants. The GAG content in the GBM as well as 'IBM was comparable in both groups. Only the GAG composition of the GBM of the patient was clearly different and more than 50% (Normally 1020%.) of the total GAG content consisted of chondroitin sulfate (CS). The urinary GAG content (expressed mg GAG/retool creatine) was elevated in the DDS patient due to an increased heparan sulfate (HIS(GAG)) excretion. Indirect immunofluorescence studies on kidney tissue from normal human infants, using a monoclonal antibody directed against the HS chain of heparan sulfate proteoglycan (HSPG; MoAb 403) displayed a strong GBM and a weak TBM staining. Kidney tissue from the DDS patient displayed a reduced staining of the GBM with MoAb 403. A monoclonal antibody against the CS chain of chondroitin sulfate proteoglycan showed an increased staining of the GBM from the DDS patient compared to the GBM of normal human infants. No differences in the distribution or quality of staining with other antibodies against the core protein of GBM HSPG, collagen type IV and laminin were observed. These data indicate that in our patient the proteoglycan composition of the GBM is altered and this could play a role in the pathogenesis of proteinuria. This alteration may be due to a disturbed proteoglycan synthesis by the epithelial ceils because of the mutation in the WT1 gene. Department of Pediatrics, University of Niimegen, Nijmegen, The Netherlands.

Department of Paedlatric Nephrology, The Children's Hospitals and Department of Immunology1, Biomedical Research Floor, St Mary's Hospital, Manchester UK

C 44 FC033

FC034

INFLUENCE OF SERUM ALBUMIN CONCENTRATION ON R E N A L F U N C T I O N IN CHILDHOOD NEPHROTIC SYNDROMI~ E. Nyberg* and U. Berg**

COMPARISON OF ALTERATION IN BONE MASS IN CHILDREN WITH CONGENITAI./INFANTILEANDMINIMALCHANGENEPHROTICSYNDROME U.K. Kala, E. Daniels, D. Jacobs,G.P. Moodley, D. Zachen, J.M. Pettifor Universityof the Witwatersrand,BaragwanathHospital - Johannesburg,SouthAfrica.

Renal function was evaluated as glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) determined by the cleranees of inulin and PAH i~ children with different types of the nephrotic syndrome.119 children (70 boys), 0.6-17.3 (median 4.4) years of age at onset of the disease, were investigated in different stages: the nephrotic stage defined as S-albumin<25 g/l, in the stage of recovery (25-35 g/l) and in remission (>35 g/l). 109 patients were biopsieta with the following diagnoses: minimal changes (MCNS) in 65, diffus~ mesangial proliferation (DMP) in 9, focal segmental glomerulosclerosi~ (FSOS) in 20, mesangioeapillary glomerulonephritis (MCGN) in 10 an~ membranous nephropathy (MN) in 5. 10 patients with a typical clinical history of MCNS (MCNS?) were not biopsied. GFR in the nephrotic stage was significantly lower than in the recovery stage~ in remission and in controls (86_+_5, 11 l:L-4, 117_-4-4and 119+_2 ml/min per 1.73 m 2 respectively). The same tendency of changes in GFR was seen in the~ different diagnostic groups. ERPF, however, was significantly higher in th~ nephrotic stage than in the recovery and remission stages and compared with controls. The higher ERPF in the nephrotic stage was seen in the DMP, FSGS~ MCGN and MN but not in the MCNS children, in whom ERPF did not differ between the different nephrotic stages. Thus the filtration fraction (FF) wa~ severely decreased in the nephrotic stage. When studying individual MCNS and DMP children, GFR and FF increased significantly (paired t-test) from th~ nephrotic to the remission stage. There was a direct correlation between serum albumin concentration and GFR and FF (r=0.495 and 0.54, p<0.001 respectively) and a weak inverse correlation between serum albumin and ERPF. In conclusion, GFR was significantly decreased in the nephrotic stage in all different diagnostic groups in spite of the low oncotic pressure within thcl glomerular capillaries secondary to the low serum albumin concentration~ which ought to lead to an increased ultrafiltration pressure.

Aim: To identify the effects of nephrotic syndromeon the bone massin children.

Departments of Pediatrics, Karolinska Institute, Danderyd* and Huddinge** Hospitals, Sweden

Methods: Prospectively measured lumber spine bone mineral density, total and ionised calcium, serum phosphate, magnesium,albumin, creatinine, alkaline phosphatase,25 hydroxy and 1.25 dihydroxy vitamin D, PTH, fractional excretion of g2 microglobulin, urinary calcium, magnesiumand phosphateexcretion, blood pH and calculated GFR in children withcongenital/infantile(CNS)and minimalchangenephroticsyndrome(MCNS) that was biopsyproven. We also evaluated the age of presentationand duration of clinical nephrotic state. All data analysedusingWilcoxon2-sampletest. Results: Total of seventeen (17) children, eight (8) being MCNS and nine (9) CNS. Mean age of presentation of MCNS was 3.60 years and CNS was 0.88 years. The duration of onset of nephrosisbeing0.4 yearsfor MCNS and 1.3 yearsfor CNS. There was no statistical difference in serum phosphate, magnesium,creatinine, alkaline phosphatase, 25 hydroxy and 1.25 dihydroxy vitamin D, PTH, glomeralar filtration rate (GFR), fractional excretion of g2 microglobulin,pH, urinary calcium excretion between MCNS and CNS. The only statistically significantdifferences noted in the total serumcalcium 1.8 vs. 2.02, ionised calcium 0.89 vs. 1.03 and albumin 12.9 vs. 18 in CNS vs. MCNS respectively. 67% of CNS had decreased spine bone mineral density (BMD) greater than two standard deviations for age vs. 25% of MCNS. (Fisher'sexact 0.15) Serum magnesiumwas low in both groups0.75 vs. 0.78 mmol/I. Conclusion: Decrease in total and ionised calcium and spine BMD was noted in both MCNS and CNS but greater in the latter, withouta concomitantrise in PTH and normal serumphosphatefor age and serumpH in bothgroups. It would seem that children with relapsingor protracted nephroticsyndromeare at risk of developing metabolic bone diseases, even without impaired GFR possibly related to abnormalcalciummetabolism.

FC035

FC036

TREATMENT OF HYPERLIPIDEMIA IN CHILDREN WITH PERSISTING NEPHROTIC SYNDROME: PRELIMINARY DATA OF A MULTICENTER STUDY USING PROBUCOL. U. Querfeld1, D.E. M011er-Wiefel2, K. Sch~.rer3, B. KohP, W. Fiehn4, D.V. Michalk1

HYDROSTRATIC INTRAPERITONEAL PRESSURE (IPP) IN INFANTS ON PERITONEAL DIALYSIS (PD) : INTEREST AFTER SURGICAL PERITONEAL CATHETER IMPLANTATION M. Fischbach*, A. Lahlou*, F. Becmeur*, P. Desprez*, J. Geisert*

Probucol has antioxidative and lipid-lowering properties and reduces proteinuria and the development of focal sclerosis in rats; positive experience has been documented in the treatment of primary hyperlipidemia (HLP) in children. We have initiated a pilot study evaluating tolerability and side effects of probucol in children with HLP associated with the nephrotic syndrome (NS). Patients over 4 years of age with persisting nephrotic proteinuria (>1 g/m2/d), LDL-Cholesterol >160 mg/dl and a GFR > 20 mllmin11.73m2 were admitted to the study after informed consent by their parents. Probucol (2x250 rag) was administered for a total of 12 weeks. Lipoprotein profiles, serum malondialdehyde (MDA) levels (indicator of lipid peroxidation), proteinuria, and creatinine clearance as well as ECG were monitored every 4 weeks. Side effects were recorded by questionaire. Results: Treatment was completed by 6 patients (aged 5-19.5 years); it was discontinued in 1 patient because of (asymptomaUc) QT-prolongation on ECG. At the end of treatment, reductions in total serum lipids averaged 17% in tdglycerides and 25% in cholesterol. Cholesterol concentrations in VLDL (26%), LDL (-31%) and HDL (-19%), as well as apo A-I (-15%), and apo B (21%) were also reduced. Proteinuda was reduced by 28% (+3%to - 49%) and the creatinine clearance increased by 157% (6.5% - 198%) compared to start of treatment. A significant reduction in serum MDA levels was observed after 3 months. These preliminary data indicate that probucol treatment in children with HLP and NS was well tolerated by most patients and had beneficial effects on serum lipoproteins. Further data are needed to evaluate the effects of probucol on proteinuria and renal function. Therefore, the study has been redesigned to include a treatment period of 24 weeks with measurement of GFR by inulin clearance before and after treatment. At present, 8 children are enrolled in this extended study. University Children's Hospitals, Cologne1, Hamburg2 and Heidelberg3, Department of Intemal Medicine4, University of Heidelberg, Germany.

9 IPP is easy to measure routinely in children on PD (especially with the twin bag Y set) : value expressed in centimeters of water with point zero located on the midaxillary line while the patient rests in a perfectly supine position. We use it to limit the risks (pain, dyspnea, leakage, etc ....) of too elevated IPP in the imediate post-operative period. 9 IPP Was followed after 10 catheter implantations (Tenckhof0, replacement of a second catheter in two cases. Following surgery (after peritoneal lavages), PD was immediatly started with 10ml/kg of dialysate inflow volume, manually, using a twin bag Y set (Baxter). The volume of dialysate was then increased by 10ml/kg every 3 or more days (up to 50ml/kg) only iflPP stayed under the upper fixed limit (8cm in infants under 2 years age). The dwell time was similary lenghtned to 4 hours. Afterwards dialysate volume (800 to 1100ml/m2) and dwell time were prescribed and ajusted to adequate dialysis dosis. IPP was measured at each new connection to the peritoneal catheter extension tubing thus at least every 4th hour. IPP was related to postoperative time, dialysate volume and tolerance (pain, leakage, need of analgesic drugs). 9 IPP was significantly higher (10 + 4cm) during the 2-3 days post-operative despite low dialysate volume than afterwards (5 _+ 3cm). IPP remained relatively stable after the third day despite increasing volume to 50ml/kg over a 13 day period. Need of analgesic drugs (pains or high IPP) deacreased over time : 2.8 +/- 0.6 dosis the first day, 1.1 + 0.3 dosis the second day, 0 from the third day. Each dosis induced a deacrease of IPP. No leakage was noted. 9 Currently, we use IPP post-operatively not only to decide whether to progress with peritoneal dialysate volume, but to decide whether to administer analgesic drugs. * Nephrology-Dialysis-Transplantation-Children's Unit - Strasbourg - France.

C 45 FREE COMMUNICATION

(FC) - Dialysis FC038

FC037 PULSE CALCITRIOL THERAPY: A PROSPECTIVE RANDOMIZED TRIAL. Isidro B. Salusky, Jorge A. Ramirez, Thomas Belin, Barbara Gales, Herald Juppner, Gino V. Segre, & William G. Goodman.

UREA KINETIC MODEUNG IN HEMODIALYZED CHILDREN: NITROGEN BALANCE AND DIALYSIS EFFICIENCY C. Abitbol*, G. Zilleruelo*, J. Strauss*, G. Thompson*, M. StYli*, S. Coakley*

Intermittent 1,25D therapy (Rx) is widely used for the treatment of 2 ~ hyperparathyroidism (HPT). It is not known, however, whether the route of 1,25D administration influences the biochemical and skeletal responses to Rx. Thus, 25 patients, aged 12• (SE) years, undergoing CCPD (dialysate [Ca]=3.5 mEq/L for 29_+15mos. were randomly assigned to intermittent 1,25D Rx, given orally (PO), n=15) or intraperitoneally (IP, n=lO) for 12 mos. CaCO3 was used as the only phosphate-binding agent, and all patients underwent bone biopsy (BBx) after double tetracycline labeling before and after Rx. All pts had initial BBx findings of 2 ~ HPT. The initial dose of 1,25D was 1.0 ug thrice weekly and doses were adjusted according to serum (S) Ca and S-PO4 levels. Total (TCa) and ionized (ICa), Alk.P'Tase, PTH 1-84 (IRMA) and 1,25 levels were measured monthly, and baseline values did not differ between groups. Pre-Rx SPTH levels were 769+_180in IP and 671+_121pg/ml in PO, NS. S-TCa and ICa increased from baseline in IP and PO, but these values did not differ during Rx. S-PTH levels decreased in IP to 202_+88pg/ml, p<0.04 but remained unchanged in PO during follow-up. Although S-1,25D levels were within the normal range in both groups, but values were higher in IP p
Dialyzer urea clearances relative to body weight (Kt/V) have been correlated with improved survival in adults when Kt/V > 1 .O. No studies have been performed to test the appropriateness of these recommendations in pediatric patients. Twenty-three treatments in 8 children on chronic hemodialysis (mean age 8.8 yrs; range 0.5 to 14 yrs) were included in our evaluation. All were receiving hemodialysis three times weekly on Cobee hollow fiber dialyzers with the prescribed treatment designed to comply with the recommended Kt/V > 1 ;0. Dialysis efficiency was estimated by calculating urea clearance (K) from the urea reduction ratio. Actual K was measured by collecting the dialysis effluent and assaying for total urea cleared. Urea nitrogen appearance (UNA) was determined from the interdialytic accumulation of total body urea and urinary urea nitrogen. Nitrogen balance (NB) was determined from the difference of dietary nitrogen intake (NI) and UNA, Comparison of prescribed, calculated and measured Kt/V (mean • S.D.) are shown below:

UCLA Sch Med, LA,CA & Harvard Mad Sch, Boston, MA.

(n)

Prescribed (23)

Calculated (23)

Measured (16)

ANOVA

Kt/V

1.41 + 0.5 1.25 + 0.4 0.88 + 0.5* F=6.2; p =.004 ificantly different from other measurements p < O.01.

Dialysis efficiency was significantly underestimated by both prescribed and calculated Kt/V. Nitrogen balance correlated significantly (r=0.85;p<.01) with measured Kt/V suggesting improved nutritional status with improved dialysis clearances. Continued studies are necessary to better define an optimum dialysis prescription in children. *Pediatric Nephrology, University of Miami/Jackson Memorial Medical Center, Miami, Florida, USA

FC039

FC040

MODULATION BY MEMBRANE AND DIALYSATE PROPERTIES OF NITRIC OXIDE (NO) PRODUCTION DURING IN VITRO DIALYSIS *A.Amore, *R. Bonaudo,#D. Ghigo,# S Mitola, * B Gianoglio, * P Cirina and * R.Coppo.

CONTINUOUS VS: INTERMITTENT TREATMENT OF PERITONITIS 1N CHILDREN ON CONTINUOUS PERITONEAL DIALYSIS - RESULTS OF A PROSPECTIVE RANDOMIZED TRIAL F. Sehaefer~ G. Klaus, D.E. MtiUer-Wiefel, O. Mehls and Mid European Study Group for Pediatric CAPD/CCPD

Nitric oxide (NO) is a powerful vasoactive product of endothelial origin. This study was focused to evaluate whether endotelial cell (EC) NO synthase (NOS) could be modulated by the exposure of healthy blood to hemodialysis materials, including different membranes and dialysis solution in endotoxin free or not conditions. Twelve "in vitro" dialysis sessions were performed using Cuprophan (Cu), Polymethylmethacrylate (PMMA) and Polyacrylonytrile (AN69) membranes. Recirculating donor blood samples at 0,5,15,30 and 60 rain were coincubated with murine EC for 6 h. Then, mRNA for inducible NOS and NOS activity(H3-citrulline produced from H3-arginine) were evaluated. ILland TNF released from lympho-monocytes cultured for 6 hours were detected. Moreover, the effects of different dialysis solutions [acetate (AC) 38 mEq/I, Bicarbonate 35 mEq/I plus Acetate 4 mEq/I (g), acetate-free dialysis solution (AFB), each without and with the addition of LPS - (1, 5, 10 pg/ml)] on NOS activity and its specific mRNA expression were investigated. The NOS activity of EC was stimulated by blood dialysed with Cu, peaking at 15 min (15 fold increase in comparison to basal values), while PMMA and AN69 were uneffective (p
The recently recommended intermittent antibiotic administration is a promising treatment option for families with children on CAPD/CCPD. Teicoplanin, a new glycopeptide antibiotic, due to its increased plasma binding, appears to be particularly suitable for intermittent use. A randomized prospective multicenter trial has therefore been initiated to evaluate the efficacy and safety of (i) intermittent vs. continuous and (ii) teicoplanin vs. vancomyein treatment in children with CPD-associated peritonitis. The glycopepride antibiotic is administered either continuously with each bag of dialysate for two weeks, or as two single doses on day 1 and 8 of treatment. In addition, cefiazidime, covering the gram-negative spectrum, is applied either continuously or in only one dialysate per day. At the time of writing, 92 episodes of bacterial peritonitis (74 primary, 15 first and 3 second relapses) have been treated according to this protocol. 37 primary episodes were caused by staphylococci (16 epidermidis, 21 aurens), 11 by other grampositive, 14 by gram-negative organisms, and in 12 cases cultures remained sterile. A primary treatment response was observed in 100 % (35/35) o f the continuously and in 90 % (26/29) of the intermittently treated episodes of gram-positive or sterile peritonitis (n.s.), but only in 5 of 14 gram-negative peritonitis episodes treated either way. Relapsing peritonitis within 4 weeks aider termination of treatment occurred in 10 of 43 (23 %) continuously and in 5 of 35 (14 %) intermittently treated peritonitis episodes (n.s.). All relapses were caused by staphylococci. No difference in primary response or relapse rates were observed between the groups treated with vancomycin and teicoplanin. Early reloading (day 5) was necessary due to low plasma levels in two patients treated intermittently with vancomycin, but in none of the teicoplanin-treated patients. These preliminary results suggest that first-line intermittent glycopeptide/cettazidime treat-ment o f CPD-associated peritonitis in children is equally effective and safe as continuous treatment; however poor outcome of gram-negative peritonitis and high incidence of relapses in staphylococcal peritonitis remain unsolved problems. Pediatric Nephrology Division, University Children's Hospital, Heidelberg, Germany

C 46 FC041 HEPATITISC VIRUS(HCV)RNA AND ANTI-HCVIN PEDIATRICPATIENTSUNDERGOIN9CAPDAND HEMODIALYSIS(HD) L. Bisigniano* J. Fernandez* *, N. del Pine* *, P. Rondo* *, A. Tureoni* We studied 23 CAPDpatients [mean age 5.3 years (r= 1.18)] and 20 lid patients [mean age 13.4 years (r=4-12)] to determine the epidemiology and clinical impllcanees of HCV infection. Months under dialysis, ALT levels, and transfusional and surgical antecedents wore recorded. IlCV RNA (nested PCR) and anti.HCV (ELISA 2) were initially detected. 19 CAPD patients and 14 liD patients were followed up during six months with HCV RNA and anti-HCV determinations to detect subsequent HCV contagion. Anti.HgV was positive in l (4.3%) CAPD patient and in 2 (10%) liD patients (N2). HCV RNA was positive in 2 (3.6%) CAPDpatients and in 2 (10%) HE patients (NS). The table shows epidcmiological data of CAPD and liD children.

ana-HCV(+) Mean dialysis time (mont~)

12

1

15.9

30

ALT elevation (paUents)

0

O

0

1

Transfns[ons (ineanUin last2 yrs)

5.9

4.5

9

11.5

Surgery (meanproceduresin last 2 Fs)

1A

1.5

1.4

2

Both HCV RNA and anti-HCV were positive in 1 CAPDand 2 HE patients. They entered our unit with anti-HeY posltivity and they had previously received blood transfusions. One of these HII patients had ALT elevation and chronic active hepatitis. HCV RNA was positive and antiHCV negative in 1 boy without significant antecedents and recent CAPDbeginning. HCVRNA became detectable during the inllow.up period in t CAPDand 2 HD patients, without anti-HCV sereconvereion and without any related epidemiological or clinical event. We conclude that HCV infection had a low prevalence in our dialysed patients, without statistical difference between CAPD and liD patients, in 3 patients with detectable HCV we could establish a probable source of contagion but in the other 4 no related cpidemiological event was observed. HCV coursed with ALT elevation in only t of 7 infected patients. There are infected patients without detectable anti-HCV and this finding questions isolation criteria based on anti-HCV status. * Nephmlogy Unit- Hospital de Pediatria Juan P. Garrahan - Buenos Aires - Argentina * * Department of Clinical investigation - Bio Sidas - Buenos Aires. Argentina

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0FC) - U r i n a r y T r a c t I n f e c t i o n s

FC042 UR1NARY TRACT MORBIDITY IN 159 CHILDREN WITH MYELOMENINGOCELE G. Filler*, P. LOdige**, J.H.H. Ehrich*, and J. Brodehl**

Urinary tract morbidity was investigated in all 159 patients with myelomeningocele (MMC) treated at the University Children's Hospital Hannover in a retrospective study. At last investigation, 88 female and 71 male patients had a mean age of 11.5 years • 6.1 SD. Mean observation time was 5.7 years (range 0.1 to 18.2 years). Eight percent of patients had congenital malformations of the urinary tract including horseshoe kidney, duplication, hypoplasia or malrotation of the kidneys. The prevalence of neurogenic bladder dysfunction (NGB) in the first year of life was 87%. In those 138 patients with urinary tract morbidity, mictionary cysturethrogram (MCU) was abnormal in 87% of patients, ultrasonography in 48% and intravenous pyelogram (IVP) in 8% in the first year of life. Occurrence of urinary tract infections (UTI) was investigated by life table analysis. 50% of 159 patients experienced at least one UTI until the age of 15 months and 81% &patients until the age of 15 years. By the age of 9 years, 50% of patients had developed a vesicoureteric reflux (VUR), 22% grade I and II, 33% grade III, 33% grade IV and V, 12% not determined. One out of 159 patients developed a mild and reversible increase of serum creatinine at the age of two years. Unilateral renal dysfunction was detected by isotope nephrograms (ING) in 50% of patients at 15 years of age. Unilateral renal impairment was significantly worse in patients with VUR Morbidity of urinary tract was considerable in children with MMC and increased with age, however, bilateral progression of renal dysfunction was rare in children treated in a specialised center providing multidisciplinary care. * Department of Pediatric Nephrology - Humboldt University - Berlin - Germany **Departmentof Pediniric Nephrology - Medical School - Hannover - Germany

FC043 FREQUENCY OF LOW BACTERIAL COUNTS IN URINARY TRACT INFECTION IN INFANTS U. Jodal*, P BrandstrSm*, S Hansson* and P Larsson *^

The discrimination of true bacteriuria from contamination is an important clinical problem; a cut-off level of 105 bacteria/mL for voided urine is commonlyemployed. However, women with acute voiding symptoms often have lower counts in midstream specimens verified by simultaneousbladder aspiration. Since the frequency of low counts in infants with urinary tract infection (UTI) is unknown, we analyzed the files of 366 infants 1 strain. Results: Low counts with <105 bacteria/mL were recorded in 73 (20%) children; <50 leukocytes/mL were found in 26%. Low counts were significantly associated with low numbers of lenkocytes in the urine. Reflux was shown in 38% of children with low counts and in 30% of those with >105. There was no sex difference. Conclusion: The 20% with low bacterial counts constitute a large proportion of the UTI infants; they are not a low-risk group as judged by the frequency of reflux. The diagnosis of UTI in this group can easily be missed by a cut-off level of 105 bacteria/mL, especially as they also tend to have low numbers of leukocytes in the urine. The findings emphasize the need for a reliable urine sampling technique in infants. Bladder aspiration avoids the problem of contamination and is the method of choice; it eliminates the risk that a diagnosisof UTI is missed because of a low bacterial count since bladder urine should be sterile. *Departments of Pediatrics and **Clinical Bacteriology, Ostra University Hospital, S-416 85 Gfteborg, Sweden

C 47 FC045

FC044 IS YOUNGER AGE A RISK F A C T O R FOR RENAL PYELONEPHRITIS ? D. B e n a d o r * , N. B e n a d o r * , D. Slosman**, E. Girardin*

DAMAGE

IN

Pyelonephritis in children m a y lead to renal damage and previous studies suggest that renal involvement is the highest during the first year of life and lower after the age of 5 years. In this prospective study, the relative risk to develop renal involvement in relation to age was assessed with dimercaptosuccinic acid scintigraphy (DMSA scan), a method more sensitive than ultrasonography or intravenous urography to diagnose renal lesions. One hundred eighty three patients 1 week to 16 years of age (median 7.1 months), with a positive urine culture and a DMSA scan performed within the first 5 days of the hospitalization were included in the study. DMSA scan was repeated in 34 children al%er a m e a n follow-up of 10.2 months. Children were divided in 3 groups: <1 year, 1-5 years and >5 years. Results < 1 year

1-5 y e a r s

> 5 years

n

(%)

n

(%)

n

(%)

66/114

(58)

21/32

(66)

32/37

(86)

7/18

(39)

3/5

(60)

9/11

(82)

Initial work up renal lesions Follow up scars

The comparison of the 3 groups of age showed that the incidence of renal lesions at initial work up increased with age (P=0.006). For the children with a follow up DMSA scan, the incidence of renal scars wasn't significantly different between the 3 groups (P=0.07). Among patients investigated by a voiding cystourethrogram, vesicoureteric reflux was absent in 56 of 94 children with renal lesions at initial work up and in 4 of 19 children with scars. C o n c l u s i o n . In this study, we did not confirm the higher incidence of renal damage in young children. On the contrary, our results show in older patients a tendancy to develop more lesions. Therefore, we suggest that all children with suspected pyelonephritis, regardless of the age, require effective diagnostic and therapeutic measures as usually performed in infants.

IS ACUTE PYELONEPHRITIS IN INFANTS A DIFFERENT ENTITY? STUDY OF BLOOD G R O U P S A N D SECRETOR STATE MH Albarus 1, FM Salzano 1 and NP Goldraich 2 The aim of this prospective study was to compare the prevalence of blood groups ABO, Rh, MN, P, Lewis and secretor state in infants with acute pyelonephritis (APN) due to Escherichia coil and in a control-group. APN was defined by a positive urine culture obtained by suprapubic bladder aspiration and fever. The criteria for entering the study were: (a) Caucasian; (b) age 1-12 months. Sixty-five infants (44 females, 21 males) were enrolled. The udnary tract w a s assessed by ultrasound, micturating cystourethrography and DMSA renal scan. According to findings on imaging, patients were classified into 2 groups: I: normal urinary tract (n=40); I1: with primary vesicouretedc reflux (n=25). Sixty Caucasian children from the same geographic area without history of urinary tract infection (UTI) formed the control-group. There were no significant associations (p>0.05) among these genetic markers and APN when infants from groups I and II were compared and when they were individually compared to the control-group. Considering: (1) our findings on blood groups and secretor s t a t e a r e different from the data reported in the literature in patients with UTI; (2) as far as we a r e aware, no previous study was performed including only infants with febrile UTI due to Escherichia coil; (3) the different outcome of febrile UTI in infants compared to older children; - can we speculate that this is a different entity? 19Departmentof Genehcs, UniversidadeFederaldo Rio Grandedo Sul 2. Pediatric NephrologyUnit, Hospitalde Clinicas de PortoAlegre Porto Alegre, RS, Brazil

*D6partemant de P6diatrie - Gen~ve - Suisse **Division de M~decine Nucl6aire - Gen~ve - Suisse

FC046

CAN CHEMOMETRIC ANALYSIS OF CYTOKINES AND BACTERIA PREDICT RENAL SCARRING? BensonM*, Joda[U*, RosbergS*, Agace**W, AndreassonA**. HellstrbmM*. M&nld S*, Stokland E*, Sixt R*, Wettergren B*: SvanborgC**.

Purpose: To predict renal scarring through chemometric analysis of cytokines, bacterial and host properties. Background; High IL-6 was reported in reflux and scarring (ESPN 1993) High IL-6 and IL-8 in febrile urinary tract infection (UTI) but not in ABU. Multivariate analysis showed association of the interleukins to bacterial and host properties. (ESPN 1994). Material: 1) 61 children with febrile UTI, same as above, but now analyzed with urography. 2) 132 prospectively enrolled children<2 years with unselected UTI admitted to aspecialized ward that were examined according to a protocol with serial urine and serum samples until DMSA. Methods: IL-6 and IL-8 with ELIZA. P, prs, TYPE 1 fimbriae and hemolysin analyzed both geno- and phenotypically. Chemometrics is a multivariate analysis based on simplifying data to computer models. Results: Material 1) 15 % of the children had renal scarring. Chemometric analysis showed two subgroups within the febrile group; - Boys with P fimbriae and hemolysin positive infections, high urine IL-8 and urine leukocytes and no reflux or scarring. - Girls with nonvirulent infections, high urine and serum IL-6, reflux and scarring9 Multivariate chemometric analysis showed that scarring was associated to age, CRP, reflux, urine IL-6 and negatively to hemolysin and P fimbriae (r~=0.4). Material 2) is currently analyzed using the models developed above. Conclusions; Chemometric analysis suggest that renal scarring is associated with reflux, nonvirulent bacteria, high CRP and urine IL-6. Virulent bacteria appear to cause a high mucosal response heralded by urine IL-8 and urine leukocytes and less risk of scarring. * Departmentsof Pediatrics, PediatricRadiology,PediatricClinical Physiology,East HospitaI-G6teborgUniversity-Goteborg-Sweden ** Department of Clinical Immunology-Lund University-Lund-Sweden

FC047 EFFECT OF LONG TERM ANTIBIOTIC PROPHYLAXIS ON THE STOOL FLORA OF CHILDREN WITH VESICOURETERIC REFLUX

J a d r e s i c L, Wylie P, M c G r a w M, M c G o w a n A.

Bowker K,

A n t i b i o t i c p r o p h y l a x i s is recommended for infants and children with v e s i c o u r e t e r i c r e f l u x (VUR) to prevent infections which m a y l e a d to r e n a l s c a r f o r m a t i o n . T h e m a j o r i t y of u r i n a r y p a t h o g e n s o r i g i n a t e in the gut and an effective p r o p h y l a c t i c a n t i b i o t i c is one that is well tolerated, prevents the recurrence of u r i n a r y infections a n d d o e s n o t g i v e r i s e to r e s i s t a n t gut flora. In this country, the c o m m o n e s t p r o p h y l a c t i c antibiotic used is t r i m e t h o p r i m (TMP). In a controlled study we a n a l y s e d the resistance pattern to TMP in the stools of children with VUR on TMP p r o p h y l a x i s and compared it to that seen in an age m a t c h e d control group. The mean a g e of c h i l d r e n w i t h V U R was 3 . 0 4 y and 3.00y in the control group. The period on prophylaxis r a n g e d f r o m 4 m o n t h s to 4 years. There was a heavy growth of c o l i f o r m s in b o t h groups. TMP r e s i s t a n t c o l i f o r m s w e r e p r e s e n t in the s t o o l s in 20 of 23 c h i l d r e n w i t h V U R (87%) and in 14 of 30 c o n t r o l s (46.7%), p<0.01. TMP is well tolerated but breakthrough infections were commonly d u e to T M P resistant organisms. The clinical i m p l i c a t i o n s of t h e s e f i n d i n g s w i l l be discussed. Southmead Hospital, Bristol, Great Britain.

C 48 F R E E C O M M U N I C A T I O N (FC) - Acute Renal Failure FC048 MILD HYPOTHERMIA OR HYPERTHERMIA SIGNIFICANTLY A F F E C T R E N A L F U N C T I O N IN I M M A T U R E RABBITS. P. Gilfi~ron, M. T b o n n e y , P. C o c h a t a n d J.-P. G u i g n a r d D e p a r t m e n t of P a e d i a t r i c s , CHUV, L a u s a n n e , Switzerland. The effect of m i l d hypo- a n d h y p e r t h e r m i a (+ 2~ was i n v e s t i g a t e d in t h r e e g r o u p s of 9 p e n t o b a r b i t a i - a n e s t h e t i z e d a n d m e c h a n i c a l l y v e n t i l a t e d n e w b o r n rabbits. After a l h control period, h y p o t h e r m i a or h y p e r t h e r m i a was i n d u c e d by c h a n g i n g the t e m p e r a t u r e of a n heating i n f r a - r e d l a m p p l a c e d a b o v e the a n i m a l . G I o m e r u l a r f i l t r a t i o n rate (GFR) a n d r e n a l blood flow (RBF) w e r e assessed by the c l e a r a n c e ol inulin a n d p a r a - a m i n o h i p p u r i c acid, respectively. Group 1 :Hypothermia i n d u c e d a fall in diuresis ( -18 %), p o t a s s i u m ( - 6 1 % ) a n d chloride (-19 %) excretion, a n d a rise in s o d i u m excretion (+40 %). G F R a n d R B F both d e c r e a s e d s i g n i f i c a n t l y by 20 + 5 % (p<0.05) a n d 31 + 4 % (p<0.05), respectively. Intense vasoconstriction a n d d e c r e a s e d active solute t r a n s p o r t explain the changes i n d u c e d by mild hypothermia. Group 2 : Hyperthermia i n d u c e d a s i g n i f i c a n t i n c r e a s e in d i u r e s i s (+45%), s o d i u m (+171%), p o t a s s i u m (+118%) a n d chloride (+109%), respectively. T h e s e c h a n g e s w e r e a s s o c i a t e d with an i n c r e a s e in G F R (+16 + 5 % ; p<0.01) in s p i t e of a n i n c r e a s e in the r e n a l v a s c u l a r r e s i s t a n c e (+15 + 4 % ; p< 0.01) a n d a d e c r e a s e in R B F (-10 + 3 % ; p<0.01). This finding suggests that hyperthermia induces p r e d o m i n a n t efferent a r t e r i o l a r vasoconstriction. Group 3 : H y p e r t h e r m i a w a s s i m i l a r l y i n d u c e d in a n i m a l s p r e t r e a t e d with p e r i n d o p r i l a t e , an a n g i o t e n s i n c o n v e r t i n g e n z y m e i n h i b i t o r . In this g r o u p , h y p e r t h e r m i a failed to i n d u c e c h a n g e s in G F R , R V R a n d RBF, s u g g e s t i n g t h a t a n g i o t e n s i n I I p l a y s a c r u c i a l r o l e in the response to h y p e r t h e r m i a . Conclusion : m i l d c h a n g e s in b o d y t e m p e r a t u r e s i g n i f i c a n t l y affecl renal function in i m m a t u r e animals.

FC050 THE VEROCYTOTOXIN-I (VT-I) OF HEMOLYTIC UREMIC SYNDROME INCREASES THE SENSITIVITY OF HUMAN MESANGIAL CELLS (MC) TO NEUTROPHIL (N) ADHERENCE AND N-MEDIATED CYTOTOXICITY. J.D. Mahan*, C. MeAllister*, M. Karmali**. Infection with VT producing E.coli is strongly implicated in the pathogenesis of the epidemic form of hemolytic uremic syndrome (HUS). A role for leukoeytes in the glomerular injury in HUS is suggested by the fact that leukoeytosis and neutrophilia (WBC > 20,000, N > 15,000) predict for poor prognosis. In addition, N involvement in glomeruli has been described in renal biopsies from children with HUS. VT-I is a direct cytotoxin for glomerular cells. However, the recruitment and adherence of N to glnmerular capillary cells may augment the damage seen in HUS. To determine whether N augment the eytotoxie effects of VT1 on glomerular cells, normal human MC were exposed to VT-I (0.I pM to 1 nM) and incubated with resting or activated (FMLP and/or TNF) N for up to 2 hr. N adherence was determined at several time points. Cytotexici~y to MC was assessed before and after exposure to N. Adherence of N to VT-I treated MC was increased in a dose and time dependent manner. After 24 hr exposure of MC to VTi, N adherence with 20 pM VT-I was increased to 127% of control MC and with 1 n M V T - I to 141% of control MC. VT-I was cytotoxie for MC with cell survival only 57.7% of untreated MC after 48 hr 1 n M V T - I . A 1 hr incubation of activated N with VT-i treated MC increased MC death by an additional 20%. Exposure of N to VT-I (0.i pM to 1 ~M) for 2 hr resulted in no N eytotoxicity. Human MG are susceptible to the toxic effects of VT-I and display increased adhesiveness for unstimulated and activated N after exposure to VT-I. N adherence results in more MC death than seen with exposure of MC to VT-I alone. This study provides a rationale for further investigation of the role of circulating N in the development of glomerular capillary thrombosis and injury seen in HUS. * - Dept of Pediatrics, The Ohio State University - Columbus, Ohio - USA; ** Dept. Microbiology, Hospital for Sick Children, Toronto - Canada

FC049 CONTINUOUS VENO-VENOUS HEMODIAFILTRATION (CVVHD) USING BICARBONATE CONTAINING DIALYSATE IN CRITICALLY ILL CHILDREN. R.H. Hogg. P.W. Wilby. S. Owen. D. Roy. N. Malthew*, P.H. Henning, K.F. Jureidini. Renal and Intensive Care* Units, Women's & Children's Hospital, North Adelaide, South Australia 5006. To avoid the risk of lactic acidosis when using lactate buffered dialysate for continuous vcno-vcnous hcmodiafilteration (CVVHD) in patients with hepatic and renal dysfunction, we have used a bicarbonate buffered solution. We report our experience with 14 children treated in tbis manner. Their mean age was 4.5 + 5.5 years (range: 3 days - 14 years). Vascular access is via dual-lumen subclavian or femoral vein cathclcrs. Hacmofillcrs are chosen on the basis of patient size and dialysis requirements. The bicarbonate buffered dialysate is prepared at the bedside. A base solution derived by us is now made commercially by Baxter Healthcare Pty Ltd in 3 litre bags. Each bag contains Sodium 331 mmol, Calcium 5 mmol, Magnesium 2 retool, Chloride 329 mmol and Acetate 16 mmol. Following a protocol for various end concentration solutions, sodium bicarbonate, potassium chloride, sodium chloride and calcium chloride are added at the bedside. The acetate in the base solution prevents precipitation of calcium carbonate for at least 24 hours. The mean ultmfiltration rate was 41.4 + 35 ml/bour. Urea and crcatinine clearauccs were 15.3 + 6.6 and 16.4 + 8.62 ml/minute respectively. Metabolic acidosis was readily controlled in all patients and ten of the 14 ultimately recovered normal rena] fimction.

FC051 VEROTOXIN-1 BINDING TO HUMAN MONOCYTES RESULTS IN INDUCTION OF CYTOKINE RELEASE. P.A. van Setten, H.G.G. Verstraten, L.P.W.J. van den Heuvel, M.A~ Karmali, L.A.H. Monnens. Infection with a verotoxin-1 (VT) producing E. coli mainly 0157H7, has been strongly implicated in the etiology of the epidemic form of the hemolytic uremic syndrome (HUS). Endothelial damage of glomeruli and/or arterioles has a pivotal role in the pathogenesis of HUS. Locally released cytokines can be involved in this process. Monocytes (MO) and macrophages, able to produce and release inflammatory mediators, can be the culprits. For this reason we studied the binding of VT to human MO as well as the effect of VT on protein synthesis and cytokine production by MO. The MO were isolated by apheresis followed by Percoll gradient and finally counterflow centrifugation. In earlier experiments a specific binding of VT was established. The binding was enhanced by bacterial lipopolysaceharide (LPS). Cellular protein synthesis was measuredby assaying the incorporation of 3H-leu into total cellular protein. Incubation of MO with VT alone did not affect the protein synthesis over a 24 hour period. In comparison with endothelial cells (HUVEC) no or only a slight effect of VT on protein synthesis of LPS stimulated MO was observed. Our studies also revealed that VT at 10-gM is able to induce the release of considerable amounts of ILl-b, IL-6, IL-8 and TNF-a by MO. In unstimulated MO IL-lb mRNA was undetectable by RT-PCR, but stimulation with LPS and/or VT resulted in a marked increase of 1L-lb mRNA. These data may present an indication of the mechanism by which VT results in cytokine release by MO. We conclude from this study that under basal circumstances MO contain a receptor for VT, which can be induced by LPS, in a time and concentration dependent way. The binding of VT to MO is followed by the production of cytokines. These locally released proinflammatory mediators may contribute to the pathogenic mechanism of CT infection. Dept of Pediatrics, University Hospital Nijmegen, The Netherlands.

C 49 FC053

FC052 PROSPECTIVE STUDY ON COAGULATION AND FIBRINOLYSIS IN CHILDHOOD HEMOLYTIC UREMIC SYNDROME (HUS) W. Proesmans*, C. Van Geet*, J. Arnout**, P. Declerck** Coagulation and fibrinolytic parameters were studied prospectively in 19 children with HUS and 8 control patients with other etiologies of acute renal failure (ARF). Blood samples were collected at diagnosis and every other day thereafter. PT, aPTr, fibrinogen levels, prothrombin fragments 1 & 2 and factor VI/I concentrations were within the normal ranges in both groups, von WiUebrand factor antigen was increased but not different in the two groups of patients. Thrombin-antithromin complexes were also elevated in all patients but significantly higher in HUS. Only HUS patients had significantly elevated D-dimer concentrations (2087-17825 ng/ml-ni <500). Plasminogen and ~2 antiplasmin activity as well as tissue-type plasminogen activator and urokinase-type plasminogen activator antigen levels were within the normal ranges in both groups. Cl-esterase inhibitor levels were slightly increased but comparable in both groups of patients. Plasminogen activator inhibitor (PAI-1) antigen, measured with ELISA sensitive to both active (from plasma) and latent (from platelets) PAT-1 was increased in both groups. However, specific assay (method not measuring the latent form) of active PAI-1 activity and antigen levels revealed normal PAI-1 levels in both groups. CONCLUSIONS (1) This study points to some but limited intravascular coagulation in HUS as well as in other forms of ARF. (2) It does not show, however, evidence of inhibited fibrinolysis. In other words, these data do not support a role for active PAI-1 in the pathogenesis of childhood HUS as postulated by a.o. Bergstein et al (N Engl J Med, 1992). * Deparmaent of Pediatrics ** Centre for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium

FREE COMMUNICATION

CANADIAN STUDY OF E.COLI 0157:H7 AND HEMOLYTIC UREMIC SYNDROME IN CHILDHOOD. Peter C. Rowe, Elaine Orrbine, Hermy Lior, George A. Wells, Peter N. McLaine and the Canadian Pediatric Kidney Disease Research Centre (CPKDRC), U. of Ottawa, Ottawa, Ontario. Patients with E.coli 0157:H7 infection (EC) and Hemolytic Uremic Syndrome (HUS) were recruited in a 3 year study (1991-94) from 18 medical centres across Canada. Risk factors associated with progression from EC to HUS were evaluated using a cohort study design. A case-contrel design comparing children with EC to healthy controls was used to evaluate risk factors for infection. In total 1353 patients were enrolled: 207 HUS, 541 EC and 605 healthy controls. Results:. (OR:HUS vs EC): EC patients that progressed to HUS were younger (OR=0.58); were more often female (OR=1.64); had more severe symptoms (OR=1.99); had higher admission WBC (OR=5.31) and were treated more often with antibiotics (OR=5.07). (OR:EC vs Healthy Controls): After removing the well known risk factors of person-to-person spread (OR=5.45) and the ingestion of undercooked ground beef (OR=2.78), the risks for EC included untreated well water (OR=4.55) and rural residency (OR=2.58). In conclusion, age, gender and severity of EC symptoms are important risk factors for HUS. In this study E.coli 0157:H7 gastroenteritis in childhood was more commonly acquired by personto-person spread than by direct ingestion of undercooked ground beef. Beyond these two factors, untreated well water and rural residency were also found to be significant risk factors for EC infection.

(FC) - T r a n s p l a n t a t i o n

FC054 A MULTI-CENTRE, OPEN, RANDOMIZED, CONTROLLED STUDY EVALUATING THE EFFECT OF GROWTH HORMONE THERAPY IN SHORT CHILDREN AFTER RENAL TRANSPLANTATION M. Broyer on behalf of the study group Recombinant human growth hormone (rhGH) has a documented effect on growth in children with chronic renal insufficiency and short stature. To assess the efficacy and safety of rhGH therapy in children who remain short after renal transplantation, an open controlled multi-centre study was initiated. 172 renal transplanted children with a height below -2SD were evaluated after receiving either growth hormone treatment or no treatment for the first year of study, The study was conducted in 41 clinics in 11 countries, with the majority of patients in France, The transplantation had been performed at least 12 months prior to inclusion into the study and the renal function was stable with a GFR >25ml/min/1.73m 2. The 122 boys and 50 girls evaluated had ages ranging between 3.8 and 18.7 years. 64% of these patients were prepubertal at inclusion. The patients who entered puberty during the first year of study are analysed in the pubertal group. The preliminary analysis shows that the height velocity at inclusion was 3.9 cm/year (n=40) in the treated group and 4.1 cm/year (n--42) in the untreated group for the prepubertal patients. After 12 months of growth hormone treatment the treated patients had a height v e l o ~ increase of 2.6 cm/year. During the same period the height velocity of the untreated patients decreased 0.5 cm/year. For the pubertal patients the height velocity at inclusion was 3.8 cm/year (n---47)in the treated group and 4.0 cm/year in the untreated group (n=43). The height velocity increased with 3.5 cra/year for the treated patients and with 0.5 cm/year for the untreated patients after 12 months. The proportion of patients with a decline in renal function of more than 10 ml/min/1.73m" in the first year proved to be almost equal in the treated and the untreated groups. However, from our preliminary results, an increased risk of acute rejection episodes should be taken into consideration. Conclusive data will be presented at the conference. Growth hormone has both a statistically and clinically significant effect on growth in children who remain short after renal transplantation. The decline in renal function of the treated group of patients did not differ from the decline in the untreated group of patients.

FC055 EFFECTS OF RECOMBINANTHLq~AN GROWTH HORMONE TREATMENT ON RENAL ALLOGRAFTFUNCTIONAND HISTOPATHOLOGY J.Laine, L.ga'ogerus,I.Sipil[i, K.R6nnholmand C.Holmberg Purpose: Recombinant human growth hormone (rhGH) is a potent therapy for poor growth after renal transplantation. However, rhGH has pro-inflammatory properties and may induce acute rejection or accelerate chronic rejection. The purpose of this study was to investigate the role of rhGH treatment in the progression of chronic rejection by analyzing changes in renal function and histopathology. Methods/material: 8 pre-pubertal rhGH-treated renal transplanted children and 8 pair-matched controls were studied 18 (before the start of rhGH) and 36 months after transplantation (mean duration of rhGHtreatment 14 months). 51Cr-EDTA- and PAH-clearances were performed. A protocol renal biopsy was done at 36 months. 72 separate parameters of renal histopathology were blindly semiquantitatively scored by two investigators. Results: The mean growth velocity increased from 6.3 to 9.0cm/year during rhGH treatment (p<0.01). One graft loss occurred in both groups. One acute rejection was seen in the control group. There was no difference in the rate of change in 51Cr-EDTA- or PAH-clearance between the groups. Renal histopathological findings were mostly mild. Of the individual histopathological findings only proximal tubular atrophy was more extensive in the rhGH-treated patients (p<0.05), but there was no uniform trend towards more severe findings. The chronic allograft damage index was slightly, but not significantly higher in the rhGH-treated patients (mean value 8.3 vs 5.9, p=0.35). Conclusion: In our patients the benefits of rhGH outweighed the risks. Evidence for functional or histopathological acceleration of chronic renal allograft rejection during rhGH treatment was not found. Children's Hospital.Universityof Helsinki - Helsinki - Finland.

C 50 FC057

FC056

Catch-up Growth and Improved Final Height in Children on Steroid-free Immunsuppression with Cyclosporin A (Cy A) after Renal Transplantation. B. Klare2,C.R. Montoya~ H. Schneeberger ~ and IV..Land a .

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Growth retardation and stunted final height ffI-I) in children remain unsolved problems after transplantation TX.. The use of steroids has been accused as a major etiological factor We report on a pediatric TX population who recewed mainly a steriod-free immunosupprassion. From 1981-1995 56 cadaver Tx were performed in 48 children aged 5-18 years Mean observation time was 7(O.5-14) ~s, Immunsuppression was started with:l.)Cy A 130 mg/m~- i v./d Further oral dosis being adapted to reach Cy A blood levels of 450 ng/ml (polyclonal measured) 2.) Azathioprine 3mg/kg BW/d for 2-4 weeks until Cy A blood levels were in in the desired range and 3.)prednison (Pr) was given initially 60 m~lmZ/d It was tapered weekly. Two to 6 month post TX Pr was definitely stopped in 41/56 TX. (gr. A ). In 8/41 Pr was later resumed because of rejection episodes Pr could not be stopped in 15/56 TX (gr B).5of these 15 had renal vein thrombosis of TX Results: In the ftrst year after stopping Pr(A) mean growth rate increased to 9.4+'4.1 cm/year in 24 prepuberal and 6.5+/-1.2 era/year in t2 puberal children in contrast to 3.5 cm/year for 7 steroid-treated pts..~together 23/48 pts. in both groups attained FH.The mean FH was -10 SDS in A (n=16) vs -2.3 SDS in B (n=7). The pts in A who stopped Pr before start of puberty (n=9) reached a greater FH than those grafted later (mean -0.35 vs -1.6 SDS). First graft survival was 8 3 , 7 2 and 53% at 1 ; 5 and 14 years.The half live-time of all TX was 15,2 years in A vs 3.7 yrs in B. Mean crcatinine-clearance was 59 ml/m~q.73 mz in A vs 40 ml/min in B. The number of rejection episodes in the fn'st year after stopping Pr was 0.8/TX. 57% of children never had rejection episodes. Conr Long-term immunsuppression without steroids is associated with catch-up growth in prepuberal- and improved growth in puberat children.The FH is improved and often reaches normal range especially in prepuberal transplanted children.

2Children's Hospital, Technical University and 3 Dept. of Transplantat~on Surgery, University of Munwh Germany

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It has been recently suggested that L-arginine (L-Arg) supplementation might have beneficial effects on progression of renal damage and cyclosporine nephrotoxicity. We have studied the effect of oral L-Arg intake on and renal hemodynamics in renal allograft recipients. 11 patients, six males, (range of age 11-22 yrs), post-TX time: 2-7 yrs, with mild-to-moderate renal insufficiency (range of Cr.CI. 30-70 ml/min/1.73 sqm) and with proteinuria (range 0.5-1.8 g/day), none of them treated with ACEI, were randomly assigned to: Group 1: a 6-week treatment period with Placebo (Pla), followed by 2 subsequent six-week periods with L-Arg; Group 2: a 6-week treatment period with L-Arg, followed by 2 subsequent six-week periods with Pla. Arginine was administered as L-Arginine hydrochloride at the dosage of 0.2 g/kg/day (max 8 g/day). At the end of each treatment period, GFR (CI. Inutest), RPF (CI. PAH) and urinary albumin excretion (AIb.u) were determined. Urinary excretion of cGMP and urea (U.u) were evaluated in order to study the metabolic pathway of L-Arg. Data are given as mean.+_sd * p
FC059

FC058

URINF FLOW cYrOMFTRY (UFC) IN ]HE EVALUATION OF ACUTF RENAL ~IOGRAFT DYSRINCTION. I. Roberti*, L."Reismon*, K.V. Lieberman,, M. Panico**,.L Burrows** In a recently published prospective double-blind study of 40 renal allograft recipients we demonstrate the ability of UFC to diagnose early acute rejections. We were also able to show that the presence of an active urine sediment defined by flow cytometry in opporenUy clinically stable ollograft recipients was associated with worsening renal function during the first posttransplant year. In the present study we analyze the preliminary UFC data obtained from 16 renal ollogroft recipients on the first day of hospital admission for evaluation of rising serum creatinine. UFC analysis was done blinded to the clinical evaluation and results were compared to the patient's discharge diagnosis: Acute rejection(M) -N=IO, Chronic

rejection (biopsy proven)- N=3, cyclosporine toxicity -N=2, undetermined (normal biopsy)-N=l. UFC results obtained from 10 stable renal ol[ograft recipients were used as control. UFC analysis was done in fresh urine sediments utilizing the following fIuorescinated monoclonal antibodies: anti-HI_A-DR, anti-CD3, anti-CD14 (LEU-M3), onti-CD54 (ICAM)and anti-/12R. All UFCs obtained durin9 AIRs had >7500 cells with at least 5% of HLA-DR positive cells (p
L-ARGININE SUPPLEMENTATION IN YOUNG PATIENTS WITH RENAL TRANSPLANTATION: A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY XZ. Zhang, GL. Ardissino,L. Ghio, AS. Tirelli, V. Dacca", D. Colombo, F. Marchesi, A. Claris-Appiani

18

OXIDATIVE STRESS AND ANTIOXIDANT DEFENSE MECHANISM IN CHRONIC ALLOGRAFr REJECTION S. Tdri*, P. Szenochradszky**, A. Torkos*, L. Sdghy*, -I.Nbneth*, L Varga***, B. Matkovics*** 45 adult patients (pts) (aged 21-44 years) with kidney transplantation and 17 controls were investigated for a possible role of oxidant injury in chronic allograft rejection (CAR). 20 pts were symptom-free with normal kidney function (serum creatinine < 120 /~mol/1) (group 1), 15 pts had moderate symptoms of CAR (se.ereatinine 121-200 t~mol/l) group 2), and 9 pts developed more severe symptoms of the disease (se.ereatinine > 200/zmol/l) (group 3). The changes of red blood cell (RBC) redueed (GSI-I) and oxidized glutathione (GSSG) concentration, hemoglobin (Hb) oxidation, antioxidant enzyme (superoxide dismutase [SOD], catalase [Cat], GSH-peroxidase [GP-ase]) activities, RBC and plasma malonyl-dialdehyde (MDA) concentrations were investigated. Plasma MDA was significantly elevated in all pts comparing with the controls (0.29+0.02, 0.34+0.05, 0.31+0.04 and 0.21+0.02 aM/rag RBC protein in group 1, 2, 3 and controls respectively), but RBC GSSG level was significantly higher in group 3 only (p<0.01). No difference was observed in RBC MDA concentrations. RBC Cat activity was significantly lower in all pts than in the controls (0.40+0.12, O. 38+10, 0.34+0.09 and 0.85+0.10 U/nag RBC protein in group 1, 2, 3 and controls respectively). A eompensatery increase in GPase activities was observed in group 1 and 2 compared with the controls (p <0.05) but not in group 3. There was a non-significant increase in the level of MetHb with the increase of se. creatinine concentration. Free oxygen radicals have a major role in the pathomeehanism of chronic rejection of the renal allografic. Plasma MDA may be elevated even in normal transplanted pts, which become more expressed in the more severe cases, but RBC GSSG is a specific marker for the increased oxidative stress in the more advanced rejection. The decreased Cat activity of RBCs can be compensated by an increased GPase level in normal and moderate CAR but not in more severe cases. Department of Pediatrics* and Transplant Surgery**, Isotope Laboratory***, University of Szeged, Hungary

C51 FREE COMMUNICATION (FC) Mineral Metabolism -

FC060 ROLE OF PARATHYROID HORMONE (PTH) IN PHOSPHATEINDUCED NEPHROCALCINOSIS IN THE RAT. U. S. Alon*, R. Kaplan*, D. Blowey*, S. Hellerstein*, B. Warady*, C. Langman** Treatment of children with familial hypophosphatemic rickets with high oral phosphate (P) often results in simultaneous development of hyperparathyroidism and nephrocalcinosis (NC). To investigate the role of PTH in P-induced NC we studied the effect of high oral P intake on the development of NC in intact and parathyroidectomized (PTX) rats. Four groups of 6-wks old female Sprague-Dawley rats were studied for 35-day periods: (a) intact controls, (n=7) (b) intact + 1.93 gm/L elemental P in drinking water, (n=7) (c) PTX control, (n=6) (d) PTX + P as in group (b), (n=5). At the end of the study 72-hr urines were collected in metabolic cages and blood obtained. One kidney was studied histologically and the other ashed. Group (b) rats developed intratubular calcifications with kidney Ca content 2.65 _+ 1.49 mg/grn dry weight Vs. (a) 0.47 +_0.16 (P<0.01) and had higher urinary Ca x P product 0.656 + 0.422 Vs. 0.071 + 0.038 (P<0.01). Staining with alizarin red showed the calcifications to be composed of CaP. Group (b) serum Ca x P product 67.0 + 3.9 was similar to gr. (a) 62.7 _+ 15.9. Serum ionized Ca++ in gr. Co) 0.95 + 0.09 mmol/1 was lower than in gr. (a) 1.06 _+ 0.09 (P<0.05) and PTH tended to be higher 83.0 _+ 45.3 Vs. 43.2 _+ 20.1 pg/ml (0.1> P> 0.05). Group (d) rats urine Ca x P product 1.558 _+ 1.037 was higher than gr. (c) 0.052 + 0.062 (P<0.01) however, no NC was observed and kidney calcium contents were the same in both groups. There were no differences between groups (d) and (b) in the serum and urine Ca x P products, but gr. (d) had lower urine pH 6.44 + 0.47 Vs. gr. (b) 8.40 _+ 0.50 (P<0.001). Conclusions: 1. High P intake results in decreased serum ionized Ca and increased PTH concentrations. 2. PTH promotes precipitation of CaP complexes in the kidney presumably by maintaining alkaline intratubular milieu. * Children's Mercy Hosp., Univ. of Missouri at Kansas City, MO, and ** Children's Memorial Hosp. Northwestern Univ. Chicago, IL, USA

FC062 BONE MINERAL PARAMETERS IN CHILDREN WITH CHRONIC RENAL FAILURE (CRF) RECEIVING RECOMBINANT GROWTH HORMONE (GH) THERAPY. A REPORT OF THE SOUTHWEST PEDIATRIC NEPHROLOGY STUDY GROUP. SL Watkins*, RJ Hogg+, ED Brewer1, DR Powellw I Boechat82 D Brown~, J Kuntzer Sixty-nine prepubertat children with CRF (GFR= 10-40 ml/min/1.73m 2, mean age 6.8 yr, range 2.1-14.7, 58 male, 11 female) entered a 2-year randomized, controlled study of the use of GH. Forty-six received Nutmpir~ 0.05mg/kg sc qd; 23 were untreated controls. Mean height(ht) was 2.7 SD below the mean for age at entry. Serum calcium(Ca), ionized Ca, phosphorus(P), and alkaline phosphatase(alk phos), and urinary Ca, phosphorus and creatinine were measured quarterly; intact parathormone(PTH) semiannually in all patients(pts). Radiographs oftha hand/wrist for bone age(BA) were obtained semi-annually. Radiographs of hip and knee were evaluated annually for renal osteodystrophy (ROD). The variations in serum Ca and ionized Ca were not clinically significant. Mean serum P was unchanged at 12 months in controls but increased from a mean of 5.2 mg/dl to 5.9 mg/dl in treated pts (p=0.006). AIk phos was not significantly changed in the control group at 12 months, while the treated group increased from a mean of 267 IU/L at baseline to 377 IU/L at month 12 (p = 0.0002). Mean alk phos ratumed to baseline levels for pts evaluated at months 24. FExCa and FExP did not change significantly at 12 or 24 mos in either group. Median PTH (n1<65 pg/ml) was unchanged from baseline to month 12 in the untreated group, but rose from 90 pg/ml at baseline to 142 pg/ml at month 12 in the treated group (p=0.03). For those patients with 24 month results median PTH rose from 103 to 135 in 8 controls (NS) and fell from 103 to 93 in 23 Nutropine patients (NS). Elevated baseline PTH was correlated with decreased growth rate byANCOVA(p=0.01). ROD scoreswere not significantly different between groups at 12 mos in 33 pts. No pts have developed slipped capital femoral epiphysis. Two pts had avascular necrosis (AVN) of the femoral head at baseline. One of these pts improved his height SD score by 0.6 during the first 12 mos, compared to mean 0.8 for all prepubertal pts. The other pt was transplanted at mo 9. No new cases of AVN have developed to date in 24 treated pts and 9 controls. These preliminary data demonstrate an increased serum P as well as a transient increase in elk phos and PTH in GH-treated pts. No other significant differences in bone metabolism between treated pts and controls are apparent.

Sponsored by Genentech, Inc., South San Francisco, CA. *U of WA, Seattle WA; +Bay/or UMC, Dallas TX; sBaylor Coil Med, Houston TX; ~UCLA, Los Angeles CA; and ~Genantech, Inc., So San Francisco CA.

FC061 BONE MINERAL CONTENT STUDY IN IDIOPATHIC HYPERCALCIURIA OF CHILDHOOD JL. Fern~ndez-Gonz~lez, V. Garc~a-Nieto, C. Ferr~ndez, J. Chahin, G. Rizo, MV. Fern~ndez-Gonz~lez, M. Ruiz-Pons, M. Monge We have studied bone mineral density (BMD) in 70 children who had been diagnosed of idiopathic hypercalciuria (IH) (35 M,35F; 8.26• 3.83 years). Hypercalciuria was dietindependent (HIDI) in 33 (47.1%) and diet dependent (HIDD) in 37 (52.8 %). BMD was measured with an Hologic QDR-1000W densitometer. Results were reported as standard desviation score (SDSBMD) and as percentage in relation to the mean value for age and sex. Bone mass lost was defined when SDS-CMO was lesser than -I. Creatinine clearance (CCr) basal values and some other parameters related to bone metabolism were investigated too. None of the children had been on tiazides treatment. Intact PTH levels were normal in all patients. SDS-CMO was lower than -I in 32 children (16 HIDI, 16 HIDD). When we compared these children with those who suffer IH and normal bone mass, the first ones showed significant decreased levels of CCr (135.0• vs 162.0• ml/min/1.73 m2; p<0.01) and citraturia (663.1• vs 803.6• mg/day/1.73 mZ; p<0.05) and a higher urinary volume (V) (1.1• vs 0.8• p<0.05). DMO percentage was inversely correlated to age at diagnostic (r=-0.31), with tartrate resistant phosphatase acid levels (TRFA) (r=-0.41) and with PGE 2 urinary excretion (r=-0.26). This last parameter was directly correlated to TRFA (r=0.49) and V (r=0.38). Osteocalcin levels are directly correlated to TRFA (r=0.47). In summary, we found a decreased BMD in 45.7% of the children suffering of IH, both HIDI and HIDD. Increased bone resorption in IH probably cause a decreased BMD and may be mediated by PGE 2. This higher PGE z activity would decrease water reabsorption in the collecting duct favouring a certain volume contraction. Hospital Nuestra Sefiora de la Candelaria-Tenerife-Canary Islands-Spain.

FC063 RELATIONSHIP BETWEEN URINARY (U) PROSTAGLANDIN AND CALCIUM EXCRETION DURING IMMOBILIZATION. CD. Garcia*, L. Debeni*, F Cerata*, A. Uhlmann*, V. Pizzato*, L. Nascimento*, W Koff*, E. Camargo Neto*, HW. Seyberth ~, FB. Stapleton**. Increased urinary prostaglandin E2 excretion (U PAGE) has been associated with hypercalciuria (HCU) and impaired renal concentration capacity. These relationship have not been examined in immobilized patients. We examined U Ca and PGE2 excretion and maximal urinary osmolaUty in 15 healthy patients (ages 5 -12 years), immobilized following orthopedic procedures, dudng 4 sequential periods: A - in first 3 days of immobilization; B - 9 4 days of immobilization during hipercalciuria; C - after 3 days of indomethacin ; D - > 3 days after discontinuing indomethacin. Serum creatinine concentration was normal in all patients and did not vary during the study. Hypercalcemia (serum Ca>10,5 mg%) occurred in 1 patient (10,7 mg%) during A period and 4 other patients had at least one episode o1 hypercalcemia during immobilization. The table demonstrates urinary findings during the study. Study Period n PGE~ ng/pmol Cr x 103 A 14 16_+ 19 B 14 64_+ 33* C 15 40 _+ 52* D 13 45 + 35 *significantly different from preceding period.

Ca/Cr (mg/mg) 0.11 + 0,24. 0.36_+ 0.21" 0.29 + 0.22 0.37 + 0.22

All patients had HCU (U Ca/Cr>0.2) during B period; 6/15 became normocalciuric during C. U PGE2 was not related to U Ca/Cr during the 4 study periods. Urinary osmolality after 12 hours of fasting was > 800 mOsm/Kg in 6/11 patients (54%) during A; 2/12 (17%) in B* and 3/13 (23%) in C. DDAVP did not increase Uosm significantly during B or C. This study demonstrates that U Ca and PGE2 increase during immobilization. Our data do not support s direct causative relationship between the U PGE2 and U Ca. Indomethacin therapy reduced U Ca in 6/11 patients, however, 3 patients developed mild hypercalcemia. Neither U Ca nor PGE2 explains the impaired urinary concentration ability in immobilization. * Irmandade Santa Casa - FFFCMPA/UFRGS - Porto Alegre - Brazil Klinikum der Philipps - Universlt~tt - Marburg - Germany ~Children's Hospital - University of Buffalo - USA,

C 52 FC065

FC064

Z-ZrP~CALC~UR~C) A POSSm~ CAUS~ OF RECLmRmer

RENAL MAGNESIUM HOMEOSTASIS IN INFANTS AND CHILDREN

LIRINARY TRACT INFECTION (UTI) IN CHILDREN. M i c l ~ r M, Lbl~.* Lyssis A. Ce..qillo.* Juan B. Chttvez.* Carlnen ~.Ramoncs.*

G. Ariceta, J. Rodrlguez Soriano, A. Vallo

~ has not bee~ widely xecognized as a possible etiologic factor in recummt UTI in children. We describe 42 children (8 boys and 34 girls) whom ln~Sonted two or m c ~ episodes of UTI. whose renal ultrasonnd and voiding cystogram were normal and whose renal function studies demonstrated hypercakimia. Mcan ege of th,Jt UTI was 2 years, with a nmsc betwt~n 1 month and 9 year~ Most common clinical manif~lations were: fever (100 %). dysmia

(35 %), and mainitm with mictmieon (34 %). Less fmquont clinkal findings w ~ : miettmo~ or Sp~nsh e m m ~ polye~ abdomlml pain and failm to thrive, A positive family histmy tbr urolithiads was I X e S ~ in 13 c a s ~ (30 %). Mean m i n a ~ cakium/cttmtin~ talio was 0.36, with a range from 0 2 2 to 0.9. fllnO]on ~ also inf.J.uded ~ ejl~llinin~ (0.5 • 0.09 mg %), serum bicarbonate (21.18 • 3.28 mEq/l), utinmy-blood pCO 2 with glkMinr urine (11.38 • 11.13 mmHg), urinary acid excretion with ammonium chloride lindin8 (62.62 • 31.13 ixEq/min/1,73 m2), phe~aatc tubular re,absent,ion (81.11

•

%), uric ~kl fl~etto~l exea~tion(13.08 4- 12.43 %), and m~r,imal mi-

onty osmolality efler 12 hours o f water deprivation (920 • 236 mOsm/Kg). Hypercalciuria was asaochtcd with other tubular defers as distal ttdmlar aci. doris in 32 I ~ C/0%) and hylmrmicomria in 4 l~ficats (9%), Treatment con,dst~ of dict~y modifications (n = 30), potassium dtratr (n = 21), hydro.

chlorothi~de

(n =

19) or sodium citm~ plus citric acid (n

= 8).

Follow-up

ranged Mtwcen 1 and 13 years. Forty palients achieved normslizati6n of urinary calcium cxcraion and had no further recurrences of UTL Cendusiom. Hypercakiuria m y be a conditioning or predisposing factor in recunent UTI in children with normal urinmy ~act. evidenced by sonography and voiding cystogram. In most c a s ~ r e c k s may be avoided

Renal handling of magnesium (Mg) has been incompletely studied during infancy and childhood due to the difficulty, until recently, of measuring the diffusible fraction of plasma Mg. We have used this methodology to assess renal Mg homeostasis in 45 healthy infants, aged 1 to 12 months, and in 63 healthy children, aged 1 to 15 years. When compared to children, infants had significantly higher plasma values for both totai (1.86 -+ 0.20 vs 1.70 _+ 0.15 mg/dl, P <0.001) and ultra-filteredMg (1.24 _+0.17 vs 1.18 + 0.I0 mg/dl, P <0.05). No significant correlations were present between values of plasma Mg and plasma concentrations of calcium, creatinine, total protein or albumin. The ratio UMg/Ucr, calculated in the second morning urine, was also significantly higher during infaney (0.13 _+ 0.08 vs 0.08 _+0.04, P <0.001). On the contrary, fractional excretion of Mg was identical in both age groups and did not correlate significantly with age (infants: 3.77 -+ 2.09 %, children 3.93 -+ 1.72 % P = NS). Data from our laboratory had already established that urinary Mg excretion is not statistically different in infants vs children (1.46 + 0.94 vs 1.68 -+ 0.88 mg/kg/day,respectively. During MgSO 4 infusion, carded out in 6 children, we could establish values for renal Mg threshold (1.25 mg per 100 ml GF) and MgTm (1.4 mg per 100 ml GF) close to those found in adults. These results indicate that no functional immaturity is present during infancy for renal tubular reabsorption of Mg and that the high UMgFLICr ratio observed in this age goup is a phenomenon not dependent on a higher urinary Mg excretion but probably related to a lower urinary creatinine excretion per unit of lean body mass.

by normalizationof urinarycalcium exr.mtion. *Depefencnt ofPedie~c Nephrology. Hospitalde Nifios 3. M. de los Rios. Caracas. Venezue~

FREE

COMMUNICATION

Depaslment of Pediatrics,Hospitalde Cruces and Basque UniversitySchool of Medicine, Bilbao,Spain.

0FC) - H y p e r t e n s i o n

FC066 AMBULATORY BLOOD PRESSURE MONITORING (ABPM) IN HYPERTENSIVE CHILDREN APPARENTLY WELL CONTROLLED BY STANDARD BLOOD PRESSURE MONITORING Koch VII*, Furnsa~a EA*. lgnes EC**+ Okay Y*, Mion Jr,D** Traditional office measurements of bloed pressure may presenl technical difficulties which hinder proper assessment of antih)~crtensive therapy adequacy in children. We evaluated 17 hypertensive children (9 femaic,g male), mean age 10.2 yrs(4-17), who were refeixing apparently adcqnate antihypertensive medication, according to casual office blood pressure m~u~menls, using ABPM (Spacelabs 90207,measurements ~,,ea), l0 tnin. 24h). electrocardiograph)-,echocardiography and funduscopic examination. The etiology of arterial hypartenaion in this patient population '~as: chronic renal failure 6/17, chronic pyeloncphritis I 3/17, renm'asenlar hypertcusion 2/17, polyc3,stic kidney d i m 2/17, unilateral renal b3~oplasia 2/17, essential hypertemion 1/17 and tuberous sclerosis 1/17. ABPM showed abnormal results in 16/17 pts. ~ith mean systolic and/or diastolic diurnal and/or nocturnal pressures higher tb~tn the upper limit of normal (90th percentile. Task Force, 1987) and a diurnal and /or not.turnal s)~olic and/or diastolic BP load > 40~ The mean s3~olic nocturnal drop was 8.8% and the mean diastolic nocturnal drop was 15.2%, End-organ dan~ge could be dcmoustratc~l in 8/17 pts, lack of ~'stolic and/or diastolic nocturnaJ BP drop re'aspresent in 6 of these children.This preliminaD' results suggest that ABPM can bc more dficient than traditionalo~cc BP measurements to evalnate anti~'pertensive therapy adequacy in children. ABPM data shov.'~da good correlation with end-organ damage. * Ser~fo de Ncfrnlogia Pedi:itriea do lnatituto da Crinn~ do HCFMUSP- $5o Paulo-Brasil **Liga de Hipcrleus~o Arterial da Disciplina dc Nefrologta do HCFMUSP

FC067

HYPERTENSION IN CHILDREN POST-HEMOLYTIC UREMIC SINDROME. ITS RELATION TO ESSENTIAL HYPERTENSION. B.Grunfeld*, M. Deregibus **. R.Simsolo*, M.Gimenez *, H.A. Repetto**. Hypertension is an important sequelae in 20% of children who had an Hermolytic Uremic Syndrome (HUS) in infancy. This hypertension has usually been related to chronic renal failure However, we studied 8 hypertensive post HUS patients (x=13 ys,r:7-18ys) with no proteinuria and normal serum creatinine and offspring of essential hypertensive parents (HF+). In order to elucidate wether hypertension was related to HUS or essential hypertension sodium transport system: Na:K cotransport (Co) Na.Li. counter transport (CTT), markers of essential hypertension were measured in red blood cell membranes. Data were compared to those of 13 normotensive post HUS children (x=11ys;r:4-15ys) (NF-)and 6 hypertensive post HUS patients(x=13 ys;r:8-17ys)(HF-) without a family history of hypertension. Data were analyzed with the Fisher Exact Test. All HF + patients had abnormalities in transport systems: 4 disminished Co and 4 increased CTT. 1 of 6 HF - had a diminished Co, and 3 of 13 NF-:I diminished Co and 2 increased CTT (p<0.002). Only 20% of children post HUS without family history of hypertension presented abnormalities in sodium transport system, In conclussion, abnormalities in sodium transport systems are significantly more frequent in children post HUS with family history of hypertension. Essential hypertension could account for hypertension in children post-HUS with no evidence of chronic nephropaty. * Hospital de Nifios R. Gutierrez. Buenos Aires. Argentina ** Hospital Posadas. Buenos Aires. Argentina.

C 53 FC068

FC069

A 10-12-YEAR FOLLOW-UP OF OPTIC FUNDUS IN CHILDREN AND ADOLESCENTS WITH ESSENTIAL HYPERTENSION A.Gregori~*, S.Jurinec-Va~da**, B.Gra~ner**

A M B U L A T O R Y BLOOD PRESSURE (ABP) IN HEALTHY CHILDREN AND ADOLESCENTS: A MULTICENTER TRIAL INCLUDING 1176 SUBJECTS. for the Arbeitsgruppe P~diatrische Hypertonie, Germany : M Soergel

The relationship hetween blood pressure elevation in childhood and target-organ complications occurring in adulthood remains largely unknown. The aim of our research was a longitudinal follow-up of optic fundus in children and adolescents (schoolchildren) with essential hypertension (EH). From 1978 to 1981 blood pressure was measured during regular systematic check-ups in 8583 children and adolescents of both sexes, aged from 7-19 years, using a mercury manometer according to recommedations of the 1977 Report of the Task Force on blood pressure control in children. 96(93%) schoolchildren in this study had EH. In all 96 schoolchildren with EH, fundoscopic examination was performe d according to adapted standard protocol (Keith, Wagener and Barker, 1939) by one of two experienced ophthalmologists. After the 10-12-year follow-up, 62(65%) out of 96 investigated individuals with EH came for a control check-up. They received no antihypertensive drug therapy. Among these 62 individuals 21 (34%) had hypertension, 29(47%) borderline hypertension and 12 (19%) normotension. In all 62 individuals the previously mentioned fundoscopic examination was performed. The 10-12-year follow-up of pathological retinal vascular changes in the optic fundi of schoolchildren with EH is given in the table: Number of individuals with pathological findings Optic fundus 0 years 10-12 years Grade i i (1%) 6 (10%) Grade 2 0 2 (3%) Grade 3 and 4 0 0 Conclusion: The results of our 10-12-year follow-up of optic fundus in children and adolescents with EH (without antihypertensive drug therapy) show a progression of pathological retinal vascular changes.

ABP monitoring is increasingly used to evaluate the blood pressure of children and adolescents. The upper normal ABP values in the pediatric age group are still unknown, since reference values based on a sufficiently high number of healthy children have not yet been published. In this multicenter trial, we pooled ABP records of 1176 healthy children and adolescents, aged 5 - 21 years with a body height between 120 and 180 cm. They were investigated by seven centers according to a common protocol. An oscillometric device (SpaceLabs 90207 or Meditech) was used in 1102 children and the auscultatory Medilog monitor in 74. The monitors were programmed to measure a blood pressure every 15 or 20 minutes during the daytime and every 30-50 minutes during the night. To rule out bias by individually different bed rest habits, we choose to analyze our data for standardized daytime (8.00 am - 8.00 pro) and nighttime (0.00 - 6.00 am) periods which hold true for the whole range of ages investigated. The 50th pc for daytime systolic ABP increased moderately with height, from 110 to 118 mmHg in girls and from 112 to 124 mmHg in boys. The 50th pc for diastolic daytime means was 72-74 mmHg, irrespective of height or sex, which is remarkably high compared to reference values for casual blood pressure (CBP). The 95th pc for systolic and diastolic ABP was 13-15 mmHg above the 50th pc for any height. The median nocturnal blood pressure de~'.reased by 13:L-6% and 23:~9 % of daytime means for systolic and ,.liastolic ABP, respectively. All nocturnal "clippings" were independent of age or height. This multicenter study provides well-based limits of normal ABP in the pediatric age group. Since there is a stnking difference between normal ABP and normal CBP in children, reference values for CBP should no longer be used to evaluate ABP measurements.

*Department of Paediatrics and **Department of Ophthalmology, Maribor Teaching Hospital, Maribor, Slovenia.

University Childrens Hospital, Deutschhausstr.12, Marburg (FRG)

FC070 A I T B I I A L HFP~iITB~WSIONI N C I l I L D I t ~ N - 81GNIPIC4NU~ O F ~NDOTIIB L I N A N D Na* - If' - ,4 TP -

A. PC'CO- Anal', M. Popovl~ - RoIovI~', D. NXSII~- Mit~ "e,

r AdmJs "', D. Topslov " " , M . Kosdl~ *, O. M m m i ~ ", V. Psdpovl~ *,0. Jovsnovl~ ", D. Klala~"

Concentmionof plasma endothelmand the a~dv~,yof Nd"-K'-ATP-ase weve determined in 3 different groups of cl~dren: the 1~ gro~ comprised 13 children csscutial hypcflensien, aged 12,9 +/- 4,8; the 2~ 16 ~ with venal but with preswced 81obalvenal function, abed 13,7 +/-2,8 and the e n d e d of 27 hcalthy children, agcd 11,6 +/- 6,.~ years. Plasma ondothelm c o n c e n t ~ were meam'cd by radioiw.amological method, using a set raem~cttwed by "Biomedica". The activity of Na*-K%ATP-ase was detonninod in etythrocyte hemolymc by m e m n ~ the quantity of released inorganic phosphate in samples with and without ouabaino. Concentr~on of plasma endothelin was not signiflcsutiy different between the clnldvenwith ~mial hypertension and healthy children ( 1.49 + 0.95 and I j 7 :f 0,98 vs. 2,08 4- 1,47; p > 0.05 ), and there was not "mni~mt conekdon between endothdin concenlrafion and blood presstwe in either of the 3 groups of 'investigated,r The activity of Na+-K+-ATP-ase was ~il~ficandy decreasedonly in the 1~*group of children(93,2 + 14,4 vs. 112,4 4.24,4;p <

0,01 ). There was no evidonce of corrcMion between the NI~K+-ATP-asc activity and blood pressure or plasma ondothelin, ncither in healthy, nor h

hyperten~vechild~ Convhnlon: Endothclln in blood circulation does not have any significance h vegulsfingblood pvesmve in henlthy childveo.It also does not have s dkect role inl the development of esscntiel and venal hypcrtcmion in cldldve~ The o c ~ y of Na*-K+-ATP-ase is decreased in children with essential hypmemion, but it seems that it has not a direct impact on hype/~qH/on. Endothe~ in circulation md Na+-K+-ATP-ase activity are not interdependant 9m k m ~

cM~m': R ~ .

~,mtv

~*Mmv Mm~s/Am~b~- ~/Em~, Fallav~

C 54 POSTER

SESSION

- (P) - R e n a l P h y s i o l o g y

P001 PROTEINURIA IN VERY LOW BIRTH WEIGHT INFANTS DURING TEICOPLANIN AND VANCOMYCIN PROPHYLAXIS FOR INFECTION M. Kirschstein, R. Jensen, I. Nelskamp, J. M611er Vancomycin (V) prophylaxis effectively reduces catheter related sepsis in very low birth weight infants (VLBW). Teicoplanin (T) presents itself as an altemative antibiotic for this indication. Both drugs are regarded as potentially nephrotoxic in older patients but little is known about their renal toxicity in VLBW, Concomitant to a prospective, randomized trial to evaluate the effectivness of V and T prophylaxis a comparative study of the nephrotoxicity of both antibiotics was performed by serially measuring urinary excretion of albumin (AIb), transferrin (Trf) and alpha-1 microglobulin (A1 M) by an immunoluminometric assay as well as s- and ucreatinine. V and T concentrations were also determined. Patients: 21 VLBW received T (5mg/kg/d) and 15 V (10mg/kg/d); median birth weigh t (1169 g), gestational age (29,1 wk), s-bilirubin and screatinine did not differ between both groups as well as treatment duration (T 10,9 d, V 12,5 d). Results: V and T effectively reduced infections in VLBW. Urinary protein/creatinine ratios did not differ significantly for Trf and A1M in all patients before and during the treatment period, only AIb excretion slowly decreased with maturation. No significant differences were found for any of the measured urinary proteins between both groups, but s-creatinine values differed significantly (T 60,5 pmol/I, V 84,4 pmol/I; p=0,002) during treatment. V and T are both equally effective in reducing catheter-related sepsis in the neonatal intensive care unit. Both antibiotics do not potentiate the per se existing physiological tubular proteinuria of preterm infants.

Med. University of LObeck, Dept. of Pediatrics, D-23538 LObeck, Germany

P002 INFLUENCE OF HEPARIN ON IL6 SYNTHESIS B Y RAT G L O M E R U L A R MESANGIAL CELLS N. Benador, C. Ruef, E. Girardin Interleukin 6 (IL6) is produced by mesangial cells (MC) and was shown to induce MC proliferation, acting as an autocrine growth factor. It is involved in the pathogenesis o f glomerulonephritis. Heparin is a known inhibitor of MC proliferation both in vitro and in vivo in a variety of experimental glomerulonephritis. It was shown to modulate extracellular matrix synthesis by cultured MC. Normal glomeruli contain mainly type IV collagen. Type I and III collagens are found in various forms ofglomerulonephritis. The action o f heparin on IL6 synthesis by MC is presently unknown. In order to investigate the effect of heparin on IL6 synthesis by MC and the role of coUagens type I and II[ in modulating IL6 secretion, MC were cultured with and without Vitrogel coating, a mixture of collagen I and III. Heparin was added at concentrations o f 0.5, 5 and 50 U/ml. In other experiments, TNF-ct, an inducer o f l L 6 secretion was added at concentrations o f 1 to 100 ng/ml in order to see ifVitrogel also had an influence when MC were stimulated to produce IL6. When MC were cultured without coating, heparin decreased IL6 production by 20.7%, 15.9% and 45.8% respectively at concentrations of 0.5, 5 and 50 U/ml (Friedman, p = 0.01). When MC were cultured on Vitrogel, heparin did not change their IL6 production (p = 0.72). When TNF-ct was added on MC, their IL6 secretion increased as expected (+75%, +113% and +1234% at concentrations of 1, 10 and 100 ng/ml) p < 0.001. When MC were cultured on Vitrogel, their IL6 secretion also increased with TNF-ct stimulation by +92.0%, +412.0% and + 1311% respectively at the same concentrations (p = 001). These data show that heparin decreases IL6 production by MC. Close contact between MC and collagen I and ItI abolishes this inhibitory effect but does not change TNF-ct induced ]L6 secretion. This indicates that the composition of the extracellular matrix influences MC function in vitro. D~partement de prdiatrie - H C U G - Gen~ve - Suisse

P003

Less anionic albumin in idiopathic nephrotic syndrome Hitoshi Mio*, Akiko Maruyama*, Keiji Doi*, Tuguo shibawaka*, Masaaki Ikoma*, Shigenobu Takayama**, Takashi Meguro** and Yasushi Koitabashi* The state of the electrical charge of serum and urinary albumin was investigated in both the nephrotic and remission stage of idiopathic nephrotie syndrome (INS), using isoelectric focushing (IEF). 1) Both a b2 band (a main albumin band appearing at the site of isoelectric point ; pl 4.7) and b3 band (a more anionic albumin band than b2 band) were detected commonly in all samples of urine and serum of INS patients in nephrotic and remission stage and of healthy volunteer controls even if the applied albumin in urine and serum amounted to 20 pg or 100 pg. 2) When applied aiubumin amounted to 20 pg, bl bands (less anionic albumin band) were detected between pl 4.7 and pl 8.5 in urine and in both serum and purified albumin fractionafed from serum of INS patients in nephrotic stage. However, bl bands were not detected at all in the urine and serum of either INS patients in remission stage and healthy volunteer controls. 3) when applied albumin amounted to 100/.tg, bl bands were detected also in serum of healthy volunteer controls. From these results, it was confirmed that less anionic albumin existed also in serum of healthy volunteer controls although the amount was extremely small. Moreover, it was suggested that less anionic albumin appeared in greator quantity in the serum of INS patients in nephrotic stage than in serum of healthy volunteer controls, and that this increased amount of less anionic albumin would leak more easily into urine through the anionic charge barrier of the glomerular basement membrane than the main albumin (b2 and b3 bands) would. "The Department of Pediatrics. St. Marianna Univ. School of Medicine, Kwasaki, Japan. **Division of Research Laboratory St.Mariannna Univ Yokohama- shi Seibu Hosp.

P004 ACUTE AND CHRONIC EFFECTS OF CISPLATIN TI-IERAPY ON RENAL MAGNESIUM HOMEOSTASIS G. Ariceta, J. Rodrfguez Soriano, A. Vallo, A. Navajas Although the acute effects of cisplatin on Mg metabolism has been well documented, longterm follow-up studies in cisplatin-treated children are scanty. We have evaluated the incidence of both acute and chronic nephrotoxicity in 22 cisplatin-treated children (median age 8 years). Acute effects. Plasma total Mg and altrafiltered Mg (UfMg) were significantly lower than values found by us in normal children: 1.51 +- 0.38 vs 1.70 + 0.15 mg/dl, p <0.001; 0.71 -+ 0.34 vs 1.18 + 0.10 mg/dl, p <0.05, respectively. A significant correlation was observed between cumulated dose of cisplatin and lowest value of plasma Mg observed after each therapy course (r = -0.66, p<0.001). Acute hypomagnesemia, secondary to renal Mg loss, was detected in 10 children and it was dose-dependent. Minimal and median cumulated doses inducing hypumagnesemia were 300 and 500 mg/m~, respectively. Chronic effects. 18 patients were studied 6 moths to 2 years after arrest of cisplatin therapy. Plasma Mg and UfMg were significantly lower than control values (1.51 _+0.21, p<0.001 and 1.02 + 0.16, p<0.01, respectively). FEMg persisted also moderately elevated (6.8 -+ 4.1%, p<0.05). No correlations could be established between plasma Mg and either the amount of cisplatin received or the time elapsed since its administration. In 6 patients (33%), significant hypomagnesemia was still present, with plasma Mg and UfMg values ranging between 1.0-1.4 and 0.7-1.1 mg/dl, respectively. Other renal abnormalities detected were moderate elevation of plasma Cr in 6 patients, hypokalemia in 1 patient and hypocalciuria in 5 patients. MgSO 4 infusion revealed low reabsorption rates of Mg in the 3 patients with more profound hypomagnesemia. During the infusion, rates of Ca excretion related to rates of Mg excretion were similar than in control children. We conclude that the functional characteristics of chronic cisplatin nephrotoxicity are not comparable to those present in Gitelman's syndrome as it has been previously reported. Deparlment of Pediatrics, Hospital de Cruces and Basque University School of Medicine, Bilbao, Spain.

C 55 P005 INTERACTION BEWTEEN NITRIC OXIDE AND RENAL SYMPATHETIC NERVES IN THE REGULATION OF RENAL HEMODYNAMICS IN THE DEVELOPING PIGLET. Solhaug MJ, Wallace MR, Adelman RA, Granger JP. Depts of Pediatrics and Physiology, Eastern Virginia Medical School, Norfolk, VA 23507, Dept of Physiology, Univ of Mississippi Med Ctr, Jackson, MS 39219. We have reported that intrarenal nitric oxide, NO, synthesis inhibition produces greater renal hemodynamic responses in the developing kidney. Intrarenal L-NAME decreases renal blood flow, RBF 29% in developing piglets (3 wks) compared to adult pigs, 9.5% (Solhaug, et al, Pediatr Res 34:750-754, 1993). These findings indicate that NO modulates highly activated vasoconstrictors in the developing kidney, such as the renal sympathetic nerves, RSN. To determine the importance of RSN in mediating the piglet's greater responses to L-NAME, these experiments measured the renal hemodynamic responses to intrarenal L-NAME, 3tag/kg/min, following RSN inhibition with intrarenal preinfusion of the adrenergic receptor inhibitor, phentolamine, 2p.g/kg/min (ARX), in piglets (3wks), n=4, and adult pigs, n=4. Intrarenal ARX produced significantly greater increases in RBF in piglets, 46.1%, than adult pigs, 13.2%. However, intrarenal ARX did not significantly alter the L-NAME reductions ira RBF in either piglets, 26%, or adult pigs, 7.3%. Glomerular filtration rate, GFR, and mean arterial pressure, MAP, did not significantly change with ARX or L-NAME in combination with ARX. Summary: Although RSN inhibition with intrarenal phentolamine, ARX, produces significantly greater increases in RBF in the developing piglet compared to the adult pig, ARX preinfusion does not alter the renal hemodynamic responses to intrarenal L-NAME. Conclusion: RSN may be a more important vasoconstrictor mechanism in the developing piglet than the adult pig, but the greater renal hemodynamic responses to intrarenal NO inhibition in the developing piglet are not due to an enhanced effect of RSN.

PO07 CELLULAR DISTRIBUTION OF BRADYKININ B2 RECEPTOR IN THE RAT KIDNEY: COLOCALISATIONWITH A BRADYKININANTAGONIST(HOE 140). CP. Vio*, V. Velarde*, W. MiJller-Ested** The B2-BK receptor has been identified in the kidney, its specific antagonist (HOE 140) has been extensively used to study the contribution of BK to renal function, however, its cellular distribution and fate within the kidney is unknown. The aim of the present work was to study the cellular distribution of HOE 140 in relation to the BK receptor Iocatisation; Mate SD rats (n=36) injected with HOE 140 (0.5mg/kg, iv) or saline were sacrificed 30 min, 1, 2, 4, and 6 hr. after. The kidneys were fixed and embedded in paraplast. Alternate serial sections were stained with antibodies against HOE 140 (As255) or with a mixture of 8 antibodies raised against peptides from intra and extracellular receptor domains. ~,t 30 minutes after the administration of HOE 140, proximal tubules lying in the cortex were more intensely stained against HOE 140 than juxtamedular ones. The staining was concentrated on the brush border on endosomes. Some distal and collecting tubules in the medullary rays were also stained. With time, the staining begun to disappear from the apical membrane and appeared on lysosornes and endosomes near the basal membrane of proximal tubules. Two hours after, a faint staining was still present on distal tubules and in medullary tubufes. Some scattered ceils from collecting tubutes were intensely stained until 4 hr. No staining was observed in saline treated rats. The BK receptor was found on distal or connecting tubules and in cortical and medullary collecting tubules. The staining was Iocalised on the apical and basal membranes and occasionally over the cell cytoplasm. A faint staining was also observed on glomeruli and blood vessels. The Iocalisation of HOE 140 on theS1 and $2 segments of the proximal tubules is consistent with the function of these segments on the absorption and metabolism of peptides. This process does not involve angiotensin converting enzyme since this enzyme it is Iocalised in a more distal segment ($3). The presence of HOE 140 in distal segments for 2-4h is consistent with the long lasting effect of the antagonist. The colocalisetion of both HOE 140 and the BK B2 receptor on distal tubutes and cotIecting tubules provides further evidence on the site of action of the BK antagonist. *Department of Physiology, Pontificia UniversJdad Cat61ica, Santiago, Chile. **Institute for Physiological Chemistry and Pathobiochemistry, University of Mainz, Germany.

PO06 PREDICTIVE VALUE OF RENAL RESERVE CAPACITY (RRC) FOR THE DEVELOPEMENT OF RENAL FUNCTION IN CHILDREN WITH RENAL SEQUELAE O. Amon, S. Uenzelmann, D. E. M~iller-Wiefel To evaluate the prognostic value of RRC we investigated this parameter in 12 children (mean age 11.3 yrs.) after hemolytic uremic syndrome (N = 8), acute postoperative renal failure (1), unilateral nephrectomy (1) and during chronic glomerulonephritis (2). The findings were compared with the alteration of spontaneous GFR according to Schwartz over a mean pedod of 20 (range 17 to 23) months. RRC was measured by the difference of a 3 hour baseline single injection inulin clearance (coefficient of correlation with Cr 51 EDTA clearance 0.80) and a consecutive GFR stimulated by an amino acid infusion of 0.75 g/kg. Mean baseline GFR was 142.8 _+ 32.6 ml/min/1.73m 2, mean stimulated GFR 178,5 +_ 36.0 ml/min/l.73m 2, resulting in a mean percentage of RRC of 27.2 _+20 %. The spontaneous GFR decreased from 117 to 112 ml/min/1.73m 2 resulting in a mean of - 5 (range - 26 to + 25) ml/min/1.73m 2. RRC significantly (p < 0.05) correlated (r = 0.61) with the change of spontaneous GFR in a way that a decrease of renal function could be expected if the RRC did not exceed 3 1 % (y = 0.78 x + 31). So for data suggest that RRC might be helpful in at least roughly predicting the course of renal function in children after acute renal failure or during an apparently stable nephropathy. To what extend RRC will be able to forecast the individual rate of deterioration of renal function has to be elaborated by further longitudinal studies. University Children's Hospital Hamburg, Martinistra~e 52, D - 20246 Hamburg, Germany

PO08 DIFFERENTIAL DISTRIBUTIONOF ANGIOTENSINI-CONVERTINGENZYME IN NORMALAND REMNANTRAT KIDNEYS. CP. Vio, L. Montero, MS. Loyola The Angiotensin I-Converting Enzyme (ACE) is expressed abundantly in renal tissue of most mammals with the notable exception of the rat, where its tissue levels are believed to be very low. Therefore the available data its Iocalisation in the rat kidney is scarce and controversial. Taking advantage of newly developed antibodies (Ab) raised against the C-terminal and N-terminal amino acid sequences of the enzyme, we re-examined its Iocalisation in normat and remnant rat kidneys. Renal tissue (n=16) from normal and remnant rats (5/6 nephrectomy) was immunostained by the PAP method with polyclonal Ab (1:500-1:2000) raised against the ACE C-terminal sequence (last 20 amino acids). The specificity of the antisera has been previously published (Sibony, Hypertension 21:827, 1993). Additional controls were made by staining lung, testis and jejunal rat tissue. In normal and remnant kidneys, the tubular structures containing ACE in the brush border corresponded to straight proximal ($3) segments of cortical nephrons and juxtamedultary nephrons lying in the outer medulla. No ACE was observed in other tubular structures of the cortex. ACE was more abundant in $3 proximal segment in remnant kidneys than normal kidneys. ACE was nearly absent from glomeruli or cortical peritubular capillaries in both models, being more concentrated in peritubular capillaries and vessels lying in the inner medulla. In remnant kidneys, ACE was consistenly observed also in peritubular fibrous tissue (stained positive with picrosidus red) associated to fibroblasts-like cells. The presence of ACE in medullary vessels contribute to explain the influence that converting enzyme inhibitors and kinins exerts on renal papillary circulation, and on sodium and water excretion. The presence of ACE in peritubular fibrous tissue from remnant kidneys suggests that ACE is inducible in the kidney interstitium, and may be the pathological basis for a deleterious role of ACE in renal disease through its local angiotensin II generation and bradykinin degradation. Furthermore, it provides the anatomical ground for the effectiveness of converting enzyme inhibifors in slowing the progression of renal fibrosis. De0artment of Phvsioloav, Pontificia Universidad Catolica, Santiago. Chile

C 56 P010

P009

SIGNIFICANT SEASONAL DIFFERENCES IN URINARY ALPHA 1-MICROGLOBULIN LEVELS IN MASS SCREENING K. Satomura* and T. Michigami* Alpha 1-microglobulin (AMG) is a useful marker of renal tubular dysfunction. In the course of feasibility study for renal tubular dysfunction screening, we discovered the seasonal differences in urinary AMG values. AMG levels were measured in 2467 urine samples which were sent for neuroblastoma screenIng from August in 1993 to September in 1994. The urinary levels of AMG were determined by latex agglutination. The data were expressed as AMG/urine creatinine ratio (AMG/Cr). The data were examined weather they were different in four seasons by one-way factorial ANOVA and multiple comparison tests. Significant differences between each groups except for spring vs. autumn were demonstrated. The differences may be accounted for by rapid degradation of urinary AMG in high temperature or seasonal variations of production and/or reabsorption of AMG in infants. Table 1

season

n

winter

949

AMG/Cr (mg/g Cr) 3.54-.+.0.08

spring

888

3.06,-0.08

summer

136

2.28-+0.15

autumn

510

2.78-+0.09

Values are expressed as mean_+SE *Department of Pediatrics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan

POll L-THYROXINE ('1'4) PROLONGS SURVIVALIN MURINE CONG~ClTAL POLYCYSTIC KIDNEY DISRASE. P.D. Acott*, C~I. Mahoney*, W.S. Furey*, A.T.J. McDonald*, J.F.S. Crocker*. Homozygous cpk/cpk mice, w h i c h are coisogenic with the C57BI/6J inbred strain, die with polycystic k i d n e y disease (PKD) in the first 3-5 w e e k s of life. We have previously reported triiodothyronine decreases incidence and severity of a similar cystic disease induced by parenteral glucocortieoids in newborn C57BI/6J mice. In the current study we address the affect of exogenous thyroid hormone on the survival of the cph/cpk mouse. An experimental and a control group, a total of 148 mice, were monitored e a c h day. The number of mice s u r v i v i n g in both groups was recorded and the kidneys from dead mice were r e m o v e d for histological study. Starting in the first postnatal week, 67 newborn pups (9 litters) of proven heterozygous (+/cpk) parents, w e r e administered daily, for 21 days, 100 pg/kg of T4 levothyroxine sodium (T4) suspended in 0.04 M sodium hydroxide. Seventeen of these w e r e later confirmed histologically to h a v e PKD. From the offspring of a pool of potential breeding pairs (a mixture of +/+ and +/cpk), 12 litters (82 mice) with at least one affected pup were identified as controls. O f t h e s e , 31 mice were later confirmed to h a v e PIG). Analysis w a s confined to mice with proven PKD. Kaplan-Meier survivor function estimates were calculated for graphical presentation. A log-rank test for comparison of c u r v e s estimated from a proportional hazards model for grouped survival time revealed a significant increase in survival for mice treated with T4 (g2= 5.832, pffi0.016). This study demonstrates that thyroid hormone prolongs survival in the cpk/cpk mouse. This is the opposite of the effect of glucocorticoids w h i c h aggravate cyst progression. Although all cpk/cpk mice h a v e identical genetic material, changes in the microe n v i r o n m e n t a l hormonal milieu can alter their life span. *IWK Children's Hospital and Dalhousie University, Halifax, Nova Scotia, Canada

CYTOKINE mRNA PROFILE FROM GLOMERULI IN THE RAT MODEL OF CHRONIC CATIONIC BOVINE SERUM ALBUMIN (cBSA) NEPHRITIS HK.Yap*, E.Firzli**, ES.Kamil**,AH.Cohen**, M.Toyoda**, SC.Jordan** We have previously shown that rats receiving cBSA injections daily for 6 weeks developed severe nephrotic syndrome with mixed mesangial and membranous lesions, which ultimately lead to glomerulosclerosis (GS) at 3 months. This study aimed at evaluating eytokine mRNA profiles at different stages of evolution of the nephritis. Male Sprague Dawley rats were preimmunizedwith either complete Freund's adjuvant (CFA) or 1 mg of cBSA (pI 8-9) in CFA, followingwhich the cBSA rats were injected with cBSA daily for 6 wks, cBSA rats were sacrificed at 2, 6 10 and 12 wks after onset of cBSA injections (n=3/group). CFA rats at 2 wks formed the control group (11=5). Glomemli were isolated from renal cortices by sieving, and RNA was extracted+ Cytokine mRNA expression was studied after RT-PCR. A cytokine index was derived from densitometrie readings: Ct = [X(~ple)/y(sample) ] + [X(stand~d~/y(standard) ] }hilin. Mean CI (SEM) are shown. where x=m Cytokine " Ctrl (CFtk) cBSA2wk cBSA6wk cBSA10wk cBSA12wk IL-13 0.45 (0.17) 6.30 (1.55) 0.36 (0.13) 0.46 (0.21) 0.14 (0.07) GRO 0.39 (0.13) 2.17 (0.32) 2.56 (1.55) 1.25 (0.18) 1.01 (0.21) IL-6 0.78 (0.18) 1.91 (0.39) 1.71 (0.38) 1.47 (0.23) 1.57 (0.39) TGF-[31 0.96 (0.17) 1.40 (0.40) 1.04 (0.07) 1.00 (0.18) 0.59 (0.12) TGF-[~2 0.62 (0.03) 0.98 (0.39) 0.63 (0.15) 0.56(0.07) 0.35 (0.05) TGF-133 0.56 (0.07) 0.88 (0.36) 0.86 (0.18) 2.09 (0.65) 1.36 (1.02) IGF-1 0.88 (0.23) 3.10(0.79) 2.58 (0.83) 2.11 (0.70) 1.74 (0.40) Significant differences between cBSA groups and CFA group in italics (p
In sum, GRO, IL-6, TGF-I31 and IGF-1 genes expressed early at 2 and 6 wks, and appeared to be associated with early events in the cBSA-induced immune injury, i.e. mesangial proliferation and matrix expression. IL-6, IGF-1 and TGF-133 gene transcription were present during the late stages of GS in this model, and may be important in the progression of the sclerotic process. IL-13 gene expressed only at 2 wks, and appeared to be important during the induction of immune injury, possibly related to its regulatory role on macrophages. Further work using cytokine inhibitors will be useful to delineate the roles of these cytokines in chronic cBSA nephritis. * Dept. of Pediatrics, National University of Singapore, Singapore. ** Depts. of Pediatrics and Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

P012

STUDY OF THE ACUTE EFFECTS OF PERITONEAL EFFLUENTS (PE) ON CULTURED MESOTHELIAL CELLS (MC). Several dam suggest that soluble factors present in PE during peritoneal infections can have potential cytotoxic effects ott peritoneal membrane even if their role during peritonitis and their potential eytotoxic effects are not yet fully clarified. The aim o f this study was to evaluate the acute effects o f PE on MC in culture. The PE were obtained both on stable conditions and during peritonitis episodes from children on CPD and immadiately centrifusated and filtered (0.2 u) in order to remove cells, MC cultures from omentum were maintained on 5% CO2 on M199 with 15% FCS, In addition to morphological aspects, vitality by trypan blen, cellular proliferation by H3-thymidine incorporation (TI) and expression o f extr~',~llular matrix (ECM) by SDS-Page o f collagens was evaltmted. It has been observed a morphological ( cellular stratification) and functional ( T I ) increase o f proliferation. The rr~ximal increase Of cell proliferation was induced by infected PE (+300%), whereas noninfected PE induced only minor increases. In addition also the ECM expression by MC in~ream~ with the greatest effects on interstitial collagens (+130% cell III, +80% cell I). These observations suggest that the stimulating activity on cell proliferation and ECM production by MC are induced by soluble factors present in infected PE. The long-term effects o f t h e s e substauces could play an important pathogenetic role in the development o f peritoneal fibrosis. M.L. Degl~nneecnti, P. Altieri, A. Trivelli, O.M. Ohiggcri, F Perfume, R Ousmano. Nephroiogy Dept., G Gaslini Children Hospital, Gealoa~Italy

C 57 P014

P013 ANALYSI~ OF T LYMPHOCYTE LINES OBTAINED FROM PERITONEAL EFFLUENT CEI.J..,SCULTURED WITH IL2.

MINIMAL LESION DISEASE AND LIPOXYGENASE METABOLITES OF ARACHIDONIC ACID S.Mir*. M.Kantar*. A. Cura*,I. ~oker*, AH,aseyinov *.

A high Imrcentagc (10-20%) of I' lymphoeytes with markers of activauon (HL class II:DR;IL2 rr is present in peritoneatl eflluen~s of patients on CPD. Iu order to better investigate their physiopathological role and the cruises of activation we have expanded activaIed T cr lines.The c~lls have been isolated from p~ritoneal emuents of 4 children on CPD and cultured with 11,2 (501U/ml) for 15 days. The . . . . Its are reported in the table: number of cells obtained from the effluent tmtbre (T1) and al~r (1"21 culture; surface markers (% of positive cells) at T1 and T2; cytotoxicity against HL60R cells,) positivity for two markers. Pts 1 4 2 3 Time T1 T2 T1 T2 T1 T2 T1 T2 CcllNrx 106 1 4.8 2.4 32,5 0.8 12 1 11 CD3 42 95 78 87 48 66 30 91 CD3/DR l1 90 27 88 2 5 11 82 DR 17 95 27 94 21 4 14 88 CD25 2 88 14 87 3 21 5 91 CIM 16 60 48 83 25 18 6 72 CD8 15 39 2 15 8 60 4 16 HL6ORcdls no no Commem: 1) cultures from pts 1,2 and 4 originated T lines actively proliferating (phcnotypr CD4+, DR+,CD25+, compatible with activamd T belpe0; 2) culture

.

from pt 3 originatedan expansion ot'CD8+ T cells(compatiblewith suppressor/ scytotoxicT); 3) lines I and 2 showed no toxicityagainstH L 6 0 R cells,suggesting that proliferationand activationof T is not an aspccificphenomenon linked to the culture with IL2 (LAK activity: lymphokinc-a~tivaled-killcr),but it represents the proliferation of T cells activated by, unknown antigenic stimuli in dxc peritoneum. In conclusion thrthcr studies on the characteristics of these T lines could better define the functions of peritoneal T cells and allow the identification of morphefunctional patterns that might predict the individual risk of itffe.r and peritone,a l sclerosis, G. Barbano ~ F. Cappa~ P. Facchetti*, F. Peffumo~ Pistoia*, A. Trivelli~ M.L. Dagl~mno~nti, R. Gusmano ~ Nephtology Dept and Ontology Lab., O. C-aslini CHildren Inst, Genoa, Italy

P015

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ht recent experimental studies lipid-derivated mediators of inflammation originated from the cell membrane known as leukotricns (LT) and hydroxTeicosatetraenoic acids (HETE) have been implicated to play an important role in the pathogenesis of glomcrular diseases. This study aimed to demonstrate the role of these mediators in the pathophysiology of MLD by detecting LTs and HETEs in biologic materials. The study included 9 patients ~ith MLD aged bemxen 3-I6 (3 girls and 6 boys), and age- and gender-matched control group cousisted of 8 children. The samples '~,ere taken in attack phase before instution of steroid treatment. The levels of peptide LTs (LTC4.LTD4.LTE4). uonpeptide chemotactic factor-LTB4, and HETEs (I5-HETE, 12HETE_ 5-HETE) were detected in the plasma and urine samples. The Ieukocy~.esisolated from peripheral blood were stimulated in vitro by Ca ionophore-A23187, and synthetic PAF ,ahich is also a potent inflammatory mediator, to release LTs and HETEs. Their levels xrere also investigated. The HPLC method was used to detect LT and HETE levels. Data received was sho'a~nin the table. Uioh)gic material l.l)lasma 2.Urine

Parameters Leukotriens C4 114 E4 Normal (-) (-) (-) I MH) (-) (-) 1.2 ]Nomaal (-) (-) 0.22 MLD 1.4 01 36 Normal (-) (-) (-) I MLD 2.8 0.0 3 2

I Groups

3.l,eukocyte culture+ PAF 4.Leukocyte cu ture+A23187 MLD

15.5 05

7.1

B4 (-) 074 (-) 12 (-) 9.5

IIETEs 15- 120-12 0-3.5 6.4 2.g 0-4 5 0-1.4 101 4 1 14 6 17.9 31.5 23,2

lg.1

27.7 20.3 43.5

50-10 g.7 0-80 13.2 20.4 42.1

AS seen in the table, endogenous LTs and HETEs were found in the plasma and urine samples of the children "r MLD. and in vitro stimulated leukomtes of these children have been observed to release LTs and HETEs. These results were considered as changes which might occur in the lipid structure of the cytoplasmic membrane of the leukocytes, in the membrane receptors and Ca channels, and during activit.v of the phospholipase enzyme in MLD. The determined endogenous LTs in the plasma, increased excretion of both LTs and HETEs in the urine, and in vitro high releasing activity of LTs and HETEs by stimulated leukocytes suggest the important role of these mediators in the pathophysioloD, of MLD. *Egc Univcrsity. Medical Faculty. Pediatric NephroloD'- [zmir-TURKEY

P016 NEONATAL BAR-rrER IN COSTA RICA. REPORT OF 19 CASES. G. MADRIGAL, P. SABORIO, ?. MORA

Nineteen patients with neonatal Bartter diagnosed durLng 22 years (1972-1994) have been reviewed. 17 were female and 2 were male. Diagnosis was made at ave 7 ~ 5 years, but symptomatology had started at 2 + 2 months. Gestatton wae complicated by hydramntos, and all-were deltvered prematurely (vest. ave 32.7 weeks). In 7/19 of bhe mothers there was a history of hydramntos in previous pregnanctes. Two female pts. had a stster with Bartter. Exclussion criteria: history of K or C1 G.I. losses, arterial hypertension, cystic fibrosts, use of diuretics, laxatives, steroids. Inclussion criteria: Bartter syndrome w/early presentatton plus a fractional distal solute reabsorptton (CH20 CH O+CLCL) of less of 0 65 under maximal water dturests induced 2 " by t/v infusion of 5% DW. Clinical features: a peculiar face (68%), slight to moderate mental retardation (80%) poltdtpsta, polyurs fever, dehydratton, faLlure to thr~ve, and normal blood pressure, (100%). Laboratory: hypochloremtc metabolic alkalosts, htpokalemia, hyperaldosterontsm, and N1. ~UN and serwn c~eattn~ne. (P~aema renan and urinary prostaglandins were not determtned). Urinary Ca/oreattntne was 0.48 + 0.33. Renal ultrasound: nephrocalctnosis tn 7/19. One female pt. whose sister has Ldenttcal disease, developed C.H.L at ave 16 years old and she was enrolled s the H.D. and transplanton program. Another pt. Was btopsted at ave 4 y/o because she was azotemtc initially, and revealed juxtaglomerular hyperplasta. All pts. were ststemattcally treated with KC~. To some of them aldactone o~ tndomethactn was added. All pts. showed improved activity, gained weight and grew up betwen 4,5em. to 11 cm. per year. However, none of them was able to recover thetr statural pretreatmed deftctt, and eerum K was never normal. Conelusione: Z) Neonatal Barrier in Costa Rtea has an tnctdence of 1.2 aaees per 100.000 deItvertes per year. However, Lf we only take the preterm deliveries, the ~nctdence ts 25.4 cases per 100. 000 deliveries. 2) The overwhelming predominance of dLsease tn female~ts, and its presence tn a second female pt. within the same yamtly, and also perhaps there pecultar fa-

INFLUENCE OF P A R A T H Y R O I D H O R M O N E O N R E N A L FUNCTION OF RATS TREATED WITH G E N T A M I C I N R.Q.Glashan, V.L.Costa Silva, F.Zaladak Gil

The objetive of this study was to evaluate the effects of thyrolmrathymidectcmy (TPTX) on mini function ofrats tnmted during 10 day~ with 4mg/k#day and 40 mR&g/day doses of gentamicin. In normal acid base steady state, both doses of gcntamiein causod significantly lower 81omcmlar filtration rate (OFR) and urine/plasma (U/Pinulin) compar(~ with control group, GFR (O4:5.86 + 0.11; G 4 0 : 4 . 9 4 + 0.25 vs 7.17 • 0.42 in C) and U/P inulin ((34:39,17 + 1.21; (}40: 30.24 9 0.55 vs 52.93 • 2.09 in C) which suggesta an imixa-tant imtmirnamt of function and ~ r mcohanisrms. Motabolic acidosis induction did not secta to h a w further impaired nmal futmtion as (xantmmd with non acidotic httermates. Thyroparathyroid~tomy (TPTX) ~ low~ OFR (C: 19.97 • 1.87; TPTX: 13.93 • 0.53) and U/P ratio (C: 52.93 4- 2.09; TPTX: 32.46 + 2.51) ~ r with control group, which shows a n imtxa'tant role of parathommm (FrH) on rmal har High doses of

gentamicin aad TPTX actin8 together trader normal acid ba,m condition caused serious impairmma of GFR (3.17 • 0.1 O) and U/P inulin ratio (20.75 • 1.561 as c o m p a r ~ with animals treated with only either antibiotic or tl~ TPTX, which suggests additive effects. Acid balance (BH) was redlmed after

T P T X (2.75 • 0A5 vs 6.34 • 0.14 in C). Under m~labolic acidosis this disturbance was more evident (8.01 • 0.60 in A T P T X vs 23.79 :i:1.44 in AC). Gentamicin treatment caused strong decrease in B H under acid ox~,~rload(AO4: 9.41 • 0.35; AO40:12.84 • 0.93 vs 23.79 + 1.44 in AC), re,stiltwhich agree with the literature. Under normal acid b a ~ condifiom, 8ontamicin and TPTX acting together showed impalrrmnt o f B H (TVI~: 2.75 4- 0.15, TlrrXG4 : 2.75 • 0.21, T P T X G 4 0 : 2 . 1 1 • 0.34 vs 6.34 • 0.14 in C). During motabolic acidosis, B H calculated per m l o f GFR was equally deer(rased in ATPTX, ATPTX (34 and ATPTXG40, when c o m l m r ~ to data of AC group, which shows the importmme of PTH upon r e m l acid excretion,

Degmt~ent of Physiology - Eseola Pauliata de Medicine - Sic Paulo - Bmail Suot~rted lay FAPESP and C N P q

C 58 P018

1'017 PTH AND CALCIUM - EFFECT ON URINARY ACIDIFICATION. F 7-qlmtlekOil, V.L.Coeta Silva, G.Malnic In im~6otw i n ~ a i ~ l i ~ it was found that rats depleted in parathyroid hrmnr~. (TFrx mrs) had reduced rates of pltoximal b i b l e r ~ l ~ q ~ o n intl"gead~ on blood calcium level. [Clin. Sei.(1992) 83, 711-715]. In the ~

'WOl'k, the ro~ of caleillm (C&2+) in ra~ ~r

tllbBle8

bieatbo~e reabeorption was studied by/n v~o stationary m i ~ i ~ withbi~te P..iaset solutitms mad d~mmin,~tion of lum~ pI-I Tubules were ~ at ~ l,ma,m Ca2+concentrations in the presea~ sad of the ealc~tma ionopho~ A23187. B i O t a roabsorption was not affcet~ by C ~ + in the raase of 0 to I raM, but was signifiumtly ns:hced when 0.5 mM EGTA was added to the 0 Ca2+ peffusal~ i n d i e a ~ that o~y at very low hw.inA] Ca2+ level., bieazbo~te mabaa~fion (= H+~m~fion) waa impain~l. After addition of A23187 to the I.mlrdl solution, bieeflx~te reabsorption was si~ifleently aegmmted when the l~fesion solution contained 0.1 mM Ca2+, less with 0.5 m_M Ca2+ and w u not altered with lmM Ca2+. These obeervatiom indieale that Ca2+ in the tubele kmaen is important for the ,';m,i.tm,-,,.,.v~ of normal imy,tlr~l bicatbomte (H+) tmmtx~ but that low ~ Ca2+ level, to ~ this transport ll~r were achieved om'y in the ~ e ~ n e e of EGTA. ~ t of l~ysiolosy - Eseol" Paulista de Medieina and Univetsidade de Sao Paulo, Branil

Supportedby FAPF_~ and CNPq

ALTERED SODIUM-LITHIUM COUNTERTRANSPORT, RENAL EXCRETION OF PROSTANOIDS AND ENDOTHELIN IN CYSTIC FIBROSIS Tulassay T, Luczay A, Dobos M, Holics K,* Ujhelyi R,* M~ittyus I, Seyberth HW, **

To characterize the alterations in sodium metabolism in cystic fibrosis regulatory mechanisms of sodium homeostasis were studied in 13 children and adolescents. Being on normal sodium diet, CF patients had normal concentrations of plasma electrolytes. Renal tubular handling of sodium and potassium characterized by the fractional excretions, as well as intracellular sodium content were within the physiological range. Red cell's sodiumdithium countertransport activity was elevated in CF patients when compared to healthy children (381_+106 iJmol/hour/L RBC's vs 281_+64; p
1'019

P020

NON-ENZYMATICALLY

configurated)

GLYCATED

ENHANCES NITRIC

ALBUMIN

OXIDE (NO)

(Amadori SYNTHASE

ACTIVITY IN CULTURED ENDOTHELIAL CELLS,

*A Amore, *P Cirina, *S Mitola, * B Gianoglio, #1 Rabbone, #F Cerutti, "C Grillo and

R Coppo

It has been recently suggested that the link between hyperglycemia and the pathogenesis of diabetic nephropathy is represented by non-enzymatically glycated proteins. High glucose concentrations are known to affect several mesangial and endothelial cell (EC) functions some of them, including mesangial cell proliferation and matrix synthesis, through Amadori reaction modified glycated albumin. I Since hyperfiltration is considered the initial pathogenetical mechanism ;in the development of diabetic nephropathy and NO is a powerful ;vasodilating mediator, we investigated the modulation of EC NO synthase (NOS) activity by non-enzymatically glycated albumin (GlycA) compared to normal albumin (A) at 3.5g/dl (mimicking maximal serum albumin :concentration) and 1.7 g/dl. Moreover, 0.005 M aminoguanidine (AMG), a ifunctional inhibitor of glycosylated molecules, or bacterial lyposaccharyde Iwere added as negative and positive controls respectively. NOS activity was measured as production of H3 citruliine from H3 arginine. In addition the specific mRNA for inducible (i) NOS was evaluated by PCR. Mean results of NOS activity expressed as fold increase in comparison to basal values were: Solution NOS activity Solution NOS activitv GlycA 3.5 g/dl 16.4 A 3.5 g/dl 1.9 GlycA1.7 g/dl 4.6 A 1.7 g/dl 1.7 LPS 22.3 LPS+AMG 12.2 GA 3.5 g/I +AMG 8 AMG 1 The mRNA encoding for iNOS was highly expressed in EC incubated with GlycA. In conclusion, NOS activity of cultured EC was enhanced by non-enzymatically glycated albumin: this phenomenon might play a role in the hyperfiltration and microvasculature damage of diabetic nephropathy. *Nephrology and Dialysis, #Pediatric Clinic, ~ Margherita Children's Hospital Tonno, Italy.

Regina

RENAL FUNCTION IN CHILDREN WITH SICKLE CELL ANEMIA R. Campos*,D. Ortega*,E. Barillas*,N. Caviedes*, L. Tortes*, A. Bercowsky*,E. Bercowsky*,R. Medrano*, G. Torres*. Several alterations of renal functions have been described in patients with sickle cell anemia. In order to evaluate this situation, 21 children(13 males) aged 2-13 years(X=5.5• with the disease,were selected; 76.1% were heterozygous. Microhematuria was present in 20% of patients. These are the results: Homozygous Heterozygous 7.3+0.1 Hemoglobin(gr/dl) 10.74• 89.09+37.8 Creat. Cl.(ml/min/173M2SC) 144.9• Urinary Osmolality 378• (m0sm/kg. H20) 472• 5.5• pHur 5.4• 79.1• UVH (~Eq/min/l.73M2SC) 89.7• 19.8• U-Bp CO~(mm Hg) 21• Maximun urinary concentration capacity was below normal values in both groups, but urinary acidification was normal. It is important to note that creatinine clearance l~cks above normal in the heterozygous group (hyperfiltration?).In conclusion,children with sickle cell anemia,especially the heterozygous group may present hyperfiltration with the consecuences this situation might represent for the future of the renal funtcion.

* Hospital General del Oeste. Caracas.Venezuela

C 59 P022

P021 R E T I N O L B I N D I N G P R O T E I N (RBP) C O N C E N T R A T I O N IN A M N I O T I C F L U I D D U R I N G THE EARLY STAGE OF G E S T A T I O N . Fanos V*, Mussap M ~ Khoory BJ*, Plebani M ~ Padovani E.M.*, Amniotic fluid consists of many substances, fetal urine being one of its main components. Retino] binding protein (RBP) is a low molecular mass protein of 21,000 Dalton; the free RBP molecule is rapidly filtered by the glomerulus and catabolized in the renal tubules after reabsorption by the proximal tubular ceils. We measured RBP in two groups of amniotic fluid samples, obtained from 58 healthy pregnant women by transabdominal amniocenteses between the 14th and the 19th week of gestation. In group A (n=28), fetal cariotype was found normal (46xx or 46xy), while in group B (n=30), fetal chromosomic abnormalities and/or abnormal cariotype were demonstrated. RBP levels were compared with those of ct Imicrog/ob~lin (al-m) and with N-acetyI-~-D-glucosaminidase (NAG) activity, in order to establish the amount of RBP in amniotic fluid and its clinical utility for the evaluation of renal development and maturation in the early stages of gestation. Results were optimized to creatinine amniotic fluid concentration; they are listed in table. GROUP A

GROUP B

x+_SD

xJ=S D

r a_..Zza_nZ.~__

pH Osmotic concentration (mOsm/L)

8.01_+0.45

Ctl-m (mg/mmol Creatinine) NAG (Ulmmol Creatinine)

RhGH improves growth in renal disease; it has been suggested that this is due to an increase in the ratio of IGF-I to its main binding protein, IGFBP3. In pregnancy, IGFBP3 undergoes proteolysis, so increasing the availability of IGF-I. We hypothesized that IGFBP3 protease activity may be increased in renal disease, and that the anabolic effects of rhGH might include both a relative increase in the ratio of IGF-I to IGFBP3 and a reduction in protease activity, RhGH was given for I year, at a dose of liu/kg/week. 19 children with chronic renal failure (CRF) and 17 with renal transplants (RT) were studied. CRF: i mean (SD) age 8.8(2.8) (yrs), GFR 20(13)(mls/min/1,73m2), HtSDS -3.1(0.7) and! height velocity (HV) 4.8(1.5) cm/yr. RT: age 13.1(2.2), GFR 52(28), HtSDS -2.9(0.8) and HV 4.0(1.7) and prednisolone 8.8(3.6) mg/m=/alternate days. HV on rhGH increased to 9.5(2.3) in CRF and 8.8(2.8) in RT.

8.31-.+.0.33

(7.5-9.7)

(7.6-8.8)

285_+6.4

27/+16.1

(275-299) RBP (mg/mmol Creatinine)

INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN3 PROTEASE ACTIVITY IN RENAL DISEASE BEFORE AND AFTER RECOMBINANT HUMAN GROWTH HORMONE (RHGH) TREATMENT *H Maxwell, J Jones, L Rees, A Flyvbjerg.

(207-285)

86.6_+22.15

82.1+19.4

(61.2-158.6)

(57.0-126.9)

624_+159

641_+144

(382.980)

(337-859)

58.0_+16.7

50.5_+24.4

24,4-134,6 No statistically significant differences were found between group A and B for each biochemical substance, suggesting that RBP as well as ctl-m and NAG may be used as early markers of renal tubular impairment during pregnancy, as described elsewhere(0. REFERENCE 1. Padovani EM, Fanos V, Mussap M, Plebani M, Budina A. Tubular proteins and enzyme content in the amniotic fluid. Eur J Obstet Gynecol Reprod Biol 1994;55:129-33 * Pediatrics Department, Neonatal Intensive Care Unit, University of Verona ~ Department of Laboratory Medicine, Central Laboratory, University of Padova "~Center of Biomedical Research, Castelfranco Veneto (TV), University of Padova

P023 INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 3 (IGFBP3) IN RENAL DISEASE: THE EFFECTS OF RECOMBINANT HUMAN GROWTH HORMONE * H. Maxwell, J Jones, L.Rees, A Flyvbjerg Poor growth can be a problem in renal disease; elevated levels of IGFBP3 are thought to interfere with the action of IGF-I. We have measured IGFBP3 by RIA, Western ligand blot (WLB) and Westem immunoblot in short children with chronic renal failure (CRF) and renal transplants (RT) before and after I year of rhGH. Patients: 17 children (3 gids) with CRF: mean (SD) age 8.7(3.1)yrs; GFR 20

(13)mls/min/1.73m2; HtSDS -2.8(0.6); and 16 with RT (4 gids): age 13.1(2.2); GFR 52(28); HtSDS -3.0(0.8); prednisolone 9.9(2.8) mg/m2/alternate days. Results: Height velocity increased from 4.8(1.5) to 10.0(2.0)* cm/yr in CRF and

from 3.6(1.7) to 8.8(2.6)* in RT. CRF RT Day1 1Yr Day1 f Yr IGF-I (ng/ml) 148 (82) 362 (217)* 255 (64) 696 (168)* IGFBP3 (mg/l) 3.8 (0.7 6.5 (1.8)* 4.0 (I,0) 5.5 (1.3)** IGFBP30NLB)#102 (74) 183 (93) 56 (45) 168 (86)* * p < 0.001, ** p <0.01 versus day1. # measured in arbitrary absorption units. IGFBP3 in RT was lower by WLB than RIA. WLB measures only intact IGFBP3, whereas RIA also measures fragments. Western immunoblot gives a quantitative assessment of IGFBP3 fragments: CRF (n=6); 46(13)% was present as intact IGFBP3; 48(12)% as a 30 kDa fragment; 6(4)% as smaller fragments. This was no different from controls, RT (n=6): 30(10)% as intact IGFBP3; 62(9)% as 30kDa (p = 0.07 v CRF), 8(3)% small fragments. The trend for an increase in fragments in RT provides an explanation for the discrepant RIA and WLB results. RhGH did no1 significantly alter the pattern of IGFBP3 fragments. Conclusion: IGF-I is normal in CRF and RT; IGFBP3 is at the upper limit of normal. IGFBP3 increases with rhGH treatment, but there is a proportionally greater increase in IGF-I. The pattern of IGFBP3 fragments in CRF was no different from controls, but surprisingly there was a trend for a higher proportion o1 fragments in RT, the cause and significance of which is unclear. *Paediatric Nephrology, Royal Free Hospital, London UK.

IGF-ISDS IGFBP3 SDS day1 6ruth lyr day1 6ruth lyr CRF-1.1(1.9) 3.6(3.0) 3.6(2,9) 0,4(0.8) 3.1(1,4) 3.8(2.6) RT-1.1(2.0) 6.7(4,3) 5,5(3.0) 0.3(0.9) 2.0(1,5) 2.5(1.2) HV, IGF-I, IGFBP3; all 6ruth & 1 yr values in CRF & RT, p
P024

ANGIOTENSIN II (ANG ]I) UPREGULATES AQP-CHIP PROTEIN AND mRNA EXPRESSION IN I M M O R T A L I Z E D , TRANSFORMED RAT PROXIMAL TUBULE CELLS (IRPTC) IN A TIME DEPENDENT MANNER. Flavia F. Jung*, Shiow-Shih Tang*, Ivan Sabolic**, Jean-Marc Verbavatz***, Daniel Diamant*, Dennis Brown*, and Julie R. Ingelfinger*, AQP-CHIP is a membrane protein identified as a water channel in red blood cells and in renal proximal tubule (PT) and descending loop of Henle. Immunofluorescence technique has demonstrated AQP-CHIP in both brush border and basolateral membranes of PT. As Ang II is involved in a biphasic manner in water and solute reabsorption in PT, we sought to explore Ang II effects on AQPCHIP. We previously reported 2 immortalized PT cell lines (AJP 268: F435-446 1995 and Exp Nephrol 2: 127, 1994) one of which is transformed with temperature-sensitive SV40, the other, with origindefective SV40. IRPTC were first examined for AQP-CHIP; both lines express AQP-CHIP mRNA and protein in a stable manner at baseline. We then examined the effect of Ang II on AQP-CHIP mRNA and protein expression. After both 6 and 12 h exposure, Ang II (10 -9 to 10-7 M) increased AQP- mRNA in a dose dependent manner. After 24-h exposure, AQP-CHIP mRNA levels appeared to be down-regulated. This effect may be receptor mediated, as Ang II effect on AQP-CHIP mRNA expression was blocked by the selective AT1 receptor antagonist losartan (10-5M). Western blotting demonstrated that AQP-CHIP protein however increased after t h Ang II 10-8 M stimulation and decreased after 6 and 12h Ang II stimulation Taken together, these data suggest that Ang II upregulates AQPCHIP in a dose- and time-dependent manner, mediated via AT1 receptors in IRPTC. * Massachusetts General Hospital and Harvard Medical School, Boston, MA. ** Institute for Medical Research, Zagreb, Croatia *** C.E. de Saclay- Gif-sur-Yvette, France

C 60 POSTER

SESSION

-

OP) -

Glomerulonephritis

P025

P026 THE ACUTE PROLit:ER~TIVE POSTSTREPTOCOr~,CAL GLOMERULONEPRRmS ONILATERAL RENAL AGENE~I~ - J . K l ~ z ~ m ~ . u m *, G, B d l r ~ o n a

PROSPECTVE STUDY ON THE LONG -TERM PROGNOSIS OF POSTSTREPTOCOCCAL ACUTE GLOMERULONEPHRITIS IN JAPANESE CHILDREN M.Tsuchlya, N.Tatsuma, H.Taugu, K.Ambo, E.Munaksta, M . M u r a k a m l , H.Yamamoto

IN

The frlgl~lJ~O~r Of tmllateral r~qaal @~t~esis in lhe gen~'~l gogulation ~ 1 e ~ h BOO people, Since the beglnnlng of the re~al uhraeo~gral)hy, is m u c h more fre~.l~nlt the fir~ Of unJ~lef~l r ~ l a{l~lssls, w40h ldl US ~ [ ~ r ~ ll~ t ~ n orthodcr svdiuIJonof sorn~ frecuent d~eaeee tn Pediatrics as the ASPGN,

Our~g19•1,

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

from a total of 1873 d ~ e ~ nletonm of the P~islriO S~vi~ "C' of the

Pet~ra f ~ | Hos=tdi, were find 16 cas~ of A~i~GN. that m e a ~ 0.9%, Clurm3lj many year~, we haws fred only 3 o~e~ of ASP(~ in unilateral rlmdi ~ l m t l ~ ~r~ s ~ w~ did no~ lind ar~ bibllo~'aghi~ ~ e f l w ~ e ~ on this ~ubll~l. we d ~ i d e d to inve~ t~gate. Petient ~ 1 was inid~l;y in the pr~-uhr~or~l~ratdw era. II vr ~n eigth years d d oi~ld, with r~ora~ of a ;~-e~o~ bad treat~ angina, wioh oonsuhvd b e e l i n e of a ~ p i e t e n~hr al s y n d r ~ s with a rr~eelve protelnuda ~1dO,j1 The olinldal and =~oohernl~ oontrol~ v~re normal 3 month~ aft~r the beglnnlng, finding ~ yeae I~tl~ thrOLlOh ,~trasono~raDhv a r~n~ ag~ru~la on the right side, like one of hie ~as~srs ~a1~nt # 2. a two ve~m o~d chad. w ~ Ixeeent~d as a~ im~ure evn~rome neoP-t,mo~: m~B~ve g r o l ~ u r i a , a z o t e ~ a , hitch levdi of rxeatinthe and ~n A~O of 15OO Todd uni~, These svnthoms were n~rma~iz~l in an adeouate p ~ o d . ThroLRh the u~tra~o~ra~hu urogra~hy ~nd r:~diosotoP~6 61Udlm was find a Fens agene~a on the r~h! e~al, F~t~enl Nf.3 was a 13 y~a~ old boy, with reoords of a ~evi~,,~ angina a~d ~ r e d ~ of a ~omglete n e ~ h n t i ~ syndrome w d h a ~ a t oardlovasc~uisr r~ecot~elor~ The d i ~ o ~ B Was oonfirn'~d "~th a~ A~O+ ourve and an oorn~l~n~nt ~ 3 , whioh normahzed in t t ~ adequate oer~od~. To control de e ~ e r e hYp~tt~miol~ r'~3~6~ry the UBe Of Camogril. The d t r a s o n ~ l r ~ h v showed a renal ager~l~l on the r~r,~ side. W~ rs~lZ~ thal 11"11913umber of D3tierlt@ ~tud~ed iS ~tl~ lOW, wh~oh do nO[ ~lOW LI~ I0 m~ke vadid 81at~tmdi r but d ~ p i t e thle faint ~ n ~ the o m m pre~nted ~ o w o d lrr~ort~nt alt~rallone ( ~ l v e grot~uriae, l ~ h levele of artelddi ~reeeure, el~) ~lth ren~ ~ we etate the hypoth~is that th~ a~atomloal taot ha~ oa~udi r~atio~ with the d~ioal eYnthon~. We e~lf~k~ the i ~ r t ~ of the r~n~l u h r ~ m o g r ~ o h y when 8tudvinq the Dali~r with A ~ G N , Since IS ~ hermlee~ ~ a m ~,nd ~rve irw~ort~t informatir, n about t h ~ ~obt~m,

Objective: A proapective study was performed to investigate the longterm prognosis of poststraptococcal acute glomsrulonephritis (PSAGN) in Japanese children. Subjects and methods: The subjects were 65 children ( 44 boys and 21 girls ) examined at the Department of Pediatrics of Nippon Medical School in the 10-years period between 1976 and 1985 and diagnos~r as having PSAGN using estabfished diagnostic criteria. The age of the subjects at the time of onset was 3- 16 years ( mean:7.0 years ), and all subjects were hospitalized in the initial stage. A questionnaire survey on the results of urinalysis in 1985, 1990, and 1994 was done by mail, and the long-term prognosis was evaluated. Results: Within one year of onset, urinary abnormalities had resolved in 60 out of 65 patients ( 92.3% ). In the survey performed in 1985 more than 2 years after the onset, th e urinary findings hadbecome normal in 64 patients ( 98.5% ). In the 1990 survey, replies were obtained from 58 out of 65 subjects, and none of the respondents had any urinary abnormalities. In the 1994 questionnaire survey ( age range of subjects: 13-30 years [ mean : 2 I. 3 years ], follow-up period; 7- 18 years [ mean: 13.5 years ] ), replies were obtained from 57 out of 65 patients, and none of the respondents showed any urinary abnormalities. Conclusion: Tha prognosis of PSAGN was good in Japanese children followed to after puberty. Growth appeared to be unaffected.

~l~dt3trlo C~n~oI~ pSre~r3 I ~ d i l Ho~pltaI-Mvdeo, Uruguay,

Department of Pediatrics-Noppon Medical School-Tokyo-Japan

P027

MYCOPLASMAPNEUMONIAEASSOCIATED NEPHRITIS IN CHILDREN MH Said, MP Layani, S Colon, G Faraj, A Mahmoud, P Cochat Unit6 de Ndphrologie Ptdiatriqur htpital E Herriot, Lyon, France

Mycoplasma pneumoniae (Mp) infection is rarely considered as a cause of acute glomerulonephritis (GN). Six children (3 girls, aged 5 tol0 years), presented concomitantly with renal involvement and IMp infection. The diagnosis of Mp infection was done by serology: IgM on immunofiuorescence (IF) (n=l) and ELISA (n=5). Four children had a renal biopsy (light and electron microscopy + IF). The search for Mp components in the renal parenchyma included indirect IF (rabbit anti-Mp antibodies + rabbit anti-IgG antiserum produced in the goat) and gene amplification (Polymerase Chain Reaction). The extra-renal manifestations were respiratory (n=3), ENT (n=2), digestive (n=3), hepatic (n=l), neurologic (n=l), articular (n=l) and hematologic (n=l). Five patients presented with acute nephritis (one had a nephrotie range proteinuria) and one had an acute renal failure with hematuria and proteinuria. The pathological findings were as follow: type 1 membranoproliferative GN (n= 1), proliferative endocapillary GN (n=2), minimal change disease with mild deposits (n=l). The patient with type 1 membranoproliferative GN progressed rapidly to ESRF probably because of an associated congenital solitary kidney, one of the 2 children with endocapillary GN relapsed 6 months later and remained proteinuric, while the other one as well as the child with minimal change disease recovered completely. In the 4 patients with kidney biopsy, the search for Mp antigens and nucleic acid were negative on renal tissue. In conclusion, such as for most post-infectious glomerulonephritis with immunological support - e.g. streptococcus - , we found no direct evidence of Mycoplasma pneumoniae in the kidney. However, this does not rule out the role of Mycoplasma pneumoniae in some cases of post infectious acute renal syndromes.

P028 H E N O C H - S C H O E N L E I N SYNDROME A T H I G H A L T I T U D E A R E A E X P E R I E N C E FROM S O U T H E R N P A R T OF B A U D I A R A B I A .

Naffaa N. A1 Harbi, Assistant Professor, Department of Child Health, College of Medicine, King Saud University, PO Box 641, Abha, Saudi Arabia ABSTRACT

This is a retrospective study of 55 children admitted to A s s i r Central Hospital, in a high altitude area in southern part of Saudi Arabia w i t h i n the last 6 years (September 1988 - September 1994) with H e n o c h - S c h o e n l e i n syndrome (HSS). Of the 55 children 29 were girls and 26 were boys with the ratio of i.i:i. The age ranged from 8 month to 18 years with a m e a n of 8 years,73% of our patients were older than 5 years at initial presentation. Most of the cases occurred between July and January. 100% had the typical rash, 78% had abdominal pain on presentation with significant GI bleed in 11%. 76% had joints pain or discomfort, 20% had n e p h r i t i s or nephrotic syndrome, of these 55% had nephrotic range proteinuria on presentation. R e c u r r e n c e occurred in 7 children (13%); only 2 w i t h renal manifestation, renal i n s u f f i c i e n c y and nephrotic range proteinuria. So it was concluded that in high altitude area HSS affect older patients than usual (73% older than 5 years) w i t h less renal involvement.

C 61 P030

P029 HEMOLYTIC-UREMIC

SYNDROME

IN SAUDI C H I L D R E N

N a f f a a N. A1 Harbi, M.E. EiAwad and M. A1 Homrani D e p a r t m e n t of Child H e a l t h and M e d i c i n e College of Medicine, King Saud U n i v e r s i t y PO Box 641, A b h a Saudi A r a b i a

ABSTRACT. Twenty four patients with typioal post d i a r r h o e a h e m o l y t i o - u r e m i c syndrome (H.U.S) w e r e seen in A s i r Central Hospital (ACH) b e t w e e n J a n u a r y 1989 and D e o e m b e r 1994. of the 24 p a t i e n t s 15 w e r e boys and 9 girls with sex ratio 1.7=1. Ages ranged from 7 month to 11 years with a mean of 38 months. Clustering of oases w e r e during spring and summer time. Shigella dysentery was isolated from stool in 5 patients. Complloations occurred in 9 patients (38%). 8 had C.N.S. c o m p l i c a t i o n (33%), 5 of those (21%) had g e n e r a l i s e d seizures during the acute phase of the disease, 3 (12.5%) had oortical blindness, 1 p a t i e n t (4%) had d e p r e s s e d level of c o n s c i o u s n e s s only and 1 (4%) died after she had seizure and deep coma. One patient left with chronic renal failure. In comparing patients with and without complications, patient with complioatlons were y o u n g e r at p r e s e n t a t i o n (30 m o n t h Vs 43 months), had lower platelet count and higher w h i t e cell count but the d i f f e r e n c e did not reach statistical significance.

URATE METABOLISM DISORDERS IN IgA NEPHROPATHY Z.Konopielko, J.Zawadzki, A.Wieteska-Klimczak, T.Wyszy6ska Clinical data indicate that uric acid metabolism is disturbed dudng exacerbations of IgA nephropathy. Some aspects of this metabolism were studied in 10 patients aged 5-18 years with IgA nephropathy during exacerbation (I) and remission (11).All of the patients were on a low pudne diet. The results are summarized in the table. It should be added that all of the children experienced abdominal pain, urinary tract infections and urinar ~H below 6. Six of them formed udna~ tract stones. Clearance UAs UA u FEuA UA I creatinine I

rag%

mq/kq/d

%

ml/min/1.73m z

I

5.7_+0.7*

19.2_+8.2"

9.8_+5.1" 11.9_+5.2" 124-+25.0

II

4.2-+0.6*

7.2+2.1"

5.5_+1.2" 6.6+~?..0"

124+~21.9

*p<0.01 Deterioration of renal function and hyperudcemia unproportionate to serum creatinine levels were observed in two boys during a successive exacerbation. In the first, an 8-year-old boy, the serum uric acid level (UA s) was 10.4 mg/dl at a serum creatinine level of 1.2 mg/dl, and fractional urate excretion (FEUA) of 2.5%, while in the second, a 12-year-old boy, the serum uric acid level equalled 13.9mg/dl at a2.Smg/dl creatinine level. Good results were obtained with conservative management including high fluid intake and urine alkalization. Conclusions: 1. In children with IgA nephropathy, increased urinary udc acid excretion may be dependent on elevated endogenous production. 2. Overproduction of urate and disturbed tubular transport regulating renal excretion of udc acid were probable the course of hyperudcemia dudng exacerbation of IgA nephropathy. 3. It is possible that hyperudcosuda and hyperudcemia are responsible for some of the clinical manifestations of IgA nephropathy. Department of Nephrology, Child Health Center, Warsaw, Poland

P031 HENOCH-SCHOENLEIN 'NEPHRITIS (HSPN) IN CHILDREN AND IN ADULTS: AN ITALIAN MULTICENTER STUDY ON 219 PATIENTS R.Coppo

P032 INITIAL LONG IGA

In this retrospective collaborative study 219 patients (pts)(136 adults (Ad)_>16 year old (yrs) and 83 children (Ch) <16 yrs) with HPSN were enrolled from 43 Italian Centers of Nephrology (14 of whom Pediatric). The select~ion criteria included palpable purpura and/or bowel angina in presence of IgA dominant renal deposits. Each renal biopsy was re-classified according to absence (63% of HSPN) or presence of crescents (31.6%, in 3% extensive); 5.3% had pseudo-membranoproliferativeaspects. Frequencies of histologic changes were similar in Ad and Ch. Minimal urinary abnormalities were found in 34% Ad and 19% Ch, nephrotic range proteinuria in 14% Ad and 25% Ch, seldom with impaired renal function (IRF)(9.5% both in Ad and Ch). IRF was found in 24% Ad and 31% Ch, in 1/3 of the cases severe.In 152 HSPN pts with >1 year follow-up (mean 4.8 yrs up to 20 yrs) the outcomes of Ad and Ch were almost superimposable for remission rates (33% Ad, 31% Ch) and IRF (15% Ad and 17% Ch), while the prevalence of dialysis (D) was higher in Ad (16%) than in Ch (7%). No Ch died. The Ad survival was 97% at 5 yrs. The renal survival at 5 yrs was not significantly different in Ad (85.5%) vs Ch (95%). The extrarenal signs did not influence the renal features and outcome. Initial IRF was associated with crescent formations (75%) and unfavourable outcome (61%). Proteinuria (P) <1 gr/day for Ad or <10 mg/kg/day for Ch predicted no crescents in 87% and good outcome in 59%. Ad with P>1.5 gr/day had significantly unfavourable evolution to D (Cox p<0.02). In Ch even moderate P was associated with both crescent formations and negative prognosis and no P discriminating value was identified. Hypertension was a negative prognostic factor in Ad (p<0.001) as well as in Ch (p<0.01). No treatment was done in 21% Ad and 29% Ch. Steroids were used in 72% Ad and 60% Ch often in association with immunosuppressive drugs (22% Ad and 14% Ch). In Ad and Ch with nephrotic syndrome and/or > 50% crescents the outcome of treated vs not-treated was similar. This study does not support the assumption that the prognosis of HSPN in Ch is more favourable than in Ad,

PREDONISOLONE TERM F O L L O W - U P

THERAPY OF

AND

CHILDREN

WITH

NEPHROPATHY

T.Shimizu,

H.Yamazaki,

Y.Nomura,

S.Tateishi

[Purpose] To assess the effectiveness of early predonisolone therapy on the children with IgA nephropathy. 9[Methods] The outcome of 43 children with IgA-N, who were followed for more than 8 years after the initial biopsy, was assessed according to the initial histological findings and therapy. Initiation of predonisolone therapy within 2 months of heavy proteinuria was defined as early steroid therapy. [Results] The 17 patients in whom glomeruli showed no focal segmental lesions (crescents, sclerosis and adhesions) had normal or minor udnary abnormalities at the 8 ~ l O t h year of follow-up regardless of the early steroid therapy. Among the 1 2 patients in whom less than 20% of glomeruli showed F/S lesions, none of the8 patients with early steroid therapy developed heavy proteinuria nor chronic renal failure, while one of the 4 patients with no therapy had heavy proteinuria and another one developed chronic renal failure. Among the 8 patients in whom more than 20% of glomeruli showed F/S lesions, three of the 6 patients with eady steroid therapy developed heavy proteinuria and one developed chronic renal failure. One of the 2 patients with no early steroid therapy developed heavy proteinuria. [Conclusions] A prospective control trial of more intensive therapy is warranted for IgA-N with a significant number of glomeruli showing F/S lesions.

For the Italian Group of Renal Immunopathology (GIPR) Department of Pediatrics, Kyoto City Hospital, Kyoto, Japan

C 62 P033

P034

TWO RARE NEUROLOGIC MANIFESTATIONSOF HENOCH-SCHONLEINPURPURA (HSP) N.Bwan',K.GOcOyener",Z.Bircan"*,O.S6ylemezo~in*,EHesene~)in'

Although neurologicalinvolvementis nota prominentpefl ol HSP, Ihe association with mental slatus changes,seizures, focal neurologicdeficits and peripheral nervous system Involvement have rarely been repoded.We present two boys aged 18 and 14 respectively with HSP and extremely rare neurologic manifestationsof mononeuritls multtploxand ooflical blindness.The first patient presented with the complaints of left leg poin, mild muscle weakness,palpable puvpuricrash and arthritis of rlflhtwrist and elbow. The kidney biopsyshowed focal segmental necrotizlng giomemienephritis and immunoflournecenlstudy revealed diffuse masengiel igA deposition; characteristicof lISP. Shortlyalter he developed mononeuritismultiplex."rite latter boy preseated with mentalconfusion,seizure, diffuse rash, acute cortical blindness, gross hemstorla and meiena. On lollow up, he develepnd psthologlsaity proven myosltls, leuknoytoclasticvasculitls,hypedesslonandgastrointestinalperforationasnondaffto necrosis which neededoperstbn.Aitthe laboratoryinvestigationsruledout PAN end other vasoulitldas includingDSA, Doppler ultrasound, p-ANCA, HbsAg, C3, CA. Both patients were treated with cortlcosteroids,pulse methylprednlsoloneand endoxen raspectlvsty. As the assesiaiton between mononeuritls multiplex and cortical blindness with HSP is extremely rare In literature, we thoughtthese patientsworth to report. Gazl University,Departmentof Pediabics Units of Nephroiogy' and Neurology*' Ankara-Turkey

P R O G N O S T I C I N D I C A T O R S IN H E N O C H S C H O N L E I N PURPURA R J Mann and E J Tizard. Clinical outcome in Henoch Schonlein Purpura (HSP) is variable and in individual patients is difficult to predict. We have studied initial investigations for their use in prediction ofdisease severity. The severity of symptoms were graded mild, moderate or severe. All initial investigations were recorded and correlation with clinical course analysed. Follow up ranged from 7 months to 6.3 years. Of 53 patients, 6 were not investigated. The remaining 47 patients underwent a mean of 4 investigations with 23 different tests performed. Maximal platelet count during the acute phase (assayed in 46 patients) and detection of IgA class antineutrophil cytoplasm antibodies (ANCA) (assayed in 22 patients) were the only investigations found to be of use in prediction of outcome. Platelet count was higher in patients with most severe renal disease compared to those with less severe disease (median platelet count 625xl 09/L and 450x109/L) p=0.001. Platelet count was also higher in patients with significant gastrointestinal involvement compared to" those with mild symptoms: median platelet count 622x109/L and 452x109/L (p=0.007). O f 12 patients with a platelet count >600, there were significant gastrointestinal and renal complications in 9, whereas none of those with platelets <600 had significant complications, lgA class ANCA were detected in 10%, 17% and 67% of patients with mild, moderate and severe renal involvement respectively. Platelet count was higher in patients who were ANCA positive compared to those who were ANCA negative (p=0.01) Maximal platelet count at presentation and the detection of IgA class ANCA are useful predictors of severe disease in HSP. Department of Paediatrics - Soulhmead Hospital - Bristol - United Kingdom.

Dicls Univedty,Depedmentof Pediabics'" Diyar

P035 PROGNOSIS OF HENOCH-SCHO'NLEIN NEPHROPA THY I N CHILDREN: A CLINICAL EVAL UA TION 0 F 3 8 PA T[ENTS S.Emre*, LBilge, LKtfi~aslan, A.~irin, A.Naytr, U.Uysal, H.Alpa); F. Tanman

We evaluated fide correlation bet~vean clinical presentation, histopathological findings and prognosis in clfildren with Henoch-Sch0nlein nephropathy diagnosed and follo~w,,d-upbetween 1983 and 1994. The study,group cousistcd of 38 children (13 girls. 25 boys) ~ith a mean age of 9.25+3.75 )'ears (range 4-t5 )'ears) at the onset. The patients ~ere grouped according to the findings at presentation; 4 patients ~ith odaly tuicroscopic hematuria were evaluated in Group I, 19 patients with proteinuria and uticroscopic or macroscopichematuria in Group H, 2 patients with hen~ataria, oliguria. h)~ertension and/or raised plasma creatinine levels in Group I/I, 8 patients ~Jfll proteinuria above I g/d/m~"and hypealbuminemia in Group IV, and 5 patients with mixed nephritic-nephrotie fiudings in Group V. All of the clfildren were investigated ~renal biopsy, and histopathologicai findings ~ere classified according to the modified Heaton's criteria. Oral prcdnisolone (n:6), pre~htisolone and chlorambucil or c),clophosplmn~de (n: 8), high dose intravenous methylprednisolone (n: 19) ~ere given as theraW. Five patients were not treated. The mean duration of fotlo~up ia fide sta~" group was 4.8 years (range 1-11 years). In all of the Group I patients and 8 of the Group II, 2 of the Group IV and I of the Group V, normal urine microscopy,protein excretion. creatinine levels and aormotension were observed during fide foUow-upperiod. Minor urinary" abnormalities (proteinurial g/d/m:, ~l~ertension or raised plasma creatiinne levels) persisted in 6 patients who presented with nephritic, nepltrotic or mixed illness. At fize end of the third year. end stage renal failure d~veloped in t~o patients classified as IV A-B lfistotrathelogieany. One patient received a kidney transplant 6 years 'after the onset of nephritis and the other patient died with progressive glomerdionepltritis. As a result of this study,, clinical presentation ~as not an absolute prognostic grade in the stud), group, hog,ever. the severity of the initial biopsy findings ~vere fom]d to be correlated ~ith the outcome. Children "~ith more than 50 % crescent formation had a poor outcome compared to fewer or no crescents in file study group. *Udiversity of IstanbuL Medical Facnity, Depamnent of Pediatric Nepltrolo~, Gape. Istanbul -TURKEY.

P036 EOSINOPHIL ACTIVATION IN MESANGIAL PROLIFERATIVE DISORDERS: (H~4OCH-SCHOM,EIN PURPURA AND Ig A NEPHROPATHY) HK. Namgoong, BK Lira, JS Kim Dept. of Pediatrics, Yonsei University, Wonju College of Medicine, Wonju, Korea It is well known that activated eosinephil secretes eosinophil cationic protein (ECP) and major basic proteins. There is activated eosinophil in type I hypersensitivity and various skin disorders. Recent reports claim that mesangial cell has the gene containing IL-6. IL-6 stimulates T cell giving IL-2 and IL-5. IL2 and IL5 stimulate eosinophil, resulting in ECP and major basic proteins. The number of mesangial cells increases in mesangial proliferative disorders such as HSP & Ig A nephropathy. We have studied whether or not eosinophil activation is in mesangial proliferative disorders. The eosinophil activation was measured by the level of ECP. The results are as follows: The levels of ECP in HSP, Ig A nephropathy & control group were 13.1+12.4, 8.6+4.3 and 6.3+3.1 (ng/1) respectively. But there was only significant increase of ECP in HSP among them.These results demonstrate that the eosinophil activation behaves like one of the important mechanisms in HSP rather than Ig A nephropathy.

C 63 P038

P037 Ig A NEPHOPATHY IN A PEDIATRIC PATIENT WITH CHRONIC FATIGUE SYNDROME. P. C a l v o , G. C o l a n t o n i o , G, Damilano.~

Ig A n e p h r o p a t h y has n o t b e e n f r e c u e n t l y r e l a t e d t o c h r o n i c i n f e c t i o n d i s e a s e s . We r e p o r t a case associated to chronic E p s t e i n - B a r r v i r u s i n f e c t i o n . Case: A boy aged 9 was a d m i t t e d t o o u r h o s p i t a l i n 1992 p r e s e n t i n g f a t i g u e , p o l y a d e n o o a t h i e s , m i g r a t o r y a r t h r a l g i a s , abdominal p a i n and m i l d f e v e r f o r the l a s t 5 months. S e r o l o g y a g a i n : E p s t e i n - B a r r v i r u s was found p o s i t i v e : a n t i VCA Ig M + 1/160 ( l a t e r became n e g a t i v e l , a n t i VEA Ig G + I / i 6 0 , a n t i EBNA + i / 1 6 0 . P e r s i s t i n g symptoms and s e r o l o g y led us t o diagnose a c h r o n i c f a t i g u e syndrome. One y e a r l a t e r symptoms s t i l l remained and macroscopic h e m a t u r i a appeared. L a b o r a t o r y and image t e s t s were normal but serum c u a n t t f i c a t i o n o f Ig A was p e r s i s t e n t l y e l e v a t e d i n two samples: 312 and 225 m g / d l . A percutaneous r e n a l biopsy was performed and k i d n e y t i s s u e wa~ processed f o r i n m u n o f l u o r e s c e n c e and l i q t h m~croscopy: f o c a l mesangial c e l l p r o l i f e r a t i o n w l t h Ig A d e p o s i t s w~re found: B e r g e r ' s d i s e a s e . Up t o d a t e , symptoms and serokogy remain unchanged( r e n a l f u n c t i o n i s normal and no p r o t e i n u r i a ' i s observed. No t r e a t m e n t was t n s t a u r e d .

t Departamento Artlen tJ n a .

de

Pediatrs

CEMI~.

Buenos

Churg-Strauss granulomatosis ( CSG ) in one 4,5 years old boy Saraga M*, Vuki~ O*, PavIov N*, Ljuti~ D**, Glavina M***, Bio~id M.... A 4,5 years old celiacic boy has been addmited at our Dept. with working diagnosis of anaphylactic reaction on mosquito's bite and penicillin. Three days before hospitalisation he had local swelling and itch after mosquito's bite. Three days later, after recieving penicillin he developed real anaphylactic reaction. After cesation of anaphylactic reaction patient gradually developed intractable cough, malaise, skin rash ( erythema exudativa multiforme type ), gastrointestinal pain, pneumonitis, cardiomyopathia, enlarged liver, and multiple heavy allergy to several antibiotics. Three months later patient developed glomerulonephritis ( enlarged kidneys with changed US structure, proteinuria and erytrocituria ). Laboratory testing showed rised leukocyte count, especially eosinophils ( > 1500 in mm3 ) in peripheral blood, and in bone marrow. Moreover, the CRP, circulating immune complexes, and total serum IgE were significantly elevated. Also, he has had anemia. After all presented signs and symptoms, CSG has been suspected. Skin and kidney biopsy confirmed that very rare condition in children. Large eosinophilic infiltration throughoot the skin and kidney, especially arround small blood vessels have been observed. The answer to corticosteroid therapy has been spectacular. All symptoms regressed and patient is doing well.

~ires,

*Pediatric Department, Clinical Hospital Split, CROATIA ** Internal Department, Clinical Hospital Split, CROATIA ***Pathologic Department, Clinical Hospital Split, CROATIA .... Pediatric Surgery Department, Clinical Hospital Split, CROATIA

P039

P040

Intrarenal Infusion of Supernatants from Cytokine Activated Human Mesangial Cells May Cause GIomerular Damage

WP Cheu*,**, A Chen***, CY Lin*,***

Membranous glomerulonephropathy Japanese children Kaori Tomonaga 1.2, Kikuo fitaka 1.3, Shinya Shunsuke Moriya 1 and Midori Hojoi 1.

The pathogenesis of glomerular damage in glomerulonepluitis (GN) is not fully understood. Several studies have suggested that reactive oxygen molecules may play a role

in

Nakamura 1 ,

Department c~ Pediatric 1 Kitasato University ,Kanagawa,JaparzThe Kitasato Institute Medical Center Hospital 2, Yamato City Hospital 3.

in renal disease. During Gig, mesangial cells are activated. In our previous study, we demonstrated that in vitro interleukin-1 (IL-I) plus interleukin-6 0L-6) could stimulate cultured human cell (HMC) activation and release of free oxygen radicals. Iin the present study, first, we mesured the hydrogen peroxide 01202) and superoxide anion (02") after stimulated by IL-1 plus IL..6 in cultured HMCs. Then we infused hydrogen peroxide (H202) directly into left renal arteries of Sprague-Dawley rats.

We also infused the culture

supernatants of FIMCs after stimulated by IL-I plus IL-6 into the left renal arteries of rats. Two hours after the stop of infusion, the kidneys were removed and fixed by Carson's modified Millunig's buffer for electron microscopic observation. The results show that both 100 pfvl H202 and supernatants of HMCs stimulated by IL-1 10 U/nil plus IL-6 1000 U/nil caused similar glomerular damages including blebbing and sloughing of endothelial cells, and denuded basement membrane in glomeruli.

One hundred }aM concentration of

hydrogen peroxide or supernatants of eytukine-activated HMCs when infused into renal arteries, also caused hematuria and proteinuria. These results suggest that activated HMC can secrete free radical and may cause glomerular damage. *Department of Pediatrics, Veterans General Hospital-Taipei*; Taiwan. **Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, ***Department of Pathology, Tri-Service General Hospital, National Defense Medical Center; Taiwan, ROC. 9

Since 1973, 12 patients,7 boys and 5 gifts,were diagnosed to have membranous glomerulonepbropathy (MN).Average age at deteetioa was 8 years (2-14years). Presenting sympton was edema in 1, and in all others abnormal urinalysis was detected by school or chance urinalysis.Surface antigen of hepatitis B virus (HBs) was positive in 6 patients and negative in 6. Anti-nuclear antibody (ANA) was positive i n 3 and negative in 8 . In one patient ANA was not tested. One patient who had positive ANA was diagnosed to have SLE 4 years . A t last follow up, 8 patients continued to have urinary abnormalities. Among them one who had positive HBs antigen went into end stage renal failure. In other 11 patients,serum creatinine level was below 1.4 mg/dl. AU patients showed normal mesangitma or mild mesangial proriferafion .The patient who was diagnosed to have SLE 4 years latter showed mesangial deposits at first renal biopsy.In our experience most of patients with MN were detected by school or chance urinalysis and half of them had positive HBs antigerz Lupus nephritis must be ruled out in making diagnosis of Idiopathic MN.

C 64 P041

P E C U L / A R G L O M E R U L A R A N D TUBULAR INJURIES IN YOUNG CHILD VICTIM OF C H E R N O B Y L N U C L E A R P O W E R INCIDENT (1986),AFFECTED BY PROTE/NURIA AND HAEMATURIA. A~Ciofani*, A.Angelone**, G.Maggiano***,P.Rampa*,M.Lodi*, R.Stat~ale* M.S.Vero*, G. G-uerrieri*,T.D'Andre&*

P042

8 years old child referred to our hospital far persistent microscopic haematuria, intermttlent episodes of 8ross haematuria, non-nephrotic inconstont proteinurta..4namnestic salient notes: at the age of 3 months expo~tion to Chernobyl nuclear power incident; at the age of 6 years, serious high-tension domestic electrical incident caused a~ffused burns, cardiac damages, two distal phalanges amputation of foot due to seriously injured extremities and permanent changes in right crystalline len& Investigation revealed: renal f~nctions not affected; proteinuria < 2 g/24 hr;microscopie hnematurta; immunological profile and all other laboratory and instrumental investigations not affected;cultures and haematalogisi advice negative.Renal biopsy was performed, it showed 25 glomerules of wich only" 1 in hyalinosis ,mesan~al proliferation, signs of crescems, perigtomerutar fibrosis somewhat diffused," few glomerulor eeta~c capitta~es_Tubules showed peritubutor fibrosis with few atrophic phenomena.Interstitial spaces demonstrated sufficient hyalinosis with light &mphocitic infiltrations.lmmunoflorescence investigation negative. Electronic microscope showed a substonaal confirmation of optical observation,portial fusion of foot processes , absence of immune deposits. The lesions observed are diff~cuh to classify. No similar cases founded in scientific literature but, according to our hypotesiz;the lesions could be attributed to nuclear power incident.To come to a definite conclusion.more clinical and hystotogical data is necessary in order to confront our findings with that of other centre& For this reason, we have begun a collaboration with the Scientific Centre o f Radiation Medicine of the (fkranian Academy of Medical Sciences.

MICROALBUMINUR1A I N CHILDREN WITH I N S U L I N - D E P E N D E N T DIABETES S. Lopez*. RGalindez**. M. Blando*. L. Lucero ***. EFemandez ***. E. Corrr **** Introduction About 45-50% of patients with insulin-dependent diabetes will develop diabetic nephropathy ( DN ) and chronic renal insufficiency during the disease.Increase in urinary excretion of albumin (microalbuminuria) has been demostrated in some patientsMost of the information on this matter comes from studies performed in adults; few data are availablein children. The purpose of the study was to evaluate the presence of microalbuminuria in diabetics children and its relatioship with the degree of metabolic control and duration of diabetes. Patients and Methods 27 diabetic children were studied ( 19 boys, 8 girls ).The age range was between 5 and 20 years ( mean 12.07 ~ 3.9 years ) and disease duration from 6 months to 13 years ( mean 4.1 ~ 4 years ). Patients were divided in three groups, according to diabetes duration; group I : 6 months- 5 years; group II : 5.1- 10 years; group III : 10.1 years or more. 20 ( 74.07% ) of the children had a diabetes duration less than 5 years, 2 ( 7.4% ) between 5.1 and 10 years and 5 (18.5 % ) more than 10 years. All received two daily injections of an insulin mixture. All were normotensive, albustix reaction was negative for all and routine urinalysis were normal. Metabolic control was assessed by blood glucose determination by the glucose-oxidase method and HbAIC measured by microparticle enzyme immunoassay ( MEIA ). Albumin was determined by albumin double-antibody I 125 radioimmunoassay( Diagnostic Product Corporation.U.S.A,). Results: Microalbuminufia above 15 ug /rain ( reported as predictive of overt diabetic nephropathy in adults)was observed only hi three diabetic children, two from group I and one from group III. The mean HbAIC in the two patients from group I was 8.59, whereas in patient from group III was 9.97 Conclusions : No relationship could be established between urinary albumin excretion ( microaibuminuria ) and the degree of metabolic control as well as the duration of diabetes.Only prospective work will allow an assessment of the sigrfificance of the abnormalities observed.

* Division o f NephralogF and Dialysis and Unit of Pediatric Nephrology - Ospedale Civile - Pescara - Italia` ** Service o f Pathology - Ospedale Civile - Pescara - Italia. *** Service of Pathology - Universita Cattalica - Roma -Italia.

* ServiciodeEndeczmologiay Diabetes,HospitalInfanfil,C6rdobe,Argentina. **Servir deNeffologia,HospitalInfantil,C6rdoba,A~enfina. ***LaboratofioF~mdaeionparael Pmgresodela Medicina. ****Laborator~oHospitalInfamil,C6rdoba,Argentina.

P043

P044

RENAL H I S T O P A T N O L O G Y AND CO[~tffLEI~[ENT P R O F I L E S IN ~RANOPROLIFERATIVE GLOMERULONEPHRITIS T Y P E I I I (MPGN I I I ) MAY BE D I S C O R D A N T KEC.Meyers*, CF.Strife**, BS.Kaplan* P a t i e n t s w i t h MPGN I I I a n d low C3 t e n d to h a v e e v i d e n c e f o r a n e p h r i t i c f a c t o r of t h e t e r m i n a l complement pathway (NFt) characterized by decreased p r o p e r d i n , C5 a n d t e r m i n a l c o m p o n e n t s . T h e d e g r e e of l o w e r e d termil~al c o m p o n e n t s i s d i r e c t l y r e l a t e d to t h e d e p r e s s i o n of C3 w i t h low p r o p e r d i n , C5 a n d t e r m i n a l c o m p o n e n t s i n all p a t i e n t s w i t h C3 < 30 m g / d l . T h r e e c h i l d r e n w i t h EM c o n f i r m e d MPGN III a n d C3 < 30 m g / d l w e r e t r e a t e d w i t h d a i l y a n d t h e n a l t e r n a t e d a y c o r t i c e s t e r o i d s . I n t w o , t h e C3 i n c r e a s e d to n e a r n o r m a l a f t e r a m o n t h of t r e a t m e n t ; C3 t h e n decreased after and did not increase again after restarting corticostereids. Complement profiles were p e r f o r m e d i n all t h r e e , 6m, 2 y r s a n d 9 y r s a f t e r d i a g n o s i s . C3 l e v e l s w e r e 52, 21. a n d 14 (83-177 m g / d l ) . C l q , C2, C4, p r o p e r d i n a n d C5 l e v e l s w e r e n o r m a l i n a l l , w h e r e a s 2 p a t i e n t s h a d a s l i g h t d e p r e s s i o n of C7 o r C8. T h e p a t t e r n of c o m p l i m e n t a c t i v a t i o n r e s e m b l e s t h a t s e e n w i t h MPGN I I . i n w h i c h a n e p h r i t i c f a c t o r a c t i v a t e s t h e a m p l i f i c a t i o n loop ( N F a ) . We c o n c l u d e t h a t i n p a t i e n t s w i t h MPGN I I I w h o h a v e C3 < 30 m g / d l , a c o m p l e m e n t p r o f i l e s u g e s t i n g t h e p r e s e n c e of NFt i s not always found. * C h i l d r e n ' s H o s p i t a l of P h i l a d e l p h i a ** C h i l d r e n ' s H o s p i t a l of C i n c i n n a t i

IS PREDIALYTIC CHRONIC GLOMERULONEPHROPATHY REFRACTORY TO TREATMENT ? P FUTRAKUL, V SINGKHWA, N FUTRAKUL, D WATANA. R SENSIRIWATANA, Chulalongkorn Med Sch Hnsp, Bangkok. Chronic glomerulonephropathy (CGN) with histopathologic characteristics of arteriolosclerosis, tubulointerstitial fibrosis and severe renal dysfunction is generally refractory to treatment. We herein presented 6 cases of such CGN (mesangial proliferative(3), focal segmental glomernlosclerosis(2) and (1) crescentic lesion) with remaining I0 percent renal function who had responded to the enhanced-renal-perfusion (ERP) formula. Initially, all 6 patients were delineated by the severe degree of glomerular dysfunction including low glomerular filtration rate (7+3, normal I00 ml/m/l.73m2), ultrafiltration coefficient (0.004_+0.003, normal 0.06 ml/s/mmHg) and increased intraglomerular hydrostatic pressure (55+1, normal <53 mmHg); of tubular dysfunction including defect in transporting solute which was reflected by increasing fractional excretion of filtered solutes (sodium 7+5%, calcium 11+8%, phosphate 120+149%, uric acid 36+21%, magnesium 19+14%), in concentrating and acidifying the urine, and of vascular dysfunction including marked elevation of renal arteriolar resistance (37697_+21901, normal <2700 dyne.s.cm "5) and severe reduction of renal plasma flow (100_+52, normal 500 ml/m/1.73m2) and peritubular capillary blood flow (93+53, normal 400 ml/m/1.73m2). In relevant to the preceding observation, therapeutic intervention was aimed to improve the renal perfusion with ERP formula which included antiplatetet agent, calcium channel blocker, angiotensin converting enzyme inhibitor, anticoagulant and hydration. In addition, prednisolone was added to 4 patients associated with heavy proteinuria. Following such treatment, a slowly progressive and persistent improvement in glomerular, tubular and vascular functions had been substantiated in all of these 6 patients. Thus, this mode of improving circulatory blood volume, reducing renal vascular resistance and improving hemorheology is likely to prevent the disease progression in patients otherwise proning to chronic renal replacement therapy.

C 65 P046

P045 ~Oh~.A~O~IAflV~ b fUDl OT IDIOPATHIC MEMBRANOI~ROLIFERATIVE GLOMERULONEPHRITIS (IMPGN) IN CHILDREN. _RESULTS OF PREDNISONE TREATMENT. R. Urizar*, R. Munoz**, L. Ve lazquez-Jones**, B. Romero**, R. Gomez-Chico**, J. Cerda* ,M. Neumann*, J. Singh*** IMPGN causes end stage renal disease. 66 children seen at the Albany Medical Center Children's and the Mexico City Children's Hospitals (AMCCH and MCCH) between 1969 and 1993 had biopsy (KB~ proven IMPGN: 53 of 66 (80.3) Type I; age i0 (+--3.09) yrs, 27 females (F) and 26 males (M). 8 of 66 (12.1%), Type II; age was 7 (+--3.24) yrs, 2 F and 6 M, and Type III, 5 (7.60%), 3 F and 2 M with average age 9.8 (+-2.13) yrs. 39 of 66 received Prednis o n e (P,I to 2 mg/kg;max 60 mgs) as a single QOD dose for 3 to 7 years. 28 of 39 had daily aspirin (A,2 to 5 mg/kg) and Persantine (Pe,l mg/kg) for similar periods; followup lasted 3 to 20 years. 27 of 66 remained untreated (0). Initial followup consisted of trimestral physical and routine ophthalmologic, height, weight and blood pressure evaluations. UA, 24 hour urine protein and creatinine excretion, CBC, ESR, BUN, serum electrolytes, C3, C4, CH50, ASO and ANA titers were done thrice yearly. 39 of 66 had one or more followup KB. Results: 32 of 39 (82%) of the P/APe treated patients had initial average serum creatinine equal or less than 1.5 mg/dl (in 7 of 39, 18%, was greater than 1.5 mg/dl) while in 26 of 39 (66.7%) of this group the final creatinine remained at or below 1.5 mg/dl. In 17 of 27 (63%) of 0 initial serum creatinine was less than 1.5 mg/dl (in i0 of 27, 37%, was greater than 1.5 mg/ dl) and 16 of 27 or almost 2/3rds had creatinines greater than 1.5 mg/dl. These differences were statistically significant (p 60.05). In addition, semiquantitative analysis of the second KB showed decreased inflammation with occasional increased scarring when compared with the initial biopsy specimens. These results agree with those of others and suggest that P may have Successfully slowed down glomerular inflam~aation in patients with IMPGN. *Nephrology,Albany Medical Center,Albany NY USA 12208 r162 Nephrology,Hospital Infantil,Mexico City,Mexico DF ~**Nephropathology,VA Medical Center,Albany, NY USA 12208

P047 IN~TION

USE OF LOW DOSE INTRAVENOUS PULSE cYcLoPHOSPHAMIDE IN CHILDREN WITH LUPUS NEPHRITIS *JYN Lim, ML Lee, Indon L a j i n

We r e p o r t o u r e x p e r i e n c e c o n c e r n i n g 26 c h i l d r e n (20 f e m a l e s ) , mean a g e 9.7 years (range 34 m o n t h s t o 13 y e a r s ) who r e c e i v e d low dose intravenous (IV) pulse cyclophosphamide. Criteria tar treatment were that they fulfilled t h e m o d i f i e d ARA c r i t e r i a f o r SLE, and h a d f o c a l or diffuse proliferative glomerulonephritis. 10 r e c e i v e d m e t h y l p r e d n i s o l o n e (10mg/kg for 3 doses) at the start of treatment. IV c y c l o p h o s p h a m l d e was g i v e n at the d o s e o f 250 mg/m 2 m o n t h l y f o r 7 doses then 350 mg/m 2 3 monthly for 6 doses. Oral steroids were given a t 60 mg/m2 f o r 6 t o 8 w e e k s f o l l o w e d by s l o w tailing. At l a s t f o l l o w - u p the mean duration after starting c y c l o p h o s p h a m i d e was 2 0 . 5 m o n t h s ( r a n g e 1 - 63 m o n t h s ) . 10 h a d completed the whole c o u r s e . 19 h a d normal renal function, 2 were lost to follow-up after 2 y e a r s but had normal renal function at last r e v i e w . 3 had impaired renal function. 2 died one f r o m a c t i v e SLE after defaulting t r e a t m e n t and 1 f r o m c e r e b r i t i s of unknown c a u s e 2 m o n t h s a f t e r d i a g n o s i s .

r Hospital

of Paediatrics, K u a l a Lumpur, K u a l a Lumpur,

Malaysia

P048 BETWEEN

TONSILI,ITIS

AND

GLOMERULONEPHRITIS, STUDY OF F O L L I C U L A R AND GLOMERULAR MACROPHAGE INFILTRATION H. Shiraga, M. Nagata, T. Tanaka, H. Kawaguchi, K. Ito Worsening of urinary findings immediately after tonsillitis is frequently observed. Although therapeutic tonsillectomy has been introduced, the effectiveness of tonsillectomy on chronic glomerulonephritis (CGN) is not universal. To investigate this heterogeneity, we evaluated macrophage (M r ) infiltration on both kidney and tonsil. Seventeen CGN children who underwent both renal biopsy and therapeutic tonsillectomy were investigated. Patients were divided into two groups (good, n=lO; poor, n=7) according to their improvement of urinalysis following to tonsillectomy. Glomerular and follicular M r in each individual was investigated. Results are as follows. Tonsiller hypertrophy was more frequently seen in good-group. There was high correlation between the degree of tonsiller hypertrophy and the degree of follicular M qb infiltration. There was no difference of glomerular M r infiltration among two groups. There also was no difference of follicular M qb infiltration among two groups. Comparison between glomerular M r and follicular M r infiltration revealed high correlation in good-group and low correlation in poor-group. These findings support the concept of tonsillitis as an attack factor of CGN, and will partially explain the anti-nephritis effect of tonsillectomy. Dept. of Pediatric Nephrology, Kidney Center, Tokyo Women's Medical College - Tokyo - Japan.

A Review of 55 Children with Lupus Nephritis M C Chiu 1, K C Tse', F T Yau2, S N Wong3 for the Hong Kong Paediatric Nephrology Study Group

Abstract 55 SLE children under 15 years old with renal involvement presented between January 1984 to December 1993 were reviewed. 54 were Chinese with only 1 Indian. Family history of SLE was presented in 1 girl (1.8%). There was a predominance of female to male ratio of 10 to 1. The mean age of onset was 10 year 10 months and the mean duration of follow-up was 3 years 11 months. Fever (67.3%), malar rash (61.8%) and arthritis (52.7%) were the commonest clinical features. 29 children (52.8%) had nephrotic syndrome and 19 children had hypertension (32.7%) at presentation. Renal biopsy was done in 53 patients. Diffuse proliferative GN was the commonest histopathology (58.2%). Renal biopsy was repeated in 6 patients in whom 5 revealed a change in histology. Six patients died, of whom 3 were having renal failure, with a mortality rate of 12.7%, and the commonest cause was sepsis. Most of the patients (93.2%) were able to attend normal school or having employment.

1 Department of Paediatrics, Princess Margaret Hospital, Hong Kong 2 Department of Paediatrics, Pamela YoudeNethersole Eastern Hospital, Hong Kong 3 Department of Paediatrics, Tuen Mun Hospital, Hong Kong

C 66 P049

P050

CICLOSPORIN OF SYSTEMIC

A AND PLASMAPHERESIS IN THE TREATMENT LUPUS ERYTHEMATOSUS IN CHILDREN

K. V o n d r & k ,

A.

Kolsk~,

J.

Novfikov&,

J.

EVALUATION THE ORIGIN OF ASYMPTOMATIC HEMATURIA (AH) BY PHASE MYCROSCOPY (PM) D.Z.Mass6*, L.Alonso~, L.A.Vazquez*, M.Deregibus*, H.A.Repetto*.

Stejskal.

Obietive: To demonstrate the efficacy of the examination of erythrocyte morphology with PM to differentiate betwen glomerular hematuda (GH) and extraglomerular hematuria (EGH) in children. Matedal and Methodos: 1 to 4 samples of 77 children (46 s were examined. The patients were divided in: Group1 (G1) 30 patients with proven GH (7 acutePostestreptococ. Glomerulonephdtis (GN), 6 Idiopathic Nephrotic Syndrome, 4 LES GN, 4 Idiopathic Mesangial GN, 3 Henoch Schonlein GN, 3 Extracapillary GN, 1 IgA GN, 1 Focal glomerular sclerosis and 1Membrano proliferative GN) Group2 (G2)): 16 patients with proven EGH (8 urological surgery, 3 renal trauma, 2 urolitiasis, 2 urethral trauma and 1 Urethral stenosis) Group _3 ((33) 31 patients with hematuria of undetermined odgin (25 recurrent hematuda [4 familial], 2 acute lymphocytic leukemia, 1 chickenpox, 1 idiopatic hypercalciuda, 1 malignancy and 1 acute tubular nechrosis. Results

The study deals with 4 children suffering from systemic lupus. All the patients are girls.The age of the onset of the disease was from 9 1/2 till 17 years.The first and dominant signs were renal involvment - nephrotic syndrom accompanied by further different symptoms of systemic lupus. The diagnosis was established on the clinical picture, immunological investigation and histological confirmation. The treatment started by i.v. Methylprednisolone pulses continued by the combination of Prednison + Cyclophosphamid or Azathioprine. The previous treatment had to be changed because of unfavourable clinical and immunological course, using twice Ciclosporin A, twice Plasmapheresis. The first patient has been already treated for 7 years. Authors compare clinical and immunological changes depending on the way of the treatment.

Group 1 2 3 * p< 0,001

Dept. of Paediatrics, Postgraduate Medical School, Thomayer's Teaching Hospital, Prague. *Institute of Pathology, II. Medical Faculty, Prague, Czech Republic

Nro. 30 16 31

%

dismorphia range 59*## (16- 90) 5* ( 1 - 18) 48.5## ( 5 - 8 1 )

## p< 0,05

% with erythrocyte cats 63.5 @ 0 29 @

@ p<0,05

Conclusion: 1) Samples belonging to GH showed more then 25% dismorphia in 97 % of patients. 2) Samples from EGH showed less than 10 % dysmorphia in 94 % of patients. 3) 7f% of hematuria of undetermined origin and 100 % of familial hematudas showed more then 25 % dysmorphia, suggesting their glomerular odgin. 4) Eady examination with PM helps in a better selection and a reduction of the studies required for the diagnosis of the odgin of AH. * Pediatric Nephrolegy. A. Posadas.Hospital Bs.As. Argentina ** Laboratory. A. Posadas. Hospital Bs.As. Argentina.

P051 ISOLATED HEMATURIA IN CHILDREN- A PROSPECTIVE STUDY OF 128 PATIENTS Fajimura MD*, Vaisbich MH*, Furusawa EA, Saldanha LB**, Schvm'tsman BGS*, Rueha RB*, Koch VH*. Okay Y* Hematuria is a frequent clinical problem in Ix~liatrics, its invostigation requires carfful diagnostic work-up. In order to ~'ainate palicnts with isolaled hemaluria, a prospcclJvc pretueol was d~ised in our servic~ including clinical, image and Jaboralol), data and a renal biopa3' whenever a glomerular origin was suspactod. Dunng a 16 ),car period (1978 to 1994), 128 children (78 male, 50 female) completed evaluation, 104 with recurrent or persistent gross hematuria and 24 with persistem microscopic hemaluria, mean age at presenmLion was 8.2 years and the mean period of follow-up was 3.3 years. The patients could be classified according to the following diagnostic groups: N# OF CASES % Metabolic Disorder 45 35.2 Primary Glomerular Disorder 32 25.0 Metabolic Disorder + Urinao" Lithiasis 27 21.0 Idiopanc Urinal)' Lithiasis 12 9.3 Inconclusive 4.7 Renal Tuberculosis 0.8 ' Vasodar Malformation 08 Wilms Turnout 08 Sickle Cell Anemia 0.8 Alpun S)~drome + Hipcrcalciuna o,8 Renal Tuberculosis + Hiperealciuria 0.8 TOTAL 128 1000 In the putienls with hematuria of glomerular origin, acute gloruerulonephritis was diagnosed in 11/32 cases, Alport Syndrome in 8/32, lgA Nephropathy in 7/32, Hcnueh Schoniein purpura in 3/32, thimming of the GBM in 1/32, Dense Deposit Disease in 1/32 and Focal Segmental Glomendusclerosis in 1/32. Hipercalciurla (59/128) followed ~' the association of hiperealciuria and hiperuricosuria (12/1283 were the most common metabolic disorders detected. In conclusion, our data confirm the neod of a careful and well planned work-up for the invostigation of isolated bematurla in children, in our experience, most cases were caused by metabolic disorders specially hiperealciuria and prmmO" glomerniar diseases. 4.7% cases remained inconchisive despite complete investisation. * Servi~:o de Nefrologia Pedidtrica do insthuto da Crianfa H.C.F.M.U.S.P.S~o Paulo -Brasil ** Sert'ifo de Analomia Patol6gica do H.C.F.M.U.S.P,- S~o Paulo - Brasil

P052 PERCUTANEOUS RENAL BIOPSY WITH ULTRASOUND GUIDED SPRING LOADED NEEDLE - STUDY OF 50 CASES Koch V.H*.;Andrade MR**', RuehaRB.*; Soatigno A**., Okay.',Y*, Percutancous renal biops3 is an important procedure for pabents with renal disease. This prueedure has slfffered man3, technical modifications since it was first described (Bal~19343. Renal localization by ultrasuund and the use of an automated biopsy inslrumenl seem to have contributed to patient safety and quali.ty of the cores of tissue obtained. In the 2 year period of 12/92 to ] i/94, 50 patients (26 male, 24 female) were submitted in our scnice to a percotancous renal biopsy with real time ultrasound guidance (Diasonics SPAi000 5 and 7.5 mHz tmnsducors) and a spring loaded biopsy de~ice (Bioply| Patients' mean age was 10.7 • 3.2 years and mean weight was 36.4 • I 1.3 kg. Biopsy indication was: nephrotic syndrome (40%), bematuria (26%), s3'stemic lupus eythematosus (26%), s3,stemic vasculLiis (6%), other (2%). The right kidn~' was biopsied in 48/50 cases. A 16 G Tin-.cat needle was utiLized in 48/50 cases, a 14 G needle in 2/50 cases. The average number of passes nccessa U to obtain two cores of tissue, one for optic microscopy and the other for immanefluorescence and eletronic microsco~" (EM) was 3.1• (range 2.0 - 8,0), The average number of glomeruli per specimen was 14.5 + 8.8 for optic microscopy and 7.5 + 5.5 for imunefluoresconcc. Renal tissue obtained was not diagnostic in 1/50 cases. Ultrasound cvaloation 24 hours after the procedure ~as normal in 38/50 patients and revealed perirenal hematoma in 12/50 patients.. 45/50 patients showed no clinical alterations after the biopsy procedure. 4/50 developed gross bematuria of short duration and 1/50 had a neurogenic shock secundary' to formation of a capsular hemaloma withent concomitan! bematmia. There was no correlation between the number of biopsy passes and the incidence of complical/ons. In conclusion, pereutancous kidney biopsy using the described technique has been in our experience a safe and useful procedure. We recommend, close ebscn'atian of the patients for 24 hours after the procedure for detection of possible complications. * Sen~ifo de Nefrologia Pcdbitrica do lnstitmo da Crian~t do H.C.F.M.U.S.P.S~o Paulo- Bmsil ** Servifo de Radiologia de ]nsl Crianfa do H.C.F.M,U.S.P.- S~o Paulo- Brasi]

C 67 P053 MORE SPECIFIC AND UNINVASIVE DIAGNOSIS OF NUTCRACKER PHENOMENON (NP) USING DOPPLER ULTRASOUND TECHNIQUE H.Yagishita*, H.Kawaguchi*, M.Hattori*, H.Shiraga*, T.Yoshioka*,

t'054 The evaluation of tubulo-interstitial change (TI change) and glomerularsclerosis at the first renal biopsy Masaaki Ikoma, Akiko Maruyama,Keiji Doi, Hitoshi Mio, TuguoShibawaka, and YasushiKoitabashi Weinvestigatedthe role of TI change and glomerularsclerosis at the first renal biopsy played

K.Ito*, S.Miyagawa**, M.Awagon**

in die prognosis of childhoodrenal diseases. The relationship betweenTI change and glomerular

The disturbance of the left renal vein flow (Nutcracker phenomenon:NP)

sclerosis at the first re,at biopsy and the prognosis werestudiedin 106 cases who had been followedduring 5 years or more after the first biopsy. TI change was gradedaccordingto the

often causes hematuria and occasional orthostatic proteinuria. Ultra-sonography(US) has been availabe to detect NP as uninvasive and simple method. But diagnostic criteria on US were not recognized to be widely accepted. Thus we tried to establish criteria on US diagnosticaly more specific to NP using Doppler US technique. From the preliminary

proportion occupiedby TI change in the samplearea of LM slides(
blood flow velocity(left renal vein)<10cm/sec,Ratio of Max. blood flow

constantly 2.0 mg/dl or moreofsarumcreafinine. The frequeneyaccompanyingTlehange(1/3<) at the first renal biopsy was as follows. IgA-Nephropathy40 cases:CRF(+),4/4 cases(100%),

velocity of rt./It, hirus renal v e i n > l . 4 and disapperance of wave-flow pattern

CRF(-),14/36 cases(39%), MPGN14 cases:CRF(+),0cases, CRF(-)-6/14 cases(43%), FGS

study, we adopted the following criteria: Nutcraker distance<5mm, Max.

of It. renal vein. Using such criteria, a total of 88 children with abnormal

5 cases:CRF(+)-5/5 cases(100%), CRF(-),0 cases, MN 9 cases:5 cases:CRF(+),0cases, CRF(-),

urinary findings detected on school mass screening were examined. As a

2/9 cases(22%), Alport 8 cases:CRF,7/7 cases(100%), CRF(-),I/1 cases(100%), so called CGN

result, 8 of 3 1 children with non-glomerular hematuria, 10 of 15 children

30 cases:CRF(+),4/4 eases(100%), CRF(-),8/26 cases(31%), Regardingthe frequencyof the cases

with orthostatic proteinuria and 2 of 10 chidren with hematoproteinuria were

showing 10% or more of % sclerosis, IgA-Nephropadiy:CRF(+),0/4cases(0%),CRF(-),4/36

diagnosed as NP. It was noticed that no one was diagnosed as N P in all

cases(1I%),MPGN:CRF(+),0 cases, CRF(-),l/14 cases(7%),MN:CRF(+),0 cases, CRF(-),

children showing glomerular hematuria and/or non-orthostatic proteinuria.

0/9 eases(0%), Alport:CRF(+),5/7 cases(71%), CRF(-),0/1 cases(0%),CGN:CRF(+),4/4 cases(100%), CRF(-),0/26 cases(0%). It was suggestedthat it was necessary to follow carefully

W e concluded that our criteria of NP on Doppler US examination was more specific for diagnosing NP than those on ordinary US without Doppler tecnique. *Dept. of Pediatric Nephrology, Kidney Center, Tokyo Women's Medical Collage

the prognosis in suchcases as accompanyinghigh % sclerosis or wideTI change even if their renal function was within normal range at the first renal biopsy. Departmentof Pediatrics.gt.MariannaUniersity School of Medicine, KwasakiJapan.

** Dept. of Pediatrics and Loboratory Unit, Saiseikai Kurihashi Hosp.

P055

IgM NEPHOROPATHY IN PEDIATRICS: FREQUENCY AND CLINICOPATHOLOGICAL CORELATIONS. S. Miceli*, A. Aralde*, L. De Marco**, S. Lopez**, R. Perez Alamino***.

Seventy three renal biopsies in pediatric patients were studied, twenty presented messangial igA deposits, alone or associated with IgM, in the immunofluorescence studies. The average age was 6.1 years old (range 3-12). Among 20 patients (pts), 12 pts (16.4%) presented only deposits of IgM; in 4 pts IgM and IgA were found and in the remaining 4 left IgA and IgM were found. By light microscopy, from the group with pure IgM deposits 41% (5/12 p) presented messangial proliferative diffused Glomerutonephritis, 41% messangial proliferative focal glomerulonephritis and 18% focal and segmental glomerulosclerosis. The clinic display of this group was the following: 33% neprhotic syndrome with hematuria, 33% pure nephrotic syndrome, and 33% recurrent hematuria without proteinuria. Our observations would indicate a slightly higher frequency of IgM nephropathy than described in the literature, which could be due to the age of the group studied in comparison to other groups reported. * Servicio de Nefrologia-Hospital del Nifio Jesus-Pie. Hungria 750 ** Laboratorio de Anatomia Patologica-Marcos Pas 265 *** Laboratorio de Analisis Immunologicos-Marcos Pas 283 (4000) Tucuman-Argentina

P056 A R E V I E W OF P A E D I A T R I C RENAL BIOPSIES 1N HONG KONG S.N. Wong*, K.W. Chan#, M.C. Chiu** for Hong Kong Paediatric Nephrology Study Group To study the pattern and clinical correlation of childhood glomerulonephritis (GN) in the local community, we undertook a retrospective review o f all renal biopsies performed for children < 16 )rears old in all public hospitals in Hong Kong. From Jan 1, 1991 to Dec 31, 1993, a total of 151 renal biopsies were performed. There was a male predominance for young children (M:F ratio were 3.4:1 for < 5 year; 1.5:1 for 5-10 year; 0.9:1 for > 10 years). The commonest pathological diagnosis were Minimal Change Disease (MCD) 25%, Lupus nephritis 16%, IgA nephropathy (IgAN) 11%, Diffuse mesangial proliferation (DMp) 9%, Henoch-Schonlein nephritis (HSN) 9%. Seventy-five children with nephrotic syndrome had renal biopsy which showed MCD in 37 cases, DMP in 13, HBV-associated membranous GN in 7, and focal segmental glomerulosclerosis (FSGS) in 6. Diseases other than the MCD-DMP-FSGS spectrum were diagnosed in 19 cases and all except 2 occurred in children presenting with atypical features such as gross haematuria, hypertension, renal impairment, HBsAg carriage or steroid resistance. Thirty-four cases were biopsied for persistent urinary abnormalities (haematufia +/- proteinuria). The commonest pathologies found in children with isolated haematuria were IgAN (10 cases), Alport's syndrome (4), benign haematuria (6). For the 13 children with proteinuria +/- haematuria, the diagnosis were variable including IgAN (3), proliferative endocapillary GN(2), MGN(1), MPGN(1), P-ANCA +ve, Crescentic GN(1), FSGS(1), MCD(1), and no pathological diagnosis(3). Renal biopsy was useful in diagnosis and assessment of various glomerulonephritis. Our findings indicate a high incidence of lupus nephritis, DMP and HBV-MGN in the local childhood population. * Paediatric Unit, Tuen Mun Hospital - Hong Kong #Pathology Department, Queen Mary Hospital - Hong Kong **Paediatric Unit, Princess Margaret Hospital - Hong Kong

C 68 P057

P058

ACUTE F O C A L B A C T E R I A L NEPHRITIS IN C H I L D H O O D R. Mallmann, D. Emons Acute focal bacterial nephritis (AFBN), synonymous with acute lobar nephronia or focal nonliquefactive pyelonephritis, represents a localized area of renal inflammation. Clinically the disease presents as acute septic pyelonephritis with flank pain and often negative urine cultures. Abdominal ultrasound reveals an enlarged volume of the kidney involved. Typically a focal hypoechogenic mass with scattered low level echoes disrupting normal corticomedullary differentiation can be demonstrated. Even without detection of lenkocytes and bacteria in the urine broad spectrum intravenous antibiotic treatment is obligatory. We report on two boys 7 and 5 years of age resp. who both after an uneventful history concerning urinary tract infection presented with acute onset of high fever, rapid deterioration of general condition and severe flank pain. In case 1 Proteus mirabilis could be detected in urine culture. The boy was successfully treated with mezlocillin and gentamicin. Despite sterile blood as well as urine cultures boy #2 received cefuroxim and gentamicin intravenously. In this case an abdominal contrast CT scan was able to better confirm focal renal alterations in terms of focal hypoperfusion at the very beginning. Repeated renal ultrasound had been suggestive of AFBN. [n both cases voiding cystourethrography later, demonstrated grade 3 vesicorenal reflux ([nternational classification). Adequate treatment usually leads to complete clinical recovery within 2 - 4 weeks including normalization of the ultrasound picture. In childhood bacterial infecion of other organs preceeding AFBN is said to be more common than anomalies of the urinary tract as predisposing factors. Therefore a hemotogenous route of infection must be presumed and its focus discovered and eliminated. Otherwise recurrences of AFBN may occur. Department of Pediatrics, University of Bonn, Pediatric Nephrology, Adenauerallee 119, D-53113 Bonn, Germany

POSTER

OUTGROWTH OF T AND ~ CELL LINES FROM BIOPSIES O1r CI-~.,DILEN WITH PROLIFERATIVE GLOMERULONEPHRITIS (PG). There is a growing body of evidence that both lymphocytts infiltrating renal intra~titinm and pm~nal tubular epithelial cells (PTEC) are involved in cellmediated immune mechanisms of progression of renal danmge in different type,s ofglometulonephritis, In order to expand in cell lines activated iymphocytes infiltrating renal interstitinm, we cultured in presence oi" rIL2 (50 IU/ml) small fragments of renal medulla obtained from clinically mandated biopsies in 5 children with PG ('IgA 2, SHP 1, MPO 2). After the growth and confluence of a population of adherent cells, characterized as PTEC, it was observed an outgrowth of lymphocytcs on PTEC layer. Immunophenotypic study is reported in the table as percentage of positive cells: Cell line: 1 2 3 4 5

CD3 CD25

CD4 CD8 CD16 C.D56 P75

70 30 44 28 1 30 2

30 <1 2 65 70 65 76

98 24 63 26 5 25 70

97 68 95 1 4 4 4

99 75 97 4 <1 2 -

Re.turks: 1) lines 1, 3, 4, 5 showed a predominant phenotypr of T Itdtmr cell (CD3+ CD4+) 2) line 2 was predominantly composed of NK cells (65% CD 16+ CD56+ CDS+). This finding is of particular interest since NK cells has never been previously suspected to br involved in the mechanism of renal interstitium damage. These results show that activated lymphocytes intiltmtmg renal inmrstitinm can be expanded in lines wheu cultured in presence of rlL2.. Further studies arc needed on these lines (cytokine production and cellular interactions with PTEC) in order to assess their role in the immune me,zhanism of progression of renal damage hi PG. Barbeno G. ~ Facchetti P.*, Cappa F. ~ Prigione I.*, Trivelli A.~, Pistoia V. *, Peffumo F. ~ Gusmano R. ~ Nephrology Dept. ~ and Oncology Lab.*, (3, CrasliniChildren Inst., Genoa. Italy.

S E S S I O N - 0P) - C h r o n i c R e n a l F a i l u r e

P060

P059 CHRONIC RENAL FAILURE IN CHILDHOOD : A 1994 CHILEAN SURVEY

E. Lagomarsino, A. Valenzuela, F. Cavagnaro and E. Solar. (*) Since the previous report of Chronic Renal Failure (CRF) in chilean children from 1989, a marked improvement in diagnosis, medical supportive treatment, dialytic therapy and renal transplantation has happened, changing apparently the survival and quality of life of these children. In 1994, the nephrology branch of the Chilean Pediatric Society carried out a survey in order to get epidemiological data about CRF in children younger than 18 years old, information essential for planning future renal replacement therapy programs in this country. A questionary concerning this subject was sent to all pediatnc nephrologist and pediatric hospitals in Chile. CRF was defined as a glomemlar filtration rate below 30 ml/min/1.73 m2 for at least 6 months. Compared to 112 children in the previous report, this survey detected a total of 204 children, 109 gids, giving a prevalence of 50 / million children population under 18 years old. The main groups of primary renal diseases leading to CRF were Obstructive Uropathy (19.1%), Glomerular diseases and Pyelonephritis/Reflux Nephrepaty (17.6% each), and Hypoplasia/Dysplasia (15.2%). In 1989, the main cause of CRF was Pyelonephritis/Reflux Nephropaty (44%). Fifty one of these patients (25%) have undergone renal transplantation, all of them older than 5 years old. Ten percent of this group has lost the graft, mainly due to rejection. Thirty children (14.7%) are currently on dialysis therapy, 90 of them on hemodialysis. Peritoneal dialysis patients were significantly younger than those on hemodialysis. Call our atention that 17.6 % of the total group are lost from follow up Conclusion: In comparisson with previous report, we have noted a more active participation and notification of pediatricians taking care of children with CRF. The CRF secondary to preventable diseases have decreased. Peritoneal dialysis is still underutilized in our country. Renal transplantation is markedly increasing as a choice of renal replacement therapy in children with CRF.

(*) Revising Group of the Nephrology Branch of the Chilean Pediab'ic Society

CHRONIC RENAL FAILURE IN PAKISTANI CHILDREN R a m z a n A.,* J a m r o S.,* L a k h a n i B.* National Institute of Child Health, Karachi Chronic renalfailure (CRF) is the stage of progressive loss of renal function with GFR less than 30% with adaptive changes to maintain life. The salient features of this prospective study of 2 years duration were to: 1 . Stndy the clinical presentation of CRFfor udequate diagnosis 2. Determine fhe under lying cause leading to CRF, if possible,for early treatment Total number of 53 cases were included in the study on the basis of creatinine clearance less than 30% and p r ~ e offeatures of CRF.

Cases were collected from out patient department and admitted patients Medical amt Surgical Paediatric wards of National Institute of Child Health, Karachi. Detailed history and thorough examination was filled in special proforma and routine and spec~c investigations for diagnosis were done. As for age is concerned more common in age group 2-10 years. Male to female ration was 1.8:1. As for clinical presentation is concerned the most common presentation was with anaemia (94%) followed by growth retardation (79%) non specific symptoms (64%), symptoms related e to urinary tract (77%), hypertension / cardiac failure (58.5 o~), bone pain/deforrnity/tentany (49%) and some terminal renalfailure presentation with osdema, breathlessness, convulsion and coma. Among the causes chronic pyelonephritis was the most common single cause in 30% of patients. This was followed by obstructive nephropathy (15%), glomerulonephritis (15~ urolithiasis (13.2%), juvenile nsphronophisis (11.3%), multioystic disease (7.5%) and 1.9% of each haemolytic uremic syndrome, Alport's syndrome, congenital nephritic syndrome and renal tuberculosis.

In conclusion, we found that reversible or treatable causes of CRF are very common in our circumstance which include re/tux, obstructive nephropathy, uro!ithiasis and renal tuberculosis, etc. In our study these cause makes 66% of total number~of causes and we feel that these cases need early and appropriate management beforeand after development of CRF to prevent or delay progress of CRF.

C 69 P061 P O P U L A T I O N - B A S E D R E G I S T R Y OF C H I L D H O O D C H R O N I C R E N A L I N S U F F I C I E N C Y ON C O N S E R V A T I V E T R E A T M E N T GL Ardissino*, R Bonaudo**, V Daou6*, for the Italian Registry of Childhood Chronic Renal Insufficiency in Conservative Treatment (ITALKID). In order to study the epidemiology and better understand the natural history of chronic renal insufficiency in children, a population-based registry of the condition has been kept in several Italian regions since 1990. The inclusion criteria are as follows: 1.ereatinine clearance (CrCI) (according to Schwartz) <75 ml/min/1.73 m2 or for age <1 yr: sCr > (mean+2sd) for age and sex; 2. patient on conservative treatment; 3. age -<15.0 yr at time of registration; 4. patient resident in one of the regions participating in the initiative. All of the pediatric hospitals, pediatric nephrology, pediatric surgery, nephrology and urology units in the Involved regions are required to provide annual reports of all new cases meeting the inclusion criteria and to update clinical findings concerning previously registered patients. The registry currently had a reference population of 27.3 million (population <15 yrs: 4.3 million). The number of patients registered during the first three years was 290 (66% males), of whom 264 still met the inclusion criteria on December 31, 1993; the remaining 26 subjects had been excluded due to end-stage renal failure (22), death (3) or change of residence (1). The estimated time prevalence (year 1993) of the disease is 9.6/milliom general population and 61.3/milliun pediatric population (males 78.6/mpp; females 36.1/mpp). 6.6 cases/year/100 registered patients reached tg~:minalrenal failure. In terms of primary cause of renal insufficiency, the cases secondary to congenital uropathy accounted for 45;0% of the patients (of which VUR: 58.1%; PUV: 20.3%; Neurogenic Bladder:. 8.1%; UPJ stenosis: 7.4%; Other: 6.1%). The remaining cases were secondary to: renal hypo-dysplasia: 18.8%; glomernlar and vascular nephropathy: 10.4%; hereditary nephropathy: 8.8%; miscellaneous: 17.0%. For those cases secondary to congenital uropathy the male-tu-female ratio was 4.1:1 (VUR: 3.5:1). 67% of the registered patients had a severe organ (other than the kidney) associated diseases. At least 2 subsequent controls were available for 117 patients (age > 1 y r ) f o r whom the drop in CrCI (ml/min/1.73 m2/year) was calculated. This loss in CrCI was directly correlated with age (r:0.34; p<0.0001). In particular we observed that for the age group <5 yr a ACrCl/yr of +3.1!-6.8 ml/min/l.73 m2 (with a net increase in renal function); patients aged 5-10 yr a ACrCI/yr of -0.5+7.2 and for those aged >10 yr a ACrCVyr of -2.6+6.7. The loss in CrCl/yr inversely correlated with HSDS @:0.23; p<0.05), but no correlation was found with the level of CrCI at the beginning of observation. On the long run, we expect that this registry will provide us With important details on renal diseases with loss of function in children, with special enphasis on epidamiological issues, growth, rate of progression of the disease, influence of diet, treatment and socio-ecoaomic faetuis. * Dept. of Pediatrics - University of Milano - Milano- Italy ** Children's Hospital "Regina Margherita" - Torino - Italy

P063

P062 PATIENT REHABILITATION: SUPPORT BY PSYCHOSOCIAL SERVICES IN PAEDIATRIC RENAL CENTRES E. Reichwald-Klugger, J. Rosenkranz, O. Mehls, K. Sch[irer The importance of professional psychosocial care in children and adolescents with chi'onic renal failure (CRF) has been generally recognized during the last two decades. However, the question ,,wheather psychosociaI patient care is pure luxory or not" arises at the latest when psychosecinl services are planned to be installed and f'mancial resources for corresponding staff are required. For our country we are able to present data of a long term multicentre study which indicate that psychosocial patient care does not only cost a lot of money but also promotes and improves the economic independence of young adult patients. In 1987 comprehensive psychosocial services, including 15 new members, were newly established in 5 paediatric renal centres in Germany active in renal replacement therapy as part of a governmental programme. We performed three multicentre surveys in these centres comprising more than 500 patients at different stages of CRF in 1987 (479), 1990 (525), and 1993 (547) to obtain a representative view on the state of vocational rehabilitation in adolescent and young adult renal patients. Results: 1. The proportion of patients having started a vocational training after school graduation increased from 52% in 1987 to 79% in 1990 and 83% in 1993. 2. There is a continuous increase in the percentage of patients having achieved occupational degrees from 26% in 1987 to 40% in 1990 and 59% in 1993. 3. Employment rate for patients older then 16 years, having left school and not undergoing vocational training at the time of assessment was 71% in 1990 and 77% in 1993, whereas only 43% of patients were found having been employed in 1987. The data of the first investigation in 1987 can be seen as a baseline indicating the state of rehabilitation right at the beginning of the establishment of psychosocial services at the 5 eentres. These services were obviously able to support vocational rehabilitation of their patients as indicated by the results of the study. A follow-up study in 43 young adult patients (mean age 23.6) who meanwhile had been transfered from our paediatric centre into adult care documents that the degree of vocational rehabilitation achieved was stable over the following yearsl The results of both studies suggest that the introduction of psychosocial services in paediatric nephrology units support the lung-term adaptation to the chronic renal disease. Based on a 20 year experience efficient strategies of comprehensive psychosocial care for these patients will be proposed. University Children's Hospital, Heidelberg, Germany Supported by Kuraturium fllr Dialyse und Nierentransplantatiun e.V., Neu Isenburg

P064 STRESS. ANXI~i-Y AND ~ S I O N IN PARENTS OF CI4m.DREN WITH END STA(3HE RENAL FAILURE COMPARI~ TO DIABE~-~ M~.I_rlI/S AND C o N ' r R O I ~ Watson AR, Collier J, McKJnlay DE, Shaard CE, Pattison HM.

Previous 'snapshot'studies have shown that the extra demands on caters of a chronically fll child are associated with increased stress and a greater incidenc~ of related disorders such as depression and anxiety. We have carried out a longitudinal study over 2 yeats in parents of children with end stage renal failure (ESRF) (n=51) in an attempt to correlate stress in the parents with clinical events in the child's illness and with information and support needs. We compared the F-,SRF families with those of insulin diabetes mellitus (IDDM) (n=47). All were asked to complete questionnaires including Perceived Stress Scale and the Hospital Anxiety and Depression Scale on 7 occasions over 2 yeats. The questionnaires from control parents were compared with the study parents first returned questionnaires. Using ANOVA's for statistical analysis, mothers appeared to be significantly more anxious than fathers (p=0.001) and ESRF parents were significantly more anxious than controls (p=<0.02). ESRF parents were significantly more depressed than controls (p=<0.05). Parents of chronically ill children were more likely to have a depression score within the borderline and probable disorder range (p=<0.05). Longitudinal data confirmed significant correlations of stress, anxiety and depression scores with parental information needs, illness intrusion and/or general health of the child. Most parents of children with ESRF and IDDM may not perceive thenkselves as being more stressed than do other parents. They do however report more anxiety and depression. The fluctuation of anxiety scores with time in one family from 6 (<7 is 'normal') to 19 (>10 is 'probable disorder') illustrates how support from the multi-disciplinary team may be of greater benefit for the child and family if targeted during periods associated with high stress scores.

Paediatric Renal Unit, Nottingham City Hospital, HncknalI Road, Nottingham NG5 1PB, U.K:

PLASMAAND TISSUE ZINC CONCENTRATIONIN YOUNGGROWING RATS WITH CHRONIC RENAL FAILURE (CRF)AND PROTEIN ENERGY MALNUTRITION(PEM). AML Peraire~ BRM Santos ~ , JTA Carvel~es ~ PCK Nogueim ~ MC Ar~'ede ~ The purpose of this study was to evaluate if plasma and tissue zinc concentrations am me,tied by induction CRF and PEM during growth period. Wistar male young growing rats (43 to 73 days old) ware dMdad into six expadmentel groups: Uremic (U) - mrs with CRF induced by renal tissue mass reduction (initially resection of two poles and pert of the remaining cortex of right kidney, followed by a total nephrectomy of left kidney one week later); ialncudshed-1 ( i l ) - rats fed with the same amount of food consumed by uremic rats (pair-fed of U); Uremic-malnourished(U-M) - rats with CRF induced by the same model of uremic group and malnounshed by drastic food resection (8.0g/day); Malnourished 2 (M2) - rats with PEM induced by drastic food restriction of 8.0g/day (pair-fed of U-M); Sham-operated (S) - rats submitad to sham operation (without renal tissue mass reduction); Control (C) - rats remained intact throughout the experiment. The U, S and C animals consumed "ad libitum' food. All groups received non-restrict waterand ware submited to a 24 hour fasting in the first day of the experiment. In order to obtain biochemical data in an evotutive pattern, each group was divided in three subgroups of 15, 30 and 45 days from the beginning of the study, when the animals were sa~ifisad and the tissues were collected. Plasma creatinine, urea, total protein and albumin were assessed. Plama and tissue (encephalon, liver, muscle and bone) zinc concentration were measured by atomic absorption spectrephotomalry (Perkin Elmer- Mad.460) in all grot~. The results of this study showed: (a) U and U-M animals presented specific signals of CRF, such as plasma creatinine and urea levels significantly higher than in S and C animals; (b) there was no statistical sfgnifisant among groups concerning plasma total pmtain, albumin and z~nc; (e} PEM alone induced a significant increase of liver zinc levels in M2 animals; (d) there was a significant increase of muscle zinc concentration in M1 and U-M groups (e) CRF 'per ,re' induced a significant reduction of bone zinc levels while PEM increased significantly its conc.enlration. Zn(pg/dl) U (45) M1(45) U-M(45) I M2(45) S(45) C {451 Plasma 13'1• 1.47• 1.29=0.16 I 1.37=k0.12 1.46• 1.45=0.14 Eneel~alon 25A3• 25.~5• 28.24=294 I 29.t8==4.t7 ~.38• 25.51• Liver 43.83• 48.20,4.78 43.03• 54.14,5.38' 4284• 44.44~528 Muscle 32.48• 6.6~ 35.73• 7.11' 34.92• 4.'29' 33.58:=7.00 28.61• 25.97• 2.96 Bone 1~ 67• 252 15• 191.8.9~:50.41 181.24• 185.68,23.72 205.21• '* P<0.~5 Our results suggest that in young growing rats with PEM or CRF associated with PEM, zinc is redis~ibutad in ~ssue pools (liver, muscle and l:x:~ne)in order to maintain homeostasis. o PediatricNephrologyClinic * UniversidadeFederalde S~o Paulo (EscolaPaulistade Mecfcina),$~o Paulo, Br"~=il 9

C 70 P065

P066

Long-tenm growth preservation after short-term growth hormone therapy in a child with chronic renal insaffici~cy (CRI). Barry Warshaw*, M.D., Margaret Shaw*, R.N., Richard Fine**, M.D. Emory University, Atlanta, GA., and State Univm's~ty of New York, Stony Brook, New York.

NITROGEN B A ] ~ C E I N C H I L D ~ N ON CHRONIC RENAL FAILURE (CRF). M.Navarro, A.Alonso. R.Lama, MaJ.Martfnez Debora, R.Codoceo. ~ n a l and Nutritional Unit. Children's Hospital "La paz,'.~drid. At the moment we don't know the ideal diet for an adecuated nutritional state of children on CRF. We analyze the factors influencing Nitrogen Balance (NB) on 65 children, 46 on CRF (39 ~, 7 ~) aged 12.4• y, followed-up 8• y and 19 (14 ~, 5 ~) aged I0.2• y, followed-up 3.4• y on ambulatory peritoneal -dyalisis (APD). Renal function was measured by 51Cr-EDTA. Nutr! tional assesment evaluated by: anthropo~etry, bioimpedance, indirect calorimetry, 7 days diet-intake. NB was calculated after collecting dyalizate, urine and stool, 43% of CRF children and 31% of APD were on negative NB. Results are given in two groups positive (NB+) and negative NB (NB-). DATES: Mean (SD) NB + (36) NB - (29) NB gr,N,24h +2.86• -2.19• Age/y. 8.15• 13.16• Body Density gr/cc 1.060• 1.05• Height 2/Resistance 21.31• 37.25• E E R / EEC 0.9• 1.04• Kcal, kg,d 94.8• 50.9• Kcal Intake/OMS 1.17• 0.82• % Fat cal Intake 35.9%*** 39%*** 51Cr-EDTA ml/m/l,73 22.5• NS 25.8• NS

Recombinant human growth hormone (rhGH) was recently approved for treatmentof short stature resulting from CRI. Previous reports have shown that, following a period of catch-up growth, some patients may reach a normal height standard deviation score (SDS) based upon parental heights. Discontinuation of therapy at this point, as reported for a small number of patients, has generally resulted in a reduction in growth velocity with "catchdown" growth, suggesting that treatment with growth hormone may be required throughout childhood to sustain normal growth rates. In this report, we describe a patient who required only short term rhGH therapy to maintain long-term growth targets. A boy with CRI attributedto per• hypoxia, with baseline scram creatinine of 1.9 mg/di, began rhGH treatment at 3 B/12 years of age. Height SDS improved from -2.34 to -0.60 over 20 months, at which point treatmentwas discontinued because the patient had reached a predetermined target height SDS based upon mid-parental height. Growth essentially ceased during the ensuing 3 months off of therapy and height SDS fell to -0.87, but by 6 months growth had normalized again without resuming treatment. Throughout an additional 4 years of follow-up, growth velocity has averaged 5.5 emlyr and height SDS has remained near the target range without rhGH therapy. At 10 years of age, his height SDS is -0.63 and his serum ereatinine is 4.2 mg/dl. In conclusion, growth deceleration during the first few months after discontinuing rhGH therapy may be followed by spontaneous resumption of normal growth velocity and maintenance of target height SD scores. This important observation should be extended by appropriate studies in other patients to determine how often CRI patients may benefit from short term rhGH therapy.

EER: Expenditure Energy at Rest. EEC: Expenditure Energy Calculated. *P~ O.O01; **P~O.OI; ***P~ 0.005. Not ~ifferenceswerefound in Nitrogen intake between both groups. 48 children on a dally oral suplement had a significant higher NB (+0.85• VS -I.A• gr.N.24h) (P~O.05). CONCLUSIONS: NB is non influenced by GFR. Children on positive NB have a sig nil• improve in body composition by both anthropometry and bioimpedance. Positive NB is more difficult to achieve in adoles cent patients and may be due to their higher metabolic rate. Positive NB is mainly influence by total caloric intake and over 100% daily energy intake / OMS, was achieved with an oral d a i l y suplement in 75% of patients.

P067 GROWTH HORMONE (GH) STIMULATES GROWTH AND ALTERS THE SERUM INSUUN-UKE GROWTH FACTOR (IGF) AXIS OF CHILDREN WITH CHRONIC RENAL FAILURE (CRF)-REPORT OF THE SOUTHWEST PEDIATRIC NEPHROLOGY STUDY GROUP. DR Powallw K AttieL RL Hintz82F Liuql, B BakerL J Kuntzet, D Brown!, S Watkins+, ED Brewer~, RJ Hogg= 69 prepubertal children with growth failure and CRF (GFR = 10-40 mi/min/1.73m2) were'randomized (balanced for age and GFR) to receive either sc daily doses of GH (Nutropin, 0.05 mg/kg; N-46) or no treetment (control or C, N=23). We evaluated the effect of GH on growth parameters, and related these effects to changes in the serum IGF axis. Patients were followed for change (&) in height (ht), weight (wt), bone age (BA), triceps skin-fold thickness (TSF), mid-arm muscle circumference (MAMC), serum IGF-I and IGF-II levels (RIA), and IGFBP-1 (BP1), IGFBP-3 (BP3) and free IGF-I levels (IRMA, Diagnostic Systems Laboratories, Inc., Webster, TX). Baseline values did not differ significantly between groups for any parameter evaluated. Changes found dudng the first 12 mo of study are shown (meen• N Ahtlcm) Ah/t(SDS) ABA(yr) Awtlka~ ATSFfmm)AMAMC(cm) GH 36 9.4=2.8* 0.6=0.5* 1.0=0.3 3.3=1.5" -2.2=2.7* 1.1=0.9" C 15 5.6=1.8 0.0=0.3 0.6=0.3 2 . 1 = 0 . 9 0 . 6 = 1 . 5 -0.1• *GH vs C, p<0.02 Mo N IGF-Ilna/ml) IGF-Illna/ml) BP1 (na/mfi BP3(nq/ml) GH 0 31 130=90 768=227 440=236 3945=1656 12 31 228=153" 1013=468" 227=149" 5550=1968" C 0 14 106=t02 768=326 420=551 3170=800 12 14 83=30 710=229 400=302 3706=1311 *value differs from baseline, p<0.05 by paired t-test In further studies, baseline and 12 mo sera from GH and C children were pooled and studied: i) free IGF-I levels rose in GH but not C sera; ii) by immunoblot, IGFBP2 levels fall in GH but not C sera; iii) size exclusion chromatography at pH 7.4 found the increased BP3 of GH sera at 150 kD while the increased IGFs, which usually circulate complexed with BP3, were found not only at 150 kD but also at 35 kD. Conclusions: GH stimulates linear growth, body weight and muscle mass but decreases fat stores in CRF children. The increased growth may result from a rise in serum growth stimulators (free and total IGF-I), a fall in growth inhibitors (BP1, BP2) and/or a change in the normal association of IGFs with BP3.

Sponsored by zGenentech, Inc., S. San Francisco, CA. sDept Peds, Bay/or Co// Med, Houston, TX; tStanford Univ Med School, Stanford, CA; =Bay/or Univ Med Ctr, Dallas, 7X; + Univ Wash, Seattle, WA

*Emory University, Atlanta, CA. **State University of New York, Stony Brook, New York

P068 A WIDE APPLICABILITY OF GROWTH HORMONE( GROWTH HORMONE:GENOTROPIN) TO GROWTH IMPAIRMENT IN CHILDREN SUFFERING FROM VARIOUS RENAL DISEASES K.Ito, H.Kawaguchi~ and Multieenter S T U D Y G r o u p of G H in Japan

Growth failure(GF)is a serious complication in children with chronic renal insufficiency(CRl). However short stature also retnains one of the important therapeutic problems especially in children, treated with a long-term corticosteroids(CS), suffering from nephrotic syndrome(NS) and renal transplantation(RTx). A well-documented clinical studies including ours(Ito,K, et al. Clin Pediatr Endocrinol,1994) has shown that growth can be stimulated by GH. Furthermore we have shown that the growth suppressing effects o[ CS also can be overcome by treatment of GH in nephrotic rats(Kawaguchi, H. et al. Pediatr Nephrol,1993). Those results support that GH can be available in various renal diseases affecting growth in children. In this paper we report overall efficacy and wide applicability of GH to GF in children with above renal diseases. Our study included 112 children with CRl(non-dialysis:39), 27 with RTx and 22 with NS. Recombinant human growth hormone(r-hGH, Genotropin, Kay• was used with doses of 0.5(nondialysis)and either 0.5 or l.OIU/kg/week in dialysis, RTx and NS.Overalt growth velocity (GV) was increased around two times in average after GH treatment. When an increase of GV,over 2cm/year than before GH therapy, is defined as therapeutically effective, 54.4% of CRI, 67.1% of RTx and 68.2% of NS benefitted from GH therapy. No serious side effects also was noted except 2 children with RTx showing graft dysfuntion. From our clinial results, we conclude that GH therapy should be warranted and~or tried in not only CRI and RTx but also in various renal diseases, disturbing growth hormonal axis especially in NS and glomerulonephritis, necessitating a long-term CS therapy. Dept. o/Pediatric Nephrology, Kidney Center, Tokyo Women's Medical College-Tokyo-Japan

C71 P069

POT0

A DOSE MODIFYING EFFECTS OF GROWTH HORMONE (GH:NN-798,NORDITROPIN) IN CHILDREN WITH CHRONIC RENAL INSUFFICIENCY(CRI) K~|to~ H.KawaguchL and Japanese Multicenter Study Group

The influence of n u t r i t i o n on the recombinant human growth hormone (rHGH)treatment in s h o r t c h i l d r e n with ESRD H. I t o ' , N.Yoshikawa", T. S a k a i " ' : Cooperative Study Group of SJ-0011 Therapy in Children with ESRD

Growth retardation (GR)has been a major problem in children. Recent clinical studies convincingly indicate that GH stimulates growth signifiacntly in those children. However the optimal clinical dose of GH has not been yet established with regard to its growth promoting and adverse effects. We tried to treat CRI children with GR using two doses of GH to set up the optimal dose in Japan.The study population comprised 58 prepubertal children(Mean age:8.7+-3.1 years old) without dialysis as well as 54dialysis treated children (Mean age:lO.O+-3.8years old). Patients were randomly assigned to either 0.5 or 1.0lU/kg/week of recombinant human growth hormone:NN-798).The study evaluated the differences in efficacy and safety after 6 months and 1 year treatment. Predialysis children: In 0.5IU group, growth velocity(GV) was increased from 3.8+1.5 to 7.8+-2.5 at 6 months and 7.3+-2.0cm/year at 1 year. In 1.01U group, GV from 4.5+-1.4 to 10.3+-2.9 and 8.7+-2.7era/year, respectively. Stimulation of GV was significantly greater in 1.01U group than that in 0.51U group(P2cm/year) were significantly greater in 1.0IU group than 0.51U. Incidences of side effects were not significantly different between 0.5IU and 1.0IUgroup. In com:lusion , we suggest that 1.01U is preferable to 0.51U to expect growth improvement in children with CRI.

We studied the influence of the n u t r i t i o n a l s t a t e on the e f f e c t s of rHGH in s h o r t c h i l d r e n with ESRD. Nineteen prepubertal c h i l d r e n on d i a l y s i s received 0.5-1.OIU/ kg/W of SJ-O011 for 6-12 months. The median height v e l o c i t y (MHV)increased from 3.4• to 6.6• (p<0.05), MHV-SDS from -3.1• 1.5~3.7 (p
Dept. of Pediatric,Nephrology, Kidney Cenler, Tokyo Women's Medical College-Tokyo-Japan

"National C h i l d r e n ' s Hospital. " ' D e p t . of Ped., gobe Univ. H o s p i t a l . " " D e p t of Urology, Kiatazato Univ. Hospital.

P071 GROWTH, DEVELOPMENT AND FOLLOW-UP OF NEONATES WITH RENAL HYPODYSPLASIA AND END STAGE RENAL DISEASE. F. JANSSEN, K. ISMAILI, CI. VAN AELST, M. CAMUS, M. HALL, Th. SCHURMANS, L.HOOGHE and P. KINNAERT. Hopital universitaire des enfants -Reine Fabiola. Univsrsite libre de Bruxellss - BELGIUM. Children with congenital renal disease and chronic renal failure are the most severely growth retarded. The right time to start aggressive nutritional support, dialysis and transplantation is still controversial. Therefore we reviewed the charts of 10 newborn-infants ( 6 males, 4 females ) with an ultrasonographic diagnosis of renal hypodysplasia and severe renal failure ( median serum creatinine level : 3.2 m g / dl at 1 week of age ) followed for 2 to 9 years.All babies received calcium carbonate, caleitriol, and sodium bicarbonate as well as sodium chloride according to the needs.Oral caloric and protein intake were above 100% of the recommended dietary allowances (RDA) and re.estimated every two weeks.All infants showed a drastic deficit of 1.9 SD in height and 2.4 SD in weight after 3 months of life. Half of them were subsequently submitted to nasogastric feeding during night in addition to their oral intake with the aim to reach 150% of caloric RDA. However the main statural growth remained under 2.4 SD after two years. The glomerular filtration rate did not change from 15 m l / ' / 1.73 m2 ( 5-25 ) at 3 months of age to 20 ml / ' / 1.73 m2 ( 5-30 ) at 24 months.Developmentally all infants were functioning in the normal range, only delayed language was observed in 60% of children.Three boys were transplanted at 2, 4 and 5 years but remained growth retarded, two of them are now treated by rhGH injections with a catch up growth.Infants with congenital hypodysplasia can be treated conservatively for a long time before transplantation hut in order to avoid the loss of first months life growth potential, it seems that aggressive nutritional support should start at birth instead of at 3 months of age. Preliminary results also suggest that rhGH could be beneficial.

P072 ANTHROPOIVIETRY A N D B O D Y COMPOSITION C H A N G E S IN C H I L D R E N W I T H C H R O N I C R E N A L FAILURE (CRF) T R E A T E D W]TH RECOMBINANT HUMAN GROWTH HORMONE (rHGH). The effects of rItGIt treatment on-anthropometric parameters a n d body composition have been evaluated in 18 prepubertal children (3.6-14.5 years of age) with CRF followed lbr 12-24 months of therapy (mean GH dose 4 IU/m2/day). C r r o ~ velocity increased flora 3.4_+0.5 cm/yr to 8.7+1.9 cm/yr in file first year and to 7,3+ 2.0 enff,vr in the second. The dietetic intakes, evaluated on the basis of 3-4 day records every 2 months and expressed as % of RDA tbr chronological age, showed an increase in protein int,xke (98+15% beIbre treatment vs 107+13% during treatment) ~ d no change in calorie int~&e (96-~12% vs 98• Anthropomett)" showed a sie~ificant increase or" parameters of muscle mass such as mid-arm muscle circumference (from 153• mm to 166_+27 turn, p<0.tXI01) and upper ann muscle area (1841+580 ram2 vs 2203+671 nma2. p<0.0001), wifll no change of indicators of fat stores, skinfold-thickness, upper ann tat area (641+449 n~n2 vs 682+384 rm12) and boch/mass index 1.16.2XI.9 vs 16,8Z1.7). BMy c~mlposition evaluated by biohnpedance analysis showed art increase of fat-flee mass (81.1+3.1% vs 84.7=4.6%, p<0.01) and no change of total body water, extracellular water and intraeallular/extracellular water ratio. There was a sigafi.ficant direct correlation between the increase of body weight and fat-free umss 0"-=0.7956, p<0.O001) and between uppel mxn muscle m~a and fat-free mass (r~).6118, p<0.01). The results of this experience show, m addition to the well-haown efle,cts on growth, that during GH trealanent there is art increase ill protein consumption, an hnprovement of parameters of muscle nlftss: no change of indexes of Ixxty tht and, important to note ill relauon m previous reports, no expansion of extracellular water. F. Pettimao, A. Trivelli, P. Delucclfi, P. Saeeo. A. Canepa. R. Gusmano. Nephrology Department, G Gaslini Children histitute, Genoa, Italy.

C 72 P074

P073 THE E F F E C T O F R E C O M B I N A N T H U M A N G R O W T H H O R M O N E (rhGH) ON H E I G H T VELOCITY AND N U T R I T I O N A L STATUS IN U R E M I C C H I L D R E N N.Ivanovsld *,Z, Antova *,G.Masin *,D. Kuzmanovska* * We studied the effect of rhGH (Norditropin-Novonordisk) on six children (4 boys and 2 girls) on maintenance hemodialysis, age 13.8 (range 11-17). The rhGH has been given in doses of 4 IU/m2/day subcutaneously. The height velocity was followed six months sistematically before starting the therapy and six months after. Growth was estimated by the use of Holtain stadiometer. The nutritional status was estimated by anthropometric measurements including triceps skinfold thickness (TST), midarm muscle circumference(MAMC) and lean body mass (LBM) as well as serum albumin concentration. Mean height velocity increased from 1.59"s in the last six months before treatment to 3.25+1.22 after six months of therapy, which means double height velocity compared to that before therapy. In the same time body weight also increased from 31.62+5.98 to 33.7+_6.7 six months after, as well as body surface area from L02+0.12 to 1.12+_0.14m 2. L B M (kg) also increased from 26.85+5.04 before, to 30.01+6.05 six months after the therapy. We noticed the decrease of TST from 7.14+1.73 to 6.7+2.12 whereas M A M C increased from 15.36_+2.36 to 16.72+2.43. The serum albumin concentration also increased from 33.3+1.25 to 36.16+2.11.The nutritional parameters confirmed the beneficial anabolic effect of rhGH therapy. The authors recommend the rhGH therapy in uremic children with growth retardation as well as in any case of malnutrition in these patients. * Department of Nephrology, Medical Faculty, Skopje,Macedonia ** pPdiatr~r Clinic. Medical Faculty. Sknnie. Macedonia

P075 RESPONSE TO RECOMBINANT HEPATITIS B VACCINE (RECOMBIVAX HBe) IN CHILDREN WITH CHRONIC RENAL FAILURE (CRF). S.L. Watkins*, R.J. Hogg**, S.R. Alexander***, E.D. Brewer****, S.M Bailey*, J.L Burns*. Hepatitis B infection remains a significant problem in the dialysis and transplant population. Previous studies have shown diminished seroconversion following hepatitis vaccination in pts with CRF leading to the use of higher doses of vaccine in adults with CRF. This report descdbes the response to 20 ~g/O.5 ml dose of RECOMBIVAX HB| in children with CRF (defined as estimated creatinine clearance <60 ml/min/l.73m 2 or progression to chronic dialysis or renal transplantation). 68 CRF children, age 1-19 yrs (mean 9.7 yrs) have been immunized with a full course of three 20 pg doses (baseline, 1 mo and 6 mo) with HBsAb titers at 1, 3, 6, 7, and 12 mos post-initial dose. 58 also have 12 mo HBsAb tlters. 23 were prelOmlU/ml) with 23/23 (100%) PreD and 31/33 (94%) dialysis pts having seroconvarted after 3 doses, compared to only 8 of 12 (67%)transplants. Two transplant patients seroconverted after a fourth dose, two did not. Further, 22/23 (96%) of PreD and 25/33 (76%) dialysis pts seroconverted after only 2 doses. Seven of 53 (i3%) seropositive pts had titars falling to <10 mlU/ml at 12 mo. No serious adverse events could be attflbuted to vaccine. This study finds encouraging HB vaccine seroconversion rates after three 20 ~g doses in pediatric pts with CRF, including those on dialysis. Conversion in the post-transplant population is less encouraging. This has important implications for pediatric nephrologists. Attempts should be made to vaccinate children with CRF against HB pdor to transplantation. Delaying transplantation by one month would allow 2 vaccine doses, which was protective in the majority of unvaccinated pre-transplant children in this study (47/56, 84%). A third vaccine dose 6 months after the initial dose further increases sercconvarsion rates in children with CRF. Sub-responsive pts should be considered for a fourth dose. Sponsored by Merck Research Laboratories, Division of Merck & Co., Inc. *U of WA, Sea#le WA; **Baylor UMC and ***UTSWMC, Dallas TX; ****Baylor Coil Med, Houston TX:

EFFECTS OF A N ORAL ABSORBENT ON CISPLATININDUCED NEPHROPATHY IN YOUNG A D U L T RATS T. S a t o , S. M i y a z a k i

We studied the effects o f an oral absorbent, AST-120 (Kureha Chemical Ind. Co., Tokyo), on lO-week-old rats with cisplatin-induced nephropathy. At first, cisplatin was intraperitoneally administered for16 weeks in two groups, a control group (n=lO) and an AST-120-treated group (n=lO), but there was no significant difference in serum creatinine, creatinine clearance, or blood u r e a n / trogen between the groups. The second experiment lasting 26 weeks was designed to see the effect o f AST-120 in rats with cisplatin-induced chronic renal failure. AST120 was started during the14th week. We found that creatinine c l e a r a n c e was significantly higher in the AST120-treated rats (n=11) than in the control animals (n-10) (1.09 +_0.48, vs 0.63+_0.39 ml/min; p <0.05). Also, a pathological study analyzed by a computerized image scan reavealed that the AST-120-treated rats had a significantly lower tubular/cortex a r e a ratio than the control group (0.28 +_0.08 vs 0.36+-0.06;p<0.05). Conclusion: A beneficial effect of oral absorbent, AST-120, was not observed in subacute renal failure due to tubulotoxic nephropathy; however, it blunted progressive deterioration o f renal function and nephron architecture in chronic renal failure. Department of Pediatrics, Saga Medical School, Saga, Japan.

P076 LIPID PEROXIDATION IN CHILDREN WITH CHRONIC'RENAL DISEASE U. Querfeld 1, S. HSfer1, D.V. Michalk 1, H.J. B6hles2 Estimation of lipid peroxidation in children with renal diseases might provide useful information regarding the stherosclerotic and nephrotoxic potential of dystipidemia in the individual patient. Serum malondialdehyde (MDA) has been used as an indicator of peroxidation; however, the assay has been fraught with problems. Usually MDA is measured by spectrophotometry after reacting with thiobarbitudc acid (TBA); a method with poor specificity, with MDA being only one of the thiobarbituric-acid reactive substances (TBARS). We have employed a sensitive and specific assay for MDA in serum (Wong et al., Clin Chem 33, 214, 1987). After reacting with TBA, MDA is separated from Other TBARS by HPLC and measured by spectrophotometry at 532 nm. Normal limits for MDA in children with this method were established (0.4-0.9 i~mol/L). 32 patients aged 2.6-22.5 years were studied: patients with nephrotic syndrome with normal (NS) or diminished (NS+CRF) rena function, chronic renal failure (CRF), peritoneal dialysis (PD) and transplantation (TPL). l

GROUP

N I MDA (Serum)

I

GFR (ml/min/1.73 m2

U.-Pretein (g/m2/d)

NS

6

3.66 + 2.32

104-280

4.9 + 6.2

NS+ CRF

6

2.00+ 1.15

7 -

46

3.6+3.6

CRF

5

1.93+0.58

10-48

0.2+0.2

PD

9

2.46 + 1.2

0

0

TPL

6

2.18+1.66

47-150

0.12+0.07

Thus, increased MDA levels were found in serum of patients in all groups. Measurement of MDA with this method may be helpful in evaluating the effect of antioxidants and/or lipid Iowenng drugs. University Children's Hospitals, 1Cologne and 2Frankfurt, Germany.

C 73 P077 HELICOBACTER PYLORI IN CHILDREN WITH CHRONIC RENAL FAILURE H. AIpay*, M. (~elergen*, F. (~ullu**, I". Kutlu**, H. Yazgan*, M. Alik~ifol~lu*, S. 0z~y* A number of causes and mechanisms arc held responsible for the gastrointestinalchanges in chronic renal failure (CRF). Besides hypergastrinemia and hypochlorhldria,now it is shown that helicobacler pylori (liP) infection may also be responsible. In this study, by observing the endoscopic and histopathologic changes in the gastrointestinal system of children with CRF we searched for the relation between these changeSand the presenceof liP infection. Between 1994 and 1995, in 25 children (11 boys, 14 girls) that were followed up with the diagnosisof chronic renal failure in our clinic, gastroduodenal pathology and incidenceof kiP infection is investigated by gaslroscopy (Olympus GIF X P20). The mean age of the patients was 11.13 + 6.73 years (1 to 15 years). Duodenal (n=l), gastric (corpus n=2, antrum n=3), oesophagea] biopsies were taken from all cases.,-Theinvestigationof HP was done by culture (antrum n=l, corpus n=l), histopalhologie observation (Giemsa, antrum n=2, corpus n=l), urease test (Clo test, antrum n=l) and serologic scanning studies (anti liP IgG, ELISA.) The diagnosis of HPinfeelion is confirmed by the positive culture and / or histopathologicresults or by the concominenl positivily of serology and urease. In the endoscopic examination, abnormalities in the gastrointestinal system was found in 64 % of the patients, anlral gastritis (with or without duodenit, oesaphagitis, bile reflux and duodena] lymph hyperp]asia) in 44 %, peptic ulcus in 4 %, hiatal hernia in 4 %, duodenit in 4 % (without antrai gastritis), bile reflux in 4 % of the patients. All the patients have shown histopathologica] changes in various stages: Chronic active gastritis in 76 %, chronic inactive gastritis in 8 % and minima] changes such as edema and hyperemia in t6 % of the patients was found. HP was positive in 76 % of the cases. When the patients were cvaiuated according to the gastrointestinal system symptoms,it was observed that 80 % of the patients were asypmptomatic. In asymptomaricuremic patients the incidence of HP was 73.68 %. This higb incidence of HP especially In asympinmalic patients was sn-iking. With these resulls it can be taken into consideration that besides hypergastrineroia and hypochlorhydria lip may be responsible for the gastrointestinal changes and bleeding in CRF. Routine HP investigation should be recommendedfor the uremic patients who are being prepared for transplantation. * G~ztepe Social Security Hospital, Istanbul-TURKEY. ** lstanbul Universt y, Ceaxahpa~a Medical School, Istar&eI-TURKEY.

P079 O R A L VERSUS I N T R A V E N O U S GLUCOSE T O L E R A N C E TEST IN C H I L D R E N W I T H CHRONIC R E N A L FAILURE G. Filler, U. Bade, P. Amendt, S. Devaux, and J.H.H. Ehrich

Glucose tolerance was studied by oral (OGTT) and intravenous (IVTT) glucose tolerance test in 20 children (6 female and 14 male) with ehronie renal failure (CRF) due to primary renal disease other than infantile cystinosis. 7 patients were in CRY, 4 were on peritoneal dialysis and 9 patients were transplanted. Mean age was 10.7 • 4.9 years (median 11.5, range 1.1 - 17.4 years)), mean height was 127 cm • 26 (median 134 em) and mean weight was 31 • 15 k g (median 30 kg, range 8 - 62 kg). Median serum creatinine was 189 gmol/1 (mean 328 • 334 gmol/l). After OGTT serum glucose rose from 4.9 J: 0.8 mmol/1 to 8.1 • 1.3 mmol/1 after 30', 7.7 • 2.2 mmol/l after 60', 6.9 • 2.0 mmol/1 after 120' and 5.2 • 1.3 mmol/1 after 180'. 10 out o f 20 patients had impaired glucose tolerance according to WHO-criteria (120' value between 6.7 and 10.0 mmol/l in venous blood) and one out o f 20 patients had diabetes mellitus (120' blood glucose > 10.0 retool/l). None o f the patients had a blood glucose > 6.7 mmol/l after 180'. Insulin rose from 14.0 • 9.2 to 75.4 • 42.5 gU/ml after 30', 60.1 • 34.1 gU/ml after 60', 52.1 • 28.0 gU/ml after 120' and 32.7 • 25.1 gU/ml after 180'. C-peptide was normal in all patients. Mean H b A l c was 5.25 • 0.78 %, o n l y two patients had a H b A l c o f above 6.0%. It is noteworthy that modality o f treatment o f CRF had no influence on the results, transplanted children with steroids did not differ from children on conservative treatment o f CRF. Only serum creatinine differed statistically significant from patients on PD when compared to CRF and transplanted children. ARer IVTT none o f the patients had a pathological k-value (mean 2.06 • 0.46) or a pathological 1' and 3' insulin sum in IVTT. The data suggest that OGTT may not be suitable in patients with CRF and may give false pathological results, W e conclude that glucose tolerance in children with CRF should be tested by IVTT only. Department of Pediatric Nephrology - Humboldt University - Berlin - Germany

P078

LONG TERM EVALUATION OF LONGITUDINAL GROWTH IN CHILDREN WITH PRETERMINAL RENAL FAILURE (PTRF) UNDER TREATMENT WITH RECOMBINANT HUMAN ERYTHROPOIETIN (rhEPO) D. E. MGIler-Wiefel, K. Daniel, O. Amon

In contrast to the situation in terminal renal failure we previously had been able to demonstrate a significant short term effect of rhEPO on longitudinal growth in children with PTRF when the hemoglobin concentration was normalized. We now evaluated the long term results of longitudinal growth in 25 children (aged 0.3 - 17.0, mean 5.9 yrs) whose renal anemia ( Hb 8.2 g/dl) was corrected (Hb 11.5 - 13.5 g/dl) by rhEPO for a mean period of 24 (range 6 - 42) months. During that time GFR only decreased from 18.9 to 16.8 ml/min/1.73 m 2. Height SDS for CA significantly (p < 0.05) increased from - 2.1 at start of treatment to - 1.75 after the mean observation pedod. Mean height gain was only 0.1 cm within the 6 months period before rhEPO, according to a median height velocity SDS of - 2.0, but significantly (p < 0.05) increased to 6.0 cm/yr corresponding to a mean height velocity SDS of - 0.72. During the observation period a total of 40 % of the children achieved positive height velocity SDS. The amelioration of growth velocity was less pronounced in infants up to two years of age (N = 9) and pubertal children (N = 5) with an SDS changing from - 1.25 to - 1.0 and from - 0.4 to - 0.3, respectively, whereas in the remaining 11 pts height yelocity SDS increased from - 2.4 to - 1.8. After 36 months (N = 9) of treatment mean height SDS had further increased to - 1.70 with a mean height velocity still being - 0.50. Data suggest that the correction of renal anemia in children with PTRF essentially contributes to an amelioration of longitudinal growth, so that the use of rhEPO should be started early in the course of chronic renal failure and precede the therapeutic use of growth hormone. University Children's Hospital Hamburg, MartinistraE, e 52, D - 20246 Hamburg, Germany

P080

THE EFFECT of PLASMA CARNITINE LEVELS ON TO CARDIAC FUNCTIONS in PATIENTS TAKING HEMODIALYSIS A.Cura*,S.Mir*,A.Hfiseyinov*, R.Szyfirek**, N.Betin*. Carnitine (~,-trimetilamino 13 hydroxybutirat ) is an aminoacide supplying energy via ~ oxydation in physiologic reactions by carrying fatty acids to the cytoplasmic haitochondria from the cell membrane in tissues. In this study, we examined the carnitine metabolisan and its possible effect on to the cardiac functions in patients taking hemodialysis (HI)). Twenty patients (6 girls and 14 boys) aged, 8-16 years (mean 12.9 _+0.1 years) were included in the study. The patients have been receiving HD for 6-44 months (24.85 + 1.18 months) meanly three times a week in HI) machine (302 Toray and Fresenius 2008A ) using cuprophan membrane (0.8-1 m 2) and dialisate with acetate (15 patients) and bicarbonate(5 patients). Mean duration time for HI) was 120.75+L46 rain.(60-180 min.). Cardiac functions were evaluated by telecardiogram, electrocardiography (ECG: cardiofaks), and echocardiography (ECHO: Hewlett-Paekard Sonos 1000 2D color doppler ecbocardiophy). Group 1 including 7 patients and group 2 including 13 patients were defined by these settings. Ten patients formed control group (group 3) The levels of plasma camitine were determined before (period 1 ) and soon after (period 2) and an hour after HD (period 3) in all patients by HPLC method (results given in p,g/ml plasma) using Sep-Pac-Silicagel columns for extraction. All patients had low levels of plasma carnitine in period I, especially seen in group 2. Plasma eamitine levels of period 2 were lower than those of period 1, whereas group 2 with cardiomyopathy had worn significant low levels. In period 3, carnitine levels began to rise as compared to. periods 1 and 2 while period 3 had still low levels. In conclusion we think that low levels of eamitine in plasma may play a role in causing cardiomyopathy in patients taking HD and they will benefit from carnitine replacement in therapy. *Ege University, Medical Faculty, Pediatric Nephrology- i~nir-TURKEY **Ege University, Medical Faculty, Pediatric Cardiology- lanir-TURKEY

C 74 P081 EFFICACY AND SAFETY OF ENALAPRIL IN CHILDREN WITH REDUCTION OF RENAL M~SS. M.Navarro, A.Alonso, J. Roman, A.Fernfindez, M.J.Martinez. Renal Unit. Children's Hospital "La Paz". Madrid. Spain. An~iotensin Converting Enzyme (ACE) inhibitors possess a renoprotective effect in progressive chronic renal disease. We analyzed the effects of enalapril treatment on 43 children (37 ~, 6 5 ) , aged 13.9• y (range 4.6-22.7 y) included in a prospective study. Primary renal disease were reflux nehpropathy, obs tructive uropathy and renal dysplasia. Inclusion criterions: G F R < 8 0 ml/m/l.73, proteinuria~ 4 mg/m2/h or microalbuminuria>40 mcg/m in two visits during a 6 months period and BP< P90 for each age. Clinical visits were every 3 months. We analyzed a 2 years period pre and post-enalapril -treatment. Initial dose was 2.5 m g < 20 kg and 5 m g > 20 kg. The dose was increase in relationship to protein excretion. DATES. Mean SSD -24 m. +24 m P Wheight {SSD) -0.47• -0.34• NS Height (SSD) -0.73• -0.58ii.2 NS SBP • mmHg ~90 -13• -19• 0.001 DBP • mmHg Pgo -13• -17• 0.01 SNa mEq/l 141.7• 140.5• 0.001 SK mEq/l 4.4• 4.6• 0.001 Plasma Renine pg/ml/h 3.4!6.4 5.7• 0.01 51Cr-EDTA ml/m/l.73 42.9• 36.8• 0.01 Proteinuria mg/m2/h 31.8• 25.4• NS Enalapril mg/kg/d 0.01• 0.07• 0.001 Hb gr/dl 13.7• 13• 0.001 White CxlO6 6.6• 6• 0.05 SBP and DBP decreased (r=O.14, r=O.13; P
1'083

MODELISATION O F STATURAL DEVELOPMENT AND BONE M A T U R A T I O N IN CHILDREN W I T H END STAGE R E N A L FAILURE. M. Foulard* K. Kherbek* M. Dehennault* P. Saunier* C. Grave,* A. Duhamel .** Statural development and bone maturation are temporal continious process. They can be modelised in normal individual. J.P:P:S model is particularly -applicable,: Primary and secondary derivatives of the model give a good idea of the fluctuations in the speed and rate of maturatiori~which can be very useful to point specific events. The aim o f the study is to find out if modelisation of stamral growth and bone maturation is feasable in children with end stage renal failure. MEthod: 118 end stage renal failure patients who have reached puberty and have not been treated with growth hormone, but who had at least six heigth measurements and six X-rays of left hand and wrist at six months interval have been included in this retrospective study. Heigth was measured in the standing position. Analysis of the 637 X-rays was performed using 22 bony criteria which determine the degree of maturation and the percentage of maturation achieved (SEMPE method). Confirmation of fit to the model has been made using 3 methods: graphical method, non linear GAUSS MARQUARDT repeated algoryhtm and chi square test with nk degrees of freedom. Conclusion: Statural development and bone maturation are modelisable in chronique renal failure. J.P.P.S model is particularly appropriate. Modelisation could be useful in follow up of growth retardation in chronic renal failure and o f its treatment. *Unit6 de Ngphrologie Ptdiatrique-Lille-France ** Dtpartement d'informatique mtdicale-Lille-France

P082 ORAL CALCITRIOL PULSE TIIERAPHY IN CtlILDREN WITI{ RENAL OSTEODYSTROPHY Drs. Cano Sch F, Delucchl B. MA., Wolff P. E., Rodrlguez S. E.

Nine uremic-dialyzedchilds, 2 to 14 years old, 5 males, were treated with an oral p~se calcitdol protocol for 6 months, in order to reach an oplimal control of renal osteodystrophy. A plasma paratohormone (PTH) level at least over 10 limes the normal value was required before tire protocol was started. Calcitriulwas admbfisteredtwice a week, 4 ug each time for childrensover 30 kg, and 3 ug for patients under 30 kg. Calcium, phosphorus and alkaline phosphatasaswere carefullycontrolled duringthe protocol. The youngest child, 2 year-uld, received 1-alphavitDoral drops,because she was not able to swall vitD capsules.RIA mid- region assay was used to measure PTH in 8 patients, and the ELISAintact moleculewas used in 1 patient. PTH plasma levels decrease by 68% and 56% at the 2rid and 6th month of the study in 7 patients. Eigth hypercalcamie episodes for 77 calcium plasma mcasuremeats were found. All of them easily recovered after I week of vitD withdrawal. No changein.PTH plasma levels could be observed in two patients with a Focal Segmental GtomemloSclerosis Gtomengophathy and massive proteinuria. We conclude that oral calcitfiolpulses represents a good therapeutic alternative to treat renal ostandystrophyin uremic childs.A carefullPTH and calciumfollow up are needed when applyingthLskind oftheraphy.

Division of Pediatric Nepilrology, Luis Calvo Maekenna Children's Hospital Santiago de Chile

P084

RENAL OSTEODYSTROPHY IN PEDIATRIC PATIENTS WITHOUT 1,25-VITAMIN D TREATMENT. M.C.Andrade & J.T.A.Carvalhaes We have assessed the renal osteodystrophy in 16 pediatric patientS with chronic renal failure (Creatinine clearance < 50 ml/min/1,73 m2) aging between 3 and 15 years. Five children received hemodialysis and six peritoneal dialyis-CAPD. None of the study patients had received any form of vitamin D therapy, and CaCO 3 was the primary phosphate binder. All patients had b o n e biopsies w i t h quantitative histomorphometry. Laboratory parameters studied included serum calcium, phosphorus, alkaline phosphatase, immunoreactive PTH (NH2 terminal podion of the hormone), pH and HCO 3, besides roentgenografic and nutritional evaluations. Results demonstrate that 100% of patients had disturbs in bone histology: 50% had osteitis fibmsa, 25% aplastic lesions, 18,75% mixed lesions and 6.25% osteomalacia. Aluminium related bone disease was not observed. The type of bone disease could only be accurately assessed histologically. No predictive parameters of bone disease were found from biochemistry or radiology. Nutritional assessment has showed that 94% of all patients were short for chronological age. In sumary, bone disease was a common finding in this patients and adynamic bone disease with negative aluminium staining was observed in 31.25% of pediatric patients without 1,25-vitamin D treatment. Section of Pediatric Nephmlogy. Department of Pediatrics. Universidade Federal de S~o Paulo. Escola Paulista de Medicina. S~o Paulo. S~o Paulo. Brazil.

C 75 P085

BONE MINERAL DENSITY EVALUATED BY DUAL ENERGY X-RAY ABSORPTIOMETRY (DEXA) IN CHILDREN WITH ,ENDSTAGE RENAL DISEASE (ESRD) DURING rhGH TREATMENT PRELIMINARY REPORT M. Sieniawska 1, M. Panczyk-Tomaszewska 1, H. Zi6/kowska1, J.W~glarska 1, J. Przedlacki 2, R`. Bednorz3, A.Kanik 4, K. Wilkosz 5, The aim of the study was to evaluate bone mineral density of total body (TB-BMD), lumbar spine (LS) and distal radius (DR.) using dual energy Xray absorptiometry in children with ESRD during first 6 months of rhGH treatment. Thirteen children (aged 6-13 years) were observed; 6 on CAPD, 7 on HD The following doses were given: rhGH I-I,1 IU/kg/week every day in the evening, alfacalcidol 0,038-1,13 ug/kg/week, calcium carbonate 50190 mg/kg/day. Before rhGH treatment, SDS for TB-BMD were from -2,0 to 0,92 (mean -0,85). After 3 and 6 months SDS for TB-BMD decreased in 9 out of 13 children and DR. in 8 out of 13 treated with rhGH SDS for LS were various in individual children; the mean value increased slightly. The mean dose of alfacalcidol (0,09 ug/kg/week) was higher in children in whom SDS for TB-BMD increased or was unchanged in comparision with children with decreasing TB-BMD (mean 0,06 ug/kg/week). In 6 of these children serum PTH intact level increased during 6 months of rhGH treatment. There was no relationship beetwen bone mineral density and growth velocity. Conclusions: In children with ESRD during rhGH treatment bone mineral density, particularly total body and distal radius, tends to decrease. In some of them PTH intact level increased in the early period ofrhGH tratment. One can speculate that during rhGH treatment higher doses of active metabolites of vitamin D are needed, especially in children with increasing growth velocity. 1 University Children's Hospital,Warsaw, Poland 2 Department of Internal Medicine ,Warsaw Medical Academy, Poland 3 University Children's Hospital,Wroclaw, Poland 4 Regional Hospital, Rzeszow, Poland 5 Pol-Amer. Inst. Pediatr.CMUJ, Krakow, Poland

P087 BONE MINERAL CONTENT (BMC) IN CHILDREN WITH CHRONIC RENAL FAILURE {CRF) AND CHANGES INDUCED BY THERAPY WITH GROWTH HORMONE (rHGH).

N Orte-Slbu*, R Lanes*', R Scovino*, P Gunzcler**, L Domlnguez*, M Bosque**, JC Moriy6n*, J Weissenger*** and V Paz-Mart|nez***. Low Bone Mass (BM) and low bone mineral content have been reported in children with CRF and these disturbances play an important role in the growth retardation of these patientss. With the aim of examine the effects of rhGH therapy on BMC, BM and Growth Velocity (GV) in children with CRF, 12 prepubertal patients (chronological age X: 6.5 • 3.2 years, Range: 2.8-12 y; 10 boys and 2 girls) with severe renal failure were studied using Dual X-ray Absorpsiometry before and after 6 months treatment with rhGH at a dose of t IUIKg/week. BM was measured in total body, lumbar spina (Trabecular Bone TrBMC) and femoral neck (Cortical Bone -CoBMC). Total BMC was lower in patients compared to age matched healthy control group (440.8 ~ 150.3 vs. 900.1 • 360 g / p <0.053). After 6 months of rhGH therapy total BMC increased to 515.8 • t47 g in the group of patientes, p <0.05. TrBMC increased from 0.490 ~ 0.04 to 0.590 9 0.08 glem2 and also CoBMC from 0.60t • 0.1 to 0.650 • 0.08 glcm'. GV of patients increased significantly in all children while bone age maturation was not accelerated. Glomerular Filtration Rate (GFR) decreased during the period of study. Months 0 3 6 9 GV (ems/year) 4.7 10.2 8.1 9.3 Bone Age (years) 3.9 4.2 GFR (ml/minlt.73 m2) 20.2 t6.5 12.2 7.8 H-SDS -3.6 -3.3 2.8 Our results indicate that children with CRF and short stature have low bone mass and treatment with rhGH increases their bone mineral content and also their growth velocity. *Servicio de Nefrologia Pedifitrica. Hospital Central - Univeraidad de Carabobo. Valencia. **H. de Clinicas/H.Nifios.***H.Universitario-Caracas. Venezuela.

P086 THE CHANGES IN SERUM LEVEL OF ALKALINE PHOSPHATASE (AP),

PROCOLLAGEN TYPE 1 (PICP), OSTEOCALClN (BGP) AND PTH INTACT IN CHILDRENWITHEND-b~rAGERENALDISEASE(ESRD) DURINGrhGH TREATMENT. Sieniawska M 1, Zi61kowska I-I.1 Pa6czyk-Tomaszcwska M. 1, W~,larska jl., C-irdwoy6 A1., Bednorz R. 2, Kanik A3., Wilkosz IC4 The aim of the study was to ~ t i m ~ the c l u . ~ of bone fommaon markers and PTH intact in cluqdren with ESRD dining first 6 months of rhGH treatment. Thirteen children (age 6-13 years) were observed ; 7 on HE), 6 on CAPD; treated with rhGH (1-1,1 1U/kg/week), lct(OH)D3 (0,038 - 0,13 ug/kg/week) and calcinm carbonate (50-190 mg/kg/d). Morphometric analysis of ~ crest bone biopsies performed in 12 children before starling rhGH treatment revealed: osteitis fibrma - 1(8,3%), mild lesion of secondary hyperparathyroidism - 8 (66,8~ adynamir bone disease-1 (8,3%) and normal histology -2 (16,6%). The increment in height after 6 months in 12 cl~dren was 3,2-5,9 cm, in 1 child <1 cm. Mean (SD) levels of bone formation's markers and PTH intact in time T - 0 - before treaanent and after 1,3,6 months are summarized below. T n PTIt r FA (U/b PICP (ugB) BGP (ns/ml) 0 13 73,1 (62,1) 201,2 (103,7) 436,6 (216,1) 48,4 (24,3) 1 13 145,7 (182,5) 190 (77,5) 514,9 (172,1) 58,3 (41) 3 13 154,5 (156,7) 268,4 (100,2) 546,5 (106,6) 57,3 (41) 6 9 337,7 (270,1) 346,6 (119,5) 466,3 (198,4) 81,2 (52) In period < 3 months of treatment the concentration of PICP increased in 11 children, whereas BGP level increased only in 5. ~ 6 months BGP level increased in 11 patients. In 6 children PTH 1 ~ 1 was 7-28 limes higher than itfifi~ level, and higher than 200 pg/mL The increase of PTH level was probably the result of inadequate dosage of lo.(OH)D3 in children with improvcanent of growth velocity. Results: 1) In early period of ~alment with rhGH PICP level increased ea~er than BGP level. 2) Significant correlation between PICP concenlration ~ 1 months of treatment and growth acceleration has been foond, r=0,61,p<0,0005. I) UniversityChildren'sHospital Warszawa, Poland; 2) UrdversityChildren's

Hospital Wroolaw, Poland; 3) Nephrolo~ & DialysisUnit;,Regional Hospital, Rzesz6w, Poland 4) PoL-Amer. Inst.Ped. CMUJ, Krak6w, Poland

P088

COMPARISON OF INTERMITTENT AND CONTINUOUS (DAILY) ORAL CALCITRIOL FOR TREATMENT OF RENAL HYPERPARATHYROIDISM IN CHILDREN ON DIALYSIS G. Klaus*, J. Hinderer*, N. Lingens*, B. Keuth**, U. Querfeld**, O. Mehls* Intermittent calcitriol has been shown to be effective and save for suppression of parathyroid overactivity in children with end-stage renal disease. The intermittent mode of treatment is used increasingly. However, no head-on comparison of continuous (dally) and intermittent administration was performed in dialyzed children. Protocol: Oral calcitriol was stopped, if serum 1,84iPTH was < 50 pmol/1 (normal range 1-6). Patients were randomized to continuous treatment (0,5 Ixg calcitriol daily) or intermittent treatment (1.0 ~tg three times a week), if 1,84iPTH had inci-eased to more than 15 pmoVl after 4 weeks or any time 1,84iPTH > 75 pmot/l. Serum concentrations of Ca were monitored biweekly, 1,84iPTH, AP, Pi monthly. Treatment was stopped in case of 1,84iPTH dropped below 10 pmoVl or if hypercalcemia (> 2.8 mmogl) or hyperphosphatamia (> 2.5 mmoVl) occurred. Results: 9 patients were randomized into the continuous, 12 into the intermittent treated group. Patient in both groups were not statistically different with respect to age, time on dialysis, serum 1,84iPTH, Ca, Pi, AP, aluminium. Median 1,84iPTH decreased significantly from 55.9 (15.6-147) to 6.3 (2.1-30) pmol/1 (p < 0.002) and 30 (15.2-98.3) to 5.9 (0.9-26.3) pmoVl (I3 < 0.01) in the intermittent and continuous group respectively. The intergroup difference was not significant. Duration of treatment was 10 (2-24) and 8 (236) weeks (p = n.s.). Serum Ca increased significantly in both groups. Hyperealcemia was observed in 2 intermittently and 3 continuously treated patients (p = n.s.). No significant changes in Pi and amount of calcium containing phophate binder prescribed were observed. Conclusion: Continuous and intermittent oral calcitriol are similar effective and save for treatment of renal hyperparathyroidism. * Dept. of Pediatrics, University of Heidelberg, Heidelberg, Germany ** Dept. of Pediatrics, University of Cologne, Cologne, Germany

C 76 P089.1

P089

BONE DENSITOMETRY IN PEDIATRIC

RENAL TRANSPLANT. M.Navarro, D.Romero, M.Melgosa,

C.Garcia Meseguer, A.Alonso, J.Coya. Renal transplant Unit Children's Hospital "La Paz".Mad~d. SpaixL PURPOSES: Bone Mineral Content (BMC), calcium metabolism bioche mical markers, steroid schedule and growthparameters has been studied in 40 cadaver transplanted children (25 boys, 15 girls) METHODS: BMC study was done by dual x-ray absortiometry of spine lumbar (LI-L4). Results are given in SSD. GRF was calculated by Schwartz formula. Mean age at transplant (Tx): I(~3.9• and at densitometry 12.5• y. All patient were on triple therapy, 26 on daily prednisone and 18 On alternate days. Mean GRF was 78.427 ml/min/l.73 m2. BMC was +0.55 SSD at transplant time, -decresing afterwards to a maximun o -1.9 SSD between 5-21 months posTx (PC 0,05). BMC evolution was: 12y: - 2 . 1 S S D ; 2~y: - 1 . 2 4 - SSD; 32y: -1.04 SSD; 4~y: -0.49 SSD; 5~y: 0.055 SSD. We defined two groups: A : B M C > - I SSD; B : B M C < - I SSD. RESULTS: Means (SSD) Grupo A Grupo B Signif. BMC (SSD). -0.2• -2.14• P
DELIVERY OF TERTIARY CARE NEPHROLOGY SERVICES TO CANADIAN ABORIGINAL CHILDREN. Rlr Ylu,V.,MD,FRCP(C); HARLEu MD,FRCP(C), Pediatric Nephrology, Dept. of Pod. University of Alberta, Edmonton, Alberta, Canada. Under the Canada Health Act, all Canadians are eligible to be insured for medical services. Medical services to aboriginal people are treated in a special way under this act. The Imminent requirement for dialysis in a 9 year old First Nations girl, living with her grandparents and nine other children 670 km from the University of Alberta Hospital, prompted us to review our expodanae with this group of patients. We have reviewed the charts with special emphasis on those factors which may contribute to both the success end difficulty in delivering dialysis and transplant. These factors included the need for relocation, the physical environment of the family, cultural and family issues. Over a twenty year period, the Pediatric Renal Clinic of Northern Alberta has followed more than 40 aboriginal children with significant renal disease. 13 have developed end stage renal failure (E$RF) requiring renal replacement therapy. Only 2 of 9 patients while on PD needed relocation for prolonged treatment in hospital. The remaining 7 have been managed on their home reserve or in remote parts of the country ranging from 100 km to the Arctic Ocean, 2 with the use of cyclers. We chose HD as the first method of ESRF treatment in 4 children, 2 of whom we predicted would fail to comply on e PD regimen. One of the HD was treated prior to the availability of PD and was temporarily relocated. 7 children have received 9 transplants, 5 of them living-related donors. 3 children have died, I with intractable acidosis, 1 of an unknown cause, and 1 of suicide.

The delivery of dialysis and transplantation to aboriginal children living in remote areas under difficult conditions poses 9 challenge for any healthoare practitioner. In our oxpartenca, PD can be carried out over great distances provided certain conditions are mat (ag. running water). Review of tNs cohort of aboriginal patients will facilitate planning and Implement=ion of healthcare delivery in the future.

P O S T E R S E S S I O N - (P) - Hereditary Renal Disease P091

P090 G e n t a m i c i n ( G ) - I n d u c e d B a r t t e r - L i k e Syndrome

REVIEW OF FANCONI SYNDROME IN CHILDREN

D. Landau, M.D 1 & K, Kher,M.D2. Administration of Gentamicin ((3) has been implicated in the past as the cause of electrolyte imbalances similar to those found in Barner's syndrome (BS) in adults. However, few pediatric cases have been described. We present here 3 cases of severe acquired BS in which G toxicity seemed to be the only apparent offending cause.

Pt# Age (months.) G therapy length (d) Cummulative dose(mg) Cumin. dose (mg/kg)

1

2

3

144

94

4

23

28

8

7180

5880

168

120

420

56

Length OrBS (d)

30

14

7

S-Mg (mg/dL)

0.8

0.9

1.4

S-K (racq/L)

2.3

2.6

2.4

S-I-ICO3 (meq/L)

31

30

33

7

8

40

60

80

TrKG U-C1

Concomitant drugs ~/LA A M,A,N TTKG: transmbular K gradient. Normal<2 in hypokalemia; M: metronidazole; A: ampicillin; N: neomycin Cases 1 and 2 had a prolongued exposure to, and an increased cnmmulafive dose of G as risk factors. Case 3 had an hypotensive episode during G therapy, after which the BS appeared. All cases had normal renal function as assessed by serum creatinine and urine output. Urinary sediment was normal. There was no apparent proximal tubalar dysfunction or prolongued diuretic therapy. The eases here described emphasize again the potential risk of prolonged use of aminoglycosides in the pediatric population. 1Dept. of Pediatrics, Soroka Medical Center, Beer Sheva, brael and 2Dept. of Nephrology, Children's Hospital National Medical Center. Washington, DC, uSA.

pR. M.EL-AUN,

~•

H.MUGHRIBI,

E. QUDAH

KING HUSSEIN MEDICAL CENTRE (K.H.M.C) AMMAN - JORDAN. A retrospective review of cases of Fanconi syndrome d i ~ n o s e d at KHMC during the last ten years. The aim was to determine the types of Fanconi cases and recognize symptomatelegy and outcome of the involved patients. Data were obtained regarding the age,sex clinical manifestations course and outcome of the disease. There were twelve patients six males and six females, secondary types were six cases all due to cystinosis and six primary types,two of them hereditary. Major presenting manifestations were failure to thrive, rickets,polyuria, polydypsia. Four patients progressed into renal failure, all with cystinosis two died and six are being managed. Early detection and diagnosis with proper medical interVentions will reduce most of the complications seen with Fanconi syndrome. Recognizing the hereditary etiologies will provide the chance of early detection and adequate genetic councilling.

C 77 P092 EXTRA-RENAL EFFECTS OF 1-DESAMINO-8-D-ARGININE-VASOPRESSIN IN PATIENTS WITH NEPHROGENIC DIABETES INSIPIDUS CAUSED BY MUTATIONS IN THE AQUAPORIN 2 GENE. A. van Lieburg, V. Knoers, R. MaUmaan, W. Proesmans, L. van den Heuvel, L. Monnens.

P093 AUTOSOMAL-RECESBIVE NEPHROGENIC DIABETES I N S I P I D U S DUE T O A N AQUAPORINE 2 WATER CHI~'NEL DEFECT I N 2 BROTHERSz EFFECT OF EARLY VS LATE INTERVENTION

E. Let~talm*, J. Monnens***. .

Hereditary nephrogenic diabetes insipidus (NDI) is a rare disease in which the antidiuretic response to antidinretic hormone and DDAVP (1-desamino-8-Darginine vasopressin) is lacking. Patients with the X-linked recessive form of the disease lack the extra-renal responses to DDAVP, indicating a generalized V 2 receptor defect. The purpose of this study was to evaluate the extra-renal responses to DDAVP in the autosomal recessive form of NDI, resulting from mutations in the aqoaporin 2 gene. A normal extra-renal response was expected. Four patients with proven mutation in the aquaporin 2 gene were tested for their fibrinolytic and hemodynamic responses to intravenous administration of DDAVP. They all showed an increase of tissue-type plasminogen activator antigen, facial flushing, an increase of heart rate and a decrease of diastolic blood pressure. These results confirm the hypothesis that NDI patients with an aquaporin 2 gene defect can be discriminated from NDI patients with a vasopressin type 2 receptor defect by their normal extra-renal responses to DDAVP. Department of Pediatrics, University of Nijmegen, The Netherlands.

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A.F. van Lieburg***, .

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The first p a t i e n t s with congenital NDI due to a d e f e c t of the autosomal gene encoding the water channel a q u a p o r i n e 2 (AQP2) of the renal collecting d u c t have b e e n d e s c r i b e d in 1994 [Deen et al: Science 264: 92; van L i e b u r g et al: Am J Hum Genet 55:648 ]. We o b s e r v e d NDI in 2 of the 3 sons of c o n s a n g u i n e o u s p a r e n t s from Sri Lanka. The elder patient was r e f e r r e d at the age of 7 months b e c a u s e of m u s c u l a r hypotonia; serum sodium was 186 m m o l / l and urine o s m o l a l i t y was 173 mosm/kg. Despite treatment with hydrochlorothiazide and tube feeding, the patient failed to thrive and s u c c u m b e d at the age of 13 months after severe c o n v u l s i o n s and w i t h e x t e n s i v e bilateral necrosis of the basal ganglia. His y o u n g e r brother, also w i t h NDI, has been t r e a t e d since b i r t h and is at present (age 7 months) d e v e l o p i n g normally. Further studies rev e a l e d an APQ2 - d e f e c t due to a m u t a t i o n in the AQP2 gene on c h r o m o s o m e 12q13. Functional studies of the d e f e c t i v e APQ2 water channel are under way. Both p a t i e n t s h a v e - in contrast to classic (sexlinked) NDI - a p o s t r e c e p t o r defect. Congenital NDI is g e n e t i c a l l y heterogeneous, which has imp l i c a t i o n s for g e n e t i c counseling. Late diagnosis may h a v e s e r i o u s consequences. * Children's Hospital and ** Institute for Clin. P a t h o l o g y - U n i v e r s i t y of Zurich - switzerland *** Dept. of Paediatrics and Human Genetics N i j m e g e n - The Netherlands.

P094 NEPHROGENIC DIABETES INSIPIDUS: CLINICAL SYMPTOMS, GENETICS AND PATHOGENESIS. N. Knoers*, A. van Lieburg*?, M. Verdljk*, P. Deen***, C. van Os "*~ BJ~. van Oost*, L.A.H. Monnens* *.

P095

DOES rhGH TREATMENT ACCELERATE DETERIORATION OF RENAL FUNCTION IN SHORT CHILDREN WITH NEPHROPATHIC CYSTINOSIS ? E. WQhl, D. Haffner, N. Gretz, G. Offner, W. van't Hoff, M. Broyer, O. Mehls for the European Study Group on rhGH Treatment in Nephropathic Cystinosis

Congenital nephrogenie diabetes insipidus (NDI) is characterized by insensitivity of the distal renal nephron to the antidiuretic effect of arginine vasoprossin, resulting in an inability to concentrate urine. Patients present in their first year of life with aspecific symptoms like vomiting, anorexia, growth retardation and vomiting. After infanthood, the clinical picture is dominated by the less alarming symptoms polyuria and polydipsia. Without treatment, mental retardation may develop. In a psychological study of 17 NDI patients, we have found that the prevalence of mental retardation in NDI is considerably lower than suggested in the literature. In the last three years two different genetic defects causing hte NDI phenotype have been identified. The genes involved encode proteins that reside at both ends of the cellular vasopcessln signalling cascade, namely the vasopressinV 2 receptor and the aquaporin-2 water channel. In Xlinked recessive NDI, wihch is by far the most frequent form of the disease encountered, mutations in the V2 receptor gene have been identified. In autosomal recessive NDI, mutations in the aquaporin-2 gene have been found. The results of in vitro expression studies in COS cells orXenopusoocytes have confirmed that most of the identified mutations in the V2 receptor gene and all the mutations found in the aquaporin-2 gene are indeed harmful mutations and not polymorphisms. In addition, these studies give insight in the structure-fnnctionrelationship of both the receptor and the water channel. As yet, there is no significant difference in the severity of clinical symptoms between patients with X-linked recessive NDI and those with the autosomal recessive form of the disease. On the basis of extrarenal respanses to the administrationof the V2 analogue DDAVP, a differentiation between the two genetic forms can be made. Whether a third category of NDI patients exists remains to be seen. The identificotion of such patients should help to identify other proteins essential in the cellular pathway of vnsopcessin-induced antidiuresis.

Treatment with recombinant human growth hormone (rhGH)has become a new treatment modality for short children with chronic renal failure and may also be beneficial for short children with nephropathic cystinosis. However, concern was raised that rhGH treatment may accelerate the progression of renal failure in nephropathic cystinosis. We have treated 33 children with nephropathic cystinosis (median age 7.7 years) on conservative treatment with rhGH for at least one year and 13 children for at least two years. Rise in serum creatinine was compared to the rise of serum creatinine of a historical group of 117 patients not treated with rhGH. No significant difference (Fisher's exact test) compared to the natural course of the control group was seen in children on rhGH treatment. However, patients on cysteamine treatment had a slightly delayed onset of rise of serum creatinine compared to patients without cysteamine treatment (p
Departments of Human Genetics*, Pediatrics**, and Cell Physiology*", University Hospital Nijmegen, The Netherlands

Division of Pediatric Nephrology, University Children's Hospital, Heidelberg, Germany

C 78 P096

P097

HYPOTHYROIDISM COMPLICATING PRIMARY HYPEROXALURIA TYPE 1 (PH1). Y. Frlshberg, C. Rinat, S. Felnstein, A. Drukker

RENAL TUBULAR DEFECTS LEADING TO PERSISTENT HYPOCITRATURIA AND HYPERURICEMIA IN A PATIENT WITH CONGENITAL RENAL HYPOMAGNESEMIA

Patients with PH1 commonly have extrarenal involvement. We wish to report, for the first time, the occurrence of symptomatic hypothyroidism in 3 patients with PHI. The index case, the sibling of a family with known PH1, presented at 3 months with age with anuric, end-stage renal failure (ESRF). Peritoneal dialysis was initiated. Six months later severe hypothyroidism was diagnosed (T4 <2 gg/dl; TSH >500mU/l!!) in the course of an evaluation for failure to thrive, despite adequate caloric intake. Ultrasound and iradionucleide scan of the thyroid showed a normal sized gland with homogeneous uptake. No anti-thyroglobulin or anti-microsomai auto antibodies were detected. Thyroid replacement therapy induced a good clinical and laboratory response: she became more active and started to gain weight; repeat thyroid function: T4 8.3 l~g/ml, TSH 3.6 mU/l. The basic disease, however, progressed and at 15 months of age a pathologic fracture was diagnosed. She remains on dialysis. Subsequently we diagnosed symptomatic hypothyroidism in two other patients, aged 14 and 21 years respectively, with advanced PH1 and ESRF. Imaging studies in these patients were also negative. We suspect that the hypothyroidism of patients with PH1 reflects parenchymal involvement of the thyroid gland, due to the deposition of caicium-oxaiate crystals. No tissue diagnosis is available to prove this point, since an open biopsy of the thyroid gland could not be ethically justified; a fine needle aspiration was inconclusive. It is unikely that the hypothyroidism in the 3 patients is due to uremia per se. Ongoing studies in our laboratory are aimed to detect point mutations in patients with PHI. We hope that these studies will enable us to better define the genotype-phsnotype correlations in PH1 and will shed light on the defects which govern its clinical heterogeneity.

Zawadzki I

Division of Pediatric Nephrology, Shaare Zedek Medical Center, POBox 3235, Jerusalem 91031, Israel

(Introducedby WyszyfiskaT)

Our previous observation of 3 patients with isolated familial renal hypomagnesemia (IFRH) demonstratedthat Mg supplementationreverseshypocitraturia and that increased tubular urate secretion (T.Sec) is balanced by enhanced postsecretory reabsorption of urate (Post.R) resulting in normal uricemia. The echogenicity of their renal pyramids was normal. We present an 18-year-old boy with just recently recognized congenital hypomagnesemiawith the characteristic biochemical features of IFRFI (serum Mg 0.55 mmol/1,urine Mg 7.8 mmol/d, serum K 3.9 mmol/l, urine Ca 1.1 mglkg/d, serum creatininel.3 mg/dl) with marked hypocitraturia (urinecitrate 5.9 ~mol/kg/d vs normal 43.3 + 12.7 ~mol/kg/d), but with hypemricemia (serum uric acid 8.6 mg/dl), polyuria (3.5 - 4.2 l/d) and increased echogenicity of renal pyramids. Hypocitraturia with low fractional citrate excretion was maintained despite Mg supplementationwith MgO or MgC12. Five hour infusion of I0 mmol Mg (as MgSO4) increased urinary citrate excretion from 54.8 to 124.8 mg/g creatinine (in contrast with one of the above-mentionedpatients with IFRH in whom citraturia increased from 78 to 480 mg/g creatinine). Tubular urate transport evaluated by the pyrazinamide and probenecid tests demonstrated increased T.Sec. (51.6% vs normal 40.4 +7_.4%of filtered uric acid) and enhanced Post. R. (88.6% vs normal 76.6 _+ L4% of secreted uric acid). After the acute NH4CI load minimal urine pH and the urine anion gap were 5.23 and - 75 retool/l, respectively. Maximal urine osmolality in the standard dehydratation test was only 387 mmol/kg H20. Defects of renal tubular citrate and urate transport leading to persistent hypocitraturia and hyperuricemia were found in an 18-year-old boy with hitherto untreated congenital renal hypomagnesemia. Department of Nephrology, Child Health Center, A1. Dzieci Polskick 20, Warsaw, Poland

P098

P099

A D E N I N E P H O S P H O R I B O S Y L T R A N S F E R A S E DEFICIENCY: 2,8- D I H Y D R O X Y A D E N I N E U R O L I T H I A S I S IN C O N E C T I O N W I T H M U C O P O L Y S A C C H A R I D O S I S TYPE IV-THE FIRST D E S C R I B E D P A T I E N T IN A M E M B E R OF A SLAVIC NATION. K. Vondr~k, A. Kolsk~, A. H~ebi~ek, I. ~ebesta, J. Krijt, H.A. Simmonds.

CLINICOPATHOLOGICAL AND HEREDITARY ANALYSES OF ALPORT SYNDROME WITH ]KND-STAGE RE~AL DISEASE T. YOKOYAMA

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The d e f i c i e n c y of the adeninephosphoribosyltransferase enzyme (APRT) is a v e r y rare autosomal recesive disorder of the purine metabolism. Insolubile 2,8 - Dihydroxyadenine (2,8-DHA) is eliminated by renal excretion. The authors describe one year old male p a t i e n t w i t h total A P R T deficiency. The kidney ultrasound investigation b e c a u s e of h e m a t u r i a showed several stones on b o t h sides - the p o s s i b i l i t y of m e t a b o l i c cause. This p o s s i b i l i t y was c o n f i r m e d by the stone analysis and by the enzyme analysis from e r y t h r o c y t e s w i t h less than 1% of normal APRT a c t i v i t y - total deficiency. The enzyme a c t i v i t y in parents is only 25% of normal range and b o t h are symptomless heterozygotes. The first child (female) of this family has normal A P R T activity, she is healthy. Due to severe skeletal a b n o r m a l i t i e s the p a t i e n t was suspicious for m u c o p o l y s a c c h a r i d o s i s too. The enzyme d e f e c t for typ IV B - M o r q u i o was proved. The t r e a t m e n t consists of the lowpurine diet, h i g h fluid intake and Allopurinol. Allopurinol decreases the 2,8 DHA excretion. The e f f e c t i v i t y of the t r e a t m e n t depends in this p a t i e n t beside the d i e t and h i g h fluid intake on the dose of Allopurinol, w h i c h is IO mg per b o d y weight. This patient, one of the y o u n g e s t ever diagnosed, has been the first amog Slavs. Dept. of Paediatrics, P o s t g r a d u a t e M e d i c a l School , Thomayer's T e a c h i n g Hospital, V i d e ~ s k ~ 800, 140 59 Prague 4 - Krd, Czech Republic.

Alport syndrome(AS) is a progressive hereditary glfxnerulonephritis with a heterogeneous clinical picture. The nephritis is characterized by hematoproteinuria with restless progression to end-stage renal diseases(ESRD). Clinicopathological and hereditary analyses about 21 male patients of AS involved ESRD aged from 12 to 72-year-old in 7 families had been performed. ~ i i had sensorineural deafness end ocular abnormalities. 11 cases had already undergone either hemodialysis or continuous ambulatory peritoneal dialysis. The mean age of onset of renal diseases was at 21.7-year-old and it had taken for 8.7 years to ESRD on the average. 8 cases had been introduced to dialysis within four years. The living-related renal transplantation had been performed in one patient and there had been no episode of rejection. In 5 families, mere than 2 siblings had suffered from AS and all of their mothers had been diagnosed either chronic glomerulonephritis or nephrotic syndroma. 35 patients with other renal diseases such as chance proteinuria and/or hematuria, nephrotic syndrome end reflux nephropathy were detected in these 7 families. The characteristic changes such as diffuse splitting and multilamination of the lamina densa of glomerular basement membrane with interposed granular deposits on renal biopsy could be detected in I0 cases. By HLA analyses in 2 families, it was found that HLA-2 was the only co,non antigen. The type IV collagen~5 chain gene(COL4A5) of 7 cases in each families were also examined, but the different base mutation had not been identified. *Department of Nephrology, Yubari Municipal General Hospital, Hokkaido, Japan.

C 79 P101

P100 FAMILIAL MEMRANOUSNEPHROPATHY (MN) WITI-IANTI-TUBULAR BASEMENT MEMBRANE (TBM) ANTIBODIES. B Murugasu1, HK Yap1, GSC Chiang2, AH Cohen3 We describetwo Chinese families with affected males diagnosedto have MN on histology, presenting with steroid-resistant nephrotic syndrome, followed by proximal renal tubular dysfunction (renal loss of HCO3, K, PO4, glucose) and progressing to chronic renal failure. Secondary causes of MN were excluded. There was no consanguinityand other members of the immediatefamily had no evidenceof glomerular/tubular dysfunction. Family A Family B

Died from complications of Fanconi's syndrome Postmortemrenal biopsy A~,e in vrs IMF Ab Currentserum Patient Onset/CRF/Current Fanconi's Rx._.##alone TBM AntiTBMAb A-III-1 1.5/4.0/13.5 + A/P A-HI-4 0.9/No/8.5 A/P + + B-II-1 0.9/NA/1.8(died) + Nil ND ND B-II-2 0.6/4.5/8.8 + AlP +++ #A/P=azathioprine and alternate day steroidstill onset of ESRD. The occurrence of disease in these 4 boys, as well as in other familial cases reported to date, suggests an X-linked mode of inheritance although autosomal inheritance in Family B cannot be ruled out. We believe that our patientsbelong to a distinctgroup with familial MN and antiTBMdisease, with a stronglikeli-hood of progressionto ESRD and possiblerecurrence in a transplantedkidney. 1Dept of Paediatrics, National Universityof Singapore, Singapore. 2Dept of Pathology, SingaporeGeneral Hospital, Singapore. 3Pathology Dept, Cedars-SinaiMedical Center, Los Angeles, USA.

P102 JEUNE SYNDROME AND END STAGE RENAL DISEASE P.Salas*, E.Gonzalez*, C.Carranza*, V.Pinto*

Jeune Syndrome is an autosomal recessive genetic disease that present asphyxiating thoracic dystrophy, and renal and hepatic malformations. Most of the times death is caused by respiratory failure; 39% during the neonatal period and 75% during the.first six months of life. Patients that survive develop a renal dysfunction similar to familiar juvenile nephronophitisis, and evolve to an end-stage renal disease. This case is a 14-year-old girl, that presented several hospitalizations derived from pulmonary infections and bronchial symptoms because of thoracic dysplasia. At the age of two, she went into surgery (thoracic wall amplification) to minimize her restrictive condition. She did well until she was 10 years old, when developed clinical manifestations of renal disease: hypertension, metabolic acidosis, hyperkalemia and anemia; at the age of 14 she presented renal failure; a renal biopsy was carried out and revealed Focal Renal dysplasia (electronic microscope), compatible with Jeune Syndrome. Six month later she went into kidney transplantation which came from related living donor with excellent results. *Servicio de Pediatrfa. Unidad de Nefrourologla. Hospital Exequiel Gonzdlez Cortes-Santiago, Chile.

PROGRESSIVE TUBULOINTERSTITIAL NEPHROPATHY WITH HEPATIC INVOLVEMENT: A CASE FOR COMBINED LIVERKIDNEY TRANSPLANTATION MI-I Said, R Bouvier, O Boillot, M Dawhara, B Cuzin, A Lachaux, B Mousson, MF Gagnadoux, D Morin, E Berard, V Desvignes, P Cochat Unit6 de N~phrologie Ptdiatrique, htpital E Herriot, Lyon, France The association of tubulointerstitial nephritis with cortical cysts leading to ESRF and hepatic fibrosis has been first reported by Boichis (1973), but there are few information regarding the long term outcome. EM (girl) was 3 months old when hepatomegaly (with cytolysis) and CRF were discovered; she subsequently developed rapidly progressive ESRF. Microscopic examination of the kidney showed glomerular and tubular cysts in the cortex associated with interstitial fibrosis. The clinical picture of liver involvement consisted in anicteric cholestasis and portal hypertension. The liver biopsy revealed portal fibrosis and bile ductular proliferation. Moreover, she had failure to thrive and psychomotor delay. She received a 1st cadaver kidney transplant when she was 5, that was complicated by early irreversible acute rejection and liver dysfunction. She had a combined liver-kidney transplantation (LKT) when she was 13. Two years later, renal and hepatic functions tests were normal and statural growth increased dramatically (+3 SD). She had neither evidence of mitochondrial enzyme defect nor mitochondrial DNA deletion. CB (boy) presented from birth with tubulopathy and hepatic cytolysis. ESRF occurred when he was 13 months old. The microscopic examination of the kidney showed both glomerular and tubular cysts. Hepatic dysfunction consisted in cytolysis, anicteric cholestasis with severe pruritus. The liver biopsy revealed portal fibrosis and non inflammatory bile ductular proliferation. He also has failure to thrive and mild psychomotor delay. He received a combined LKT when he was 3. Nine months later, renal and hepatic functions were normal. A deficit in the mitochondrial complex I was found both in the liver (35%) and the muscle (38%). In conclusion, children with progressive tubulointerstitial nephropathy and hepatic involvement may present with early end-stage renal failure and.liver fibrosis, leading to combined liver-kidney transplantation, that was uneventful in the two reported patients. P103 RENAL ABNORMALITIES IN FANCONI ANEMIA ~EC Meyers 1 , RJ Cohn 1 , PD Thomson 1 , L McDougal 1, ?S Hartley 2, C Havenga 3, P Fridjhon 4 %ira: We report on the renal abnormalities found in South African 3atients with Fanconi anemia, and examine their relationship to :he other abnormalities found in this disease. dethods: The records from the participating centers were analyzed. Renal anomalies were identified by ultrasonography a n d / o r IVP's. dCU was performed if urinary infection occurred. Statistics: are reported from the S . A . S . system as: Means +_S . D . , md Fisher exact. All results are 2 tailed. Results: There were 52 black, 62 white and 7 children of mixed origin. The male:female ratio was 1:1. The age range at hematological diagnosis was 0.5-15 (6.24+2.71) years. Renal abnormalities were p r e s e n t in 42.5% of the patients and included: ectopia 26.7% (5% with malrotation, 1.7% with ureteric abnormalities), ureterie abnormalities 6.7%, hypoplasia 1.7%, malrotation 0.83%, horseshoe kidney 0.83%, and no data 5.83%. More females had renal problems 31]60 vs 20/60,p=0.01, as did black children 27/51 vs 21162 white children, p=0.06. The presence of a renal tract abnormality did not correlate with the, height, skull circumference, pigmentary changes, cardiac, eye, ear, intelligence, or skeletal problems. In males no association between external genitalia and kidney manifestations was found. Having a renal abnormality was associated with an increased mortality p=0.038. Renal abnormality had no influence on the time of diagnosis. Neither spontaneous nor mitogen induced breakages correlated with renal abnormalities. However only 30.6% of patients had mitogen stimulation. Conclusion: Renal abnormalities are commonly found and should be looked for. The renal abnormalities do not influence therapy, relatively few patients require nephrological care. The patients with renal abnormalities may r e p r e s e n t a genetic subgroup with a more severe expression of the disease. Department of Pediatrics, University of the Witwatersrand 1, Cape Town 2, and Bloemfontein3, and Department of Statistics 4, University of the Witwatersrand.

C 80 P104

P105

CONGENITAL ADRENAL HYPERPLASIA AND BILATERAL RENAL HYPOPLASIA IN A NEWBORN. I. Elshihabi, D. Kaspar. Bilateral renal hypoplasia is reported to be the most common cause of chrotfic renal failure (CRF) in children. I--Iypoplasia has been divided into 2 types; simple hypoplasia a n d oligonephronic hypoplasia with the latter being more common. Causes of either type axe unknown. However, there have been reported associations between simple hypoplasia a n d CNS disease a n d between oligonephronic hypoplasia a n d a variety of abnormalities of the urinary tract. There have been no previously reported associations between congenital adrenal hyperplasia (CAH) and bilateral renal hypoplasia. This is a case report of a newborn male found to have CAH (21 alpha-hydroxy deficiency) a n d bilateral renal hypoplasia. He was born at 40 weeks gestation to a 34 G3P1 mother w h o was in good health and received good prenatal care. CAH was suspected at birth as the parents h a d a prior female infant b o r n with male genitalia w h o died on DOL #11 believed to be secondary to CAH b y autopsy. There was no other history of CAN or renal disease. Labs on admission: Sodium 130 retool/L, potassium 6.8 retool/L, chloride 89 retool/L, bioarb 20 retool/L, glucose 89 m g / d L , creatinine 4.2 m g / d L , BUN 27 m g / d L 17 hydroxy progesterone was extremely high at 14,000. Secondary to increased BUN end creatinine, he underwent renal sonogram which showed bilateral small kidneys and a renal scan revealed decreased perhision to the left and no perfusion to the right. Initially he was maintained on IVF and Kayexalate, but his creatinine remained high (0.4 m g / d L ) necessitating initiation of peritoneal dialysis (PD) on DOL #4. On DOL #10 he was noted to have a tunnel infection, subsequent peritonitis, and resultant sepsis requiring removal of the PD catheter. He was restarted on Kayexalate a n d sodium bicaxb to manage acidosis and did well with creatinine decreasing to 1.8 nag/dL. He was discharged at one month of age on sodium biearb, Kayexalate, Plorinef, and hydrocortisone. He was followed by bimonthly lab analysis a n d monthly clinic visits a n d did well, At 3 months of age he h a d a creafinine of 1.0 m g / d L and his potassium and bicarb levels were acceptable. He was growing well and appropriately meeting developmental milestones.

MULTICYSTIC DYSPLASTIC KIDNEY: PRENATAL DIAGNOSIS AND POSTNATAL FOLLOW-UP Ulrike John, J. Misselwitz, Susanna Vogt, K.-H. Eichhorn, L. Patzer and M. Beintker

Multicystic dysplastic kidney (MCDK) disease is one of the most common congenital renal anomalies. The aim of this study is to report our experiences in the prenatal diagnosis, associated malformations, sonographic findings and clinical follow-up. 40 cases of MCDK disease (34 uni-,6 bilateral) were recognised in the antenatal period with a mean gestational age of 30 (min 16,max 39) weeks. In 6 cases of bilateral MCDK disease pregnancy was terminated. The postnatal investigation included ultrasound, excretory urography, voiding cystography and isotope examination. 8 of 34 patients (24%) had associated urologic abnormalities: ureteropelvic junction obstruction n=3 (9%), ureterovesical junction obstruction n=2 (6%) and vesicoureteral reflux n=3 (9%). 6 patients underwent nephrectomy at the age of 1 day to 5 months. 3 patients died because of immaturity, severe broncho-dysplasia and sudden infant death syndrome. 31 patients were followed up by sedal ultrasound examination up to 102 months (mean 39) after delivery. Partial decrease in the size of the cysts was noted in 13 cases. In 9 cases, cysts were no longer detectable after 4 to 66 months. Contralateral kidney hypertrophy was observed in most cases. Hypertension and malignancies did not occur. No dses of serum creatinin levels were noted in those children without associated malformations of the contralateral kidney. Urinary tract infection had to be treated in 2 cases. To our experience we propose: Ultrasound has to be most useful proved in utero diagnosis of MCDK. Urologic anomalies of the contralateral kidney are frequent and have to be diagnosed by radiological investigations. A nonoperative approach is justified for the MCDK because of spontaneous cyst involution. University Children's Hospital Kochstr.2, 07740 Jena, Germany

P107

P106 AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE (ARPKD): SURVIVAL BEYOND EIGHTEEN YEARS. K.E.C. Meyers*, B. Cooperstome*, P. D. Thomson#, B . S . Kaplan* A retrospective review was done to assess long-term survival of ARPKD patients. Males, 8/15. Ages, 19-36 yr. Four died at 19, 20, 24, 33 years. Ages at diagnosis: 0.1-33 years (6~8 years, mean +S.D.). Hepato-biliary manifestations: hepatomegaly and fibrosis (15), splenomegaly with portal hypertension (ii), esophageal variees (4), cholangitis (3). Surgery: porto-systemic shunts (7), splenectomy (2), and hemorrhoidectomy (I). All had enlarged kidneys. Renal complications: hypertension (9), urinary infection (3), nephrolithiasis (I). Two patients had native nephreetomies. Time from diagnosis to end-stage renal failure: 0 to 26 years: n=10(Ii~7 years). Nine of 15 were transplanted (TP). TPILRD - 4, TPICD = 5; TP2CD = 4. Actuarial first graft survival (Kaplan-Meier); i year i00%; 4 years 69%. Growth usually improved post-transplantation. The 4 who died had hepatic encephalopathy, cholangitis (2), elevated amanonia levels. The long-term prognosis for ARPKD is not as poor as suggested but late liver deeompensation is a problem. Combined liver and renal transplants need to be considered in older patients. # *

U. Witwatersrand. Johannesburg Hospital, S. Africa Univ. Pennsylvania, The Children's Hospital of Phila.,

COUNSELLING FAMILIES WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE K Verrier Jones, L Brindle. A Clarke. F Davies Departments of Child Health and Genetics. University of Wales College of Medicine, Cardiff, Wales, UK. Autosomal dominant polycystic kidney disease (ADPKD) is a common and serious disease. There is evidence that the progression of renal disease and complications of hypertension are reduced by early diagnosis and appropriate treatment. However there' are also potential disadvantages when tile diagnosis has been made in asymptomatic people and cousequently testing children before they are able to give informed consent raises ethical dilemmas. We arc exploring parental attitudes to this in a research clinic. Thirteen known ADPKD families hm'e been coutacted b.x. letter, and given an opportunity Io discuss tbe issues i~woh,ed ~ith a researcher at libme. Of these. 7 replied indicating interest in the stud). One family did not waut to be contacted at home in case tlae children learned of their at-risk status. Four families have indicated their willingness to attend the cliuic for further ilfformation, although none has kept their first clinic appointment. Families who have attended clinic, have shown strong feelings towards the question of testing children for ADPKD. la one family, the mother was insistent that the child be tested despite the conflicting concerns of the affected father. In another family, while acknowledging that the children should learn of the condition for health reasons, the mother was ver.~ anxious that her older childrcn would be distressed by the topic being raised. She thought that this information could lead to difficult reproductive decisions for them. and was cofLcerrledthai testing could lead to discrimination against them in insurance or employmcut,

USA

Conclusions: This preliminary work has shown that ADPKD families find it difficult to cmffront the possible implications of their children being affected. We intend to continue this study to learn more about comluunication within ADPKD families, and to help those families wbo want to explore these issues.

C81 P108 AUT(3S(]Iq~-DONII~g~NT POLYCYSTIC KIDNEY DISEASE (AI)PKD) I N C H I L I ) I ~ D N.Sallego,A.Sonzalo,R.Estepa,M.Rivera,3.0rtu~o.

~r i s w e l l known i n a d u l t s and f r e q u e n t l y p r o duces r e n a l death (RD). However, t h e experience i n c h i l d h o o d has been s c a n t l y r e p o r t e d . Ne d e s c r i b e 39 s u b j e c t s aged f r o m 1 t o 18 y e a r s (x=13.4 • 4.5), coming § 23 f a m i l i e s w i t h ADPKD. Males (M)lFemales (F)= 16123. 36 were studied for risk and 3 f o r symptoms ( h e m a t u r i a , urinary tract in§ 13 (33%, M/F= 3/10) met ultrasound criteria (Bear e t ai.1984) for d e f i n i t e ADPKI), 24 ( 6 1 % , M/F=12/12) were normal and 2 ( 5 % ) s u s p i c i o u s . Age was s i m i l a r in all groups (13.6• 13.3-+5, 14.2• y e a r s N.S).Renal ~ u n c t i o n Nas normal in all cases and blood p r e s s u r e was >90th P in 2 (15%) o f the affected and i n 6 (25%) o f t h e n o r m a l s . We a n a l y z e d t h e p e d i g r e e s o§ t h e families in order to know i f "anticipation" (= 10 y e a r earlier RD i n o f f s p r i n g as compared to their a f f e c t e d p a r e n t o r a c h i l d diagnosed i n the f i r s t y e a r o§ life) was p r e s e n t . Only 8 § were informative § this point of v i e w , and i n 4 o f them a n t i c i p a t i o n was d e t e c t e d . CONCLUSIONS: 1) ADPKD might be an o v e r l o o k e d entity in childhood. 2) Some o f these c h i l d r e n have b o r d e r l i n e h y p e r t e n s i o n . 3 ) A n t i c i p a t i o n was p r e s e n t i n 4 / 8 T a m i l i e s . T h i s can be i w o o r t a n t i n order t o in§ the T a e i l i e s .

Department o~ N e p h r o l m g y . Madrid (Spain).

POSTER

SESSION

Hospital

Ram6n

y Cajal.

- (P) - N e o n a t a l R e n a l P h y s i o l o g y

P109

19 CASES OF N E O N A T A L V E S I C O U R E T E R A L REFLUX D E T E C T E D BY U L T R A S O U N D S C R E E N I N G OF N E W B O R N INFANTS FOR KIDNEY A N D U R I N A R Y TRACT A B N O R M A L I T I E S A . M a t s u i ~ Y.Matsuo,**M. Hayash•"** H . Y a m a n a k a ** For the p u r p o s e of early d e t e c t i o n and early treatm e n t of k i d n e y and u r i n a r y tract abnormalities, ult r a s o u n d s c r e e n i n g of n e w b o r n infants has b e e n done. A total of 3,558 n e w b o r n infants, born at Isesaki M u n i c i p a l H o s p i t a l from O c t o b e r 1988 to D e c e m b e r 1994 w e r e e x a m i n e d by ultrasound. Most of them were scanned b e t w e e n 2 to 7 days after birth, u s i n g A l o k a SSD 650 u l t r a s o n i c s c a n n i n g s y s t e m e q u i p p e d w i t h a 5-MHz linear transducer. When a b n o r m a l scans were found serial u l t r a s o u n d studies, u r i n a l y s e s and uroradiologic e x a m i n a t i o n s were c a r r i e d out. Out of 3,558 n e w b o r n infants, 19(0.53%) r e v e a l e d v e s i c o u r e t e r a l reflux(VUR). In this paper, c l i n i c a l and l a b o r a t o r y findings of these 19 cases of neonatal VUR(14 males and 5 females) were shown. Unil a t e r a l V U R was d i a g n o s e d in i0 cases and b i l a t e r a l in 9. By u l t r a s o u n d findings, d i l a t e d renal p e l v i s was o b s e r v e d in 9 cases(13 renal units) and b r i g h t l y echogenic renal p y r a m i d s in 2 cases(4 renal units). 2 cases(3 renal units) had d u p l i c a t e d ureters. Grade II V U R was found in 9 renal units, grade III in 7, grade IV in ii and in 1 case(l renal unit) grade of V U R could not be a s s e s s e d b e c a u s e of fibrous a d h e s i o n on the k i n k e d ureter. B a c t e r i u r i a was found in 14 cases and i0 of them d e v e l o p e d episodes of u r i n a r y tract infection. Renal s c a r r i n g was found in 3 cases. S u r g i c a l o p e r a t i o n s w e r e applied in 9 cases. Spontaneous c e s s a t i o n of VUR was found in 5 cases. * D e p a r t m e n t of Pediatrics, Isesaki M u n i c i p a l H o s p i t a l Gunma, Japan. * * D e p a r t m e n t of Urology, Gunma University, School of Medicine, Gunma, Japan.

PllO T c 9 9 m M A G 3 R E N O G R A P H Y I N N E O N A T E S D U R I N G ]'Ht~ F I R S T 48 H R S O F L I F E . R E P O R T O F 4 C A S E S . ORELLANA p, BAQUEDANO P, GARCIA C, LAGOMARSINO E, CAVAGNARO F , OLEA E and J.FABRES. After the introduction of routine prenatal ultrasound, the diagnosis of renal malformations in fetnses is now frequent.The proper diagnosis and treatment is important in order to preserve renal function. Diuretic renography with Tc99m DTPA has been considered unreliable in the study of the urinary tract during the first month of life, mainly due to inmature renal function. We report our initial experience with the use of Tc99m MAG3 in four full-term newborns, between 24 and 48 hrs of life. In 3 out of 4 the study was done because of pre and postnatal ultrasound showed unilateral hydronephrosis and due to bilateral abdominal mass in the other. A diuretic renography was performed after the injection of 1-2 mCi of Tc-99m MAG3(*)in an hydrated neonate. Scintigraphic results were correlated with radiolegical studies and clinical followup. Renal scan showed an unilateral obstructive pattern in 3 neonates, 2 of them with ureteropelvic junction obstruction and the other with an ectopic ureterecele in a double collecting system (DCS). All of them went to surgery during the first month of life. The excretory pattern was normal in the contralateral kidney in all of them and also in the inferior moiety of the patient with DCS. in the fourth neonate, with a polycystic kidney disease and renal failure, the renegraphy showed decreased renal uptake and parenchymal retention. Tc99m MAG3 is an excellent renal radiopharmaceutical for the study of the urinary tract, due in part, to its high renal extraction and can be use in newborns even during the first week of life, with high degree of accuracy.It is not affected by age, weight or renal maturation, as was observed in our preliminary experience and the findings should be correlated with ultrasound and eventually with others diagnostic imaging studies. We recommend the use of this method during the first days of life in every newborn with suspected urinary tract abnormalities while the newborns are admitted in neonatal or maternity facilities because its lower cost, availability and better evaluation by a mnltidiseiplinary team. At the same time, the early diagnosis allows an opportune treatment, avoiding progression of the renal damage. (*)Chilean Commission of Atomic Energy (CCHEN) NUCLEAR MEDICINE, UROLOGY, RADIOLOGY AND PEDIATRICS. FACULTY OF MEDICINE. CATHOLIC UNIVERSITY OF CHILE.

C 82 Plll ULTRASONOGRAPHY (US) 14,000 NEWBORNS. M Bianchi and R Coppo

Pl12 SCREENING FOR NEPHRO-UROPATHIES ON

According to the EDTA Registry about 1,500 children enter a regular dialysis treatment (RDT) in Europe each year (1,154 in 1992). Congenital renal diseases (including cystic, hypoplasic, dysplasic nephropathies and chronic pyelonephritis superimposed to urinary tract malformations) account for some 40% of children on RDT. Since the decline of renal function in these diseases if often slow and overpasses the childhood, we must consider that congenital renal diseases notably influence also the need of RDT in young adults. The early diagnosis of urinary tract malformations improved the long-term outcome of these children. Over the last ten years prenatal US ameliorated the diagnosis of nephro-urologic congenital diseases, however, some limited experiences reported that newborn US may fui'ther greatly improve the diagnostic potential. In this multicenter prospective study newborn US screening (between the ZOth and 40th day) was performed in 15 Centers of an Italian Region, Piedmont, on 13,976 neonates, over the last 18 months. Abnormalities in renal echogenicity or mass as well as urinary tract dilatation (pelvis > 10 mm in transversal section) were considered congenital nephro-uropathy. Positive prenatal diagnosis were confirmed in 114/:>17 cases only. In 30 the urinary tract dilation resulted normalized in a short follow-up, leading to 84 confirmed pathologic cases diagnosed by prenatal US (0.60%). Conversely, 387 new diagnoses of nephro-uropathies were done by newborn US. In 137 patients the following US controls were normalized to leave final 250 confirmed pathologic cases detected by newborn US (1.78%). These pathologic entities included 74 cases of hydronephi'osis, 20 vesico-ureteric reflux, 18 renal ectopy, 12 megaureter, 9 agenesia, 6 renal hypoplasia, 4 renal cystis, 1 multicystic kidney, 1 nephroblastoma, 3 neuroblastoma. The severity of the diseases identified by the US screening is in favour of the usefulness of this program in newborns since the cost will be easily overpassed by the benefits. Avoiding or even delaying RDT would result in a remarkable save of money, a part from individual and social benefits. Multicenter Collaborative Piedmont Study Nephro-Urology Depts, Regina Margherita Children's Hospital. Torino. Italy

Pl13 THROMBOLYTIC THERAPY OF BILATERAL NEONATAL" RENAL VEIN THROMBOSIS (NRVT) WITH SYSTEMIC UROKINASE (UK) O. Epstein , M. Ohaly , H. Shalev & D Landau NRVT is a life threatening complication. Its therapy is usually conservative, trying to prevent further complications, and waiting for spontaneous recanalization of the thrombosed kidney We hereby report a case of NRVT treated with intravenous ([.V). urokinase (UK) A one month old female infant suffered from a severe hypernatremic dehydration (Na 177 meq/L, Scr 5.1 mg/dl; Surea 230 mg/dl; SHCO 3 11 meq/L) secondary to diarrhea and inappropriate fluid intake. On admission she was found to have bilateral flank masses and macrohematuria. Renal sonography revealed bilateral RVT with extension of the thrombus into the inferior vena cava. Anuria persisted for 48 hours in spite of fluid resuscitation. At that siage, I.V, UK (bolus of 4000 U/kg, followed by 4000 U/kg/hr for a total of 48 hrs) was administered No hemorrhagic complications occurred during UK treatment. Urine output increased gradually during treatment and persisted thereafter. Renal function improved too, reaching a best value of Scr an Surea of 0.8 and 44 mg/dl respectively. A residual hyperkalemic renal tubular acidosis is still observed 6 months after the acute episode. Serial renal sonograms showed improved echogenicity and recanalization of the renal veins. The right kidney remained focally calcified. The left kidney showed no decrease in volume but its vessels show calcifications. The inferior vena cava was still thrombosed 45 days after the intervention. The temporal relationship between the beginning of UK therapy and the improvement in renal function, together with the imaging evidence for renal vein recanalization are a suggestive evidence that UK can be a safe and potentially successful therapeutic strategy in NRVT. , :Departments o f Pediatrics, Soroka Medical Center, Beer Sheva*, and Barzilai Hospital , Ashkelon, Israel.

DOPPLERSONOGRAPHIC FINDINGS IN THE COURSE OF RENAL VENOUS THROMBOSIS - AN EARLY PROGNISTIC INDICATOR? A. BOkenkamp, P.F. Hoyer, R. Jensen ~ and J. Brodehl Background: Ultrasound plays a key role in the diagnosis of renal venous thrombosis (RVT). Gray-scale imaging shows relatively unspecific findings like organ swelling, increased echogenity and diminshed cortico-medullary differentation. With the advent of duplex Doppler-sonography a reduction in diastolic blood flow velocity has been demonstrated to be a typical finding in RVT. Aim of the study was the evolution of these changes with time in 7 neonates with unilatera/ RVT. Results : In the course of RVT three phases may be distinguished: Between days 1 and3 the affected organs showed swelling (relative volume 113 to 219% of the contralateral kidney), Doppler studies demonstrated elevated resistive indices (RI) in all patients (1.0 to 1.25) Between days 4 and 14 organ swelling decreased gradually to 106 to 147% of contralateral volume. RI was below 0.8 in all 3 children who had complete return of kidney function on follow-up, but in only 114 children with evidence of organ scarring on follow-up. Beyond day 14 organ scarring became evident in 4 children with a relative volume of 60 to 83% of the contralateral organ. This was confirmed by isotope studies showing a diminished function of 40 to 70% of normal. In this phase RI values of 0.66 to 0.82 were recorded in the 3 organs with a favourable outcome. Organs with evidence of scarring had RI values of 0.7 to 1.0. Conclusion: Thrombolysis and collateralization may lead to normalization of the perfusion pattern in intrarenal arteries before complete regression of organ swelling. A normalization of the RI below 0.8 .within the first 4 days was noted in all 3 children with a favourable outcome but only 114 neonates with organ scarring on follow-up. If these findings are confirmed in larger series, an early normalization of the RI may serve as a prognostic indicator in RVT. Kinderklinik Medizinische Hochschule Hannover, D-30623 Hannover,FRG *Univereit~itskinderklinik L0beck, D-23538 L(Jbeck, FRG -

-

-

Pl14 URINARY CALCIUM / CREATININE INDEX IN PREMATURE NEONATES I.Burianovd, J.Feber, J J a n d a , P.Zoban The aim of the study was to determine urinary calcium / creatinine index (Ca/C0 in "healthy" stabilized premature neonates. We studied 20 children with a mean (5: SD) birth weight of 1720 5:500 g and gestation age of 32 5 : 3 weeks. All urine samples were taken between 3rd and 5th day after birth. Infants received oral or parenteral nutrition. Calcium and creatinine were examined in a spot urine voided in the morning hours. Ca/Cr was relatively low (median 0.33 mmol/mmol, range 0.16 - 1.02 mmol/mmol). No significant relation was observed between Ca/Cr and gestation age as well as the way of feeding. Our data demonstrate low values of Ca/Cr in the first postnatal week of premature newborns. It may be due to the immature renal function and low urinary calcium excretion in the first week of life. Further studies are needed to follow the evolution of Ca/Cr index in premature newborns. In a previous study (1) an elevated Ca/Cr index in term neonates, infants and older children was observed. The 95th percentile of Ca/Cr index was 1.38 in neonates, 1.025 in infants, 1.26 in children up to 3 years, 0.83 in preschool children and 0.59 in school children. In conclusion, Ca/Cr index represents a valuable diagnostic help in calcium and phosphate metabolism disturbances. Postnatal and gestation age must be taken into account for a correct interpretation of Ca/Cr index. 1. Janda et al. Cs Pediatric 1.992;47:353-356

Department of Neonatology and Ist Department of Paediatrics, University Hospital Motol, 15018 Prague, Czech Republic

C 83 PII6

Pl15 EPIDERMAL GROWTH FACTOR (EGF) IN URINE OF PREMATURE NEWBORNS W I T H R E S P I R A T O R Y DISTRESS: P R E L I M I N A R Y

RESULTS,

FETAL GENITOURINARY ABNORMALITIES ASSOCIATED WITH OLIGOHYDRAMNIOS

K.Shimada',S.Hosokawa',F.Matsumoto*

Khoory BJ*, Plebani M~ De Paoli M~ Mussap M~ Fanos V*, Padovani E.M.*. Epidermal growth factor (EGF) is a polypeptide with 53 aminoacids and a molecular mass of 6045 Dalton. EGF seems to stimulate the multiplication and differentiation of normal and neoplastic cells into different tissues, such as kidney, adrenal gland, intestine, lung and liver. It has been postulated that urinary EGF derives from glomerular plasma filtration as well as kidney seems to play an active role in EGF urinary excretion. These two hypotheses do not rule each other out. We here report urinary levels of EGF in ten premature newborns with respiratory distress syndrome (RDS). Mean gestational age was 31.6+2.2 weeks (range 27-34), and mean neonatal weight was 1720!--540grams (range 9002600). Six patients were put on mechanical ventilation (Group A), while four patients in oxygen tents. Gestational age and neonatal birth weight were similar in the two selected groups. Twelwe-hour urine samples were collected during the first five days of life and EGF levels were measured by radioimmunoassay (RIA) (DSL, Webster USA). Also creatinine was measured in all samples, by enzymatic method. Results are showed in figure.

Purposes: ~e analysed u n d e r l y i n g u r o l o g i c a l d i s o r d e r s , g e s t a t i o n a l age, and u l t i m a t e outcomes in f e t u s e s with s e v e r e oligohydramnios and e s p e c i a l l y focused on c l i n i c a l c o u r s e s of I0 s u r v i v o r s . M a t e r i a l s : Among f o r t y - e i g h t f e t u s e s with s e v e r e oligohydramnios, a u t o p s y was done on 38. U r o l o g i c a l e x a m i n a t i o n s were performed in 10 s u r v i v o r s whose amniotic f l u i d volume began to decrease in the t h i r d t r i m e s t e r . A v e r a g e g e s t a t i o n a l age a t d e t e c t i o n was 30 weeksl ranging from 16 weeks in p a t i e n t with u r e t h r a l a t r e s i a . Results: C l i n i c a l and/or autopsy d i a g n o s i s included b l . r e n a l hypod y s p l a s i a , u r e t h r a l a t r e s i a , p o s t e r i o r u r e t h r a l v a l v e and the o t h e r s . Among 10 s u r v i v o r s , v e n t i l a t o r s u p p o r t s were r e q u i r e d in 5. U r o l o g i c a l emergency d r a i n a g e was n e c e s s a r y in a l l p a t i e n t s . Two p a t i e n t s have normal SCr, but another 8 have e l e v a t i o n of SCr

I

In this graph we report mean values of urinary EGF normalized to creatinine excretion over the first five days of life, every 12 hours. Group A demonstrated low levels of EGF, while group B a progressive increase. Further studies will be required in order to assess the relationship between urinary level of EGF and renal integrity and function.

f o r t h e i r age. Of 38 p a t i e n t s who died of r e s p i r a t o r y f a i l u r e a t p e r i n a t a l periods, autopsy was done on 31. Lung hypoplasia was apparent from lung/weight r a t i o and h i s t o l o g i c a l findings. C o n c l u s i o n : Based on t h e s e e x p e r i e n c e s we have t h e p o l i c y to induce d e l i v e r y in cases with t h i r d t r i m e s t e r onset of oligohydramnios from g e n i t o u r i n a r y a b n o r m a l i t i e s , and to s t a r t u r o l o g i c a l management e a r l y in n e o n a t a l periods.

* Division of Urology, Osaka Medical Center for Maternal and Child Health, Osaka-JAPAN

* Pediatrics Department, Neonatal Intensive Care Unit, University of Verona o Department of Laboratory Medicine, Central Laboratory, University of Padova t Center of Biomedical Research, Castelfranco Veneto (TV), University of Padova

Pl17

RENAL HYPERECHOGENICITY IN NEONATAL HYPOXIC ACUT SHOCK: A POSSIBLE ROLE OF URIC ACID? A. SUR~NYI, Gy., T~losi, M. Katona, K. Streitman, Io Horv~th, S. Pint,r: Departments os Pediatrics and Radiology, Albertg Szent-Gy~rgyi M e d i c a l Univ~ersity, H-6725 Szeged, Hungary OBJECTIVE: Vasomotor nephropathy frequently develop~ in hypoxic neonates. If the hypoxia becomes signif-" icantly more serious, marked precipitation of uric acid /UA/ can olccur in the renal parenchyma in the hyperuricaemic neonate, followed by acute renal insufficiency. Renal examinations were performed in such neonates by means of ultrasonography. DESIGN AND METHODS: Three full-term and one immatur~ neonate'Ts were examined within 24 hours following the development of hypoxia. Five non-hypoxic neonates served as controls. With consideration of the Apgar scores, the acid-base conditions, PaO2, and the customary laboratory methods, while the serum hypoxanthine /HX/ level was determined by HPLC /Harkness et al., Biochem Soc Transact 1979, 7: 1021/. Ultrasonographic examinations of the kidneys were made with a Hitachi Eub 450 instrument with a 5 MHz transducer. Biometric evaluation of the results was performed with Student's test. RESULTS: The 4 severely hypoxic neonates had low Ap~ar scores / 4/, pH / 7.20/ and PaO 2 / 50 mm Hg/. The serum UA level was 530 • 2.7 mR, and the creatinine was 27.0 mM. In accordance with these azotaemic levels, the urinary output in the 24 hours following the development of hypoxia was 0.4 ml/kg/hour. The urinary Ca excretion was normal / 6 mg~kg/24,hours/, while the UA excretion was pathological /UA/Cr ratio: 1.45 • 0.35 SD/. In all of these patients, nephrosonographic examination revealed various extents of e c h o g e n i c i t y enhancement in the medullary-papillary substance of the kidneys

Pl18 ACUTE RENAL FAILURE (ARF) AND NEUROLOGICAL COMPLICATION IN A SURVIVING TWIN AFTER DEATH OF THE OTHER TWIN IN UTERO N. Buyan', Y.Atalay**,K.G0c0yener~ E.Hasano~lu *

In ,multiple gestations, intrauterine death of one fetus occurs frequently and may cause serious complications for the survivor especially in cases of monochorionic twins. We report the case of a premature twin of the 35 th gestational week with ARF and neurological complicaUons.He was referred to our hospital as a surviving twin after death of the other monochorionic twin in utero.His general condition was poor with respiratory distress,cyanosie, edema ,generalised seizure and the newborn reflexes were absent. The laboratory values and clinical findings were compatible with DIC and ARF. On follow up renal function tests detodated progressively,renal ultrasound showed increased paranchimal echogenicity,99mTc -OTPA scan demonstrated no renal uptake and excretion. Cranial CT showed multiple intracranial haemorrhage in parieto-occipital area and EEG showed epileptiform abnormality. After the treatment of DIC with fresh-frozen plasma and anticoagulant drugs, laboratory tests and clinical findings improved and he was discharged at the 45th day of admission.After five months, he came with optic atrophy,mental- motor retardation and his hematologic profile and electrolite levels were within normal limits but BUN:22 mg/dl, serum creatinine: 2 mgldl. Although the 99m Tc-MAG3 renal scan improved when compared to the first study, the decreased uptake and excretion in both kidneys was taken as a permanent damage. It was concluded that DIC caused by fetal-to- fetal transfer of thromboplastic material from the dead fetus was the most possible cause of the neurological complication and ARF in this patient. We recommend that monochorionic twins should be followed up by subsequent ultrasounds.lf a twin death occurs in utero,surviving ~win should be followed up carefully for the early diagnosis of neonatal ARF. Gazi University,Department of Pediatrics Units of Nephrology*,Newborn** and Neurology***-Ankara- Turkey

C 84 POSTER

SESSION -

&) -

Nephrotic Syndrome

Pl19 PROGNOSTIC VALUE OF HLA-TYPING IN STEROID SENSITIVE NEPHROTIC SYNDROME (SSNS) M. J. Kemper, C. L61iger*, H. Altrogge, P. KOhnl*, D. E. M[iller-Wiefel To reveal eventual clinical consequences of the increased frequency of HLA DR 3 and 7 phenotypes in SSNS we investigated HLA class II antigens by means of molecular biology techniques in 37 pediatnc patients (mean age 10, range 2 -24 years) 5.9 years (0.5 - 20) after onset of the disease. The patients were classified into steroid dependent (SD, N=23), frequent relapsing (FR,N=6) and infrequent relapsing (IR, N=8) according to the criteria of the ISKDC/APN and the clinical course was correlated with the HLA findings. Statistical evalutation was performed by Chi-square test. 23 patients (62 %) were positive for HLA DR 7, 13 (35 %) for DR 3, and 8 (22 %) for both markers. 75 % (18/23) of DR 7 positive patients were SD, 17 % (4/23) FR and only 1 (4 %) was IR, whereas this benign clinical course was found however in 50 % (7/14) of DR 7 negative children. Although DR 3 positivity was mostly associated with SD patients (62 %) the same association was observed in DR negative patients (68 %). Accordingly HLA DR 7 can be calculated to be a significant indicator of a complicated i.e. SD and FR course of SSNS, whereas HLA DR 3 either isolated or in combination with DR 7 was not related to the clinical outcome (P=0.93 and 0.23, respectively). The positive predictive value of developing an SD course after onset of an SSNS is 83 % for DR 7, however, only 35 % for DR 3, and 26 % for both markers combined. From our data we conclude that HLA DR 7 can be regarded as a strong prognostic marker for the development of a complicated course in a child with SSNS. We therefore favour its use to seperate those children who mightneed an intensified initial immunosuppressive treatment. University Children's Hospital and Dept. of Transplantation Immunology* Hamburg-Eppendorf, MartinistraBe 52, D - 20246 Hamburg, Germany

P120 THE ROLE OF Fe~RII & INTERLEUKIN-4 IN THE PATHOGENESIS 0F CHILDHOODMINIMALCHANGENEPHROTICSYNDROME BS.Cho*,SH. Cha*,CE.Lee**,KH.Pyum** We have reported that peripheral B cells of patients with childhood minimal change nephrotie syndrome(MCNS) express elevated levels of FcsRII and that their T cells induce higher levels of Interleukin-4(IL-4) mRNA expression than those of controls, which in turn correlated well with elevated serum IgE, soluble FceRII and memSrane Fe~Rll levels (ASN 1992,ICN 1993). However mRNA levels of interferon-y(lFN-Y) were similar among MCNS, normal and disease controls. In in vitro cultures, IL-4 efficiently induced FceRII expression on the MCNS B cell membrane in a dose dependent manner, IL-4 induced FcsRII expressions were inhibited by treatment with methylprednisolone (MP), cyelosporin-A(CsA) and IFN-y. The degree of inhibition was greater by IFN-y & MP than CsA. Combination treatment studies revealed that a combined treatment with IFN-y and MP was the most effective to result in a synergistic inhibition of the IL-4 induced FcsRll expression at both protein and mRNA level. Steroid responder demonstrated a noticeable decrease in FceRII levels on their B cells. From these results IL-4 activities as manifested by up-regulazion of FceRII may play an important role in the pathogenesis of MCNS. 13ept.of Pediatrics,Kyumg Hee University,Seoul Korea *~ Genetic Engineering Research Institute,Taejon Korea

P121

P122

Soluble ]nlcdcu]
RETENTION OF SODIUM IN NEPHROTIC SYNDROME THE ROLE OF RENIN-ANGIOTENSIN-ALDOSTERONE

..........................................................................................

Several immtmologleal meehanlsms have been implicated in the pathoge,esis of glomerulonephritis and nephrotle s ~ d t o m e in ehildr~h including the role of varlous tnterleuldnz. In this sttdy, slL-2R mad IL-6 levels were meazurexl by lhakcd immunoabsorbcnt assay in taint and serum from 20 ddldren (mean age 8,7 years) with different glomslxtlopathies. In addition, mJbpopdatiol~s of lympho~ytes (CD4/CDS) w ~ e evaluated by two-eolour flow eytolnetry. Retml biopsies were pea'formed ha all patients, who were divided into two groups. Group A consisted of 9 children wlth a rdaps of the NS due to minimal change disease ( 6 cases) membramcous nep}u'opathy (3) and eoI~gen|tal NS (l). Group B ine]ude~l 11 patients with ehronloGN due to FSGS, ]gA nephrolmthy, membxemoprollft.~n~tive GN m~xl diffuse mesang~oprolifelalJve GN (2, 4, 2 and 3 e~e% respectively). In Croup A, signifiemat con'elaLions web's fotmd betwc.c~a mertma zIL-2R and t ~ n e slL-2R ( r~ 0,71, p<0.05) and urine I1..6 ( r = 0.80 p<0,01). Se,aau sIL-7.R weekly correlaled with CD4/CD8 (r -0.6), but there was no signifiemnt correlatlou between scrUJn sIL-2R and m.tnary protein exeretlon. In patie*ats with a relsps of fl~e NS, twine ~IL-2R correlated s|gntficamtly with t~4ne ]L-6 (1- = 0.62, p<0.05) and CD8 ( r = -0.79 p<0.05). In Group B, there v,,~ eJi even st~naBer eorrclattcrn between serum slL-2R and urine sIL-2R levels (r =0.72 ). Serum sIL-2R signtfiematly correlated also with CD4 (r = -0.61, p<0.05) or CD8 (r = 0.83 p< 0.01). Urine sIL-2R levels also directly sol,related with CD8 (r ~ 0.65 p<0.05), ha contrast to this , there were no slgni0eant c~'relations between serum or %,-ins IL-6 levels mad Ihc mlbpopulations of lymphoeytes in any of the two groups. Adthought, children in Crroup B had higher urine IL-6 levels than those in Group A, this difference did not r e ~ h a level of statlsti0,l signlfieanee (23,g2 and 0.78 pg/ml, respectively). Long{tudinal stx~d~e~ m-e needexl for fin-thor elucid~tlon of the ~li~eal t~efulnes~ of these immtatologieal markers in d~ldren with veatotm types of glomel tflopathles. Dept of pexlialVlcs, Safarik University, 0 4 0 66 Ko~i~e, Slovak Republic

V.M.S.

Belangero*,

G. A l v e s * * ,

E.F.

INCHILDHOO~ SYSTEM.

Collares**.

The role of renin-angiotensin-aldosterone system (RAAS) i n t h e s o d i u m a n d w a t e r r e t e n t l o n i n d e c o m p e n sated nephrotic syndrome was studied by using captopril. Eight episodes of decompensation were studied in c h i l d r e n a g e d 4 t o 12 y e a r s , w h o w e r e u n d e r spontaneous sodium retention and fed unrestricted diet . They were given no diuretics or corticosteroids for! at least one week before admlssion. During the studyl t h e d a i l y u r i n a r y e x c r e t i o n o f s o d i u m (DUES) , the! creatinine clearence, the 24hs proteinuria, t h e albu-i ~inemia, the body weight gain and the volume of plasma were measured. T h e p a t i e n t w e r e s p l i t i n t o t w o di E t l n c t g r o u p s : A, w i t h e x t r e m e l y l o w D U E S l e v e l s (less t h a n i0 m E q / d a y ) a n d B, w i t h h i g h e r l e v e l s . A l t h o u g h working with few subjects the DUES values appeared to he associated to the clinical status of the patients. The results from group A strongly suggest the stimul~ t i o n in t h e R A A S a s a n e s s e n t i a l mechanlsm of sodium retention. These patients were also the ones with more recent edema complalnts, lower albuminemia levels and natriuretlc response to captopril. The poor natriuretic response to captopril experlen c e d b y t h e p a t i e n t s in g r o u p B m a y i n d i c a t e that mechanisms other than the one mentioned above might be i n v o l v e d . * Assistant Professor of Pediatrics Campinas - Sao Paulo, Brazil.

- University

of

** A s s i s t a n t P r o f e s s o r o f M e d i c i n e Campinas - Sao Paulo, Brazil.

- Unlverslty

of

C 85 P123

FREE RADICALS VALUATION OF LIPIDIC PEROXIDIZATION IN CHILDREN WITH NEPHROTIC SYNDROME MMR.Chinelato*, S.Perc&-io**, C.Zuliani **, J.Felippe Jr**, V.R. Mello*, J.Toporovski* Nephrotic syndrome is cottsidered a common preaentation of a variety of clinical situations characterized by increase of renal permeability to protein filtration. Ninety percent of the eases in childhood are idiopathic. Recent studies show the participation of free radicals glomertdar injury. The aim of this study is to evaluate the presettce of fre,e radicals in children with nophrotic syndrome through lipidic peroxidizatiort Forty one patients from the Pediatric Nephrology Unit of "Santa Case de S~o Paulo" and 10 exmtrols were studied, ages varying from 3 to 14 years. Children were divided m 3 groups: group 1 ( control ), n=10, age=ll (2.6) years ; group 2 (complete remission ), n=19; age=10 (2.1) years. Group 3 ( symptomatic ) n=22, age=9 (4.2) years. All of theala have normal renal function.The lipidic peroxidization was evaluated by nmlondialdehyde dosage ( Pere~rio, S. - 1993 ). Results: control group = 441 (95) ng/ml, group 2 = 329 (169) ng/ml; group 3 = 903 (470) ng/ml. The statistic analysis showed significant diferences between the corm-el and group 3 ~<0.0 t) and between groups 2 and 3 (p<0.001). The difference between the control and the group 2 were not statistically significant (p.>0.1). The authors conclude that free radicals may play an important role in the nephrotic syndrome pathogenesis and the therapy against free radicals may be valuable therapeutic perspective in this disease * Dpto. de Pediatria da Santa Casa de Ss Paulo - Setor de Nefrologia Infantil ** Dpto.de Ci~ncias Fisiol. da Fat.de Ci~nc. Meal. da Santa Casa de Sg.o Paulo S~o Paulo - S.P. - Brazil

P125

P124 QUANTITATIVE AND QUALITATIVE ANALYSIS OF FEBRILE PROTEINURIA IN CHILDREN M. Kirschstein, R. Jensen, K. Clausen, J. Clausen

In a prospective study incidence, duration and pattern of febrile proteinuria in 31 children with febrile illness (body temperature > 38.5~ were investigated by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and quantitative measurement of urinary total protein, IgG, transferrin, a~bumin, ~ microglobulin and retinol binding protein using an immunoluminometric assay. All children had normal renal function (GFR). Urinary total protein was elevated in only 39% of all patients whereas 58% revealed pathologic patterns of. proteinuria applying SDS-PAGE and 61% had elevated urinary levels of one or more specific proteins. The urinary proteins excreted during fever showed a tubular pattern, only 4 (13%) children revealed a mixed glomerular and tubular pattern of proteinuria. A weak corcelation between level of body temperature and urinary protein excretion was only found for cxl-microglobulin. Febrile proteinuria was of short duration and already on the fourth day free of fever no longer detectable. Patterns of febrile proteinuria did not differ between viral and bacterial infections. The short duration as well as the prevalence of tubular patterns of proteinuria suggest that most likely acute phase reactants or cytokines lend to a temporary tubular dysfunction during episodes of fever rather than an antigen-antibody induced abnormal glomerular permeability. Med. University of LObeck, Dept. of Pediatrics, D-23538 LObeck, Germany

P126

Q U A N T I T A T I O N O F P R O T E I N U R I A BY T H E U S E O F SINGLE VOIDED URINE SAMPLES AND FOUR HOUR URINE SAMPLES M.G.M.G. Penido, J.S.S. Diniz, M.LS.F. Moreira, M.M.M. Guimar~es, R. Barbosa.

MORPHOMETRIC AND ULTRASTRUCTURAL STUDIES OF THE KIDNEYS AS PROGNOSTIC FACTORS IN IDIOPHATIC NEPHROTIC SYNDROME IN CHILDREN. K Sancewicz-Pach, K. Wilkosz, J. Kwinta - Rybicka, W. Mieg,yfiski, B. Urbanowicz

9 The amount of protein excreted in the urine has diagnostic and prognostic importance. The most commonly used method for the, 9quantitafion of urinary protein relics on 24 urine collections. Reports have documented a high degree of accuracy in the quantitative estimation of proteinuria from a single voided urine specimen. We measured protein-creatinine (UPr/Cr) ratio in a single voided urine samples and in a four hour urine samples collected from 114 children. The aim of the present study was to investigate the protein to creatinine concentration ratios in a morning urine sample and in a four hour urine samples. Significant positive correlation between 24h, urinary protein excretion and UPr/Cr ratio of four hour urine sample, and e r a single voided urine sample was found. (r: 0.3458, p: 0.0005 and r: 0.3417, p: 0.02 at age 7-12 years; r: 0.4936, p: 0.01 at age 1218 years)The 95th pecentile value for UPr/Cr ratio in a four hour urine sample was 1.78. The protein/creatinine ratio of a single urine specimen and a four hour urine sample seem more practical than the 24 hour urine collection.

The present work aimed at assessing whether the size of glomerules, established in morphometrie examination, and the presence of podocyte lesions influence the course of the nephrotic syndrome in children. The authors attempted to establish whether the two above factors have a prognostic value in the transformation of minimal change glomerulonephritis (MCGN) into focal segmental glomerulosclerosis (FSGS). A clinical and morphological analysis was performed on the results of 116 children with MCGN (59), mesangial glomerulonephritis (26), or FSGS (31). Ultrastructural examinations of renal biopsies revealed podoeyte lesions in 17 patients. Repeated biopsies in 12 patients showed increased lesions. The size of glomemles was evaluated in all patients by measuring their diameters using a light microscope and a micrometer eye-piece. Similar examination was performed in the control group. A statistically significant difference in glomerule size was found between the group of patients with FSGS as compared to those with MCGN and to the controls. All the children with podocyte defects and increased glomeru!es had a more severe clinical course of the disease and required a more agressive treatment. Terminal renal failure developed in 4 patients.

Unidade de Nefrologia Pedihtrica do Hospital das Clinicas da UFMG Belo Horizonte - Minas GerMs - Brasfl

Polish American Children's Hospital, Coll.Med. Jagiellonian University Dep. ofPed. Nephrol. Krak6w Poland

C 86 P127 F O C A L S E G M E N T A L GLOMERULOSCLEROSIS: L A T E RESISTANCE TO CORTICOSTERO1DS IN CHILDREN J. Kadowaki, S. Hoshii, M. Furuyama, H. Kurayama, A. Mizuno, T. Inui,M.Hiramatsu, T. Kuronuma It is very important to know there are three groups in focal segmental glomerulosclerosis (FSGS) in practical nephrology. Namely, 1) Patients are consistently unresponsive to medication, 2) Patients are consistently responsive to medication, 3) Patients intially appear to be responsive but become unresponsive to any treatment. Accordingly we decided to investigate mainly group 3) patients sending questionnaire to some of the pediatric group members in National Ryouyousho Hospitals in Japan in March 1994. The diagnosis of FSGS was established by light microscopy and either immunofluorescence microscopy or electron microscopy. Fifty four patients were included in this study. Of these, patients were divided into 3 groups based on responding attitude to medication ; group 1) 37 patients (68.5%), 2) 8 patients (14.8%), 3) 9 patients (16.7%). In the latter group so called late resistance to steroids group, sex ratio (M ; F) was 6 to 3, mean age of the disease onset was 9.6 + 3.1 years (range; 5 -13 yrs) and duration of requiring late resistance from the disease onset was 31.4 + 39.8 months (3 - 120 mos). The duration of becoming late resistance less than2 years was observed in 6 patients of this 3) group. Seven patients in group 3) have required dialysis or transplantation as a results of ESRD. In conclusion, 9 patients in total 54 FSGS patients were observed having late resistance to glucocorticoids. Six patients of these 9 become late resistance less than 2 years. In this late resistance group, 7 patients have required dialysis or transplantation. Nephrology Study Group of National Ryouyousho Hospitals, Japan.

P129

O N E YEAR G R O W T H H O R M O N E THERAPY IS SAFE AND EFFECTIVE IN STEROID DEPENDENT NEPHROTIC SYNDROME (SDNS) KY.Loke*, HK.Yap', SP.Tan', B.Mumgasu*, SM.Chan**, KO.Lcc*'*.

Children with SDNS have short stature and delayed puberty. Chronic steroid usage has growth suppressive effects through the inhibition of growth hormone (GH) production. We performed this study to determine the safety and efficacy of GH in stable, long standing SDNS. GH was administered at a mean dose of 24 U/m2/week for 1 year to 8 children (7 boys, 1 girl) with SDNS and decreased height velocity. The mean (-I- SD) chronological age was 12.6 (+3.1) years. All patients had a significant delay in pubertal stage, with a mean bone age of 9.1 (+2.0) years. During treatment, the mean height increased from 135.6 (+_ 14.3) to 145 ( _ 13.6) cm, the mean height SD score (Z-score) increased from -1.4 ( _ 1.6) to -0.3 ( _ 1.1, p < 0.05), and the mean height velocity increased from 3.7 ( + 1.4) to 9.4 (+2.2, p < 0 . 0 5 ) cm/year. GH treatment was safe, with no deterioration in renal function, diabetogenic or other side effects. Whilst prednisolone was continued at a mean dose of 16.2 mg/m2/day during GH treatment, serial creatinine clearance, fasting blood glucose levels, HbAlc levels, serum insulin levels and urine glucose monitored at 3, 6, 9 and 12 months of GH treatment remained normal. (ANOVA repeated measurements were not significant). CONCLUSION: One year GH therapy is effective in improving the Z-scores of children on chronic steroid treatment, and the absence of any diabetogenic or renal side effects of GH while on high dose steroids emphasizes its safety. Departments of Pediatrics" and Medicine'*', National University of Singapore Department of Pediatrics", Singapore General Hospital.

P128 ANTI-CD25 M O N O C L O N A L ANTIBODY INDUCES REMISSION OF STEROID RESPONSIVE NEPHROTIC SYNDROME (SRNS) - A CASE REPORT. G. Clark* and P. Amlot**

A 18yearold boywithSRNS relapsedon the 44th occasion (4+ proteiauriafor 3 days)and was treated with 14 doses of anti-CD25 monoclonal antibody (anti IL-2R IgG2.MAb; RFT5), 12mg/m:/d.MaintenanceeyelosporinA and prednisolonedoses remainedunchanged. In the previous15years,he neverhad a spontaneousremission;3 eoursesof eyelophosphamide,a 18 too. trial of levamisoleand 23 too. of eyelosporinA did not significantlydecreasehis relapserate or preducelong-lastingremission. METHOD: Bloodsampleswere takenfor renalfunctiontests, fullbloodc~untand FACSdeterminationof CD4+,CD4+CD25+,CD69+,CD8+,B-cellCD5+ ~ad Md~subpopulations.Urinaryprotein/creatinineratiosprior to RFT5 MAb,daily duringRFT5 ..,erapyand then at 1 and 2 wk post infusionwere measured. RESULTS. At relapse, Urn/Or=0.3 g/mmole, total WBC =3.86x10VL and lymphoeytes =l.03x109/L.DuringRFT5 therapy,total lymphocytesfell to O.6xI09/L,CD25+T cells fell from 29% to 1%; lowestP,~t,=31 g/L and maximum Ur~c,was 0.6 g/mmole. 28 days after starting RFT5MAb,remission occurred:P,~b=38 g/L,"tJ~c,=0.03 g/mmoleand remissionpersistedfor a further2.5 too. Changesin CD25+,CD69+,TCR-delta__Tcells subpopulationsare shownbelow.

Anti-C D25 Therapy ,,~ ,~

"*,~

m CD25

D69

,o-i!c: 3

+

Prodnl|olone

P Alb

. ~ l l a ~

12.5

mg

_J

air

dio,

o..oor

Cyr

A

125 bd

CD25+ T cells are thought to be den'angedor pathoget~eticin SRNS. Increasedcirculationof CD4+CD25+andCD69+lymphocyleswere documentedin this SRNS relapse. By using a monoclonalantibodydirected againstthe IL-2R,we depletedthis severely affected SRNS boy's CD25+ T cells and produced a 25 mo clinical remission.This clinical response supportsthe hypothesisthat CD25+ T cells are pathogeneticin SRNS and anti [L-2R Mab may providean alternativetherapyin somepalicnts. * Dept of Paediatric Nephrology,UIvff)S,Guy'sHospital,London,UK SE l 9RT ** Dept of lnmmnology,RoyalFree Hospital, London,UK NW3 2QG CONCLUSIONS.

P130

A CASE REPORT OF FOCAL GLOMERULAR SCLEROSIS (FGS) WITH MITOCHONDRIAL ENCEPHALOMYOPATHY. A. Saitoh, S. Yoshida, K. Takahashi, T. Ohya, R. Hosoya, T. Uekusa*, S. Saiki*, T. Gotoh**

We studied a 13 year 01d boy with mitochondrial encephalomyopathycomplicated with nephrotic nephritis. He developed sensory hearing loss at age 2, and chance proteinuria in his school health screening at age 8. Proteinuria increased gradually and was complicated with hematuria. His muscle atrophy, with elevation of muscle enzyme, lactic acid and pyruvate, developed at age 12. His psycho-physiological development was retarded. Muscle and renal biopsy showed degeneration of mitochondria with ragged red fibers and focal sclerosis of glomeruli without BM abnormalities. Mitochondrial encephalomyopathywith FGS was diagnosed. We discussed the relationship of Alport's syndrome, FGS and mitochondrial encephalomyopathy.

St. Luke's International Hospital, Tokyo, Department of Pediatrics*, Department of Pathology**, National Center of Neurology and Psychiatry, Japan, Department of Pediatrics.

C 87 P131

P132

STEROID-DEPENDENT NEPHROTIC SYNDROME AND HEXADACTYLY IN T W O BROTHERS R. Mallmann

MEDICAL NEPHRECTOMY WITH INDOMETHACIN IN CHILDREN WITH NEPHROTIC SYNDROME IN HEMODIALYSIS.

Two brothers of Pakistanian origin, second and third child of first degree cousins presented with postaxial hexadactyly of both hands which were surgically removed already in infancy. At the age of 4 and 2 1/2 years resp. they developed steroid-responsive nephrotic syndrome. Because of frequent relapses and obvious steroid dependency renal biopsies were performed. In both minimal changes of the glomeruli with mild mesangial hypercellularity were demonstrated. Only the older one seemed to respond to cyclephosphamide and subsequent ehlorambucil for a period of time in respect of his steroid needs whereas in the younger these effects never could be achieved. Only since the addition of ciclosporin (150 mg/m2/d) in this boy more than three years ago longer periods of complete or partial remission could be achieved. No side effects of ciclosporin in terms of impaired renal function and/or hypertension have occured so far. Physical growth as well as renal parameters are completely normal. Because of frequent relapses despite permanent alternate day steroids necessitating recurrent periodes of high prednisone consumption the older brother meanwhile has been put on ciclosporine treatment, too. In both a second renal biopsy had been able to confirm minimal changes. No signs of different histology could be demonstrated. In this family an autosomal recessive mode of inheritance can be assumed. Up to 4 % of all cases of idiopathic nephrotic syndrome are said to be familiar, the rate of minimal changes being much less than in the nonfamiliar ones. Consanguinity is reported only in a few cases. To the very best of our knowledge the coincidence of nephrotic syndrome and hexadactyly has not been rePorted before. Future will have to show whether the prognosis in the long run will be different from usual. Department of Pediatrics, University of Bonn, Pediatric Nephrology, Adenauerallee 119, D-53113 Bonn, Germany

The persistence ofa Nepl~rotic Syndrome in patientswith End Stage Renal Disease (ESRD) representsan increasedrisk of morbidity and even mortality in these unstablepatients. Great effortsto decrease massiveproteinufiamust be made in order to give a good opportunity of renal ~ansplant to these cb_ild~erLs. Sinceten years ago,the deleteriouseffectsofanti-inflamatmynonsteroidal drags on renal function are well-known, and their use has been proposed as a safe way to perform medical nephrectomy and stop massive proteinuria in nephtotic patients. "t~'o male nepkrotic hemndialyzed patients, 12 and i3 year-old, with a persiatent protei~mriaover -'10mg/m2/h, were tteatad with lndomethacin, 3 mg/kg/day for 60 days, in order to perform a medical neptueetomy and decrease urine protein losses. Purosemide (2 mg/kg/day) and a carefuU managementof thek dry weigth troughouthhemodialysiswere applied as a method to get a depleted sodium-volumestatus duringthe protocol. Both of thera became olJgufic after one week of treatment, with a 24-hour urine output droppingfrom 1500 to 150 cc in patient number I, attd from 1100 to 180 cc in patient number 2. The first patient showed a decrease in urine protein losses from 5,5 gti24 tt to 0,3 gr/day, with a concomitant increase in albuminemia from a basal value of 1,1 to 3,6 gr%. Patient number 2 reduce proteinuria from 15 gr/24 ti to 3 gr/day, with an increase in plasma albumin from 1,1 to 2,8 gr%. Oliguricstate, reduced urine proteinlosses and increased albumin plasma level were marltemed until trarLsplant, one year later for paeient 1 ~md five months in patient 2. An hypertensive crisis and two episodes'of puhaonaryedema in secondpatient were the main complicatiorLs of the thetaphy. We eoneIude that.medical neptu'ectomy with non steroidal antimflanlatory dm~ represents a safe and easy way to treat n.epluotic sindromein patients with end stage renal diseaseunder hemodiab'sis.

P133

ENAIAPRIL IN CHILDR~Swrrlt STEROIDRESIS'I~NTNEPIIROTICSYNDROME (S~UM AND iJRINARY EU~CTROPIt0RL'IIC STUDY ) MA Deluechi, F Cano, E Rodriguez, E Wolff. Thirteen patients, 10 males, 1,8 to 14 years old with corticoresistent nephrotic syndrome (CRNS) were studied. Their biopsies showed a Focal Segmental GlomeruloSclerosis in 4, Membrano Proliferative Glomerulonephritis(GN) I in 3, Crescentic ON in 3, Minimal Changes in 2 and Diffuse Mesangial Sclerosis in lpatient. Classical inmunosupressive theraphy had failed to stop urine protein losses in all of them. Enalapril was started at a dose of 0.2 mNday, increasing by 0.1 mg/kg every month in order to reach a 50% decrease of basal proteinuria. Maximal dose was 0.6 mg/kg/day. Prednisene 30 mg/m~ "~was assoctated " to enalapnl' theraphy in 12 patients. The follow-up period was 24 to 84 months. Plasma and urine samples for eiectrophoretic protein measurements were obtained pre and post enalapril [reatraent. A marked change from a non-selective urinary protein losses pattern, to an albuminselective proteinuria could be observed in the studied group. The ammount of total urinary protein losses decrease from a mean basal value of 6,51 g/day to t,21 gr/24 hrs (p<0,007). The following individual changes for each protein fraction could be observed from basal to final mean values in a 24-hour urine sample: Albumin: 3,95 to 1,13 gr (10<0,028), alphal: 0,45 to 0,008 gr (p<0,07), alpha2:0,74 to 0 gr (p<0,O139), beta: 1,06 to 0,04 gr (p<0,0029), gamma: 0,26 to 0 gr (p<0,001). Mean plasma total protein increase from a basal value of 4,62 to 5,67 mg/dl (p<0,001), and plasma albumin showed a change from 1,46 to 2,52 mg/dl (p
Drs. Wolff P. E, Cano Sch. F., Delucchi B. MA., Rodriguez S. E.

Division of Pedian'lc Nephrology, Luls Cah,o Mackenna Children's llospilal, Santiago de Chile.

P134 WHAT HAPPENED TO THE NEPHROTIC WHO WAS BIOPSIED 10 YEARS AGO? KP. Mehta From 1976-1985 414/966 children between 1-15 y e a r s age r e f e r r e d to o u r clinic p r e s e n t e d with p r i m a r y n e p h r o t i c s y n d r o m e . 35 belonged to privileged class and 205 were biopsied (50 steroid r e s i s t a n t , 1 2 3 f r e q u e n t r e l a p s e r / s t e r o i d d e p e n d e n t p r i o r to alternative immunomodulatory t h e r a p y and 32 with atypical f e a t u r e s ) . Histological diagnosis was minimal c h a n g e n e p h r o t i c syndrome(MCNS)126,proliferative glomerulon e p h r i t i s ( PGN ) 54, Membranoproliferative giomerulonephritis (MPGN)10,foeal giomeruloselerosis(FGS)11 and membranous n e p h r o p a t h y (MN)4. Fifty n e p h r o t i c s received cyelophosphamide 50 f r e q u e n t r e l a p s e r s Levamisole,lFGS I . V . m e t h y l prednisolone and 1 steroid d e p e n d e n t MCNS 2 c o u r s e s of I . V . V i n c r y s t i c i n and Cyelosporin A. Periodic check up included a s s e s s m e n t of g r o w t h , B . P . , o e d e m a , p r o t e i n u r i a , r e n a l functions and r e p e a t biopsies in 7. A 10 y e a r followup revealed following: Histology in) Not Biopsied

(109)

Proteinuria + oedema -

High B .P. Renal failure Remission o r death -

8(7%)

101(93%)

MCNS (88) 4 (5%) 2(2.5%) 82(92.5%) FGS (10) 4 (40%) 2(20%) 3(30%) 2(20%) MPGN (10) 4 (40%) 2(20%) 2(20%) 2(20%) MN (4) 2 (50%) 1(25%) 1(25%) In conclusion renal h i s t o p a t h o l o g y added a dimension and helped in seleeting t h e r a p y for N S , b u t the long term outcome in each histologie g r o u p d e p e n d e d on t h e r a p e u t i c r e s p o n s e to immunomodulatory d r u g s , c o m p l i a n c e and r e s o u r c e s for long term treatment of n e p h r o t i c s y n d r o m e , as 8 steroid r e s p o n s i v e children who died belonged to u n d e r privileged class, whilst amongst 35 children from privileged class t h e r e were no d e a t h s and only 1 with FGS is on CAPD. Nephrology Division,Bat J e r b a i Wadia Hospital for Children and R e s e a r c h C e n t r e , Parel, Bombay-400 012, India

C 88 P135

P136

LONG TERM EVALUATION OF TWO PREDNISONE TREATMENTS IN INITIAL IDIOPATHIC NEPHROTIC SYNDROME (INS) IN CHILDREN. PRELIMINARY FINDINGS. C Norero, A Delucchi, E Lagos, P Rosati *

LOW-DOSE TREATMENT (LDT) OF IDIOPATHIC NEPHROTIC SYNDROME (INS)

Over a period of 30 months, 99 initial INS patients were admitted to 9 hospitals. In 66 steroid responsive cases, no biopsy was done being randomly incorporated to 2 Prednisone treatments. Results in 56 patients after 18 m o n t h s of follow up are presented. Group A: 27 children (Prednisone 60 m g / m 2 / d a y for 4 weeks + 40 rag/m2 every other day for 4 weeks.Duration 8 weeks.Total dose 2.400 rag/m2). Group B: 29 children (Prednisone 60 m g / m 2 / d for 6 weeks + 40 m g / m 2 / e v e r y other day for 6 weeks. Duration 12 weeks.Total dose 3.600 m g / m 2 ) . Initial clinical and lab characteristics were similar in both groups. Relapses were treated as Group A in b o t h groups u n t i l the 3rd one.Results are p r e s e n t e d in p e r i o d I, II a n d III (Within 6, 12 and 18 months after 1st therapy). FIRST RELAPSE: It was mostly observed within the initial 6 months. Rates/lOG patients: I. A =37.7; B =36. II. A= 5.5, B=18.2; HI. A= 9.5; B=8.7 (NS) Rates per 100 observed weeks: I. A =1.5; B =1.4; II. A =0.2; B =0.7. III. A --0.4; B =0.3 (NS) TOTAL RELAPSES: Group A: 21 relapses in 13 out of 27 children during 1377 weeks. Rate/lO0 observed weeks =1.5. Two f r e q u e n t relapsers (Histology: nil disease). Group B: 20 relapses in 15 out of 29 children during 1338 weeks. Rate/lO0 observed weeks =1.7 (NS). One frequent relapser (nil disease). PERCENTAGE OF CUMULATIVE SUSTAINED REMISSIONS: Group A: 58.2 in 12 months and 53.3 in 18 months. Group B: 52.4 in 12 m o n t h s and 47.8 in 18 months (NS) . COMPLICATIONS: Initial C u s h i n g A: 40.796 a n d B: 58.696 H y p e r t e n s i o n and renal vein thrombosis with acute renal failure in t w o patients B, respectively. 3 initial infections in A a n d 2 in B. 7 later infections both groups. No mortality was observed. CONCLUSIONS: No significant differences were o b s e r v e d between b o t h g r o u p s in relapses frequency, timing w h e n produced, or cumulative % of sustained remissions or complications.

Obietive: Due to the side-effects of steroids treatment of INS, diferent groups have tried the use of reduced dosage or time in order to prevent them. Material and Methods: Our group started a treatment protocol for the recurrences (R) of steroid sensitive (SS) INS. wich consisted of: Prednisone 20 mg/m2/day until one week after disappearence of proteinuria, and then the same dose every other day during four weeks. 19 patients (10 o* ), ~ 9.4 y. old (r 2 - 20.7 y.) with INS that had been followed during i 6 y. (r 2 - 17 y.) were put on LDT. Follow up after LDT was ~ 1.1 y (r 0.5 - 4 y) All patients had been SS., 6 had renal biopsies (2 minimal change [M.C.], 4 Focal Glomeral Sclerosis [FGS] ).

D.Mass6, D.Gay, L. A. Vazquez, H.A.Repetto.

Results: 30135 (85.7 %) of R responded with disappearence of proteinuda. 96 % of those in the first, two weeks. 14/19 (73 %) of the patients had a response (3/4 FGS, 2/2 MC, 9/13 non - biopsied patients). The R per month before and after the LTD were similar (~ 0.27 vs. x 0.23 p NS). The interval between the R treated and the previous one was similar to that between the treated R and the first posterior one (~ 5.6 months vs ,~ 9.2 months, pNS). CONCLUSIONS: 1) 85 % of the R responded to LDT. 2) The frequency and interval between R were similar before and after the LDT. 3) All R that did not respond to LDT did so when conventional dosage was instituted. Pediatric Nephorology Section. A.Posadas Hospital. Bs.As.Argentina.

* Grant Fondecyt 1940506 Chile .

Col_laboratory Study. Pediatric Nephrology Branch. Chile.

P137 NEPHROTIC SYNDROME IN THE PEDIATRIC POPULATION OF SOUTH TEXAS. I. Elshihabi, A. Brzowski, P. Kearon. Background: Nephrotic syndrome (NS) in hispanics has not been previously addressed. In order to characterize NS in a largely hispanic pediatric population, the clinicopathologic features of NS were studied in a retrospective review of 51 patients in South Central Texas. All patients presented with edema, heavy proteinuria, and hypoalbuminemia. 72 1/2% of nephrotic patients had minimal change nephropathy (MCN). The peak age of onset was 15 months to 3 years. There was a male:female ratio of 2:1. 23% were hypertensive and 92% had hypereholesterolemia. The racial distribution of patients was 72.5% hispanic, 17.6% caucasian, 6% black, and 3.9% unknown. Methods: Patients with presumed MCN were treated with prednisone (60 mg/m2/day in 3 divided doses for 4 weeks followed by 40 mg/m2/day in a single dose for 4 weeks). Frequent relapsers and non-responders were treated with cyclophosphamide (Cytoxan), 2 mg/kg/day for 8 to 12 weeks. 3 patients were treated with chlorambucil (0.2 mg/kg/day for 8 weeks) after exhibiting frequent relapses despite Cytoxan therapy. 24 patients underwent percutaneous renal biopsy. Results: More than 83% of patients responded to prednisone, most between days 6 and 10 of therapy. Of those patients responding to initial steroid therapy, 30.5% were non-relapsers, 27.8% were frequent relapsers, and 41.7% were infrequent relapsers. Cytoxan therapy provided relapse free intervals up to 20 months in duration. 5 of 16 patients treated with Cytoxan have experienced no relapses. 2 of 3 have continued to experience infrequent relapses and 1 has remained relapse free for 4 years. The most frequent histologic diagnoses were MCN (41.7%), focal segmental glomerulosclerosis (12.5%), mesangial hypercellularity (12.5%), membranous glomerulonephritis (8.3%), and post-infectious glomerulonephritis (8.3%). Conclusion: NS in this largely hispanic pediatric population is similar to that characterized by the ISKDCand their clinicopathologic course can be predicted on the basis of those statistics.

P138 NEPHROTIC SYNDROME IN CHILDREN - A SOUTH AFRICAN PERSPECTIVE G VAN BILJON Purpose of the study; to report on the clinical features, biochemical data, histopathology and response to treatment of all children with nephrotic syndrome at the H F Verwoerd Hospital, Patients and methods: All children with NS presenting at the H F Verwoerd Hospital between June 1986 and January 1995 were investigated. The clinical and biochemical data, histological features and response to treatment were reviewed. Results: Eighty children, aged 3 months to 12 years were investigated.Fourty six (57,5%) were white, 22 (27,5%) were black, 7 (9%) were coloured and 5 (6%) were Asian. Kidney biopsies were done in 67 (84%). Thirty four children (50,7%) had Minimal Change Nephrotic Syndrome (MCNS) on histology, of whom 26 were white and 5 were black. Eleven children were presumed to have MCNS because of their clinical response to corticosteroid treatment. The total group constitute 45 (56%) of all patients. Focal segmental glomerulosclerosis (FSG) was the second most common histological feature in the black children, occuring in 18%. Eighty two percent of children with MCNS responded well to steroid treatment, and 18% exhibited early steroid resistance. Corticosteroid treatment was of benefit to only one child with FSG. For the remaining 11 children with FSG, neither steroid nor cyclophosphamide treatment was of any benefit. Membranous nephropathy occured in 4 (8,9%) patients of whom 3 were HBs Ag carriers. Overall mortality rate was 3%. Conclusions MCNS occurs less commonly in the mixed South African population compared to the 76,4% reported by the ISKDC. The different ethnic groups play some role in the distribution of the major histological types of NS. Black children with FSG respond poorly to immunosuppressive drugs. Department of Paediatrics, University of Pretoria, South Africa.

G 89 P139

P140

Initial Treatment and Long-term Prognosis in Nephrotic Children S.Ito*, K.Tsuzuki* ,M.Okada, M.Tsuyuki*, M.Shibata*, Y.Fujimoto*, A.Mizuno*, C.Tsukidate*, H.Noguchi*, S.Minowa** and T.Yasaki**.

NEPHROTIC SYNDROME IN FIRST YEAR OF LIFE C Norero,* A Dducchi,* MA Contreras, E Lagos,* P Rosatl,* V Nazal, M Verdaguer.

P u r p o s e : To evaluate the intluence o f initial treatment on long-term prognosis o f stereid-sensitive nephrotie syndrome(SSNS) in children. M e t h o d s : Retrospective analysis from ch'nieul records within these 30 yrs of S S N S chffdren(65 boys and 29 girls, onset: 6. 7 ~ 33.8 yrs) observed for more than 10 yrs from the onset. Patients were divided into three groupsaccording to their age o f onset: early onset group(1 to 5 yrs, n=39), mid-onset group(6 to 10 yrs, n=41) and late onset group(11 to 15 yrs, n=14). Correlation between long-term prognosis and im'tiul treatment, namely dosage(daffy and cumulative) o f prednisolone(PSL) and duration o f initial treatment, were analyzed. R e s u l t s : In the early onset group, length o f initial P S L administration(calculated as >2mg/kg) was significantly correlated to long-term prognosis(plmg/kg, were not correlated. In the mid-onset group, there were no significant correlation. In the late onset group, length o f initial treatment calculated as more than l m g / k g and 1.5mg/kg, cumulative dosage duzqng initial 4 and 8 weeks were significantly eorrelated(p
P141 CONGENITAL NEPHROTIC SYNDROME SECONDARY TO SYPHILIS M. G o r o e i t o @ S.Piotto#M.,_P~vslvo#C.Hius* We p r e s e n t a two m o n t h s and t w e n t y six deym old m a l e well m o u r i e h e d with d i a g n o s i s of C o n g e n i t a l N e p h r o t i ~ ~ y m d r o m a S e c o n d a r y to Syphilis. He lead the h i s t o r y of m u o o p u r u l a n t s n u f f d u r i n g F i v e days and the appes~ r a n t s of F a c i a l edemsp a a c i t i s m s a c r u s and s c r o t a l swellingj h y p e r t e n s i o n [over P 95)p m a c r o h e m a t u r i s j s k i n r a s h amd p o l y o r i f i c i a l e r i t e m a t o u s maculaa. The l a b o r a t o r y f i n d i m g a that c o m f i r m the d i a g n o s i s were: heavy p m o t e i n u r i s C5 gr% in 24 ha)~ h y p o a l b u m i n e m i a [1.7 mg/dl]j h y p e r c o l e a t e r o l e m i a C362mg/dl 3 h y p o c o m p l e m e n t e m i a [CHSO 9 C 4 25]~ i n c r e a s e d e r y t h r O cyte s a d i m e n t s t i o m rate [155]j l e u c o c i t o a i s [16.900) r e a c t i v e V D R L [2S6 dils]. His m o t h e r ' s r e a c t i o n was 32 dila. T h e X r s y s h o w e d p e r i o a t i t i s in both F e m u r and both cubitus. T h e renal a o n o g r e p h y was normal. D e r m a t o l o g y e t c o n f i r m e d his s k i m l e s i o n s as e x a m p l e s of a y p h i lie. He was t r s t e d with i n t r a v e n o u s a o d i c G p e n i c i l i n u m in d o s e s of 1DO.O00 U / K g / d a y d u r i m g F o r t e s n days. T h e s y m p t o m s r s m e t e d c o m p l e t l y in s i x t e e n d a y s of the o n s e t of the t r e a t m e n t with n o r m a l i z a t i o m of lab. Aa o o n o l u t i o n ~ we p r e s e n t this case a l t h o u g h it is not v e r y f r e c u e n t b e c a u s e it is the moat c o m m o n adq u i r a d c o n g e n i t a l n e p h r o t i c syndrome, k n o w i n g t h a t it: 's q u i c k d i a g n o s i s end Fs~t t r e a t m e n t is a b a o l u fly n e c e s s a r y For it's c o m p l e t e r e m i s s i o n w i t h o u t sequel. P r i m e r s C ~ t e d P a de P e d i a t r ~ a - 3 a l e 8 - H o s p i t a l del Centenario-Roaario-Argentins .

Over 30 montlxs, 99 patients were enrolled to a chilean multicentrie protocol on Nephrotic Syndrome (NS). 8 of them were less than 1 year of age (median .7.5 months), 5 females and 3 males. NS began before 10 days of age in 3 infants. M.icroscopic hematuria was observed in 7 cases, arterial hypertension and acute renal failure in 4 infants. LaboratoD' findings were not different to those found in older childrens. Secondary etiologies of congenital nephrotie syndrome were descarted. I-IistopathotoEr showed in 6 cases: Diffuse mesangial sclerosis (DMS) : 2 patients ( one associated to a Drash Syndrome ); Finnish type (FS): 2 patients; Focal segmental glomeroloselerosis (FSGS): 1 case and Minimal change (MCD): 1 patient. 7 patients received Prednisone: 4 were resistent ( 1 FS, 2 DMS and 1 FSGS); 2 dependent (1 MCD, 1 without biopsy) and 1 was steroid sensitive. Cyclophosphamide was used i n 2 patients (MCD and FSGS) with good response. Complicatom: Severe bacterial infections in 7 and thrombosis in 2 eases.. Mortality: 3 childrens, who had onset before 4th month, died, (2 DMS in septic shock and 1 FS with pulmonary artery thrombosis ). Currenty, 5 patients remain alive: 3 under remission~ I with persistent proteinuria ( 12 month of follow-up) and 1 chronic renal insufficiency ( FS with 30 months of follow-up). CONCLUSIONS: The onset of NS before the 6th month of life has a poor prognosis related to DMS and FS histologies. FSGS and MCD in the first year of life have the same response than in older pediatric patients. *Grant Fondecyt 1940506 Chile CollaborateD, Stu~", Pediatric Nephrology Branch. Chile

P142 CURRENT OPTIONS FOR TREATMENT OF HYPERLIPIDEMI~ IN CHILDREN WITH PERSISTING NEPHROTIC SYNDROME U. Querfeld1 and K. Sch~.rer a ............................................. r ........................................... Children with persisting nephrotic syndrome (NS) frequently have severe hyperlipidemia (HLP). HLP is a risk factor for atherosclerosis and in addition may contribute to an accelerated progression of chronic renal failure. Since a satisfactory treatment of HLP is hardly achieved with dietary regiments in these patients, pharmacological treatment has been recommended, but studies in children are virtually absent. Experience in adults with NS has been gained with HMG-CoA reductase inhibitors, bile acid sequestrants, fibdc acids and probucol. The reductase inhibitors are the most effective medication, resulting in a decrease of total cholesterol (C) levels of about 30%. However, use of these drugs is currently not recommended in children because of concems regarding potential effects on central nervous system development, e.g. myelination. Bile acid sequestrants (cholestyramine, colestipol) lower total C and LDL-C, but may increase triglyceride levels and cause mainly gastrointestinal side effects. Fibric acids (gemfibrozil, bezafibrate) lower total C and LDL-C levels while increasing HDL-C; however, these drugs can have serious side effects, e.g. myopathy, gallstones, etc. Probucol reduces total cholesterol, triglyceddes, LDL and HDL-cholesterol and inhibits oxidation of lipoproteins; it has no major side effects in adult patients with NS. Nicotinic acid might theoretically be of benefit in HLP of NS, but has not been tested in adults; occasionally, severe side effects, e.g. hepatic dysfunction have been observed. Plant sterols (sitosterol) inhibit intestinal cholesterol absorption without evident side effects, but their use has not been tested in patients with NS. Experience with drug treatment in children with primary forms of HLP is mainly confined to bile acid sequestrants and to a lesser extent probucol, fibrates and sitosterol. Therefore, these drugs currently should be regarded as candidates for pharmacological treatment of HLP in children with NS; however, their safety and efficacy remain to be evaluated in children, preferrably in a large multicenter tdaL University Children's Hospitals, Cologne1 and Heidelberg~, Germany.

C 90 P143

P144

ffa~lIl(f OF$1~0B ~ B f 2flNOLLI,II.B,;I~RI~UJO,

NEM0~ICSs

I.N.;GLIILHEN,J,r162

Wll'd II/ C~CL01ql0SPH~IDI~ SP -

CYCLOPHOSPHAMIDE PULSE THERAPY: NEW TREATMENT FOR STEROIDDEPENDENTMINIMALCHANGENEPHROTIC SYNDROME.

BR~I21L

Good t ~ a l t s obtatnnd with intraverms pelse Cgelophe~#uide (I~P) in lupes e n ~ i t l = ha= ~imlated u trgi~J this theral~etie ia s~rekl dependent ~eotlc ~ children. Wu/,een~ '91 and kcenher '94 ~ 18 children l~en trentmnt uiib PEP at a dose of 15 NJ~J BI/euenj three months, h~ the ? patients that finished the total of 6 I~P ~ 6 uere femalej and 6 caecuian. Thea ~ a g e qle at the hegitdw~ ot Ir~abe~ ~ 5.8r 9ears, :and the averege t i m of nephretic sgnd~m ma 5.4*/-3.5 9eare. Jj the t i m I1~ t m trtart~, the 24 b o ~ peotel~ria ma 5.9*/-3.4 9, zeetm a l l , in ms Z.Z*/-~.9 gfdl and revert ~eatinim eas 8.51./-8.t2 ~tdi. l(id~j btel~tu sMmd II/niml Chtn[e Blnase in 5 1~ , and Heu~jlal Preilte~ative JGlemrelem#a, itis ulth 1# &pasits in 7 p(s. 9r patients hid 19peri ~ t l o n s~iulri~J treating, lhree patients had previats aller~9 h i ~ r 9. ~ll patients I r e kept in the stereid sehndule !9 the t i m I~P was startS, and It ma ~ a l ~ d until e ~ l ~ l g ~itkl~. Xhe follo~ up t i m ~tts~ I~2P ma 14.7./-11.1 ~ , wtjln 9 tr~ 1 to 38 nmrtM. ~ll ? l~tierds aehieeed complete reni~tion at the end iot leCP treatm~t, aM 2 1~ . ~e taking 5 ~j PRdnl~re e.o.d. Jhe man prntelnmqa tree t i m m= 12s mrttM, t,ergi~J tim :1 to 38 maiM. three patients diddt relapse ulats0e~ee, and the other 4 relal~ed enee ofts~ the end of I~P trentne~. Iransient l ~ e a and o i t i M in the &ag~ folloui~j l~P ~ oheeeeed in 12pts.,andthetj ~ the enI9 side e~feets o ~ t e d . Patients thai had 19Maetemio~ are t m corrtroll~ ~itlml tl~malmtic. Felinimrtj result= wjg~.t imsible tmcest.ll t m a ~ of stsreid dependent I~)eotic ~ children.l~P t r e a t e r a l l u lower a e ~ l a t i m den of CtJclophetld~l~ and fema =l& effects, and p a t i ~ may be d ~ o t d free tot lmjer perlnd=.

P145

TREATMENT OF THE INFANTILE NEPHROTIC SYNDROME (INS) WITH CYCLOSPORIN A (CsA) R. Halevi*, B.Eisenatein **, A.Drukker*** Congenital nephrotic syndrome and INS carry a poor renal prognosis and generally do not respond to corticosteroids or 'conventional' immunosuppresive therapy. We wish to report succesful treatment with CsA of two patients suffering from INS, followed for approximately 2 years. The first patient developed a full blown picture of severe INS at 9 months of age. Renal biopsy (Bx) showed a histologic picture compatible with the so-called Finnish type of INS (FINS). He was treated with corticosteroids without success. However, one month after CsA therapy was started (6 mg/kg/d), the proteinuria subsided without a recurrence during >2 years of close follow-up. Renal function is conserved with a serum creatinine (Scr) of 0.5 mg/dl. A repeat renal biopsy, after more than one year of CsA therapy, showed a few obsolescent glomeruli and mild interstitial fibrosis. The second baby developed INS at 5 months of age. A sibling died in renal failure. Renal biopsy in this patient also showed FINS. CsA induced a significant reduction in proteinuria, which is sustained after >20 months. Scr is normal for age and he grows and develops well. Congenital and INS are difficult to manage. Both have a high mortality rate, mainly due to overwhelming intercurrent infection and thromboembolism, and progress to renal failure. The antiproteinuric effect of CsA in patients with INSis probably non-specific and long-term CsA therapy may cause renal damage. However, a therapeutic trial with CsA in these patients seems justified, in view of the dire outcome of INS. Though CsA therapy greatly fascilitates the management of INS dunng a cdtical time period, the long-term renal prognosis of children with INS, 'probably remains poor.

Pediatric Nephrology Units at the Central Emek HospitaI-Afula*, the Beilinson Medical Center-Petah Tiqvah** and the Sheare Zedek Medical Center-Jerusalem***, Israel

E. LAGOMARSINO*, E. TALES31IK*, E CAVAGNARO*, E. SOLAR'*, A. VALE.NZUELA**.

Prednisone is the usual treatment of minimal change nephrotic syndrome (MCNS). One third of these patients present frequent relapses requiring multiple or prolonged courses of steroid therapy. Oral cycluphosphamido (CP)

is used as a second choice drug iroproving the remission rate. Iotrav~ous CP pulse therapy has recently been proposed as an alternative to steroid treatment failure. A prospective protocol for normal renal function, steroid dapendetat MCNS patients was designed A_~tersigned informed consent, iv poises of CP (500 mg/mz per month) with concomitant oral prednisone (40 rng/m2 every other day) were given to patients duringsix months, followed by prednisune (same dosage) for two more weeks, q'he nnmunologie work-up included serum Lmrnunogiobulinslevels and lymphocyte subpopulation count using monoclonal antibodies, before and after the immunosuppressive therapy. Responses were rated as complete remission (proteinuria < 4 mg/m2/h and serum albumin >35g/1), no remission (proteinuria >40 mg/ mZ/h) and incomplete remission (proteinuria between 4 and 40 mg/m2/h). Three children (two girls) with age ranging from 5 to 12 years, started the protocol, two of them completed the treatment with 12 and 18 months of follow up. Complete clinical and laboratory remission was reached at a lower accumulative total dose of CP compared to the standard oral CP treatment. The pulses were well tolerated. One patient had to be withdrawn from this protocol due to an intercurrent infection (erysipella). The absolute counts of total T lymphocytes (CD 3), helpers (CD 4) and suppressors (CD 8) fell ai~r the last CP poise in comparisson with normal basal counts, except for the patient withdrawn from the study, whose initial counts were also lower. Conclusion: CP pulses are a valid therapy to induce ltmg-term remission in children with steroid dependent MCNS. Previous immunologm evaluation could predict patients with a higher risk of infections if sllbmitted to this therapy. Serviceof Pediatrics, Catholic UniversitySchool O[Medifine, Sal~j~go,CHILE, ** Serviceof Pediatrics, S6tero del Rio Hospital, Santlqgo, ~IIL~. *

P146 TREATMENT OF IDIOPATHIC NEPHROTIC SYNDROME CYCLOSPORIN A

(NS) WITH

A. Valio, Ma J. Quintela, R. Oliveros, G. Ariceta, J. Rodrfguez Soriano Cyclosporin A (CyA, SandimunR) is an accepted treatment for chll&en with steroid-dependent NS (SDNS). Its role in the therapy of steroid-resistant NS (SRNS) is less recognized. We evaluated the efficacy of CyA in 25 patients (13 SDNS, 12 SRNS) followed up during the years 1988-1995. SDNS patients were assumed to have minimal change NS (MCNS). Renal biopsy in SRNS showed: MCNS (2), mesangial proliferation with IgM deposits (4), focal and segmental glomerulusclerosis (6). fuJtial CyA dose was 5 mg/kg/day and it was adjusted according to blood CyA levels. CyA was always given as a third therapy, after prednisone and nigogen mustard or cyclophosphamide. In SRNS patients CyA was always associated to predrtisone (30 mg/m2/everyother day). The number of patients with SDNS relapsing during or after CyA therapy were the following: Dmation .Cd_&(m0nth~) 12-24 continuous 12-24 interrupted > 24 continuous > 24 interrupted

n_ 5 1 4 3

no relame 3 1 1 1

. relanse 2 0 3 2

The 7 children receiving more than 2 years of CyA (reatment were the ones relapsing more frequently and all required associated steroid treatment at high doses to control relapses. Patients with SRNS were treated with CyA for at least 6 months: 6 did not respond, 2 had a partial remission and 4 had a complete remission. Three of these 4 patients relapsed after interruption of CyA therapy and required continuous CyA treatment. One patient is on remission for more than 2 years afmr arrest of CyA therapy. We conclude that in SDNS prolonged CyA therapy is not accompanied by better remission rates but improves the clinical control of the disease. No patient presented a sustained remission once CyA was withdrawn. In SRNS partial or full remission occurs in about 50% of patients. Relapses are frequent but respond again to CyA therapy. Department of Pediatrics, Hospital de Cruces and Basque University School of Medicine, Bilbao, Spain.

C 91 P147

P148

T H E I N I T I A L T R E A T M E N T OF I D I O P A T H I C N E P H R O T I C S Y N D R O M E W I T H P R E D N I S O N E A N D C Y C L O S P O R I N A: PRELIMINARY RESULTS OF A THERAPEUTIC TRIAL P.F. Hoyer for the Arbeitsgemeinsehaft rfir Plidiatrisehe Nephrologie (APN)

Previous studies of the APN have shown that the risk for subsequent relapses in patients with steroid sensitive nephrotie syndrome (NS) depends on the intensity of the initial treatment with glueocorticosteroids (Lancet 1988;1:380, Fur

J Ped 1993;152:357 ). The aim of this randomized multicentre co-operative study was to reduce the number of subsequent relapses further by increasing the initial immunosuppression: Patients with an initial attack of a NS were randomly allocated to the new standard initial treatment with prednisone, i.e. 6 weeks 60 mg/m2/d followed by 6 weeks 40 mg/m2/48h (= Pred-group) or to new standard initial treatment p l u s 8 weeks eyelosporin A (150 mg/mVd, blood levels 80 to 150 ng/ml ; = CsA-group). 104 patients were enroled so far in this study; 19 of them had to be excluded (because of steroid resistance (n=9), infection and thrombosis (n=3), moving or deviations from the protocol (n=7)). 45 patients were treated according to the Pred-group protocol and 40 to the CsA-group protocol. In the CsA-group the first relapse occurred later compared to the Pred-group (median 241 days versus 159 days). After 6 months 17% of patients in the CsA-group experienced a first relapse versus 43% in the Pred-group, after one year 43% versus 41%. The mean relapse rate per patient in the CsA-group was 0.31 versus 0.76 after 6 months and 1.04 versus 1.30 after one year.The corresponding cumulative prednisone dosis per patient after one year was 3072 mg/m2 (CsA) versus 4072 mg/m 2(Pred). No significant side - effects were observed in regard to blood pressure or GFR. A transient hypertrichosis (in 49%) and gingival hypertrophy (in 18%) was observed in the CsA-group, while adipositas was more pronounced in the Pred-group. These preliminary results demonstrate that under additional treatment with CsA the first relapse after initial treatment occurs later and that CsA has a steroid sparing effect by reducing the number of relapses during the first year after initial treatment; however, if this holds true for two years will be demonstrated with longer observation time.

USE OF CYCLOSPORINE IN STEROID DEPENDENT NEPHROTIC SYNDROME (SDNS) KochVII*, ~ MD*, Flmas~'a EA*, Vaisbida I~i*,O1~, Y*. Cyclosporine(C~,)~as used in combinationwith prodmisone(PDZ) to treat 6 children (5 male) with SDNS. The patients' mean age was 11.9 yrs (7.3-14.7), they were trealed for a mean period of 21 mos (7-29) and the inclusion criteria for the protocolwere: normal renal function, ensatisfacloD, p~wious use of cyclophosphamide and chlorambucil and signs of ~eroid toxicity ( subeapsularcataract 3/6, hypertension2/6, bone demineralizafion1/6 patients), All tbe pali~s were r to s l~utaneous renal biopsy before initialing the treatment prol~l which ~ow~l lgM nc'phrOl~l~, 3/6, minimal change disease2/6, focal segmentalglomendosclerosis116 patients. The initial Cy dose ~as 4mg/kg/day. Cy blood levels were obtained monthly ( monocional RIA) and kepl between 50 -150 ng.ml, The initial PDZ dose varied b e ~ e n 30-60 mg/m2/day. T ~ patients were withdra~ from the prolneol after 7 and 22 mos of Cy use boeause of LFTs elevatien s~ondmy to n~' b, diagnosed hepatitis C and nemropeniadue to bone marrowIoxicily,respectively.In the other 4 patients PDZ was tapered to significantly lower levels bul otmld be diumntinued in only one. In our experience, Cy seems useful to lower steroid dependencythreshold without obviating PDZ usage in most cases. During Cy therapy a careful labomtot3, work up has to be followedin order Io screenfor Cy's multipleadverseeffects. * Senafo de NefmlogiaPedi~tricado lrmiture da Criancrado H,C.F.MU,S.P.S~O Paulo - Brasil

Centralcoordinatingoffice: Kinderklinik, Med. Hochschule, 30623 Hannover

P149

P150

PREDNISONE AND CY(SLOSPORIN A TREATMENT IN NEPHROTIC SYNDROM OF CHILDHOOD M.Dehennault*, M.Foulard*, J.Cousin*% P.Saunier* We evaluated the efficacy-of prednisone with cyclosporin A(CyA) treatment in nephrotic syndrom(NS) of 18 children. Prednisone was given at a dose of 30mg/rn2/day for 1 month,and then every other? day.CyA Was-given at a dose of !50 t o 200mg/m2/day.Both were given for 4 to 24 months. NS was steroid resistant(SR) in 10 children(3boys,7girls) who were lyearl lmonths to 1 lyearsl lmonths old at the beginning of the NS.Renal biopsy showed minimal change(MC) NS:6/9,or focal segmental glomerular sclerosis:3/9. NS was steroid dependant(SD) in 8 children(6boys,2girls) who were 19months to 15years2months old at the beginning of NS.NS relapsed at a dose of 2mg/kg every other day(5/8),or about lmg/kg every other day(3/8) before the treatment.Renal biopsy showed MCNS:8/8. Remission was obtained in 8/10 children with SRNS.The follow up is 7months to 8years since the beginning of NS. In SDNS,number of relapses whilst taking the treatment was reduced(4/8),or unchanged(4/8). Growth velocity was accelerated or normal(4/8), or reduced(2/8,both failed to respond to the treatment).The follow up is too short for the 2 other children. No serious side effects were observed. The combination of CyA and prednisone seems to have a good efficacy in achieving remission in SRNS,while efficacy is less obvious in SDNS.However,our study is too small to obtain a statistic value. *Unite de ntphrologie pediatrique.59037 LILLE cedex FRANCE. **Hopital Saint Antoine.59019 LILLE cedex FRANCE.

BENEFICIAL EFFECT OF LONG-LASTING CYCLOSPORIN A ADMINISTRATION TO CHILDREN WITH IDIOPATHIC NEPHROTIC SYNDROME K. Saneewiez-Paeh, E. SIowiaczek, J. Kwinta-Rybicka, J. Nowak The aim of the paper was to evaluate cyelosporin A (CsA, Sandimmun) treatment in children with steroid-resistant nephrotic syndrome (diagnosed according to the criteria established by ISKDC), in whom numerous attempts at other types of therapy had failed. CsA was used in 23 children aged 2-16 years. Renal biopsies revealed minimal changes in 7 children, focal-segmental glomeruloscterosis (FSGN) in 1t patients, mesangial glomerulonephritis in 4, and membrano-proliferative glomerulonephritis in one child. CsA was administered for a period 8 weeks to 28 months at the dose of 6 mg/kg, gradually decreased to 2.5 mg/kg. Blood CsA level was 40-200 ng/ml. In the course of treatment, in 21 patients proteinuria subsided or diminished and clinical improvement was seen. Seven children showed relapses of nephrotic syndrome showing very low blood CsA levels. Complete remissions were achieved in 11 children, partial remissions - in 9; no remission was seen in 3 children. Throughout the treatment and after its cessation no child manifested a deterioration of renal function. Repeated renal biopsies did not reveal any lesions that might suggest nephrotoxic CsA activity. Secondary steroid-sensitivity observed in 5 children should be emphasized. In conclusion, CsA is an effectave and well tolerated agent in children with steroid- resistant nephrotic syndrome, and the improvement noted in patients with FSGN may reduce the risk of early terminal renal failure. Polish American Children's Hospital Coll.Med.Jagidlonian University Dep. of Ped. Nephrology Krak6w Poland

C 92 POSTER

SESSION

- (P) - D i a l y s i s

P151 RELATIONSHIP BETWEEN THE MODE OF DIALYSIS AND OTHER VARIABLES AND THE PATTERN OF LEFT VENTRICULAR HYPERTROPHY (LVH) IN NORMOTENSIVE C H I L D R E N W I T H ESRD M. Litwin, W. Kawalec, J. Latoszyfiska, B. Matema, E. Cichocka, R. Grenda (intr. T.Wyszyfiska) An aim of the study was to examine if them is any link between LVH and the mode of dialysis (CAPD or HI)) and other variables (age, extension of hyperparathyroid ism (HP), time on dialysis and blood pressure) in normotensive children on dialysis. Methods: 46 normotensive children with ESRD without apparent cardiac disease were examined. 18 pts were on CAPD: mean age 14.1 ys (7 - 17), mean time on CAPD 13.7 mrs (1 - 36). 28 pts were on HD: mean age 15.4 ys (4 - 17), mean time on HD 15.1 mrs (1 - 70). Pts were examined with M-mode, 2D and Doppler echocardiography. CAPD pts were examined in an optimal hydration state, 30 minutes after emptying their peritoneal cavity. HD pts were examined on a midweek day, between two dialysis sessions, after achievement of "dry weight" on the last HD. All the results were indexed per square meter. On the week of the ECHO examination, total BMD measurementswere performed. Linear regression and step wise analysisis tests were performed to assess impact of suspected risk factors on LVH determinants. Results: * there were found significant differreaces (p<0.01 ) between CAPD and HD pts in values of: LVMi: 61.2g/m 2 vs 102g/m2, IVSd: 9.8mm/m2vs 7.9mm/m2, LVPWd 8.Tmm/m2 vs 7.3mm/m2, EDVi: 51. lml/m2 vs 92mI/m2,EDVi/LVPWd: 6.4 vs 13.2 and relative wall thickness: 0.45 vs 0.36. There were no differrences in both systolic and diastolic function between groups * there were found significant negative correllations between total BMD and LVIDs, LVIDd and LVPWd (r=0.43). * only in CAPD pts were,found positive correUations between time on dialysis and IVSd, LVMi, EDVi and EDVi/LVPWd *step wise regression test has shown that risk factors for LVH are age, time on dialysis, liP and blood pressure. Conclusions: 1) normotensive children treated with CAPD tend to have the pattern of concentric hyperkinetic LVH and normotensive children on liD tend to have eccentric LVH, 2) secondary hyperparathyroidism expressed as low total BMD, blood pressure even in normotensive children and age are risk factors for both LVH and dilation of the ventricule, 3) duration of dialysis therapy influences LVH in CAPD pts probably due to diminished peritoneal dialyzing capability. Dept. of Nephrology, Child Health Centre, A1. Dzieci Polskich 20, Warsaw, Poland.

P153

P152

HCV-RNA

WAS UNDETECTABLE IN REPEATED ANALYSES OF DIALYSIS ULTRAFILTRATES *Flichman D, "Amore A , *Bonaudo R, #Basolo B, #Martina G,

*Bonino F, *Brunetto MR, ~

R

Several attempts have recently been made to investigate the ways of transmission of hepatitis C virus (HCV) and particularly discussed is the possibility of its passage through the dialysis (HD) membranes into the ultrafiltrate (UF), making the HD monitor a way of HCV transmission. We preyiously demonstrated that the HCV does not pass in standard conditions through different dialysis membranes (Nephron, 1995 in press). In this study we explored the possibility that subclinical membrane breacks, occourdng more frequently than those detectable, may be responsible in any case of HCV passage in the dialysis fluid. We studied over one month of HD 3 HCV- RNA positive patients. HCV-RNA was tested in UF samples at the 4th hour during 36 HD sessions. HCV-RNA was measured by RT-PCR.After RT step, cDNA was amplified using a primer of the 5' non-coding region in a single step PCR of 35 cycles. The 240 bp PCR product was hybridized with a 32 P oligo probe. The assay specificity and sensitivity were proved in a control trial of the European Pathobiologists Group. To avoid cross-contaminations , negative controls were run in parallel test samples.A Chimp serum containing 106 CID 50/ml was used to assess the sensitivity, cDNA can be detected till the 10-5 dilution of the positive control corresponding to l O2/103genomes (gen) Eq/ml. The sensitivity of our assay was ] 02 and 103 gen Eq/ml.Viraemia in patients was >104gen Eq/ml during the HD. All the UF tested were negative. Albeit HCV diameter (35-60 nm) overcomes the membrane cut-off (Cu:1.0-1.3 ,nm; AN69:5.5 nm), the possibility of its membrane passage was claimed 9s due to different "in vivo" and "in vitro" membranes cut-offs or to 'microscopic breaks or passages of viral fragments istead of total virions. Our data do not support these hypotheses, as we failed to prove the passage of the HCV-RNA into the UF over a HD pedod of one month in the patients investigated. *Gastroenterololy S. Giovanni Hospital, Nephrol and Dial. *Regina Margherita Hospital # G.Bosco Hospital. Turin. Italy.

P154

GROWTH HORMONE THERAPY IN CHILDREN UNDERGOING DIALYSIS

STUDY OF PATIENTS ON CHRONIC HEMODIALYSIS W I T H LOW DOSE ERYTHROPOIETIN TREATMENT Miceli S*, tontine N*, Aralde A*.

S Emre *, A.~;irin, l~ Bundak, F. Tanman, A.Nayzr, l.Bilg~

B e c a u s e of the necessity to d e c r e a s e the transfusion risks in our patients (children and adolescents) on hemodialysls t r e a t m e n t , w e h a v e e m p l o y e d h u m a n srythropoietln (EPO 1 at low doses (one subcutaneous (SO) w e e k l y dose). In our first p e r i o d (9 months) the purpose was to maintain hematocrits w i t h o u t transfusions (>21 - <24). In the s e c o n d p e r i o d w e w a n t e d to raise t h e h e m a t o o r i t levels to 28~ with low dosage~ Objective: To evaluate the effectiveness of the w e e k l y SC l o w d o s e a f t e r s months of t r e a t m e n t . M a t e r i a l a n d Mathodst 17 patients on chronic hemodialysis w e r e f o l l o w e d d u r i n g e r t h r o p o i e t i n treatment. Their m e a n a g e w e r e 17 y e a r s (9-24), ii f e m a l e a n d 6 male. The mean t i m e on dialysis was 59 months. A w e e k l y SC d o s e of E P O w a s given w i t h the following schedule= a w e a k l y hematocrit w a s d o n e e v e r y Monday; if its level was 28~ or higher= 1S U/kg/dosa; HOT 20-28~: 30 U/kg/dose;HCT<26~: 60 U/kg/dose Results: W e h a v e e v a l u a t e d the r e s u l t s a f t e r 8 months of t r e a t m e n t = m e a n H O T 26~ § SD 3.1 m e a n Hb: I0 +/- SD I.I; m e a n EPO w e e k l y dose:960 U § SD 726. Mean dose: 2S U/kg/waekly +/- SD 20.4. According to the required dose w e c o u l d o b s e r v e t h r e e groups: A.- 6 patients (35~) required < i0 U/kg/dose/week B.- 5 patients (30~) required between 10-30

Growth retardation is a well established feature of chronic renal failure (CRF) in children. Recombinant human growth hormone (rhGH) has been shown to improve growth in children with CRF on conservative therapy and dialysis and after renal transplantation. This study was designed to evaluate the efflcaey and safety of rhGH in children on regular dialysis therapy. The study group consisted of 26 children (10 girls and 16 boys) with a mean age o f 12.77• years (range 4.5-16.5 years) on dialysis therapy for at least 6 months. All of the patients had at least six months of growth supervision and fulfilled the criteria of height below -2SDS or a height velocity below the 25 th percentile (Tanner) for chronological age. Thirteen of the patients were prepubertal and 13 pubertal. Growth hormone or thyroid hormone deficient patients were not included in the study. Patients were administered rhGH (Genotropin, Pharmaeia) subcutaneously at a dose of 1 U/kg/week every night for one year. Height velocity showed a significant increase from 2.83• cm/year (mean--~SD) to 5.02~:2.60 cm/year at the end of one year treatment. Height SDS did not change significantly. Blood haemoglobine, glycolisated haemoglobine, glucose, triglyceride, cholesterol, calcium, phosphate levels did not show significant changes throughout the study. The only untoward effects noted were the significant increases in alkaline phosphatase and parathormone levels. It was concluded that rhGH therapy is able to promote growth and imrove height in short children on regular dialysis therapy without causing significant side effects provided that care is taken to control renal osteodystrophy during therapy. *University of Istanbul, Medical Faculty, DeparUnent of Pedia~c Nephrology, (~apa, I~nbul-TURKEY.

U/kg/dose/weak c.- 6 patients

(35~) r e q u i r e d b e t w e e n 30-90

U/kg/dosa/weak Higher doses w e r e r e q u i r e d in 9 patients during the initial treatment and 1 patient chronically infected. T h e r e wasn't significant biochemical changes (Serum BUN, creatinine, potassium, ratlculoc~rbee). Six of 11 female patients r e q u i r e d d o s e i n c r e a s e during menstrual period. The t r a n s f u s i o n r e q u i r e m e n t d e c r e a s e d to 0.009 transfusion/patient/month. The cross-match d e t e r m i n a t i o n w a s nssative on 62~ of the patients. The complications w e r e = I c a s e of m e t r o r r h a g i a a n d 1 c a s e of v a s c u l a r a c c e s s obstruotion w i t h HOT 36~. Conclusions= A low EPO w e e k l y dose w a s e f f e c t i v e during a long time. It was neoeesary l o w e r d o s e s to i m p r o v e the results. C e n t r e I n f a n t i l dal Ri~on - Monteegudo 726 - 4000 S.M. de

~

- Anoint/ha

C 93 P156

P155

HYPERHOMOCYSTEINEMIA IN CHILDREN ON HEMODIALYSIS: A RISK FACTOR FOR FISTULA/GRAFr THROMBOSIS? M.N.Reddy +, K.Molteni +§ C.Pan ++, K.J.Sheth ++

E F F E C T I V E N E S S O F L O W D O S E E R Y T ~ R O P O I E N T I N IN P E D I A T R I C P A T I E N T S UNDERGOING ~ODIALYSIS TREATMENT M i e e l i S*, C o n t i n o N*, /%ralds A*o E y t h r o p o i e t i n t h e r a p y (EP0) has b e e n s h o w n to be e f f i c i e n t t o c o r r e c t t h e a n a e m i a of p a t i e n t s w i t h e n d stage renal f a i l u r e m a i n t a i n e d b y c h r o n i c hemodlalysis. U n f o r t u n a t e l y t h i s d r u g is dillies/it to be u s e d in o u r co%t~try d u e t o its cost a n d l a c k o f social s e c u r i t y support. Therefore, w e b e g a n t o u s e t h i s d r ~ g in doses a c c o r d i n g t o HCT. o u r goals worst to m a i n t a i n H C T in a range w h i c h has n o further n e e d for b l o o d t r a n s f u s i o n > 2 1 % < 24%; to d e c r e a s e t h e i n c i d e n c e of c r o s s - m a t c h p o s i t i v e p a t i e n t s a n d r e d u c e the Cost. Thus, t h i s s t u d y w a s d e s i g n e d eo s h o w if t h e doses a n d she t e c h n i q u e u s e d w e r e efficient t o m e e t t h e o b j e c t i v e s above mentioned. S e v e n t e e n p a t i e n t s w i t h e n d - s t a g e renal failure w e r e studied, w i t h a m e a n a g e of 14 years o l d {range 7-23), a m e a n w e l g h t o f 25 k g (range 16-51), m a i n t a i n e d b y h a e m o d i a l y e l e f o r a 9~ea~ t i ~ e of 52 m o n t h s (range 6-12~). They were a~/nietered EPO d u r i n g 6 m o n t h s b y e~b~qltaneous route. T h e first d o ~ e w a s 40 U/Kg. The f o l l o w i n g doses w e r e g i v e n a c c o r d i n g eo H C T w h i c h w a s m e a s u r e d w e e k l y postdiulysis, f o l l o w i n g t h i s schemes > 24% the dose w a s held; fro~a 22 to 2 4 % I0 U/Kg; f r 0 ~ 20 to 2 2 % 20 U / K ~ a n d less t h a ~ 20%, 30 U/Kg. Subsequently, the hioche~aical a n d clinical p r o f i l e s w o r e c h o c k e d a f t e r a m e a n p e r i o d of 6 m o n e h s o n therapy. Results: T h i s t h e r a p y w a s g i v e n a m e a n t i m e of 9 ~ o n e h s (range 6m13m). The ~aean d o s e w a s 1139 U + / - S D 489 w i t h a m e a n interval of 17 days (range 6-97 days). So, t h e m e a n d o s e g i v e n in r e l a t i o n t o U/Kld w a s 42 U / K +I- S D 3S.4. Thereby, w e e s t a b l i s h e d 3 ~rroupm a c c o r d i n g ohm intervals that EPO w a s adk01nlsteredz a} 2 3 % of t h e p a t i e n t s w e r e g i v e n a m e a ~ dose of S0 U / K g weekly, b) T h i s ~ T o u p included: 2 9 % of a l l p a e l e n t s g i v e n a d o s e o f 8~ U / K g w h i l e 3 5 ~ w e r e a d m i n i s t e r e d 19 U / K g twice monthly. C) 12 % of p a t i e n t s r e c e i v e d E P O w i t h intervals l o n g e r e h a n 21 days. W i t h t h e s e d o s e s t h e h a e m o g l o b i n level i n c r e a s e d f r o ~ 6,S8 ~r/~l § S D 0,63 t o 7,14 gr/dl § S D 0,62 p < 0,01 a n d t h e H C T augment frc~a 2196 +/SD I,S to 23 § SD 1,7 p<0,01. T h e n e e d for b l o o d t r a n s f u s i o n d e c r e a s e d f r o m 0,~2 t r a n s f u s i o n s / p t / m o n t h t o 0,06. The p e r c e n t o f p a t i e n e s w i t h n e g a t i v e C r o s s - m a t c h i n c r e a s e d f r o ~ 8% t o 40%; t h e u r e a a n d the p o t a s s i u m d i m i n i s h e d (p>0,Ol), t h e C r e a t l n i n e i n c r e a s e d (P> 0,01) a n ~ the Fe d e c r e a e a d f r o m 120 +/- S D 45 t o 100 Uff/dl § S D 22 (p< 0,01) I t h e p e r c e n t of s a t u r a t i o n d e c r e a s e d fro~a 3 6 ~ +/- S D 10 t o 34% +/- S D 11 (p< 0,01). The m e a n w e i g h t i n c r e a s e in 7 0 % of p a e l e n t s w a s 544 g; the b l o o d p r e s s u r e h a d no

changes

9

Conclusionst T h i s E P O a d m i n i s t r a t i o n technique, a c c o r d i n g t o HCT, w a s efficient: the n e e d of b l o o d t r a n s f u s i o n decreased, t h e C r o s s M a t c h w a s i ~ r o v e d a n d t h e cost reduced. 9 c a n e r s Infaneil del R i ~ o n - M o n t e a g u d o 726-(4000) S.M. de T u o , ~ 9_Tgent ina

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P157 CLINICAL SIGNIFICANCE OF THE TECHNIQUES TO DETERMINE THE DRY WEIGHT OF THE PATIENTS ON HEMODIALYSIS Mir S*, Cura A*, S6nmez F ~, Ozyflrek R**, Keskino~lu A*.

Hyperhomoeysteinemiais an independent risk factor for a variety of vascular diseases. Serine and vitamins B6, B12 and relate play key roles in homocysteine(HCY) metabolismby supplying methyl groups in conversionof HCY to methionine. Adults with renal failure and on hemodialysishave a higher risk for thromboticand arteriosclerotic events. However, no data are available on HCY metabolismin pediatric patients with ckroulc renal failure (CRF). We evaluated HCY metabolismin 8 pediatric patients (5M, 3F; age 11-18 yrs) with past episodes of fistula or graft thrombosisand normal coagulation studies, at pre- and post-hemodialysis. Plasma Homocysteine (~mol/L) Striae (#reel/L) Mcthionine (#molfL) Glyeine (#taol/L) Cysteine (/~taol/L) Taurine (#reel/L) Creatinine (mg/dl) BUN (mg/dl) Folate (ng/ml) Vitamin B 12 (pg/ml)

PreMialysis 22.3+7.2t** 111+34 38+10" 4174-178" 445_.+109"* 794-53 l 1.44-2.9"* 814-24.* 15.2 766

Post-dialysis t6.5+4.lt** 75+15"* 24_.+4* 2974-102 2514-35 44_+18.* 5.14-1.1 ** 314-8.5"* 14.4 894

% Reduction 25 32 36 28 43 44 55 62

Normals 8.94-2.8 1214-20 284-5 2394-30 2344-36 77+20 0.94-0.2 12.54-4 >2.3 240-850

tmea~ + S D ; p value *<0.02; **<0.00l compared to normal

Conclusions: (1) Pre-dialysis HCY is significantly elevated probably due to increased production or poor metabolism. Additionally, HCY is poorly dialyzed (25 % reduction), contributing partly, to the ongoinghyperhomocysteinemia.(2) Post-dialysis serine levels are significantly lower than normals. As serine contributes methyl group in the conversionof HCY to methinnine, low levels of serine may interfere with HCY conversion. Therefore. serine supplementationmay help to normalize HCY. (3) Elevated pre-dialysis methionine, HCY, and cysteine levels suggest a defect in the homoeysteine-methinnineremethylation pathway in hemodialyzed ped!atric CRF patients. Departments of +Pathology and ++Pediatrics, Section of Pediatric Nephrology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WisconsinUSA.

P158

EVALUATION OF ROUTINE MEASUREMENT OF BIOELECTRICAL IMPEDANCE FOR ADJUSTMENT OF DRY WEIGHT IN DIALYZED CHILDREN G. Klaus, K.-H. Heckert, A. Fritsch, B. Luik, C. Brummer, E. WOhl, O. Mehls

The aim of this study was to investigate the role of the inferior caval vein (IVC) diameter, plasma concentrationsof atrial natriuretic peptide (ANP) and plasma renin activity (PRA) in determination of the dry weight (DW). Twelve hemodialysispatients with overhydrationwere studied. 1000 cc ultrafiltratinn (UF) therapy was applied to each patient for four days, dally. Clinical, ECG, telecardiographic and echocardiographicfindings, IVC indexes, collapsibility indexes, plasma concentrations of ANP and PRA were investigated before and after UF therapies. Collapsibility index was determined as ( maximal diameter on expiration- minimal diameter on inspiration / maximal diameter on expiration) x 100, IVC index was determined as diameter ofIVC (cm) / body surface area (m2). RIA were used for measuring plasma concentrations of ANP and PRA. Twelve age equivalent normal children were studies as a control group and statistical analysis was carried out with student'st-tests. The clinical f'mdingswere disappeared after UE The heart rate (102-88/rain.) on the ECG and cardiothoracic index on the telegraphy (0.58-0.54) were found significantly decreased by UF (p<0.05). IVC collapsibility index was decreased from 42.3% to 53.6 % after UF and IVC index was decreased from 1.07 to 0.81 cm2/m2 (p<0.01). In the control group collapsibility index and IVC index were calculated as 56.9 % and 0.70, respectively. Collapsibilityand IVC Indexesof the control group were found significantly different from the values of the patients before UF, but not found significantly different from the values of the patients after UF therapy. Plasma concentrations of ANP were measured as 5.7 fmole/tube before UF, 4.3 frnole/tubeand 3.4 fmole/tube in the control group. The decrease in ANP after UF therapy and difference between the values of the control group and the values found before UF were also significantly different (p<0.001). PRA was measured as 0.82 ng/ml/hour before UF and 1.08 ng/ml/hour after UF, but the increase was not found statistically different. These results suggest that the changes in the plasma concentrationsof ANP and 1VC diameter are useful parameters in determining the DW in the pediatric patients on hemodialysis.

Assessment and adjustment of normohydration, i.e. dry weight in dialysis patients, is essential for the care of dialyzed children. In the past, chest X-rays were frequently used to exclude volume overload. Whole-body bioelectrical impedance analysis (BIA) has recently been introduced as a precise, quick and non-invasive method to assess total body water The effect of BIA on frequency of dry weight adjustment and of chest X-rays was evaluated retrospectively. Methods: BIA was measured monthly using a tetrapolar Holtain Body Composition Analyzer with 50 kHz and 800 I~A alternating current. Results: Patients in group I (n = 17, age 10.3 + 5.4 years) had been on dialysis before (period a) and after (period b) introduction of routine BIA. In group II patients (n = 15; age 10.8 _+ 5.8 years) BIA was routinely performed from the start o f dialysis onwards. In group 1 3.8 _+2.9 chest X-rays per patient and year were obtained during period a and 1.7 + 1.0 chest X-rays per patient and year in period b (p < 0.005). At the same time the frequency of adaptation of the dry-weight increased from 4.2 _+ 3.1 in period a to 6.6 _+ 3.3 (p < 0.05).per patient and year in period b. In group II, the frequency &chest X-rays was 1.3 + 1.1 per patient and year, and adaption of dry weight was performed 7.1 + 4.7 times per patient and year. The frequency of change in dry weight and chest Xrays in group II were not statistically different to the observation period b in group I patients. Conclusion: Routine measurement of BIA results in a more detailed and more frequent adjustment of dry-weight and significantly reduces the need of chest X-ray exposure. Regular measurements of BIA is a valuable tool in the care of children with end-stage renal failure.

* Ege University, Medical Faculty, Pediatric Nephrology-]zmir-TURKEY **Ege University, Medical Faculty, Pediatric Cardiology-Izmir-TURKEY

Dept. o f Pediatrics, University of Heidelberg, Heidelberg, Germany

C 94 P159 THE INFLUENCE OF MAINTENANCE HAEMODIALYSIS DURATION ON INTRADIALYTIC CARDIOVASCULAR CI'IANGES IN END-STAGE RENAL DISEASE CHILDREN *M.Szczepafi~ka~*A.Bialota.Szurkowska, *K.Szptynger, W.Grzeszcz~ *Dialysis Division, Departmem of Pasdistrics and Department and Clinic of Internal and Occupational Diseases Silesian School of Medicine, Zabrze, Poland More than 60% of deaths in dialysis involve the heart and vascular system. Each haemodialysis session is accomptmied by rapid changes of haemody.mics in treated children. The aim of the study was to estimate the differmlee of inuadialylic haemody-vanir changes in children with regard to renal replacement therapy duration, Children were examined twice with one and a half year interval. Non-invasive, continuous impedance cardiography mcmxmeamntwas performed in 7 end-stage renal disease chitdr~ daring the 14 acetate hA~modialysis sessions. First use eapillaxy caproplum dialysers were applied. Assesmmmof me~a arterial pressure (MAP), left e a r d ~ work index (LcWI), systemic vascular resistan~ index (SVRI), stroke indlm (SI), cardiac index (CO, ned-diastolic iud=x (EDI), ejecaon fraaion (EF), thoracic fluid conductivity (TFC), index of ~ t y (IC), ac0eleration index (ACI), heart rate fliP.) was done. Linem trend funaion dete-nl.ed for the whole period of dialysis has beela chosen as the mc~ure of e~rdiologieal parameters changes in time. Relative values of obtained parameters wa'e anatyzed in order to e x c h ~ an indi'vidusl vat'iability. Sis diffe~lc,e in all but MAP, FIR and EDI parameters was pointed. We have revealed sigtitic~st demiomtion of.~rdiovascul~ m a t s - loweti~ of EF, SI and cardiac conlraetil~ comparing the initial e ~ - i . ~ , t l o n with the control one a ~ r one and a half ye~. However, MAP was preserved due to decreased vascular rea~vity c,onne~xl with only minor SVRI decline.

P160 PROTECTIVE EFFECT OF THE HEPATITIS B VACCINE IN A GROUP OF PEDIATRIC AND ADOLESCENT PATIENTS ON HEMODIALYBIS TREATMENT. Contlno N,. Miceli S., Aralde A. Patients on chronic hemodielysis form a high risk group for viral diseases, specially Hepatitis B. We decided t O study systematically the markers for Hepatitis B since Merchlgl until the present ( 45 months ) in a Hemodialyeis Center for adolescents and children, it was required as basis control= ASHES - AeHBs and AeHBc. The study group included 28 pediatric end adolescent patients on chronic hemodialyeis (18 female and 10 male), with mean age of 16.5 years (8-23) and a mean time on dialysis of 57.71 months (8-132). Patients without i=~munity were vaccinated according to the scheme: 0-i-6 Dose: Less 40 kgt 10 us/dose - more than 40 kg 20 uff/dcse. Those patients who didn,t repond to this scheme received double dose. A boost inJection was given when the antibody level decreased I0%.

Results= Out of 28 patientei 2 developed Hepatitis B (7.14%) and 2 didn't produce antibodies, one patient with Down Syndrome and another with S.L.E. From all the immunized patients (85.72%), 2 patients were i---unized b y previous disease (7.14%). The 78.58% remaining (22 pts) were immunized by vaccination. Free this last group, 64,29% (18 pts) developed antibodies more than I00 U/I, only one of them needed double dose schema, and 14.29% (4) developed antibodies less then 50 U/I, corresponding to 3 patients with chronic infection end a patient with SLE. Those patients who had a good response required a boost injection every 3 years. Those patients with lower response required annual boost injection to maintain levels between 1O end 50 U/I. Concluslonstl. Low incidence of Hepatitis B 2. High degree of passive immunization 3.Good persistence of immunization for 3 years. 4 . Low or no response in patients with chronic infection end immunologic diseases. Those with low response required annual boost injections.

Centre Infantil del Riflon - Monteagudo 726 - (4000) Tucuman - A r g e n t i n a

P161 FOLLOW-UP OF PEDIATRICS PATIENTS ON HEMODIALYSIS (HD) WITH POSITIVE SEROLOGY FOR VIRUS C HEPATITIS (VCH). A. Aralde*, N. Contino*, S. Miceli*, C. Weller** On March, 1992, the prevalence of antibodies against Hepatitis Virus C (anti-HVC) in pediatric patients on HD, was (18-19). In this study 19 children and adolescent patients (pts) were evaluated. The average age was 14.5 years (+4.1), with a median time on dialysis of 44.6 months (+28.7). All of them have received transfusions. The prevalence of Anti-HCV was higher in the female patients and non significant differences were found, neither in age nor in the medium time on HD. The Anti-HCV was not together in existence with AgHBe, nor was frequent the relation of positive Anto-HCV(+)/substituting samplers (SS) (+). The tranamines were found persistently elevated in Anti-HCV patients (+). Consequently, the following measures were implemented: A) Samples of Anti-HCVAb when patients were staded on dialysis and every 6 months thereafter B) Fixed bases of HD for each patient (bases C+ and C-) C) Interdialysis hyparchlorination (between turns) of each basis (1000 pprn chlom dunng 30 minutes) D) Decreased of transfusional index (of de 0.22 a 0.08 transfusions/patients/month) because of use of human erythropoystine in 100% of patients. After 26 months: o14 patients Anti-HCV (-), 2 continued on hemodialysis and and 2 have had kidney transplant (-). IN this period 8 new patients with chronic renal insuficiancy, with an average of 12.1 years old (+3.72) and with serology (-) for the Anti-HCV, entered to the Service. They remained Anti-HCV after an average of 10.5 months on dialysis. In our opinion, the time in HD does not play a very important role, because it seems that the new measures implemented have been the decisive factor in the abscanca of new cases of Hepatitis C in our Service. *Centre Infantil del Rifion-Montoagudo 726 **Laboratorio de Analisis Bioquimicos-C.N.W.-Chacabuco 366 (4000)TucumanArgentina

S.M. de

P162 ESTIMATION OF SOME OF COAGULATION INDICES IN CHILDREN WITH ESRD TREATED WITH CONTINUOUS AMBULATORY PERITONEAL DIALYSIS (CAPD) M. Litwin, H.Lukasiewicz, R.Grenda, E.Tekliliska, LLatoszyfiska (imr. T.Wyszyfiska) An aim of the study was: 1) to estimate some of the selected coagulation parameters in uremic children and 2) to determine if the CAPD therapy exerts any influence on these parameters. Material: 10 children with ESRD were examined immediately before starting CAPD therapy and then after 3 weeks and 3 months of dialysis. Mean age of the uremic children was 7.5 ys (3 - 9), mean creatinine and blood urea levels before 1-st examination were 8. lmg% (3.1 - 16.7) and 174mg% (120 - 250). There were no pts with nephrotic range proteinuria and/or hypoalbuminemia. The control group consisted of 10 healthy blood donors. Methods: DMimeres (D-D), complexes thrombin-antythrombin lll (TAT), prothrombin fragments Fl+2 (FI+2), whole blood clotting time (WBCT), thrombin time (TT), prothrombin index (PI) and fibrinogen (FG) were measured. Children were evaluated when free of any signs and symptoms of infection, being in good general condition. Results: l)statistieally significant differences were found between children with ESRD before starting CAPD and controls in values of: DD (1700 vs 500ng/ml), TAT (26.1 vs 2.6ng/ml), Fl+2 (6.2 vs 0.7amol/ml), WBCT (27 vs 35sec). 2) after 3 weeks of CAPD despite significantly lower values of creatinine and blood urea (6.6mg% and 105mg%) there were no changes in examined coagulation parameters than before treatment. 3) after 3 months of CAPD there were found significantly higher values of FG than before dialysis therapy: 361.3 vs 290ngtml and others parameters did not differ significantly than before start of dialysis. Conclusions: 1) the obtained results suggest presence ofthrombinogenesis in children with ESRD before start of dialysis. 2) short-term, 3-weeks CAPD treatment does not significantly influence coagulation parameters, but presence of higher valu es of FG after 3 months of CAPD therapy suggests further activation of coagulation cascade leading to hypercoaguable state, despite good control of uremic toxicity. Dept. of Dialysis and Kidney Transplantation, Child Health Centre, AI. Dzieci Polskich 20, Warsaw, Poland

C 95 P163 BENIGN INTRACRANIAL HYPERTENSION AND ACUTE GLAUCOMA DURING GROWTH HORMONE THERAPY IN A CHILD WITH LONG-TERM PERITONEAL DIALYSIS. U. Querfeld, P. Wingenfeld, B. Hoppe, B. Schmidt, E. Sch0nau Treatment with recombinant human growth hormone (rhGH) is widely used to improve growth in children with growth failure due toend-stage renal disease (ESRD). Among the side effects of this treatment, benign intracranial hypertension (BIH), also termed pseudotumor cerebri, is an infrequent but serious event. After the first reports of BIH in adult subjects, 8 children with ESRD have been included in a published series of cases (Malozowsld et aL, New Engl J Med 329:665, 1993). We report a case of BIH and acute glaucoma which occurred 18 months after the onset of dlGH therapy. Case Report: A 7 year old boy was admitted to our hospital because of altered consciousness and increasing headaches, nausea and vomiting. The child had ESRD due to obstructive uropathy and had been treated with continuous cycling peritoneal dialysis since the age of 5 months. Cataracts had been removed bilaterally at age 4. Treatment with rhGH (0.1 IU/kg/d) had been administered in dally subcutaneous injections for the previous 18 months. On admission, the boy appeared drowsy and he became comatose within the next hours. The physical examination showed positive pyramidal and extrapyramidal signs. Both bulbi were extremely tender. On CT scan, diffuse cerebral edema was obsewed. Cranial Doppler ultrasound showed normal blood flow and patent extracranial vessels. Ophthalmological examination revealed acute glaucoma with excessively increased intraocular pressure, as well as bilateral papilledema. The suspected diagnosis of BIH was confirmed by a CSF opening pressure of 230 mm Hg upon insertion of an external ventdcular catheter. The CSF analysis was normal, cultures negative. Therapy with acetacolamide was started for glaucoma and rhGH therapy was discontinued. The child regained consciousness after 5 days and all pathological findings were reversible within 2 weeks. Physicians caring for children with ESRD treated with rhGH should be aware of less frequent side effects of this treatment including BIH and acute glaucoma. University Children's Hospital of Cologne, Germany.

P165 INCIDENCE OF PD ASSOCIATED PERITONITIS (PDP) AND EXIT SITE INFECTION (ESI) IN CHILDREN CONVERTED TO Y SET DISCONNECT SYSTEM. Pefialoza J. MD; Turconi A MD; Delgado N. MD; Caminiti A MD: Gonzalez E. RN; Hemandez G. RN; Sojo E. MD. PDP and ESI are the main dropout causes in children treated with CAPD. In this study we evaluate the impact of the Y Set drBconnectsystem on PDP and ESI rates, Material end Methods: During the last seven years 56 children with ESRD were treated with CAPD at our institution. Between June 93 and October 94, 13 children (mean age 3.8 years) were switched from non Y Set connect delivery system to Y set disconnect system (Uitraeet Baxter). PDP events were defined using standard critede and ESI including tunnel infections using Twardowsk'y classifmation. Pre Y Set treatment time was of 5 to 30 mos (mean 15.7 mos) and on Y Set was of 3 to 19 rues (mean 12.9 mos). Results Pre Y set On Y set T.test Treatment time (mos) 203 168 .... PDP rate (1/Ptmos.) 11.2 24.6 p=NS ESI rate (1/Ptmes) 8.1 15.2 p=NS Catheres Removed 6 5 p=NS

Positive cultures were obtained in 21/25 (84%) of PDP episodes. Staph. Aureus was isolated in 11115 pre Y Set and in 5/6 on Y Set. The same bacteda was isolated in 6/7 ESI with positive cultures pre Y Set and 3/3 on Y Set. Conclusions: The impact of Y disconnect system shows a clinically important but not yet statistically demonstrable difference between Y disconnect and non Y non disconnect systems in lowering PDP and ESI rates in children. Staph Aureus was isolated in 76% PDP and in 90% ESI. All the catheters were removed because of Staph Aureus infections. More research must be done on methods to prevent these infection in children. Nephrology Unr Hospital de Pediatrla Garrehan. Bs. As., Argentina.

P164

THE EFFECTS OF CHARCOAL HEMOPERFUSION ON THE CLINICAL COURSE OF THE PATIENTS WITH AMANITA PHALLOIDES POISONING A.$irin ~ LBilge, S.Emre, A.Naytr, M.KarabSc~o~lu,A.Ktyak,(7,. Ozeelik In this study, the clinical Course of children with Amanita Phalloides poisoning, and the effects of charcoal hemoperfusion (liP) therapy were evali~ated. Eight children (4 girls, 4 boys) with a mean age of 9.7+5.3 years (range 3.5-14 years) were hospitalized with the history o f mushroom ingestion. Vomiting, diarrhea and abdominal pain were the main symptoms that developed later than 6-12 hours postingestion in all patients. Circulating amatoxins (alpha-amanitins) were detected in the sera of every cases, and HP was performed for the extracorporeal clearence of toxins. The mean time from beginning of acute poisoning to the first HT was 27.62 hours. I-IT was performed twelve times in 8 children according to the persistence of alpha-amanitin after the first HZP. Hemoperfusion was found to be effective for the removal of toxins from circulation in the study group. However, hepatic transaminase levels showed a significant increase at the 48th hours of ingestion, and the highest enzyme levels were obtained on the third day of treatment (AST: 1634• lU/1, ALT: 2034• 1-U/l). In the study group, one patient with/ate presentation was in hepatic coma at the admission. In addition to this patient, futmmant hepatic failure and renal failure, diffuse intravascular coagulation azad convulsion developed in two patients on the third day of hospitalization. Mortality occurred in these three patients, During the follow-up, chronic active hepatitis did not develope !n five patients who recovered. We did not observe any clinically important side effect due to liP. It was concluded that, early charcoal I-IP therapy is an effective therapeutic approachment for the amanitas poisoning, if it can be performed in the first 24-48 hours of ingestion. *University of Istanbul, Medical Faculty, Department of Pediatric Nephrology, (~apa, Istanbul -TURKEY.

P166 POST-DIALYTIC UREA REBOUND IN CHILDREN M. Fischbach*, A. Lablou*, B. Boudailliez*, P. Desprez*, J. Geisert* Preliminaries studies suggested that post-dialytic urea rebound (PDUR) is relatively patient specific and that urea mass transfer coefficient (U) between the intra-extracellular body water pool (Vi, Ve) should be related to the postdialytic patient weight, thus to the size of the national imra extra-celhilar membrane. We investigated 6 children (weighing 29-34kg) with stable chronic renal failure (anuria), midweek dialysis session, for 3 consecutive weeks. Measurements of blood urea concentrations were performed during dialysis time (Co, C30 , C90 , C150, C180) (final concentration Cf) and thereafter at (Ct) 10, 20, 30, 45 and 60min (equilibration concentration, Ce). PDLIK was calculated as the percentage increase in blood urea concentration after dialysis between Cf and Ce. The value of U for each patient, at the different post-dialysis times was determined from the rebound data analysis : Ce - Cf mVi Ve nat = logn , U Ce - Ct Vi + Ve PDUR. values were spreaded in a wide range (9.8 to 14.1%). PDUR appeared inconstant in a given patient with an important intra-individual coefficient of variation 12.7 to 37.8% (mean 22.6 + 9.9%). In the same way, U appeared inconstant in a given patient over post-dialysis time and from one session to another one. Conversly, no relation could be found between U and body weight. But the profile o f the changes of U over post-dialysis time let to distinguish two groups of patient's dialysis session ; group I with a U rebound at 10 minutes post-dialysis and group II with a constant decrease of U over post-dialysis time. Ultrafiltration rate during dialysis was significantly higher in group I (0.241 + 0.047ml/min/kg) compared to group II (0.152 + 0.01 lml/min/kg). These results could not be fully explained by the intra-extracellular two pools urea ki,.etic model, but are in our mind in favor of the regional blood flow model. *Nephrology-Dialysis-Transplantation - Children's Unit - Strasbourg- France.

C 96 P167 DETERMINATION OF INDIVIDUAL ULTRAFILTRATION TIME (APEX) AND PURIFICATION PHOSPHATE TIME (PPT) BY PERITONEAL EQUILIBRATION TEST (PET). APPLICATION TO INDIVIDUAL PERITONEAL DIALYSIS (PD) MODALITY PRESCRIPTION IN CHILDREN. M. Fischbach*, A. Lahiou*, D. Eyer*, P. Desprez*, J. Geisert* r Efficiency of PD is dependent on adequate peritoneal ultr~tfiltration (UF) and on adequate purification (solute clearance). These two goals seem apparently to conflict in terms of duration of dwell time : short dwell time enhances UF capacity, long dwell time enhances solute clearance. 9 PET allows an approach of the optimal ultraflltration time : point at which the overtime urea dialysate saturation and glucose dialysate desaturation curves cross (called APEX time). PET also allows an approach o f the optimal purification time : point at which dialysate (D) to plasma (P) concentrations (D/P) over time (dialysate saturation rate) is high ; because of the value of phosphate as uremic toxin (factor of morbidity) we have chosen the time for D/P phosphate equal to 0.6 (during a PET) as purification phosphate dwell time (PPT). 9 PET was performed with 1000ml/m 2 dialysate (Dianeal, 2.25% dextrose) in 17 children (aged from 3 months to 16 years) over the 5 last years (142 determinations). The results reveal a widely distribution, APEX : 18 to 71min (39 +/- 23) and PPT : 105 to 238rain (193 +/- 69). These widely distribution is for us a supplementary argument to use individual PD prescription in children. If ultrafiltration is the major goal for a child so short dwell times have to be used (automatic PD) ; if epuration (phosphate) is the major goal for a child so long dwell times have to be used (CAPD) ; if both are a need Tidal PD should be discussed. *Nephrology-Dialysis-Transplantation-Children'sUnit - Strasbourg - France_

P169

P168

FAST PET A USEFUL TOOL FOR MEASURING PERITONEAL PERMEABILITY IN CHILDREN. Sojo E, MD; Visignano L. MD; Moyano M. MD; Grosman M. RN; D'isa G. RN. The standarized Peritoneal Equilibration test (PET) is widely used in adult and pediatric patients for measuring peritoneal permeability. The Fast Pet (FP) allows to avoid multiple lab samples, reduces staff time and helps to patient comfort. The aim of this study is to compare PET and FP results in children. Patient and Methods: Ten children aged 2.2 to t8 years (mean: 8,6_+6)with CRF maintained with CAPD for an average time of 26 months, underwent simultaneously a modified version of PET and FP as described by Twardowsky.The infusion of Dianeal 2.5% (Baxter) was of 1.100ml per m2 BSA, Results: PET (mean+_SD)=D/PCreat: 0hs=0.14_+0.07; 2hs=0.55 _+0.1; 4hs=0.79-!-_0.17. D/Do glucose: 2hs=055+_0.12; 4hs=0.38 +0,15.

Fast Pet (mean+SD)=D/P creat: 4hs=0.86+_0.16; D/glucose: 4hs=708+294 mg/dl. Conclusion: Both PET and FP coincidentaly show High Average solute transport rate for creatinine and High Average rate for glucose. Although the small number of patients studied the Fast Pet showed to be a reliable and simple test for measuring peritoneal permeability in children. Nephtology Unit, Hospital de Pediatrta Garrahan. Bs As. A~entina.

P170

END DIALYSIS SERUM PHOSPHATE VALUE : A MISLEADING PARAMETER OF DIALYSIS EFFICIENCY M. Fischbach*, A. Boudailliez, M. Foulard, and the French Society for Paediatric Nephrology

THE INFLUENCE OF DIALYSIS MODALITY ON EPO EFFICACY 1N CHILDREN M. Roszkowska-Blaim, M. Sieniawska

Depiste low end dialysis serum phosphate values (Pe) the control of phosphate retention remains often unsatisfactory in dialysed children. In order to appreciate the purification value of Pe we studied serum phosphate dialysis kinetic : before, at 45rain, immediatly and 30min after a midweek 3 hours dialysis session conducted as usual ; 147 sessions (from the 21 french hemodialysis children umts) were available. For 6 children (same unit) serum values were followed up to 360min. Phosphate reduction ratio (PRR) was calculated as percentage decrease over dialysis time and post-dialysis phosphate rebound (PDPR) was calculated as percentage increase between end and 30min alter dialysis, of the serum values, as urea reduction ratio (U ~,R) and post-dialysis urea rebound (Ps UR). Reduction ratio pre/post dialysis pre/45min 45rain/post PRR% 46.96+-11.92 39.85+-9.48 11.50+-18.28 ]URR% 72.11+-8.74 35.25+-9.81 57.13_+13.26 Rebound 30rain post/end 60min post/end 360rain post/end PDPR% 28.36 +_15.73 45.37+-19.24 89.18+_7.36 PDUR % 16.30 + 7.44 26.39 -+ 11.63 34.59 _+8.41 PRR (over all session) was lower than URR. Reduction rate profiles differed considerably : phosphate decreased similary as urea during the 45 initial dialysis minutes but thereafter (45rain to end session) serum phosphate levels stayed relatively stable, conversly urea serum levels decreased regularly. Post-dialytic rebound revealed major discrepancies between phosphate and urea : at 360rain post-dialysis phosphate serum value was already nearly the same as the pre-dialytic value. All togheter, these results point out whether serum phosphate levels over and post-dialysis times are misleading parameters of dialysis efficiency.

The study population comprised 19 children (11 on HD, 8 on CAPD) aged 4-17.5 years, mean 11.8. All children had received EPO and iron supplementation in individually adjusted effective doses for 3 to 30 months. When Hb was >10g%, Ht >30% EPO was withdrawn, and restarted in standard dose 50 U/kg/week sc, when Hb decreased to <8 g%, Ht <25%. This therapy wascontinued for 12 weeks. Before restarting EPO treatment serum erythropoietin (SE) was measured; Hb, Ht were determined weekly and serum ferritin (SF), index transferin saturation (ITS) monthly. Seven weeks after discontinuation of EPO treatment a decrease of Hb <8g% and Ht <25% were observed in 50% of children on HD and in 28% on CAPD. The remaining patients required reinstitution of EPO treatment after 8 to 14 weeks. One month after stopping EPO treatment SF level increased by 20%, ITS by 89.9% in HI9 group and by 24.5% and 26.5% respectively in CAPD group. After 8 weeks of restarting EPO treatment Hb was 8.7 +_1. lg%, Ht 25.5 +3.2% in Ill3 group, while in CAPD group Hb was 10.2 +0.3g%, Ht 31.3 +2.2%. After 12 weeks all children on CAPD and only 2 on HD achieved Hb >10g~ Ht >30% despite the fact that at the onset of the treatment the differences in SF, ITS, SE between two groups were statistically insignificant.

*Nephrology-Dialysis-Transplantation-Children'sUnit - Strasbourg - France.

After the interruption of EPO treatment the decrease of lib level was observed earlier in children on HI) then on CAPD The dose of EPO 50 U/kg/week sc is effective in children on CAPD and usually too low for children on liD. University Children's Hospital~ Department of Pediatric Nephrol0gy, Warsaw, Poland

C 97 P172

P171 GASTROSTOMY BUTION H~aJING IN CHILDRI~q ON CItRON~ DIALYSIS -STILL THE OPTIMAL ROUTE Watson AR, Coleman JE, Moore EA, Norman L, Ranee CH

Our initial experience with gastrostomy buttons (GB) for the supplementary feeding of children with CRF (J.Ren Nutr 1992, 2:3 21-25) has now been extended to over 5 years in 18 children (11 male) who commenced gastrostomy feeding at a median age of 2.2 years (range 0.2-10.3 yrs). 12 patients had the initial gastrostomy catheter at the same time as a Tenekhoff catheter and 14 wexe established on CCPD, 1 CAPE) and 3 haemodialysis. After 2-4 weeks witl; a surgically placed gastrostomy catheter a button (lg Fr) is inserted under sedation on the ward (same situation used for change of buttons). The mean doration of gastrostomy feeding was 15 months (range 2-63 mths). The mean life of the gastrostomy button was 7.1 months (range 2.7-14 mths) with 7 children requiring only one button during their dialysistreatment. Button changes were mainly due to leakage problems. 2 episodes of peritonitis occurred in 277 patient months with 1 episode attributable to incorrect button size and 1 Candida infection requiring PD catheter removal in a malnourished individual. Buttons were removed at the same time as the Tenckhoff catheter in 13 children whose appetites improved following transplantation. In 15 of the children followed for >6 months the mean protein energy intakes wexe 2.5 g/kg/body weight/day (range 1.4-3.7) and 102 keals/kg body weight/day (range 60-125 keals). The mean pereentage of total energy and protein intake delivered by the GB was 69% (33-100%) and 71% (23-100%) respectively. There was a signifieant improvement in mean weight SD scores (-1.88 and 0.75) and mean height SD scores (-2.61 and -2.26) prior to and at the end of the study period respectively. The gastrostomy button continues to be our favoured route for delivery of long term enteral feeding with promotion Of growth in most patients. Compared to nasogastrie tube feeding the GB device provides a more aesthetically appealing feeding route for nutritional support with relatively few complications. Paediatric Renal Unit, Nottingham City Hospital, Hucknall Road, Nottingham NG5 IPB, U.K.

P173

10 YEARS EXPERIENCE WITH CONTINUOUS AMBULATORY PERITONEAL DIALYSIS (CAPD) IN CHILDREN IN VALENCIA*. VENEZUELA. N. Orta-Slbu, L Dominguez. R. Scovino, J Morly6n, H.Mareano, N. Polanco. CAPD was available for children in 1980 and programs have been set up mainly in the developed world. In Latin Am6rica only a few countries have establlshed CAPD for children, and this report gives information about the results of our program, alter tan years of actlvitly (1984-93). During this period 113 children with Chronic Renal Failure (CRF) were evaluated and 46 of them (Age X: I0.2.-l: 3.2 years) reached TRF and included in CAPD. The incidence of CRF was 9.3 cases/year/million children population, and that of End Stage Renal Failure was 3.7. CRF presented predominantly in children between 5 and 15 years of age (74%). Relevant clinical features were short stature, severe anemia and arterial hypertension. Etiology corresponded to: a) Primary Glomerulopathies (52%), mainly focal and segmental glomerulosclerosis, b) Uropathies (t7%) mainly reflux nephropathy, and e) Heredo Familial Nephropathies (17%). The total experience was 1137 patient/month and patientes under treatment malntaned stable blood levels of Sodium (X : t36.9 + 2.3 meqllt),_Potessium 9 [J[: 4.08 + 0.2 meq/It), Calcium (X: 8.8 • 0.3 rags%), Phosphorus (X 5.4 + 1.29 rags%); blood nitrogen metabolites reduced significantly (~ initial plasma Creatlnlne 10.23 + 1.45, vs. final Creatinine 8.23 + 2.23 - p 0.95); initial blood Urea X 167.14 + 39.5 rag% vs. final Urea X 104.9 + 2.5, p <0.001. Cholesterol increased significantly (initial X 159.69 + 19.5 vs. final X 234.7 + 84.2, p < 0.001) and serum Albumin decreased (initial X 3.28+ 0A vs. final X 2.99 + 0.6,p < 0.08). Complications: peritonitis-It3 episodes-, t episode/t0.4 months, and the germs isolated ware : Staphilococus aureus and S. epidermidis (23.4 %), Gram neg (19.3 %) and Cand|da albicans (11.7 %); 45.6 % of cultures were negatives. The Ultra Sat system showed to be safer than others to reduce the frequency of peritonitis. Others complications: obstruction of catheter (3c), severe arterial hypertension (3c) and wall abdominal hernias (6 h). 45 % of p~tients received renal transplant. Total CAPD patient actuarial survival was 98 % at I year, 93 % at 2 years and 90 % at 5 years. Our CAPD program is one of the largest programs of chronic dialysis for children in Latin America, and the results confirm that CAPD is a valid and efficient system, which gives to children with TRF good survival before kidney transplantation, even in developing countries. 9(Sew de Nefrolog[a Pedidtrica. Hosp Central. Universidad de Carabobo}

P174

GROWTH IN SMALL CHILDREN RECEIVING CONTINUOUS AMBULATORY PERITONEAL DIALYSIS (C.A.P.D.) T n r e o n i A , M a z z a C,.Briones L,Bisignano L,Deigado N. Growth failure is c o m m o n in end-stage renal disease(ESRD).CAPD is a treatment o f choice in small patients awaiting transplantation.CAPD improves some of the metabolic and nutritional problems associated with growth failure in ESRD. The aim of the study was to evaluate growth in 20 patients (13 males and 7 girls),age ~= 14.8months( r= 4-24months) .All had been treated on CAPD over (Y~+SD) 22.3 -~2.9 months (r = 6-52 months)and early enteral tube feeding. Weigth and height were assessed at the beginning and every 3-6 months during follow-up.The measures were converted in the Z scores(Z~Z)for age and sex.Growth velocity was determined by the changes in the z~Z for heigth for age.Nutritional status was evaluated by the adecuation o f weigth for beigth. Initial

Final

+SD ~ +SD ^Z weigth/age -2.23 u 0.24 -2.26 $0.4 (p=NS) ^Z heigth/age -1.84 $0.54 -4.01 ~0.41(p=<0.004) Weight/height% 80.37 %-~2.92 100,33 %$4.63(p<0.001) These results show t h a t patients on CAPD under 2 years o f age ameliorated their nutritional state but had severe impairment o f growth . New therapeutic strategies or supportive care meassures have to be developed in order to improve their chances o f growing.

Service of Nephrology.HospitalJ.P.Garrahan.Bs.Aires,Argentina

I S PROTEIN CATABOLIC RATE (PCR) A GOOD PROTEIN INTAi~ ~RKER BUT A BAD NUTRITIONAL INDEX IN CHILDREN UNDERGOING AUTOMATIC PERITONEAL DIALYSIS (APD)?. A.Alonso Melgar*, R.Lama**, M.Navarro*, T.Gonz~lez de Garay~,C.Garela Meseguer* Nephrology* and Nutrition** Units. Children Hospital "La Paz ~'. Paseo de la Castellana, 261. Madrid. Spain. We studied Nutritional Asessment, Adecuacy Dialysis and Nitrogen Balance (NB) in 19 children (14 males, 5 females) with mean -age i0.2i3 years undergoing APD for 1.79• years. Nitrogen Balance was calculated after collecting dyalisate, uri ne and stools in all patients. Diet was registered during seven days in all of them. A very good correlation between PCR and Weekly BUN KT/V (r=0.83 P~O.OO1) and PCR and Protein Intake (r=0.75; P 0.001) were -found. We didn't found any degree of correlation between PCR and NB but a negative correlation existed between PCR and Serum Albumin (r=-0.64; P~0.05). We divided patients in two differents groups: Group A (BN pos! rive, mean +2.2 grames nitrogen/24 hours) and Group B (BN negative, mean -1.31 grames nitrogen/24 hours). Not significant -differences were found between two groups neither PCR nor KT/V. Weight (SD), Height (SDi, Body Mass Index (SD) and Triceps or subescapular Skinfold were similar i n b o t h groups. DATA BUN (mg/dl) INTAKE: KCAL/Kg/Day PROTEIN (G/Kg/Day)

A (mear~) 59 • 4

B (me~) 79 • 14

Signif. P~O.05

80 • 9 2.4 • 0.8

50 • I0 1.5 • 0.6

P 4 0.05 P~O.I

SUMMARY: - PCR is a very good index of protein intake in children undergoing APD but also could be indicating catabolic state. - With adecuated protein intake, the meaning of a decreased -plasmatic BUN is an anabolic state. - Adecuated energetic state is necesary to achieve a positive nitrogen balance.

C 98 P175

P175.1

MANAGEMENT AND CONTROL OF A F I E L D PATIENT I N CONTI NUOL~ AMBULATORY PERITONEAL D I A L Y S I S H. B o r o a i t o @

It presents a three years old boy with diagnosis of and s t a g e r e n a l d i s e a s e [ESRO] s e c o n d a r y t o o b s t r u c tive uropathy. He h a s b e e n m a k i n g c o n t i n u o u s ambulat o r y p e r i t o n e a l d i a l y s i s [CAPD] For the last s e v e n months. He lives in a Field t h i r t e e n Km. F r o m the has r e s t oity~ w h e r e ha is c o n t r o l e d by a Family physi c i a n and s i x t y Km. f r o m the H o s p i t a l w h e r e the p e d i a tric n a p h r o l o g i s t takes care of him. As to his c l i n i c a l evolution: - He had n e i t h e r p e r i t o n i t i s nor any o t h e r c o m p l i c a t i o n of CAPD. - S i n c e he s t a r t e d with CAPD his lab has b e e n improving~ d e c r e a s e d B~N [170 mg/dl] s e r u m c r e s t • [4.~ mg/dl] and p o t a s s i u m c o n c e n t r a t i o n [B.5 mEq/It] w h i l d increased s o d i u m c o n c e n t r a t i o n [140 mEq/it] and norm a l i z e d acid - base values. - His g r o w i n g up rises P 5 For his c h r o n o l o g i c age in s t a n d a r d g r o w t h c h a r t s of height, w a ~ h t and head c i r c u m f e r e n c e . He had a c a t c h - u p [ Z - s c o P e 1 . 3 ] For height. His g r o w t h r a t e has b e e n g.5 c m / y a a m CP SO ]. His bone age ia c o r r e l a t e d to his c h r o n o l o g i c age. We b e l i e v e that the satisfactory evolution of this patient is due t o a CONSTANT HUMAN NET F o r m e d by family p h y s i c i a n ~ p e d i s t r i c n e p h r o l c g i s t ~ nursaa~ social w o r k e r s and the r e s p o n s i b l e p e o p l e For the normal r e c e p t i o n of the n e c e s e a P y m a t e r i a l For his CARD. @ Primers C~cadra de Pad• Centanario-Rossrio-Argentina

B-Hospital ,

del

NITROGEN LOSSES IN CHILDREN TREATED WITH DIFFERENT PERITONEAL DIALYSIS (PD) MODALITIES A.Edefontl*, M.Picca*, G.Conealvo*, L.Ghlo*, M.Gtanl*, A.DalCoI**, R.Galsto** | Nitrogsn (N) losses assessment may be useful to individualize N dietary prescriptions and maintain an adequate nutritional status in children treated with chronic PD. No data comparing N removal during different PD sodalities sre available. However, N and particularly protein and aminoacid losses might be theoretically higher and N protein intakes might be more increased in patisnts treated with high-flux APD than in those treated with CAPD. Eight patients treated with CARD, 9 treated with nightly intermittent PD (NIPD) and 10 treated with tidal PD (TPD), of comparable age and body weight, were studied. Total N (Ntot, Kijeldahl method) and N contents of Urea (Nurse), creatinine (Ncreat), uric acid (Nua), protein (Nprot) and aminoacids (Nee) were measured in dialyeate (D), urine (U) and feces (~. NDtot

NDuma NDcreat NDau

NDprot NDaa NUto( NRcX

2.6"/:.9

:6~ .3

.3~.08 .5~.4 .7•

CAPD

3.7• 1

.1+ .03

.04+.02

NIPD

4 + 1.6

2.8r

.1+.07

.04~.03

.Se.2

,2~.1

TPD

4.3el .3

3.6e1.1

.1+ .05

.06~.03

.4+ .2

~h .05 .7+ .5

.8e1.1 .8~.2 .7+ .1

N losses were higher in D (74%) then in U (12%) and F (14%) and were mainly represented by Nurse for all PD modalitiss. The removal of Nurse in D was significantly higher during TPD than CAPD (p<0.05). NDuma losses correlated significantly with NDtot according to the following equations: CAPD Ntot=l(Nurea)+0.9, r=0.g5, pc0.0001; NIPD Ntot=l(Nurea)+l, r=l, pc0.0001; TPD Ntot=l.l(Nurea)+O.3, r=-l, pc0.0001. N losses in U and F were similar dudng CAPD, NIPD and TPD. Conclusions: 1) NDurea is highly representative of NDtot and is more easily measured and utilized for clinical purposes than NDtot; 2) APD sodalities, padicularly TPD, achieve, in comparison with CAPD, better Nurse removal, indicating higher treatment efficiency, and comparable Nprot and Nea losses, indicating no need for higher protein dietary prescriptions, in order to maintain adequate nutrition. * Clinics PediatricaII, Dialisi Infantile- Universi~ di Miiano- italia "Divisionedi Nefmlogia - Ospedale Niguarda - Milano - Italia ,

POSTER

SESSION

- 0[') - U r i n a r y T r a c t I n f e c t i o n s P177

P176 RESULT8 OF OXYBUTYNiN THERAPY ON BLADDER INgTABIUTY IN CHILDREN KP.Mem~ea, ~ D.Glmsberudino P', E.Wbdlhe The effects of o ~ were sv#u~nd ~ 42 cMdren suFedng ~ bladder In.ably. The 42 p ~ t s wem a n l e ~ u~v)gthe cNerie of an e v ~ pedud, under Ire~rn~t, of gre~or ~an four monb~%with an ave'age of 8 + 3 , ~ m The paf~nb were neuroto~cely norm~ clfidmn, wi~ an avorege age of 5 + 2years of age, 36 fem#e and 0 m~. ~ vaesroached us~g din/c# and urod~sm/c aJten~. CJnicdy we obearvedn(xturn# a n u r m in 78,5% of the cssea, day wM~ngin 88%,

urgancy In 7 8 , ~ rmquanoy I. 74~ po.qure to yuerd ~

urge Incan~ance i.

48V,. ~ in 43% and pmvtoue winory hecl infanfion in 83~ of the ce~t~. Tim m ~ n a n ~ stu~ rev~tsd: norm# or redUmd bladder o s p s ~ argl =snMan~. pmea,~ of non intsgitnd du#uear ~ dudng U~ bladdur J n g ewl normr nowmebT.AI p~br~s und~wenf I n v e s ~ v~h M ~ , n d c y s f o u r ~ (MCU), re,# ullnmonoff~phy and columnx.my. OxTbutyninw ~ prano'~an at 9 du~ OFO.~ to 0.50 mg/kg/~y for e perind of fear ~ folownd by s urndyear~c control and grndeal witt, m~el OF the o x y b u ~ , In the c ~ of ndequate r~onn~.

chan,op~y~ws w ~ Ind~,t.d for 35 ~ , , t . ,

In m r . . # ~

I r r ~ p m ~ wan #so used in 8 pel~'l, ts who pe,"s%tod~

chk~n, 22 ( $ ~ ) ~

,Y/a,f.mto~,.

nocl~mrl~anunm[s. Of 42

ws~-uraW~ r~bx, w~h ran# s~rr~g In ~

of~he

Calms. Of fhe 22 sMdhm wffh re#ux, 9 MCU toners/w~m camnd out on 11 who were ondergo~ cinic# tmMnmnf and reltux wss msolvnd ln 7cases, wlth kn~vanmnt ln the duRrse of m,lux M 3 cssss, 1 c/tfd m m ~ g wXh ~he s m db~rea OFr~qux. 3 cMdmn undervamt an~ ~ surgw), before dagno~s of bladder Instab~ and prssant norm# control. Occultspins b ~ was found in 42% OFthe cases. A response shewing total m ~ of dhlc# and urndynsmle eleraffons ocoumedIn 83% OFb~e cases. Of thsee 36 pafen~, lO ~ t n d e mbpea of fhe symptotrm, during e given pa~l of the ~ea~an~, due to v#untwy i~an'~p~tm of n ~ d ~ n In 8 canes or during #~ w i ~ # preceea in 4 ~ ' J . 13 pe~onb hew #mndy peased 7 + 6 mort#in without fm~nanf and without s relapse. We therefore eandudu the b~abr,ant of bladdorin~tsbifty with oxybutynin i~ elrr and ~ , wiehonly n~l #du ~ . To ansere good ms#is, we recommended ~ he/nO ,seesaW: adherea~ to ~he treabmmt, regular check ups, control of cons~a~m end the tMdng of el steps necessary to prevent ~ OFurinary hect.Further studMs must he can'ind out in order to beffer durme#a~group of c M ~ n who do .or present an ~ r r~pea~ Io-the~a#',lanf, ss wea the esse wllh 7 ~fdran we sfud~d. Curl#be.Brazil

A COMPARISON STUDY OF AMITRIPTYLINE, VASOPRESSIN, A N D A M I T R I P T Y L I N E W I T H V A S O P R E S S I N IN ENURESIS. Mizusawa

Y*,

B u r k e J,

Chan A,

W e b b K.

Forty-five children aged 6-14 years with primary nocturnal enuresis were randomised to d e t e r m i n e w h e t h e r desmopressin is more e f f e c t i v e than a m i t r i p t y l i n e and w h e t h e r the combination of amitriptyline-desmopressin is more effective than amitriptyline or d e s m o p r e s s i n alone. A m i t r i p t y l i n e d o s a g e was 25 m g for c h i l d r e n 6-10 y e a r s and 50 m g a g e d 10-14 Fears. D e s m o p r e s s i n 20 u g was g i v e n in the same d o s a g e for a l l age groups. A f t e r a run-in period of two weeks, c h i l d r e n were t r e a t e d for 16 w e e k s and then o b s e r v e d for 12 weeks. In the a m i t r i p t y l i n e g r o u p m e a n wet n i g h t s p e r w e e k d e c r e a s e d f r o m 5.8 • 0.9 to 3.3 • 1.9 (p < 0 . 0 0 0 5 ) ; in the d e s m o p r e s s i n g r o u p m e a n wet n i g h t s p e r w e e k d e c r e a s e d f r o m 6.0 • 0.9 to 4.7 • 1.7 (p <0.02); in the amitriptyline-desmopressin group mean wet n i g h t s p e r w e e k d e c r e a s e d from 6.3 • 0.9 to 3.3 • 2.5 (p <0.0006). W h e n c o m p a r i n g the groups a m i t r i p t y l i n e - d e s m o p r e s s i n and a m i t r i p t y line w e r e statistically more effective than d e s m o p r e s s i n in w e e k 6 (p ~ . 0 0 9 } , w e e k 8 (p ~D.03), and w e e k i0 (p <0.04). No s i g n i f i c a n t side e f f e c t s occurred. At this dose amitriptyline was more effective than desmopressin and the combination of d e s m o p r e s s i n and a m i t r i p t y l i n e d i d not c o n f e r any a d d i t i o n a l benefit. M a t e r and R o y a l C h i l d r e n s ' s H o s p i t a l s Brisbane. Australia 4101

C 99 P178

P179

INCREASED FREQUENCY OF VOIDING DYSFUNCTION AND UROLOGIC ABNORMAUTIES IN PATIENTS WITH WILLIAMS SYNDROME: IS THERE A RELATIONSHIP? S. Schulman*, S.A. Zderic**, P. Kaplan*

PRIMARY NOCTURNAL ENURESIS IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS - A CIRCADIAN DEFECT IN FREE WATER EXCRETION CONTROLLABLE BY DESMOPRESSIN TREATMENT Rittig S 1, Kov=tcs L2, Gaskill MB3, Nanninga j4, Zee p5, Robertson GL3

Urologic abnormalities such as bladder diverticula have been described in increased frequency in individuals with Williams Syndrome (WS). The multidisciplinary WS clinic at our institution follows 42 patients of which 33 are at least 5 years old and expected to be toilet trained. Twelve (36=/=) patients (7 females, 5 males) 6-39 years of age have a urologic problem. These include frequsncy (8), nocturnal enuresis (8), daytime wetting (7), bladder diverticula (4), UTI (2), undescended testis (2) and duplication (1). Urodynamic studies (UDS) were performed in 5 patients with daytime wetting showing uninhibited detrusor contractions (UDC) in 4 and were suggestive of obstruction in the other. Three patients were placed on oxybutynin plus bladder retraining with relief of frequency and daytime wetting. The symptoms of frequency in 2 patients resolved spontaneously. All 4 patients with diverticula (ages 9-39 years) have had a long history of frequency and urgency. We conclude that a history of voiding behavior should be obtained in patients with WS as there is a high frequency of these symptoms. UDS should be obtained in those patients deemed cooperative with daytime wetting for the presence of UDCs. Anticholinergic medications and bladder retraining should be offered to patients with UDCs (and considered empirically in patients not studied with symptoms) to minimize the embarrassment associated with daytime wetting. We hypothesize that the bladder diverticula may be secondary to longstanding elevated pressures on an intrinsically abnormal bladder.

Monosymptomatic nocturnal enuresis (MNE) is primarily a disease of childhood, however it still occurs in 1% of adolescents and young adults. Children with MNE have a circadian defect in urine output, which is due partly to nocturnal deficiency of plasma vasopressin (PAVP) and is controllable by desmopressin (DDAVP) treatment (Ffittig et a/, Am J Physic/256,1989,/=664). To determine, whether adolescents and young adults have a similar defect, we studied 9 healthy subjects and 9 patients aging 20:1:3 years with MNE occurring > 3 nights per, week. Under conditions of ad lib intake, plasma osmolallty (Posm) and PAVP were measured every 30 minutes while fluid intake (I), urine volume (V), solute clearance (Cosm) and free-water clearance (CH20) were determined for 3 successive 8 hour periods beginning at 7 a.m. There were no significant differences between the two groups in 24 hours diuresis (2100:1:200 vs. 2100 + 300 ml/24 hrs) or fluid intake. Enuretics, however excreted a larger part of their urine during the night (11 p.m. - 7 a.m.) as compared to the controls (515 + 53 vs. 308 + 45 ml/8h, p<0.005). Their relative nocturnal polyuria was due to higher water diuresis, as reflected by lower urine osmolality (400 + 59 vs. 712 + 73 mOsm/kg, p<0.005) and less negative C H 2 0 (-0.29 + 0.1 vs. -0.81 + 0.1 ml/min, p<0.005). Despite this nocturnal deficiency in antidiuresis, PAVP (1.1 • 0.2 vs. 0.9 + 0.1 pg/ml) as well as Posm and Cosm were similar in both groups. Treatment with DDAVP, 10 30 ~g i.n. at night, abolished MNE in all patients by reducing their nocturnal poiyuria. We conclude that adolescents and young adults with MNE also have a circadian defect in free water excretion that can be treated with DDAVP. Unlike children, however this defect cannot be attributed to a nocturnal deficiency of vasopressin and may be due to reduced renal sensitivity to the hormone.

Depts of Peds* and Urol**, University of PA School of Medicine The Children's Hospital of Philadelphia, Philadelphia, PA.

I Departmentof Nephrology, Universityof Aarhus, Aarhus, Denmark, 2Departmentof Pediatrics, CorneniusUniversity,Bratislava, Stovakia 3Departmentsof Medicine, Urology4 & Neurology5, Northwestern University, Chicago,Illinois

P180 C O U N S E L L I N G FAMILIES FOR V E S I C O U R E T E R I C REFLUX AND REFLUX NEPHROPATHY: Kate Verrier Jones, Ruberta Robc~'ts. Del)artment of Child Heallh, University of Wales College of Medicine and Royal 9 Infirmary, Cardiff, Wales, UK. Since 1980, fsllowiug the diagnosis of vesicoureterie reflux (VUR) or reflux nel)hropathy (RN) it has been the pslicy of sur unit to give advice to parents and siblings of affected cases on the risk of VUR. This advice has been accompanied by an otter to carry out ultrasound examination of the urinaD, tract to look for renal scarring and urinary tract dilatation in first degree relatives, hi addition mictm'ating cystourethrography (MCUG) has been offered fur infants during the f r s t )'ear of life because of the high risk of urinary Tract infection (UTI) and renal scarring in this age group. During pregnancy mothers are asked whether or not they would like their newborn infant tu have tests aud prophylactic antibiotics. All families are advised on She delectiua au(I management s f UTI ~vhetber or not they opt for family testing. Index cases have been defined as Ilaviug either VUR or RN or both. In 79 families at least sne other relative has had investigations and a total of 133 first degree relatives underwent renal imaging, usually sltrasouml, as a result of which 15 ( l l % ) s h o w e d evidence of RN. In addition 46 infants and chihh'en had M C U G s either as infants or because s f clinical indications sucb as urinary tract infection. O f these, 14 eases (30%) had evidence of VUR. In the fimdlies with more than sue affected member the following relationships were nstcd:Mother to snn 5 Mother to daughter 11 Father to daugllter 3 Father to snn i Siblings 13 including two sets s f twins, all male In 12 families (15%) Ihere was one afl~:cler mcml)er with chronic renal failu re due to RN, usually the index case. lu these fimlilies the i)revalence of reflux in first degree relatives tested was 9 out of 11 ~ho had MCUG. Conclusion: Many families accept cnunselliug for V U R and RN and want their children tested for these co.ditious. Most families want ultrasunography but a substantial number also want MCUG. The distribution of cases in parents and children wotlld br consistent wiU] a dominaut or i)nlygcnic mode of inheritance.

P181 THE R O L E O F R E N A L M A T U R A T I O N A N D APOPTOSIS IN T H E R E N A L RESPONSE TO URETERAL OBSTRUCTION. R. L. Chevalier*, K.H, Chung**, C.D. Smith*, R. A. Gomez*

Unilateral ureteral obstruction (UUO) impairs renal growth an~ function more severely in the neonate than in the adult. To investigate the potential role of apoptosis and of growthr e l a t e d p e p t i d e s in this r e s p o n s e , S p r a g u e - D a w l e y rats underwent UUO or sham-operation in separate groups of neonatal and adult rats, and kidneys were h a r v e s t e d 3 and 14 days later. Apoptosis was quantitated by flow cytometry, and the distribution of a p o p t o t i c cells was determined by immunocytochemistry using the TUNEL technique. Renal messenger RNA (mRNA} was quantitated by Northern and dot-blot hybridization with CDNA probes for renln, transforming growth factor-beta i (TGF-B1), epidermal growth factor (EGF), and c l u s t e r i n , a g l y c o p r o t e i n that m a y p r o t e c t c e l l s from apoptosis. U n l i k e the n e o n a t e , in w h i c h renal DNA was decreased with chronic ipsilateral UUO, renal DNA increased in the adult. Apoptosis was limited to distal tubular cells, an~ was significantly increased by 14 days" UUO in both neonates and adults. However, the fraction of apoptotic cells was t w o f o l d g r e a t e r in n e o n a t a l t h a n a d u l t k i d n e y s w i t h ipsilateral UUO (13<0.05). UUO markedly increased renal renin mRNA expression in the neonate, but not in the adult, whereas TGF-BI expression increased in the obstructed kidney in both neonates and adults. Renal EGF expression was undetectable i~ the normal neonatal kidney during the first 3 days of life, and was suppressed in the obstructed kidney in both neonatee and adults. Renal clusterin expression was increased by UUO in all rats, but was two to t h r e e - f o l d g r e a t e r in a d u l t ~ (p<0.OS). We conclude that compared to the adult, neonatal UUO induces greater apoptosis, which in turn leads to reduced renal DNA and renal growth arrest. Greater activation of the renin-anglotensin system by UUO in the neonate may contribute to enhanced apoptosis through reduced clusterin expression~ *Dept. Pediatrics, Univ. of Virginia, Charlottesville, VA, USA **Dept. Urology, Gyeong-sang Natl. University, ChinJu, Korea

C 100 P182

P183

LATE RESULTS OF CONSERVATIVE TREATMENT IN VESICO URETERAL REFLUX IN Ct-I~DREN I. Lenik, K. Saneewiez-Pach

ACE~I AND REFLUX NEPHROPATHY (RN): FOLLOW-UP LONG TERM, G.Lama, M.Esposito Salsano, G:Avino, F.Cirillo, L.Valentino, N.Pepe, M.Pedulla' and N.Marrone.

In the years 1985 - 90, among the total of 310 patients presenting at the Nephrology Clinic with urinary tract infections, vesico - ureteral reflux (VUR) grade I, II, and III was noted in 133 children (42.9%) (1 I0 girls and 23 boys aged 2 months to 13 years). VUR in patients below 3 years of age was noted in 42.8% of cases. Familial VUR was encountered in 5 eases. Unilateral reflux was observed in 60.2% of patients. Pre - diagnosis symptoms oeeuring in infants up to 1 year of age included gastro-intestinaal tract complains (69.7%0) enuresis nocturna was observed in 25% of cases, whereas pyuria - 67.7%. No correlation was observed between proteinuria (11.3%), hematuria (20.3%) and hypocaleuria 8.3% on the one hand, and the reflux stage on the other. Follow -up continued till subsidence of VUR was approximately 4 years. Unitaleral VUR cases were eUrred in 62.5%, and ambilateral - in 47.2% of eases. Sixteen patients required surgical treatment. Thirty-one patients (23.3%) dropped out. Chronic renal failure developed in one child. The results indicate the necessity of thorought and early diagnostic management of urinary tract infections, as well as of long - term conservative treatment Polish American Children's Hospital, CollMed. Jagiellonian University Dep. of Ped. Nephrol. Krak6w Poland

Several prospective studies suggest the effect on progressive renal failure of lowprotein diet and/or ACE-I. Aim of the study: evaluate the effect on the long term teatment with ACE-I, in patients with reflux nephropathy (RN). Fifteen patients with shrunken kidney aecompaned by compensatory hipertrohy of the controlateral kidney, were selected for the study and divided into two groups. Group A: 8 patients with mean follow time of 11.7 years. All patients were treated with captopril (0.5 mg/Kg/die) for 2.6 years (range 1.2-3.6). The mean duration of RN was of 9.2 yrs. Group B: 7 pts with mean follow up of 5 yrs, treated with captopril for 12 month(range 0.10-24). The treatment was begun after 4 yrs since diagnosis of RN. The age at diagnosis was not different between the two groups, while the pts of the group A had an higher mean age at follow-up (15.2 VS 9.2 yrs). In both group were evaluated: creatinine (Cr), creatinine clearance (Crcl) and Microalbuminuria (MA) at basal condition and after giving ACE-I; GFR and uptake % by DTPA renal scan. All pts had values of blood pressure between the 50-90 Pc for age and sex and normal intake of protein. At basal condition: the values of GFR and Crcl were not correlated (r=0.7, p<0.375; r=-0.79), and there was a tendency for those to reman stable after six and 12 months (0.96 vs 0.98; p<0.4; r=0.95).MA was reduced significantly (p<0.O05). In the group B, the decline of the glomerular filtrationrote was 5.5 ml/min/yrs (101.5i97 vs 96~12.5; p<0.375; r=0.20); there was no correlation between values of Crcl at basal condition and after six months of ACE-I treatment (96• vs 96.1• p<0.375; r=0.22). MA was reduced, but not significantly (1><0.4). In this group, there was a significant rise in serum Cr concentration during the six months before treatment (0.68~0. l vs 0.76• p
P184 ANTIPROTEINURIC EFFECT OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS (ACE) IN CHILDREN W I T H REFLUX NEPEIROPATY,

L.Briones, N.Deigado,M.Monteverde,A.Turconi Reflux nephropaty is one of the commonest causes of end-stage renal failure in chilhood.Once scarring has occurred,the prognosis depends on the severity of initial damage and the presence of proteinuria.It is independent of ongoing reflux or infection.. We evaluated the long-term( i=43.5 months r = 24-61 months) antipro teinuric effect of ACE inhibitors in 7 normotensive children (age ~=10.5 years, r= 5-17 years)with severely reduced nephronal mass secondary to reflux nephropaty. Five of them had had successfull antireflux surgery.Renal sonography and DMSA renal scintigraphy showed generalized damage and reduced differential renal function.All patients had persistent heavy proteinuria. Children received a controlled protein intake for RDA,sodium dietary restriction and enalapril therapy dose x= 0.2750,07 mg/kg/day(MEAN SEM, r= 0.1-0.5mg/kg/day). In the course of enalapril therapy proteinuria dropped from 64.2 ~-18.7 mg/m2/hour (MEAN +SEM) to 10A ~3.13 mg/m2/hour(p=0,015) Creatinine clearances was 80.6 qq2.7 ml/'/1.73m2 before and 67.8 12.0 ml/'/1.73m2, at the end of follow-up(p = NS). Although the number of patients is still small,the control of proteinuria with ACE inhibitors seem to arrest the .progression of renal fialure during the period of study.

Service of Nephrology.Hospital J P Garrahan.Bs. Aires,Argentina.

VESICOURETERAL REFLUX: A REVIEW OF 210 PATIENTS C. A. Cepero-Akselrad*, F. Ramirez-Seijas*, Lankau** Vesicoureteral reflux, urinary tract infection, and reflux nephropathy are sufficiently understood to provide compelling evidence o f t h e need for e a r l y d i a g n o s i s and prompt i n t e r v e n t i o n . We d i d a r e t r o s p e c t i v e a n a l y s i s o f 210 p a t i e n t s f o l l o w e d in our i n s t i t u t i o n . 135 were females and 75 males; 47~ o f these p a t i e n t s were below the age o f I y e a r . Under t h e age o f 1 month~ t h e r e was a m a l e predominance (12 males vs. 2 females). A f t e r the age of 3 months a tendency toward females was n o t i c e d . 122 p a t i e n t s s u f f e r e d u n i l a t e r a l r e f l u x ; 88 had b i l a t e r a l v e s i c o u r e t e r a l r e f l u x . A t o t a l o f 298 u r e t e r s were a f f e c t e d . Under i y e a r o f age t h e m a j o r i t y o f t h e p a t i e n t s had grade I l l v e s i c o ureteral reflux by t h e I n t e r n a t i o n a l Classific a t i o n . Above t h e age o f I y e a r , grade II vesic o u r e t e r a l r e f l u x was m o r e p r e v a l e n t . Of t h e 210 patients~ 107 were t r e a t e d m e d i c a l l y and 103 patients were s u r g i c a l l y approached. A t o t a l o f 148 ureters were treated conservatively with resolution of t h e r e f l u x in 83 ureters; 8 0 % of these resolved within 6 months. 138 u r e t e r s were re-implanted w i t h s u c c e s s in 122 u r e t e r s . In conclusion: Vesicoureteral reflux was more p r e v a l e n t in f e m a l e s e x c e p t in t h e f i r s t m o n t h of life. U n i l a t e r a l r e f l u x a n d g r a d e IIl r e f l u x were seen more frequently. Surgical re-implantation yielded a 90% resolution. * Pediatric Nephrology-Miami Miami, Florida, USA **Pediatric Surgery-Miami Miami, Florida, USA

Children's Children's

Hospital Hospital,

C 101 P186

P187

DEVELOPING PP*.EDIATRIC NEPHROLOGY IN ARMENIa: A SUOCEBSFUL PROGRJM/I/B tFNDER DIFFICULT DONDZTZONB B. L e t m a n n * , C. Leumann*, J.P. Bernhardt**, A. Babloyanee* No a d e q u a t e n e p h r o l o g y existed in A r m e n i a until 1988 - the year of the e a r t h q u a k e - a l t h o u g h it was one of the most developed r e p u b l i c s in the (former) S o v i e t union. A c u t e h a e m o d i a l y s i s for the crush syndrome done by two of us was the s t a r t i n g point for developing paediatric nephrology in Armenia. Professional training (done twice per y e a r in Yerevan) h a d first priority; in addition, 15 p a e d i a t r i c i a n s a n d 10 n u r s e s and t e c h n i c i a n s were trained in Western Europe (mainly Switzerland) in all fields o f p a e d i a t r i c n e p h r o fogy and urology. O b s t a c l e s inherent to the Soviet s y s t e m (e.g., little theoretical background, no c o m p e t i t i o n , p o o r facilities) had to be overcome. In p a r a l l e l , a p s y c h o s o c i a l p r o g r a m m e was d e v e l o ped - a m u s t for p r e s e n t day p a e d i a t r i c care - by a separate organization (VAD). Starting w i t h the r e c r u i t m e n t of t e a c h e r s o p e n to new ideas, it was e x t e n d e d to i n c l u d e educational, social and psyc h o l o g y services. B o t h the medical and psychosocial p r o j e c t h a v e s t r o n g l y improved care of sick children d e s p i t e the dramatic economic decline unforeseen some years ago. However, a h i g h p e r s o nal co~nmitment on either side and steady e f f o r t s for c o n t i n u o u s f u n d i n g are required. L o n g - t e r m cooperation, e a s e d by partnership, is an e f f e c t i v e way to improve paediatric care, taking into account the p a r t i c u l a r needs of former Soviet countries. * Univ. C h i l d r e n ' s H o s p i t a l - Zurich - S w i t z e r l a n d ** H S p i t a l R ~ g i o n a l - P o r r e n t r u y - S w i t z e r l a n d *** CMC A r a b k i r - Y e r e v a n - A r m e n i a

P188

MALAKOPLAKIA-MEGALOCYTIC INTERSTITIAL COMPLEX: A CASE P R E S E N T A T I O N A. Cepero-Akselrad*, F. R a m i r e z - S e i j a s * ,

NEPHRITIS V.Pardo**

A nine month old B/M infant was admitted with fever and irritability. The physical exam revealed a malnourished, irritable infant with palpable kidneys. Rectal t e m p e r a t u r e was 103oF. Throughout the entire hospital course peripheral WBC's ranged from 26,000 to 43,000. Serum creatinine was 0.9 mg/dl. E. coli grew in both blood and urine. The patient remained febrile for several weeks despite a n t i b i o t i c therapy. NBT stimuIation test, phagocytic index, IgS, IgA, IgM, and bone marrow aspiration were normal. T helper cells were 21~, and T suppressor cells were 8%. Renal U/S showed bilaterally enlarged kidneys with increased echogenicity. Renal biopsy showed an extensive replacement of the renal parenchyma by masses of large Histiocytes. These PAS-positive cells stained for macrophage markers (murimidase and anti-alpha antitrypsin). There were large, dense granules positive with Van K o s s a and Alizarin red. By E.M., these granular cells were large h i s t i o c y t e s - m a c r o phages with abundant lysosomes and phagolysosomes that showed variegated contents, including small dense crystals consistent with calcium deposits (Von Hansemann's histiocytes). This clinico-pathological presentation is compatible with MegaIocytic Interstitial N e p h r i t i s - M a l a k o p l a k i a complex. This disease should be included in the causes o~ F.U.O. Renal biopsy should be considered in any patient with F.U.O and enlarged kidneys. * P e d i a t r i c N e p h r o l o g y - M i a m i Children's Hospital Miami, Fl~orida, USA **Dept. of Pathology U.A. Hospital-Miami, FI. USA

P189

AUDIT OF THE DIAGNOSIS AND MANAGEMENT OF UTI IN CHILDREN UNDER TWO YEARS IN PRIMARY CARE. K Verrier Jones, J Wilkinson, R Roberts, K Santos Depts of Child Health, Public Health Medicine and General Practice, Cardiff. Wales, U K It has been demonstrated that urinary tract infection (UTI) is common in early childhood and that the first infection is most likely to occur in the first two years of life (Winberg 1975). At this age the child or ilffant usually presents with non-specific symptoms such as fever, irritability or vomiting and the diagnosis can only be made if urine is cultured, Furthermore the collection of urine from this age group is difficult particularly outside the hospih)l setting. Studies in Sweden and elsewhere have shown that renal damage is most likely to develop if UTIs occur in early childhood, if there is a delay in diagnosis and if vesicoureteric reflux is present. The aim of this study was to identify health gain potential in the management of UTI in earl), childhood. A questionnaire was sent to 155 General Practitioners throughout Wales, a region with a population of 2.8 million, and replies were received from 122 (79%). Results showed that 34% of GPs were umnvare of the non-specific nature of symNoms in this age group and only 18% considered UT1 as au important cause of fever. Many GPs had inadequate arrangements for urine collection and there were often long delays before the result was available or treatment was started. The number of urine cultures carried out in the past year varied between practices from 0 - 50. Althongh there were few problems in providing treatment of the acute UTI relativeb, few doctors were familiar with the use of prophylactic antibiotics and only 2% were aware of the current recommendation to start prophylactic antibiotics immediately after the first infection. Although 80% would refer boys for radiological investigation only 56% would refer girls after the first infection. This study has demonstrated several areas in the diagnosis and management of UTI in early childhood which may predispose to renal scarring and this topic should be regarded as an important health gain area. The results of the survey suggested that although 88% considered that urinau, tract i~ffection might he a cause of prolonged or unexplained fever only 18% considered uduary tract infection as am important cause of fever initially and 34% of GPs were unaware of the non-specific nature of ~'mptoms ill this age group.

INCIDENCE OF ABNORMALITIES IN URINALYSIS AGED 6 TO 1 0 YEARS IN JAPANESE M. Mu r a k e m l * ,N.Tatsuma*, H.Tsugu* ,E.Munakata*, K.Ambo*, Id.Ts uchlye* ,id.Achldc* ,H.Yamamoto*, K.Yamauchl** Purposes and methods: To determine the incidence of abnormalities in urinalysis aged6 to I 0 years, a prospective study was performed longitudinally in 31,552 elementary school pupils who entered a school in 1987 at6 years of nOn The first urinalysis was performed just after the entry into the elementary school, and urinalysis was then pc#creed five times annually. Urine screenings at school were performed by Tokyo method (Pediatr Nephrol[1991] 5;50), and sampling method, reagent strips, item of detailed examination and + evaluation criteria were not changedfor the 6 years period. Results:In the 5 years period, the abnormalities in urinalysis were found in 392 ( 1.3%; 132 boys and 260 girls) children. They included 300 children ( 1.0%; 97 boys and203 girls ) positive for hemeturia, 54 children (0.2%; 18boys and36 girls ) positive for proteinuria, 30 children ( O. 1%; 16 boys and 14 girls) positive for both hematuria and proteinuria, and eight children with proteinuria and/or hematuria associated witll leucocyturia. The detection of abnormalities showed no significant age difference in boys, but the incidence was a significant increase in girls at I 011years of age. The abnormalities had disappeared within one year in 59.3% ofboysand42.0% ofgiris. Conclusion:Among the Japanese children aged 6-16years, the incidence of abnormalities in urinalysis was 1-1.5%, and this abnormefities appeared to be transient among the about haft of them. * DepartmentofPedlatrics-NipponMedicalSchooI.Tokyo-Japan **Tokyo Association of Health Service- Tokyo-Japan

C 102 P190

P191

URINE [$2-MICROGLOBULIN IS A SENSITIVE M A R K E R FOR PREDICTING RENAL INJURY IN URINARY TRACT INFECTION W.U. Lee*., I.S. Kim*., E.R. Kim*.

URINARY EXTRACI~ION OF PLATELE'[ ACTIVATING FACTOR (PAF} IN CHILDREN WITH PYELONEPHRITIS S. Mir a. I. Ozunan t, A.Cura *. A. Huseyinov*

We investigated the significance of 24 hour urine 2-microglobulin (2-MG) for predicting renal injury in urinary tract infection (UTI). We evaluated 52 patients with UTI. Renal sonogram, DMSA scan, VCUG and 24 hour urine 2-MG were performed. Patients were divided into 3 groups: 24 patients without renal scarring and reflux (group A), 14 patients with renal scarring in DMSA and reflux in VCUG (group C). The mean level of 24 hour urine 132-Mgwas 0.865"0.610mg (group A), 6.5314-11.39mg (group B), 5.3384-11.390mg (group C). There was a significant difference in 24 hour urine ~2-MG between groups A and B (p>0.05). Among 14 patients with reflux in VCUG, we compared 9 patients with high grade reflux (grade III-V) and 5 patients with low grade reflux (grade M1). There was significant difference between high and low grade reflux (p<0.05). Our results show that 24 hour urine 132-MG was higher in patients with renal scarfing and high grade reflux than in patients with simple UTI and low grade reflux. Our study suggests that 24 hour urine [32-MG was a sensitive marker of UTI with renal injury.

PAF is a potent mediator of inftamation produced by leukocytes, macrophages, glomerulary cells upon immunologic and nonimmunologic stimulation PAl: reduces glomerulary filtration rate and renal blood flow which provides contraction of glomerulary and mesengial cells. If the anion, lood of glomerulary based membran changes, fibrin and immun-complex deposites come into being and proteinuria. In this study the physiopathological role of PAF in the pyelonephritis which is an inflamatory renal disease is to purpose aperture PAl: levels are determined from plasma and unne Six normal and 8 children with pyelonephrritis were used in the study. The mean age is 97 months old in- healty control and 86 months old in patients with pyelonephritis. PAF levels determined by RIA after separation with solid phase extraction method. PAF levels are 0.12 0.10 nghnl in the plasms of healty children and 0.72 0.56 nghnl in the urine.Levels of it 2.88 0.42 ng/ml are in the urine of children with pyelonephritis. These are relatively higher than healty controls but this is not meninigful statistically. High levels of PAF extraction in the urine,from its renal origin, is sent ~ the glomemlary cellsor the cells which are infiltrated on them. Positi,& correlation

*Pediatric Service - Seoul-Korea

between urine leukocyte counts and excrated PAF levels supports this throught. Although PAF levelsof plasma of the chilren with pyelonephritis are relativelyhigher than healty controls, it is not meninigful. It is very important to know PAF's influence is spesificallyfrom excrated urinary traetus, not from the general system. The result of this study showed increased syntesis and excration of PAF, the otocoide which has a lot of biological Rmctions. It is important to examine PAF influence from the beginning and continuing local inflamatory reactions of the kidney.

* Dept. of Pediatric Nephrology, Ege University, I~anir-Turkey,

P192 RESIDUAL URINE MAY HAVE A ROLE IN THE PATHOGENESIS OF URINARY TRACT INFECTION IN EARLY CHILDHOOD. M J Ellison, K Verrier Jones. Department of Child Health, University of Wales College of Medicine and -Royal Infirmary, Cardiff, UK Incomplete bladder emptying has been shown to be associated with urinary tract infection in children. Winberg et al (1974) showed that the incidence of primary (first) urinary tract infections was greatest in the first month of life, decreasing with age throughout childhood. The aim of this study was to observe bladder emptying in healthy children in order to establish normal patterns and to determine whether trends in bladder emptying could account for the variations with age and sex observed. 69 healthy children aged 3 weeks to 6 years (35 boys, 34 gMs) were studied using a portable ultrasound scanner before and after voiding. Residual urine was detected in 19 of 30 int'ants (63%), 7 ot'9 children aged l-2 years (78%) and 5 out of 30 children aged 2-6 years (17%) p <0.01. There were no sex differences observed. Conclusion Bladder emptying is often incomplete in the first two years of life and is significantly different from the pattern in older children or adults. This m@ account for the age related differences in incidence of primary urinary tract infection but cannot account for the different patterns in boys and girls.

P193 RENAL CONCENTRATING CAPACITY IN CHILDREN AT FOLLOW-UP AFTER SYMPTOMATIC URINARY TRACT INFECTION S. Mfirild% S. Hansson~ , U. Jodal ~ Transient impairment of renal concentraling capacity is known to occur in children with minary tractinfections (UTI) involving the kidneys. The purpose of thisstudy was to assess the longterm outcome of the renal concentrating capacity in children

followed after fn'st-timeUTI. Methods: Cases were selected from a computerized mgistcx of consecutive patients included prospectivelyfrom the firstknown UTI. The firstI00 days altera UTI were excluded from the analysisto allow transientdecrease in renal concentrating capacity to return. Maximal renal concentrating capacity was estimated by desmopressin testing with determination of urinary osmolality. Results: A totalof 646 female and 195 male patients were selected to the study, 353 with previous acute pyclonephritis and the remaining with other types of UTI. The mean age at startof the study was 5.9 (.SD 4.5) years. Urography showed normal kidneys in 549 cases, unilateralrenal scarring in 91, and bilateralscarring in 16. Vesicoureterlcrefluxwas found in 110 patients.Post-void residual urine was recorded in 349 patients and the mean volume was 11.4 mL (SD 30.5). The maximal renal concentrating capacity had a mean value of-0.26 standard deviation score units (p<0.01)and residualurine (p<0,01).in a stcpwise multiple regression analysis,renal scarring was the most powerful explanatory parameter, accounting for 7.9% of the totalvariance which was 8.8%; addition of vesicouretericreflux added 0.9%. Conclusion: The children in the study had a significantand permanent reduction of the maximal renal concentrating capacity that was determined mainly by renal scarring. Departments of Pediatrics, *M0indal Hospital and ** Ostra University Hospital, C~teborg, Sweden

C 103 P194

P195

RENAL CONCENTRATING CAPACITY DURING FOLLOW-UP OF GIRLS WITH UNTREATED ASYMPTOMATIC BACTERIURIA S. Hansson, U. Jodal, S. M~trild

CLINICAL CHARACTERISTICS OF URINARy TRACT INFECTION (UTI) BY ESERICHIA COLI, ASSOCIATED WITH BACTERIAL FIMBRIA ANTIGS~qS I. ECavo*, T. L~Lh~9 ~*, C. ~ b e * * , A. MISOZ**

There is no evidence that detection and treatment of children with asymptomatic bacteriuria prevent subsequent pyelonephritis or renal scarring. Many clinicians nowadayspreferto leave asymptomaticbacteriuria untreated. However, to rule out a negative influence on renal tubular function we studied the renal concentrating capacity do_ringlong-termfollow-upof girls with untreated asymptomaticbacteriuria. Methods: Maximal renal concentrating capacity was estimated by desmopressin testing with determination of osmolality. Concentratingcapacity during episodes of untreated asymptomaticbacteriuria was evaluated by calculating Spearman's rank correlation coefficients within individuals. The tendency for renal concentrating capacity was analysedby Wilcoxon's rank sum test on these correlation coefficients. Setting: A urinary tract infection clinic at the Children's Hospital. Clinical and laboratory data were prospectivelyregistered in a data base. Patients: 132 girls with untreated asymptomaticbacteriuria for a minimum duration of 3 monthswea'eselected for the study. 121 of these girls had performed at least two desmopressintests which were required for statistical calculation. Age at start of the study was 8.6 (SD 2.6) years, the follow-uptime with untreated bacteriuria 2.1 (SD 1.9) years. A total of 609 desmopressintests were performed. Results: The maximalrenal concentratingcapacity remained stable during follow-up (the mean of the correlation coefficients was 0.13). Conclusion: There was no negative effect on maximal renal concentratingcapacity during follow-up of girls with untreated asymptomaticbacteriuria. This is further support for the non-treatmentpolicy.

Adhesive capacity is a virulence factor for Eserichia COli, related to the presence on the bacterial fimbrae Of specific structures (adhesins). The relationship between these uropathogenic characteristics of the bacteria and the severity and recurrence of UTI was studied in urinary cultures obtained from 18 boys and 172 girls with UTI. Expressions of adhesins was identified in bacteria by inn ucing mannose resistant aglutined for F flmbrae and by a latex kit for the P one. N~nber of patiens with their antigen type is shown in the table below Fimb. ant. ~cfUI~ +

+

P ~F +

high Wfl low UTI sig. level ehi 2

40 35 32 83 0.0007

30 45 17 98 0.0001

43 43 36 93 0.001

28 35

recurrence of LrfI no recurrence 9f UTI sig. level chi n

ii 46 61 72 0.0009

8 49 39 94 0.03

12 59 67 77 0.0004

16 47

High UII ~

P

~ar~nce ~e

F

deflr~d b~ ~

~

+

Type 1 47 80 NS 41 86 NS

ccite~ia

AS it can be seen on the table, there is a significant correlation between the presence of P or F fimbria antigen and high UTI and a negative correlation between the presence of one of these antigens and the recurrence of UTI. Type 1 fimbrae may be not related to these charac terists of b~fI. Results confirm the idea that bacteria's charact's are important for the invasion of high' urinary tract. Also the typification of fimbrae would be desirable in any [FfI. The recurrence of UTI appears to be- negative correlated with virulence, confirming the importance of prcmpt detention of morphological alterations of urinary tract.

Department of Pediatrics, Ostra UniversityHospital, S-416 85 G6teborg, Sweden

* Dept. ~f Fed. Fac. M~. U. ~ l e

*-* t,1~d.~ . ser~oe, H:s#. R. del Rio - ~ ,

P196

TC-99M MAG3 D I U R E T I C R E N O G R A M IN C H I L D R E N WITH URINARY TRACT OBSTRUCTION DURING THE FOLLOW-UP G.Larna*, L.Valentino*, P.F.Rambaldi ~ D.Magri*, N.Pepe*, F.Orbinato* and L.Mansi ~ Aim of this study is to analyse the usefullness of associated evaluation of wash-out T1/2 and 2 minutes split function (SF) in assessing hydronephrosis in children. The diuretic renogram with MAG3 Tc-99m and furosemide, using standard doses and procedures, has been utilized. We have retrospectively evaluated T 1/2 and SF in 23 children (age range 134 months), that hadn't undergone pieloplasty at the time of the first study because of equivocal results on diuretic renogmm. In all cases a second scan 3-8 months later was performed; during this period an antibiotic prophylaxis was done and urine coltures were always negative. Three different patterns have been identified: A)worsening ofT 1/2 and SF, in 3 pts; B)improvernent of Tl/2 without changes of SF in 14 pts; C)worsening of Tl/2 without changes of SF in 6 pts. No pts demonstrated worsenin[ of SF alone, Tl/2 WASHOUT SPLIT F U N C T I O N WORSENING IMPROVEMENT <4% 3 >4% 6 14 On the basis of these results was made diagnosis: group A obstuctive uropathy; group B functional hydronephrosis and group C persistent equivocal results. In the thirth group a further evaluation, including a new diuretic renogram, was planned. We can conclude that the majority of the children showed improvement in T1/2 on second scan and stable split renal function, so in these patients radiological pielography was not performed. DepartmentofPediatrics( )-InsfituteofRadiologicai Sciences( o ) I1 University Naples Italy

Oile

P197 B A C T E R I U R I A R E L A T E D TO M I C T U R A T I N G CYSTOURETHROGRAPHY

LM Brasil, PS P&dua-Neto, A Palombini, AA Raubach, NP Goldraich Aim: to establish the prevalence of bacteriuria related to bladder catheterization for micturating cystourethrography (MCU). Criteria f o r enrolling in the study: negative urine culture prior to MCU. Period of study: January 1991 - January 1993. Patients: 132 (74 infants, 45 pre-school children, 13 school-age children) out-patients were included in the study. One hundred and twenty children were on quimioprophylaxis when underwent MCU (nitrofurantoin was used in 92.5% of them). The MCU was abnormal in 27 patients. Method: udne for culture was obtained by suprapubic bladder aspiration in all patients, prior and up to 48 hours following the MCU. Results: bacteriuria related to MCU occurred in 14% of the children (19% in infants, 7% in pre-school children). It was significantly (p<0.05) more frequent in infant males. Proteus was identified in 53% of the patients, followed by Eschedchia coil (41%). There was no significant association (p>0,05) between the occurrence of bacteduda related to MCU and the presence of abnormalities on MCU or the use of quimioprophylaxis. Conclusions: (1) Proteus was the most prevalent organism identified in bacteduria related to MCU; (2) there was a significant association (p<0.05) between lower patient-age and the occurrence of bacteriuria related to MCU; (3) there was a significant association between sex and bacteriuria related to MCU only in infants; (4) there was no significant association (p>0.05) between the presence of abnormalities on MCU and the occurrence of bacteriuria related to MCU; (5) quimioprophylaxis did not prevent the development of bacteriuria related to MCU. Pediatric Nephrology Unit, Hospital de Clinicas de Porto Alegre Porto Alegre, RS, Brazil

C 104 P198

P199

CHANGES OF RENAL SIZE DURING PUBERTY IN C H I L D R E N WITH R E C U R R E N T URINARY T R A C T INFECTIONS U. Berg*,

I. W i k s t a d * * ,

B. J o h a n s s o n *

In children with recurrent urinary tract infections (UTI) increase in renal size of a small or scarred kidney and a decline in the size of the contralateral kidney during puberty have been reported. Our experiences could not verify this fact why we performed a retrospective study on 40 children with recurrent UTI having performed at least 2 i.v. urographies, one before and one after puberty. Renal size was estimated as renal purenchymal area and parenchymal thickness was estimated in upper, lower and lateral aspects of each kidney. A small kidney was defined as a renal parenchyrnal area <-2 SD and parenchymal reduction as one or several parenchymal thicknesses <-2SD. 26 of the children had kidneys of normal size with or without parenchymal reduction, 13 one small and 1 two small kidneys at initial investigation. At last investigation 21 children had one small kidney and 7 two small kidneys. Before puberty the investigation was performed at an age of 9.3:s years and after puberty at an age of 16.6:s years. Table 1. Changes of renal size of the smallest and the contralateral kidney in children before and after puberty in relation to initial renal size (underlined). Smallest kidney Contralateral kidney n=10 Before pub. -0.2+0.3 0.1:s After pub. -1.6+0.3" -0.6+0.4 Kidnevs of normal size with oarenehvmal reduction n=16 Beforepub. -1.3:s 0.1:s After pub. -2.6+0.5** -0.7+0.3 One Small kidney + parenehvmal reduction n=13 Before pub. -3.9:s 0.0-L-0.5 After pub. -5.6+0.6* -0.1+0.6 Two small kidneys + narenchvmal reduction n=l Before pub. --4.0 -3.6 After pub. -9.1 -7.6 In conclusion there was a further decrease in renal size of the small kidney and no significant change in size of the contralateral kidney during puberty. Deps of *Pediatricsand **Radiology,KarolinskaInstitute,HuddingeHospital,Sweden

IMPORTANCE. OF 99mTc-DIMERCAPTOSUCCINIC ACID SCANNING (DMSA) IN THE DIAGNOSIS OF PYELONEPHRITIS (P) IN CHILDREN. P. Pecile*, E. Bizzarini*, C. Romanello*, A. Tenore*. Although the frequency of urinary tract infections(UTl) in children is second onl> to upper respiratory infections they frequen@ go unrecognized. In those diagnosed, only a limited fraction is subject to appropriate investigation and foUow-up. Recent evidence suggests that children with focal renal lesions from P are at high risk for developing long term complications. Since renal scanning with DMSA is considered the exam of choice .for diagnosing P but is not part of the pediatrician'~ armamentarium, the aim of the study was to see whether aspecific clinical and laboratory indicators of the inflammatory process correlated with DMSA and could aid the pediatrician in making the correct diagnosis and plans for follow-up. The initial study group consisted of 80 subjects with UT! studied with DMSA; however, only 59 were utilized becaase of completeness of inflamraatory indices. The 59 children (43F) were all in the course of their first UTI; 57% were 39~ number of days offever prior to treatment and presence of vesicoureteral reflux. Each variable was evaluated individually and by stepwise multivariate discriminant analysis. DMSA + studies were found in 34/59(57.6%) of the patients with laborator> evidence of possible upper UTI. Except for age, no significant differences wer~ observed in any of the variables studied between DMSA + and negative patients. The mean age (27.3 months) of DMSA + patients was significan@ greater than that q DMSA negative patients (12.8 mos; p
P200 URINARY TRACT ABNORMALITIF.S IN NEWBORNS : UTILITY OF RENAL SCINTIGRAPHIrC STUDIES .ORELLANA P,BAQUEDANO P, CAVAGNARO F, LAGOMARSINO E, GARCIA C , OLEA E, IGLESIAS M AND EBENSPERGER E. Urinary tract abnormalities (UTA) are common in newborns and they need a correct diagnosis and treatment in order to prevent complications and preserve renal function and this is mostly based on the diagnostic imaging studies. The aim of this study was to evaluate retrospectively the role of renal scintigraphy ORS) in 34 newborns, aged from 1 to 30 days old, who had antenatal and/or postnatal ultrasanographic diagnosis of UTA. In 11 patients (32.2%) RS was performed during the first week of life. Diuretic renography with Tc99m DTPA or MAG3 was done in 26 newborns, static RS with Tc99m DIVISAin 21 and both studies in 15. Fourteen patients (41.2%) had scintigraphic renal exclusion (SRE), that was bilateral in one case due to acute renal failure secondary to hipoxia. The 13 cases of unilateral SR.E corresponded to multicystic dyspinstic kidney in 7 and hydrenephrosis in 2.Nine out of this 14 newborns (64%) were diagnosed antenatally (KID) . Seven kidneys in 4 newborns had a significant compromise of global or relative renal function. In 9 newborns an obstructive pattern was observed, without lasix response and they corresponded to ureterepelvic junction obstruction (UPJ) in 8, ureterecele in 1 and posterior urethral valves in 1. In 5 newborns pyelocaliceal stasis was seen with normal lasix response, obstructive uropathy was ruled out in 3. In one newborn, a diuretic renogram done at the age of six months demonstrated a worsening in the lasix response and UPJ obstruction was found at surgery. In one patient with posterior urethral valves, the seintigraphic study was equivocal. In our exprinc RS gave us qualitative and quantitative information related with renal function and excretion, both vry important in the diagnosis and managment of UTA in the newborn. Due to the high incidence of renal function compromise at the time of the diagnosis (52.9% in our serie), early evaluation and treatment is important in order to avoid progression of renal damage. RS is a safe method, without contraindicatians, that uses low radiation doses and is easy to perform in newborns. Its diagnostic accuracy increases significantly when it is used in conjunction with other diagnostic imaging studies, mostly ultrasenography. Factors like prematurity, low weight, age or the presence of bilateral UTA do not seem to affect the correct interpretation of renal scintigraphic studies.

NUCLEAR MEDICI., UROLOGY, PEDIATRICS AND RADIOLOGY. FACULTY OF MEDICI.. CATHOLIC UNIVERSITY OF CHILE.

P201

LOCATION OF URINARY TRACT INFECTION (UTI): A COMPARATIVE STUDY BETWEEN THE WASH - OUT TECHNIQUE 9 DMSA - 99mTc SCAN E.B.Guidoni*,M.M.R.Chinelato*,L.Mimica**,l Mimica**, M.Marone***J.Toporovski*

Acute pyelonephritis (APN) may lead to detedoration in renal function and hipertension, particulary on the first year of life. Seventeen gids, aged to 10 year median age fulfilling the cdteda of UTI ( positive udne culture) Wash-out techinique was performed on admission together with DMSA - 9 9 m T c scintigraphy and after 6 months under control. We compared the wahs - out results in children which correleted with the results of DMSA Tc. W e observed positive wash - out (APN) in 5/17 (29%) which low uptake in DMSA Tc. All patients with APN, but one,presented DMSA scare after 6 months under control. In conclusion, we found that DMSA Tc is a sensitive marker of APN in children more than years of age. *Depto. de Pediatda; ** Depto. de Microbiologia - Santa Casa de S,5o Paulo - Brasil. ***Servicto de Medicina Nuclear - Fund. Amaldo Vieirera de Carvalho - S~o Paulo - Brasil.

C 105 P202 PRE-NRTAL HYDRONEPHROSIS; A R E V I E W ~F 67 C A S E S F. R a m i r e z - S e l j a s * , A. C e p e r o - A k s e l r a d * , C. L a n k a u * Pre-natal sonography (PS) h a s b e c o m e the most c o m m o n diagnostic method in congenital urinary anomalies, enabling early diagnosis and treatment. We reviewed retrospectively all p t ~ s r e f e r r e d to o u r division with the diagnosis of pre-natal hydronephrosis from. 1 9 9 0 1994. Of 67 infants, 41 (61%> w e r e m a l e s and 26 (39%) f e m a l e s . Renal U / S VCUS, and r e n a l s c a n w e r e o b t a i n e d , and findings w e r e c o m p a r e d to t h e P S for c o r r e l a t i o n . When obstruction was suspected, a diuretic renogram, renal doppler and resistive indices were performed. Post-natal diagnosis r e v e a l e d : U.P.J.!: o b s t r u c t i o n 3 0 (45%), V.U. r e f l u x 10 (15%), P o s t e r i o r U r e t h r a l V a l v e s 10 (15%), U.V.J. obstruction 8 (12%), Multicystic k i d n e y s 4 (6%), D u p l i c a t i o n 3 (4%), U r e t e r o c e l e i (1%), Normal I (1%). The post-natal sonographic findings correlated with the P S f i n d i n g in 4 7 c a s e s (70%), no correlation in 2 0 (30%). T r e a t m e n t c o n s i s t e d of ureprophylaxis in 5 3 p t ' s <79%) a n d s u r g e r y in 14 (21%). The i n d i c a t i o n f o r s u r g e r y w e r e r e c u r r e n t U r i n a r y T r a c t Lnfection in e v i d e n c e of significant obstruction by d~u~etic renogram and h i g h r e s i s t i v e i n d i c e s by r e n a l doppler 9 P S is a useful diagnostic method for e a r l y detection and t r e a t m e n t of c o n g e n i t a l urinary anomalies. Diagnosis must be confirmed by post-natal sonogram since its correlation with PS remains low. Most pt's are successfully managed by conservative medical therapy. Surgery is r e s e r v e d for those with r e c u r r e n t U T I ' s and s i g n i f i c a n t obstruction. Management of t h e s e pt~s require a team approach by e x p e r i e n c e d nephrol~gists, radiologists, and surgeons. *

Division'of Pediatric Nephrology and Surgery, M i a m i C h i l d r e n ' s H o s p i t a l ~ Miami, FI. U S A

P204 EVALUATION OF VESICOURETERIC REFLUX IN FEMALE CHILDREN WITH URINARY TRACT INFECTION BY DIRECT RADIONUCLIDE CYSTOGRAPHY D.Kuzmanovska *,V.Tasich *,E.Shahpazova*,N.Ivanovsld** Radionuclide cystography (RC) is preferable method for detection of vesicoureteric reflux (VUR) because of lower radiation dose. The disadvantage is nonvisualisation of urethra. There are no significant abnormalities of the female urethra, so we can use RC in evaluation of female children with L~I'I. Over a six year period, radionuclide cystography was performed in 500 girls with UTL %~;R was demonstrated in 131 of them (27%) in 162 nephroureteral units (NU).Using the criteria for grading as established by international Reflux Study Committee (IRSC) itwas graded as II grade in 71 NU, III grade in 65, IV grade in 25 and V grade in 1 NU respectively. Reflux drenage time was estimated in 71 children with VUR in 91 nephroureteral units. In 31 N U it was under 2 min, in 19 NU between 2-5 rain. and in 41 NXY it was longer than 5 ndn. In the same group, intrarenal reflux (IRR) was evaluated by use of Tc99m sulphur coloid. It was demonstrated in 38 kidneys, 64% of them had RDT longer than 5 rain. Nowadays, it is generally accepted that VUR shoud be placed not only in relation to grade, but to the other factors like age, state of proximal urotracL presence of IRR, clinical histoo', familial and social situation. In our experience, RC in combination with other methods allows adequate management. Our current policy in female children with urinary tract infection is to use direct radionuclide instead o f rentgenologic cystography. * Pediatric Clinic, Medical Faculty, Skopje, Macedonia ** Department of Nephrology, Medical Faculty, Skopje, Macedonia

/'203 DIAGNOSTIC IMAGING STUDIES IN CHILDREN WITH THE F I R S T URINARY TRACT INFECTION T h w a k h u p t P ,Rajchadara S ,Chulamokha Y , Vanapruks V* and Chaiopanont S* We designed a prospective study to evaluate the results o f diagnostic imaging in children with first urinary tract infection. From February 1993 to January 1995,50 children 1week to11 years of age (median 6 months) with urine culture positive for pathogen in Pramongkutldao Hospital were studied.99mTc- DMSA scan and ultrasonography were performed in all patients in the first week of disease to detect renal parenchymal lesions. DMSA scan showed renal changes in 25 children (50%) and ultrasonography showed renal changes in 11 children (22%) (P<0.005). In 27 children with clinical symptoms suggested pyelonephritis, renal changes were detected in 21 (78%) and 10 (37%) by DMSA scan and ultrasonography respectively. In 8 children with clinical symptoms suggested cystitis, neither DMSA scan nor ultrasonography showed renal changes. The site of infection could not be determined clinically in 15 children.4 o f them had renal infection detected by DMSA scan, and only one children had abnormal renal ultrasonography. For evaluation of the urinary tract voidingcystourethrogram was done after the urine was sterile in 41patients. 19(46%) were found to have urinary tract lesions including vesicoureteric reflux in 9 (22%). Because of a large number of urinary tract abnormalities in children with urinary tract infection, we placed emphasise on the necessity of diagnostic imaging studies in children with the first urinary tract infection. Cortical scintigraphy should be added to the initial investigation because it is more sensitive than ultrason0graphy in detecting renal parenchymal lesions. * Department of Pediatrics ** Department of Radiology, Pramongkutkla~ College of Mcdicme, Bangkok, THAILAND

P20S RENAL PATHOLOGY IN PATIENTS WITH URETEROPELVIC JUNCTION OBSTRUCTION TREATED BY SURGERY M.S.Bmwn, R.Charrois, M.Lemay The indication for surgery in patients with uretempotvic junction (U.P.J.) obstruction remains contmversal and a more conservative approach has become the norm. Improving radio isotope tests and decreasing hydronephrosis with time apparently justify this approach. However no renal histok~ic data are available. Renal tissue was obtained in patients (34) undergoing pyeloplasty (32) or nephrectomy (2) for U.P.J. obstruction over a four year period. Most patients (28) were evaluated and operated on in the first year of life (Group A) but 6 patients were initially seen after 5 years of age (Group B). In group A, 6 patients has cortical anomalies and 3 patients had medullary anomalies. In group B, 2 patients has cortical anomalies and 1 patient had medullary anomalies, In group A, 12 patients had hydronephrosis detected by sonography before 20 weeks gestation including 5 with cortical anomalies and 2 with medullary anomalies. Sonogrephy detected hydmnephmsis after 30 weeks gestation in 6 additional infants an~l 1 patient had cortical changes and another had medullary changes, 2 patients with bilateral disease had cortical anomalies. In conclusion, 12 of 34 patients with U.P.J. obstruction had pathological changes including cortical cysts, interstitial fibrosis, chronic inflammation and medullary fibrosis. Many patients had no medullary tissue on biopsy and medullary changes were probably under estimated. Early detection in pregnancy of foetal hydronephrosis especially if bilateral suggests the possibility of renal tissue anomalies. The post-natal evaluation of U.P.J. obstruction should take into account the duration of the obstruction and the possible surgical reversal or stsbilisation of any pathological change already present in the kidney.

C 106 P206

P207

UROLOGICAL DYSFUNCTION AND DIASTEMATOMYELIA Valeutino L., Conforti R., Avino G., Majorana M., Straface A., Orbinato F., Magri D. and Lama G. Diastematomyelia is a congenital dysraphism of the spinal cord in which the affected segment is longitudinally divided by a band of fibrous tissue, cartilage or bone. Diastematomyelia has been well described in the cervical, thoracic, lumbar and sacral spinal cord, but there are few informations about voiding dysfunction associated. We present a clinical ease involving lumbar and sacral spinal cord of a male patient of one years old that was referred for hydmnephrosis. Evaluation included history and physical examination, urinalysis and urine eolture, renal ultrasonography, cistography, urodinamie evaluation, Magnetic Resonance Imaging (MRI) and Computerized Tomography (CT). The patient had a normal physical examination as well as urinalysis and urine eolture. The cystography shown bladder diverticulum suspecting for a neurogenie bladder. The children underwent to neurologic examination had any neurologie sequela but the subsequent urodynamic studies revealed detrusor hyperreflexia with voiding difficulties. The MRI and the CT confirmed the diagnosis of diastematomyelia in lumbar spinal cord divided by a band of fibrous tissue. In patient with spinal dysraphism the urodynamic studies, therefore, may provide the only evidence for neuroiogic injury involving the lower spinal cord. We reccommend the urological follow-up of patients with hydronephrosis particularly if initial evaluation reveals any evidence of abnormal urodynamic finding or if new neurological or voiding symptomatology develops. Department of Pediatrics II University Naples Italy

UNUSUAL COMPLICATIONS OF CIRCUMCISION M. B e l k i e r * , P . M . Livne* In spite of intense controversies, circumcision continues to be the most frequently performed operation in the world. In our country almost 100% of the male population is circumcised and the vast majority of them from religious reasons (jewish ~nd moslem). Most of circumcisions in Israel are not performed by a Medical Doctor, but by the Mohel (jewish) or Motaher (moslem), that are religiously and technically prepared. Maybe related to this fact is a relatively high rate of complications up to 29% in some series. Bleeding - with or without hematoma - is the most common complication. Infection and dehiscence of the wound is also frequent and may rise the need for a late repair. Some examples of those complications are presented but we would like to emphasize 2 very unusual complications of circumcision. First, 2 cases of concealed penis, that results from inadequate and excessive removal of inner preputial skin and shaft skin during one or more circumcisions , and development of a concentric annular cicatrix. A formal penoplasty allowed us to achieve very good functional and cosmetic results. Second, 3 newborns with resection of a part of the glans penis including the d i s t a l p o r t i o n of the urethra. In these cases, the instrument used to cover and protect the glans failed to prevent this complication. In these cases our efforts were dedicated to keep the nee-meatus open and patent by repetedly introducing the tip of a 6 French catheter into the penile urethra.. We are deeply convinced that a high professional level will improve the results of circumcision and prevent complications, in places where this operation is a rutine procedure, even during adolescence and adulthood. Dept. of Urology - Rambam Medical Haifa - ISRAEL

P208 HIGH CUTANEOUS URETEROSTOMY M. Bolkier*, P.M. Livne* Primary reconstruction versus satisfactory drainage is a classic controversy that moved in the last years in favor of reconstruction. During the last iO years we performed high cutaneous ureterostomy in 14 children. All but one were males, and age ranged from 8 days to 18 months. The indication for diversion was an extreme dilatation of the collecting system together with renal failure and or urosepsis, caused by a lower urinary tract congenital anomaly. In ii cases diversion was performed bilaterally: 6 boys had posterior urethral valves, 3 children had primary vesicoureteral reflux, and 2 had neurogenic bladder and secondarY reflux. Catheterization of bladder and in one case vesicostomy were performed in the valves patients before ureterostomy With no success. 3 children with high grade reflux and severe urosepsis underwent unilateral diversion. In most of the cases we performed a loop high cutaneous ureterostomy with the most proximal ureteral loop. In 2 cases a Sober cutaneous ureterostomy was performed. Complete reconstruction of the urinary tract was done in two stages: a) treatment of the underlying disease (fulguration of valves, ureteral reimplantation for reflux, bladder augmentation and ureteral reimplantation); b) undiversion at a period from 16 to 39 months after ureterostomy. From a total of 12 children with moderately to severe renal failure, a categoric improvement was achieved in i0, with normal levels of creatinine. 2 cases remained with high creatinine levels, one of them developed end stage renal failure and was successfuly transplanted. 2 cases were with normal creatinine levels before and after diversion, in one boy surgical revisipn was necessary of his Sober ureterostomy due to obstruction. In our opinion, cutaneous ureterostomy can be a satisfactory treatment in children,in selected cases of a distal anomaly, where severe infection, obstruction and renal failure are present in different combinations. Dept. of Urology Haifa - ISRAEL

- Rambam Medical

Center

Center

C 107 POSTER

SESSION

- 0P) - A c u t e R e n a l F a i l u r e

P210

P209 PREVAI.RNCEOF NOHOLIGURICANDOLIGURICACU'f~REHAL FAILURE IN SKVERELYASPHYXIATED FULL-TE-BHNEONATES. H.G. Karlowlcz, R.D. Adelman, Eastern Virginia Medical S c h o o l , Department of Pediatrics, Norfolk, VA, USA. Objective: To determine the prevalence and types of acute renal failure in asphyxiated full-term neonates and to evaluate the accuracy of an asphyxia morbidity score in predicting acute renal failure. Design: Neonates adm• to one institution from 1990 through 1993 with a gestational age ~ 36 weeks and five minute Apgar score ~ 6 without congenital malformations or sepsis were studied retrospectively for occurrence of acute renal failure in the first week of life. Acute renal failure was defined as serum creatinine > 1.5 mg/dL (133 micromol/L) with normal maternal renal function. Nonoliguric renal failure was defined as renal failure with urine output > 1 cc/kg/hr after the first day. An asphyxia morbidity scoring system was used to distinguish severe from moderate asphyxia. The score ranged from 0 to 9 and was based upon fetal heart rate, Apgar score at five minutes, and base deficit in the first hour of life. The score for severe asphyxia was defined as 6 to 9 and for moderate asphyxia as I to 5, Results: Sixty-six neonates fulfilled study criteria. Acute renal failure was present in 20/33 (61%) infants with severe asphyxia scores and 0/33 with moderate asphyxia scores (P < 0.0001). Acute renal failure was nonoliguric in 12/20 (60%), oliguric in 5/20 (25%) and anuric in 3/20 (15%). Conclusions: i) acute renal failure occurred in 61% of infants with severe asphyxia, 2) acute renal failure associated with severe asphyxia was predominantly nonoliguric and 3) an asphyxia morbidity score, which can be determined at one hour of age, predicted acute ~enal failure in fullterm infants with 100% sensitivity and 72% specificity.

FUNGAL ENDOTOXIN, [~-D GLUCAN ([~DG), INDUCES GLOMERULAR ENDOTHELIAL INJURY BY STIMULATING FREE RADICAL PRODUCTION. N. Iwamoto*, K. Ito*, Y. Tsunoda*, K. Nitta**, M. Hattori*, H. Kawaguchi*, T. Yoshioka*.

Purpose and Methods: [~DG, polymers of fungal cell wall has been shown to cause vasculitis. Recently, we reported a case of renal microangiopathy associated with systemic candida albicans infection (Pediatr. Nephrol., in press). In the present study, we investigated if [~DG induce free radical production and cellular injury in glomerular endothelial cells (GEC). Free radicals released from cells were trapped by 5, 5'dimethylpyrroline-N-oxide, and were quantitated by an electron paramagnetic resonance (EPR). LDH released from GEC was also determined. Radical release LDH release Results: Average (nmol/lO 7 cells) (u/IO 7 cells) values for free Treatment (n=4-8) 1 hr 3 hr 1 hr 3 hr radical production 13DG:460 pg/ml 3.23* 1.69" 286 596* by GEC treated with 230 2.10" 1.69" 171 211 [~DG for 1 or 3 Vehicle 0.00 0.00 139 181 hours were sigrfificantly (* p<0.03) higher than those treated with vehicle. The EPR spectrum analysis confirmed that those radicals were hydroxyl radicals. When superoxide dismutase (30 u/ml) was added, no radicals were detected in [~DG-treated GEC. Thus, specific radicals released by the GEC were superoxide. LDH release increased significantly at 3 but not at 1 hour, when free radical productions were already detected. Conclusions: ~-D glucan stimulates superoxide production and induces cellular injury in glomerular endothelial cells. This injurious effect of I~-D glucan is a novel mechanism of renal microangiopathy and may constitute pathophysiology of systemic fungal infections. Depts. of Pediatric Nephrology* and Medicine IV**, Tokyo Women's Medical College, Tokyo, Japan.

P212

P211 PROGNOSIS OF r.HII)REN WHO DEVELOP ACUTE RENAL FAILURE ( A R F ) FOLLONING CARDIAC SURBERY (~3) N. Gallego,

R. Estepa,

SA. Ballego,

SSR.G6mez,

$$P. D i a z , F . L i a ~ o , O . O r t u ~ o

Mortality of children with ARF f o l l o w i n g CS remains h i g h in s p i t e of t h e development of now techniques. T h e r e f o r e we t r i e d t o e s t a b l i s h an e a r l y p r o g n o s i s and v a l i d a t e i t . Data from 58 cases w i t h ARF a f t e r CS ~mre p r o s p e c t i v e l y c o l l e c t e d (Median age=12 manths, 42 males and l& f e m a l e s ) . Mortality was 53%, 47 underwent open CS and 11 closed CS. We analyzed:Age ( 1 month), C o m p l e x i t y of heart disease, aortic cross clamping t i m e , b y pass t i m e , e a r l y onset o f ARF t=<48h a f t e r CS), h y p o t e n s i o n , need f o r v e n t i l a t o r y support (VS) and f o r dialysis, Blood urea n i t r o g e n , serum c r e a t i n i n e and d i u r e s i s < o r > l m l / K g / h , by m u l t i p l e regression analysis. Age <1month, need f o r VS and e a r l y onset o f ARF (EOARF) c o r r e l a t e d p o s i t i v e l y with mortality, while diuresis >lml/Kg/h d i s m i n i s h e s Death p r o b a b i l i t y (DP). DP can be c a l c u l a t e d by an equation: DP= 0 . 3 + 0 . 2 (age1 m l / K g / h . Presence or absence o f t h e v a r i a b l e s was scored as 1 or 0 r e s p e c t i v e l y . 0 . 3 i s a c o n s t a n t . In a v a l i d a t i o n phase, we p r o s p e c t i v e l y a p p l i e d t h i s equation t o 40 new cases, c o n f i r m i n g a h i g h accuracy f o r e a r l y p r o g n o s i s . Department of Nephrology, t i P e d i a t r i c Cardiology Unit (Hospital Ram6n y C a j a l ) gDepartment of Genetics ( U n i v e r s i d a d Complutense)Madrid.Spain.

ASSES~IF_~IT OF I~DNEYCONCEN'r~llNG ABLIW: A CLUE FOR BAGNO6B OF ACIJllE RENALFAILUREAFTER~ SURGERYINCHILDREN. P.C.K. Nogueira*, J.T.A. Carvalhaes*, D.M. Abellan. This is a clinical thai aimed for assessing kidney concentrating ability as a clue for the diagnosis of acute renal failure (ARF) following cardiac surgery in 39 children (19 boys and 20 gids). Renal ischemia is the main determinant of ARF in this setting and there are many evidences that renal medulla exhibits a remarkable susceptibility to ischemic damage, Renal function was assessed once before the surgery and twice after. Clearances (oreatinine and free water) were determined only in postoperative (PO) pedods. Main results are depicted below:. GROUP WITHOUT

MODERATE

SEVERE

PO

ARF

ARF

ARF

PARAMETER

DAY

(n = 28)

(n : 7}

(n = 4)

CREATININE CLEARANCE mlJminll.73m2 FREE WATER CLEARANCE ml/n/1.73m2 URINE OSMOLALITY mOsm/kg OSMOLAL RELATION

1aT 2ND 1ST 2ND 1ST 2ND 1 ST 2ND 15T 2NO

1(:~ + 46 79+58 16+10 1C0• 30 62• 7• - 1OD+62 - 88 • -13+6 -77• - 5 8 • 34 -7+6 623 • 170 551 • 138 412 • 70 572• 500+151 391 • 2.2 + O.6 1 .g • 0.5 1.3 • 0.4 2.1 +0.6 %8+0.8 1,2 • 0,3 FEH20 1.8• 27+20 5.6+4.8 1.4 • (~6 2.9• 7,2• * Statistical significant differenceaccordingto Kruskal-Wallis analysis of variance(I <> Ill)

p 0.002* O.0(X)4* 0.0~* 0.0033 * 0.035 * 0.06 0.0~) * 0,010" 0.502 OD01 *

There were 4 cases (10.25%) of severe ARF (creatinine clearance < 30 mllmin11.73m 2 for the 2 PO days) and 7 (18%) of moderate ARF (creatinine clearance < 50 ml/min/l.73m 2 for only 1 PO day). Two patients from the severe ARF group died. Regarding the diagnosis of ARF, traditional parameters (dse in serum creatinine, BUN and oliguda) did not identify any case of moderate ARF. On the other hand, udne osmolality was the most sensitive test, allowing the recognition of all children with the complication, v~ereas Free Water Clearance (TCH20) recognized all children with severe ARF and only 2 with moderate form. All tests of kidney concentrating ability reached a strong and significant correlation With creatinine clearance, indicating progressive loss of urine concentration ability whenever glomerular filtration rate decreased. We conclude that kidney concentrating ability tests may be useful in the diagnosis of ARF after cardiac surgery in children. * Universidade Federal de S~o Paulo, Escota Paulista de Medicina, S~o Pauto, Brazil. 9 Institute do Corag~o, S~o Paulo, Brazil, w

C 108 P214

P213 URINARY RETINOL-BINDING PROTEIN (RBP) IN ACUTE RENAL FAILURE AFTER CARDIAC SURGERY IN CHILDREN.

P.C.K. Nogueira*, J.T.A. Carvaihaes*~ Pereira, A.B*., D.M. Abe,an. Retinol-binding protein (RBP) is a low molecular weight protein (MW = 21000 d) freely filtered at the glomerulus and then reabsorved by the proximal tubule. In acute renal failure serum level of the protein is elevated due to reduced filtration, whilst urinary RBP increases as a result of impaired tubular uptake. This is a clinical trial aimed for assessing udnary RBP as a clue for the diagnosis of acUte renal failure (ARF) following cardiac surgery in 39 children (19 boys and 20 girls). RBP was assessed once before the surgery and twice after using a monodonal antibody-based immunoenzymometic assay. Creatinine clearance was determined only in postoperative (PO) pedods. There were 4 cases (10.25%) of severe ARF (creatinine clearance < 30 mllmin/1.73m 2) and 7 (18%) of moderate ARF (creatinine clearance < 50 ml/min/1.73m2). Results are expressed as the relation between RBP:unnary creatinine (pglmmol) and are depicted below PO DAY

WITHOUT ARF

GROUP MODERATE ARF

SEVEREARF (n = 4)

In = 2S] In=7~ p CREATININECLEARANCE 1ST I(36+46 79• 16+10 0.(X~* mlhnin/1.73m2 2ND 100+30 62+31 7• 0s RBP:urinaryoreatinine 1ST 35+73 17• 4142• 0.7247 pg/mmol 2ND 12 + 2B 4+6 5840+ 10~37 0.1221 * Statistical significantdifferenceaccordingto Krus~l-Wallis analysisof variance(I <> III) Before the surgery all values of RBP were in the normal range (< 174) for the age. Concerning the diagnosis of acute renal failure, RBP excretion yielded the recognition of 3 from 4 (75%) cases from severe ARF group. Contrasting, it did not identify anyone from the moderate ARF group. This is probably due to the fact that tubular reabsortion of RBP takes place in the first segments of proximal tubule ($1 and $2), which are considered relatively resistant to isquemic lesions, in oposifion to what occurs with structures located in renal medulla, which exhibit a market vulnerability in this setting. According to this point of view it is probable that udnar3 RBP is increased only when extensive tubular damage occurs as is the case ir severe ARF. We conclude that udnary RBP may be useful for the diagnosis of severe ARF, bu it may not work in less intense tubular damage. PARAMETER

ACUTE RENAL AND HEPATIC FAILURE ASSOCIATED WITH PARVOVIRUS B19 INFECTION MH Said, R Bouvier, A Calvet, A Mahmoud, A Lachaux, H Pinar, S Colon, P Cochat Unit6 de N6phrologieP6diatrique, h6pital E Herriot, Lyon, France Acute renal and hepatic involvement has not been reported in human parvovirus B19 infection. A 14 year-old girl presented initially (day l) with dysenteric syndrome, febrile rash, anemia (Hb 98 g/L) without hemolysis nor thrombopenia, acute hepatitis and acute renal failure requiring transient hemodialysis (day 3). A renal biopsy was carded out on day 8 and revealed acute tubulointerstitial nephritis with mild mesangial IgM deposits on immunofluorescence examination; no viral particles was detected on electron microscopy examination. Because of intense and persistant eholestasis and cytolysis without hepatic insufficiency, a liver biopsy was performed on day 21 that revealed centrolobulary cholestasis and mild inflammatory. Bacterial screening was negative. Antibodies against parvovirus (IgM and IgG, ELISA method) were found with significant titers. Unfortunately in situ hybridization was not available. Two years later, the GFR (inulin clearance) was 86 ml/min/1.73m2 and there was a mild proteinuria (0.25 mg/24h); liver function tests were normal. Although the virus was not directly detected in renal nor hepatic cells, parvovirus B19 is the most likely causative agent in this patient on the basis of clinical/biological presentation in association with specific serological tests.

, Universidade Federal de S~o Paulo, Escola Paulista de Medicina, S~o Paulo, Brazil. 9 Instituto do Cora~o, S~o Paulo, Brazil. 10

P216 INCREASED PLATELET RETENTION IN CHILDHOOD FAMILIAL R E C U R R E N T THROMBOTIC THROMBOCYTOPENIC PURPURA:

EFFECTIVE TREATMENT WITH FRESH FROZEN PLASMA AND FACTOR VIIINON WILLEBRAND FACTOR CONCENTRATE D. K a r p m a n * , L. Holmberg*, L. Jirg~ **, S. Lethagen** W e s t u d i e d t w o b r o t h e r s (8 a n d 6 y e a r s old) w i t h r e c u r r e n t t h r o m b o t i c t h r o m b o c y t o p e n i c p u r p u r a (TTP). P l a t e l e t r e t e n t i o n , m e a s u r e d w i t h a modified A d e p l a t S g l a s s - b e a d test, w a s f o u n d to be i n c r e a s e d d u r i n g a c u t e e p i s o d e s of T T P a n d d u r i n g r e m i s s i o n s . V a l u e s of p l a t e l e t r e t e n t i o n r a n g e d b e t w e e n 57-95% ( n o r m a l r a n g e : 16-34%). T h e c o n t i n u a l l y e l e v a t e d v a l u e s e n a b l e d u s to i n v e s t i g a t e w h i c h f r a c t i o n o f t h e p a t i e n t s ' blood w a s r e s p o n s i b l e for t h e i n c r e a s e d p l a t e l e t r e t e n t i o n a n d to e v a l u a t e t h e effect o f d i f f e r e n t t r e a t m e n t s on t h i s p a r a m e t e r . W e f o u n d t h a t t h e p a t i e n t s ' p l a s m a i n c r e a s e d t h e r e t e n t i o n of n o r m a l p l a t e l e t s a n d of p l a t e l e t s t a k e n f r o m a p a t i e n t w i t h v o n W i U e b r a n d ' s d i s e a s e t y p e III. T h i s activity w a s l o c a t e d i n t h e c r y o p r e c i p i t a t e f r a c t i o n of p l a s m a . U n u s u a l l y l a r g e y o n W i l l e b r a n d factor (vWF) m u l t i m e r s w e r e d e m o n s t r a t e d i n b o t h c h i l d r e n d u r i n g r e m i s s i o n a n d d e c r e a s e d d u r i n g relapse. B o t h fresh frozen plasma (FFP) and a commercial factor VIII/vWF concentrate reduced platelet retention when tested during r e m i s s i o n . T r e a t m e n t of b o t h siblings w i t h F F P or factor V I I I / v W F c o n c e n t r a t e w a s beneficial d u r i n g recurrences. W e conclude t h a t t h e e l e v a t e d p l a t e l e t r e t e n t i o n is d u e to a factor i n t h e cryoprecipitate of the childrens' plasma and that both FFP and factor VIII/vWF c o n c e n t r a t e a r e effective in d e c r e a s i n g platelet retention.

* Department of Pediatrics, Lund University, 22185 Lund, Sweden. D e p a r t m e n t o f C o a g u l a t i o n Disorders, U n i v e r s i t y of L u n d , M a l m 6 G e n e r a l Hospital, Sweden.

AUTOSOMALDOMINANTHEMOLYTICUREMICSYNDROME FurusawaEA*,KochVII*, Kim CA**, Fujimura MD*, Saldanha LB***,OkayY* Hemolytic uremic syndrome O-IUS) represents a heterogenoos group of ~sorders characterized by microangiopathic hemolytic anemia, thrombocytopania and renal invoh'caemt affectingpredominantly children. Familial HUS occurs rarely and its inherited form carries a worse prognosisthan clacsicalor epidemicHUS. We rvl~rt the case of a 4 year old female child who was admitled to our service with a history of fever, vomiting diarrhea and olignfia. On arrival the patient was dehydrated, seve~y hypertensiveand edematous. LabomtoD' evaluation showed hemolytic anemia, thrombocytopania and renal failure. A percutaneensrenal biopsywas performedwhich demonstratedmarked ntlerinlar involvement of HUS. The patient is the only child of a nonconsanguineunsmarriage, her father, paternal grandmotherand a cousin on her father's side died of hypertension,two paternal aunts had a previousdiagnosisof HUS. A comparativestudy of the renal biopsiesof our patient, her father and the two paternal aunts showed $imilm"bistologJcfindings. In conclusion, this is a patient with antosomal dominant HUS, this is a rare form of HUS with a poor long- term renal prognosis and peculiar aspects of genetic coen.~ng. * Servi;o de NefrologiaPedi~trica do Instilnto da Crienga do H.C,F.M.U.S.P. SAoPanlo- Brasil ** Servifo de Genr do ln~tuto do Crianfa do H.C.F.MU.S.P.- Sto Paulo- Brasil *** Servifo de AnatomiaPalolbgicado H.C.F.M.U.S.P.-Slo Paulo-Brasil

C 109 P217 GENOTYPIC PROFILES OF ESCHERICHIA COLI O157:H7 STRAINS F R O M PATIENTS W I T H OR WITHOUT CENTRAL NERVOUS SYSTEM COMPLICATIONS OF HEMOLYTIC UREMIC SYNDROME, N. Cimolal, A.C.H. Cheung, J.E. Carter, D.G. Mah, S. Basalyga, Department of Pathology and Laboratory Medicine, and Pediatrics, University of British Columbia, Vancouver, Canada We have previously defined several clinical variables which appear to be risk factors for the development of neurological complications of hemolytic uremic syndrome (HUS)(Pediatrics 90:61611992]). In the present work, we examined varied aspects of bacterial genotype of _E. coli O157:H7 strains which were isolated from patients with prototypic HUS and whose illnesses were or were not accompanied by central nervous system (CNS) complications. 51 isolates (11-HUS with CNS; 40-HUSwithont CNS disease) were acquired over the years 1983-1994. Plasmid DNA was extracted by a modified alkaline lysis method and individual plasmid content and plasmid profiles were recorded. Presence of verotoxin 1 (VT1) and verotoxin 2 (VT2) genotypes were determined by polymerase chain reaction (PCR). Verotoxin 2 subtyping was performed by PCR with GK5/GK6 primers and post-amplification endonuclease digestion for a subset (23) of more recent (1990-1994) strains, as was eaeA (attachment and effacement factor) genotyping. The gender distribution for patients with HUS was: CNS neg.-18 M/22 F; CNS pos.-2M/9F. Eight plasmid profiles were obtained and 4 patterns accounted for 90%; plasmids of 2,4,8,50,and 100 kh were identified in varied combinations. After correction for multiple comparisons, there was no association ofplasmid profile or any individual plasmid with neurological complications. VT1,VT2 and VT2 only genotype were present for 9/2 and 35/5 of strains for patients with and without CNS disease respectively. All strains were positive for eaeA amplification products. None of the strains had evidence of VT2v genotype. Given the variables which we examined, we did not find evidence for the association of bacterial genotype and the occurrence of CNS disease in HUS patients.

1'219 OUTBREAK OF HUS ASSOCIATEDWITH VEROTOXIGENICE COLI AND DRY FERMENTEDSAUSAGE. K.E JUREIDINI,P.H. HENNtNG,A. AL-ABBAD. S. KEELEY*, J.C. PATON#, A.W.. PATON#, O. Kainer+, Renal , Intensive Care* & Microbiology Units#, Women's& Children'sHospital,North Adelaide, South Australia 5006 and Dept. of Nephrology+,Prince of Wales Hospital, Sydney2000 During a period of 34 days, 2I children aged from 4 months to 12 years were admitted to the Women's & Children's Hospital with HUS. Consumptionof, or household contact with a locally produced semi-dry unpastearised fermented sausage (mettwurst)was documented in 18 who presented in the first 24 days. Faecal samplesfrom all but one of these werepositivefor Shiga-like toxin types I & II (SLT-I & SLT-II)by polymerasechain reaction (PCR) assay, SLT producingE cob belonging to serotype0111 was isolated from 14 of the cases, two of which also yielded a typeO 157 isolate. Anothercase yielded a SLT positiveE r isolate of a different serotype. SLT producingE coti of several serotypes,including Ol 11, have so far been isolated from samples of the sausage from six of the patients' homes. None of the patients consumed mcttwurst after its public recall. The subscquent 3 children (2 positive for Ol 11) had no history of ingestion or contact with mcttwurst. The tTfpicalpresentationwas extremelypainful, bloodydiarrhoea a mean 5 days after ingestion followedby the rapid onsetofHUS a mean4 days later. Dialysis was required within 2 days of onset of HUS. All children had daily haemodialysis. Three required a period of CVVHD. Parenteral nutrition was introduced at onset of dialysis. No other specific treatment was instituted. The mean period of dialysis was 14 days. One child aged 4 died on day 3 of HUS with multiple cerebral infarcts. Ten had a bizarre neurological syndrome with hallucinations for a mean of 4 days, four had seizures, one of whom developed reversible dense hemiplegia, four had prolonged hypcrglycaemia, five had severe bowel isehcmia, two reqnired bowel surgery. At the time of the abstract, 15 have been discharged with likely complcle recovery and five remain on dialysis, but are expected to recovergood kidney fonction.

P218 Effects on renal function by high dose chemotherapy (EIDC) and/or total body irradiation (TBI) before bone marrow transplantation (BMT)? P.a._t~_erLJ, RnisehnennF. ~,de Bror M3, MisselwitzJ. i, Zimme~hacklL.B?,BrandisM), ZinflFl BMT is nowadays an established element in the treaWaerJt of patients with different malignancies. We studied the renal status of these patievts before BMT and the inflmmce of ditfvrem conditioning regimes on tubular and glomerelar function. Patients and methods: We investigated 43 patients (mean age 13,1 years; 28m, 15~ before and aRer HDC and/or TBI, who underwent BMT for acute lymphoblastic leukemia (ALL, n=lS), acute non-lymphoblastic leukemia (AML, n=t2), chrmic myelogenousleukemia (CML, n=5) and others (n=8). Patients were divided into two groups according to their conditioning regime: Group A received TBI as the major myeloablative therapy; Group B was conditioned by HDC alone without TBI. Inulin clearance (GFR) and albuminuria for glomemlar function, Alpha-l-Microglobulin (AMG), N-Acetyl-B-Glucesaminidase (NAG), AlanineAmino-Psptidase (AAP), lntestinal-Alkaline-Phosphatase (IAP), fractional sodium excretion (FeNa) and maximal phosphate reabsorption (Tmp/GFR) for proximal tubular fimction and Tamm-Horsfall-Prutein(THP) for distal tubular function were analysed. Results: Before BMT proximal tubular function was frequently impaired indicated by elevated AMG (49% ofpatiems), NAG (62%), AAP (30,4%) and/or IAP (47%). Only two patients (5%) had a reduced GFR and 15% showed microalbumianria. There was no influence of the underlying diagnosis and/or the cumulative dose of ]fosfamid.After conditioning almost all patients (95%) showed moderate to severe pmxunal tubular disturbances(parameters increased up to 200-fold),but far less glomerular (4.8% with reduced G F R and 53.4 with microalbuminuria)and/or distal tubulardamage (25%). Group B was significantlym o w affectedthan Group A. Conclusions: The proximal tubulus isthe most susceptiblepart of the kidney in the settingof BMT. For monitoring kidney damage one should consequantlyinclude proxunal tubular parameters as A M G or NAG. H D C compared with TBI is significantlymore toxic in the acute period of BMT. Long term followup is needed to estimate the impact of acute tubular cell death to renal function in the long run. i Universityof Jeqa, Departmentof Pediatrics, ~ y 2 Universityof Antwerp,Departmentof Nephrology,Belgian 3UniversityofFreiburg,DepartmentofPediaUics,C-exmeny

P220

ACUIE RENAL FAILURE IN CHILDREN IN THE YEARS 1987-94 Lentk 3.,5ancewicz-Pach K.,Pietrzyk 3.3. All chlldren from the Cracow Province with acute renal failure (ARF) are referred to our Department of Nephrology. The aim of the paper was to evaluate the incidence, causes and course of ARF in children from the Cracow Province. A total of 2325 children were treated at the Department in the report period. This number included 50 children (35 girls and 15 boys) with ARF (2.15~). The youngest patient was 4 days old, and the oldest - 14.5 years of l i f e . Children below 5 years of age constituted 60~ of the entire treated group. The most common causes of ARF were hemolytic-uremic syndrome (HUS) (16t) and sepsis (16t), then surgical procedures, chemotherapy drug-related kidney damage and trauma. Twelve children were subjected to conservative treatment. Thirty-eight children were dialyzed. Twenty-five children (50~) died; out of this number 68~ children died before 3 years of age. The greatest mortality rate was noted among children subjected to cardiac surgeries (85~), with sepsis (75t) and with HUS (37~). The high mortality rate in ARF, especially in children below 3 years of age and in those subjected to cacdic surgeries nocessltates a thorough analysis of causes and development of preventing management. Polish American Children s Hospital Collegium Hedicum, 3agJeZZonian University Department of Pediatric Nephrology, Krak6w, Poland.

C 110 1)221

1)222

THE ROLE OF ENDOTOXIN AND SHIGA-LIKE TOXIN IN A MOUSE MODEL OF ESCHERICHIA COLI O157:H7 INFECTION D . K a r p m a n * , H.ConneH**, M.Svensson**, P~3m***, F.Scheutz****, C.Svanborg**

CLfiOSICALHAEBOLYTICUREffICSYNDROME(HUS)IN AROENTINEANCHILOREH: RESULTSAFTER10 YEARSOF FOLLON-UPANOPRUSNOSTICFEATURES F.Spizzirri~ S.Hahean, H.Gibilnni, J.Ruscasso, O.Asoreo I

Escherichia eoli 0157:H7 has been implicated in the development of hemolytic uremic syndrome (HUS). In order to evaluate the role of endotoxin and shiga-like toxin (SLT) in a mouse model uf Escherichia coli 0157:H7 infection, we inoculated endotoxin responder C3H/HeN and non-responder C3H/HeJ mice with bacterial strains that produced SLT-II (tox +) or did not produce SLT (tox -). The mice were inoculated with 107-108 CFU intragastrically. C3H/HeN mice inoculated with both tex + and tex - strains developed symptoms such as lethargy, anorexia, ruffled fur, shivering, tachypnea, hindleg paralysis, swelling and loose stools. Symptoms developed within 48 hours and in some cases caused death. More mice developed symptoms in the ~0up inoculated with the tex + strain as against those inoculated with the tox - strain (P<0.05). C3H/HeJ mice inoculated with a tox + strain initially developed symptoms such as weakness and ruffled fur from which most mice recovered within 48 hours. However, these mice developed severe neurological symptoms 120 hours after inoculation such as ataxia, rigidity and tremor leading to coma and death. In comparison to C3H/HeJ mice that were inoculated with the tex + strain, those inoculated with the t o x - strain did not develop symptoms (P=0.0002). When inoculated with the tex - strain, more C3H/HeN mice developed symptoms than C3H/HeJ mice (P< 0.05), no difference was found when the tex + strain was given to both groups. Bacteria were cultured from the blood of sick C3I-I/HeN and C3H/HeJ mice and fragmented red blood cells (RBC) were found in the peripheral blood film. Histepathological studies showed proliferation of giomerular mesangial cells and renal cortical inflammation in sick mice. These results suggest that both SLT and endotoxin are important for disease development in a mouse model of Escherichia coli 0157:H7 infection and thaL certain similarities to HUS were found such as fragmentation of RBC and glomerular changes.

since 1968 ne conducted a retrospective study of 118 patients (19~-198q),

*Departments of Pediatrics, **Clinical Immunology, ***Pathology, University of Lund, 22185 Lund, Sweden ****The Serum Institute of Denmark, Artillerivej 5, 2300 Copenhagen, Denmark

HUB i s a cain cause of acute renal f a i l u r e and the t h i r d cause of end-stage renal f a i l u r e (ESRF) i n c h i l d r o n ~ i n A r g e n t i n a . Aeong 600 cases of HU~seen

to evaluate their evolution after at least I0 years. All the patients, b~ buys and 55 girls ~ere under regular eedical revien, ffean follon-up .as 15b,1 eonths (l~ years). FOUREVOLUTIONPATTERNS at the end of the follo~up .ere found: l) Complete recovery (creatinine clearance (CC1})80 al/u/[.7~a2, normal blood pressure(OPt, no proteinuria (PRH: 75 patients (b~.bZ)- 2) Significant PR, norual CCI uith/eitheut high BP: 18 patienLs (15.2~)- ~) OhronJcrenal failure (CRF) (CC] ( 80 al/a/1.7~a2 and ) 5el/e/i.7~e2t: 21 patients (17.RZ)- 4) ERRF (CCI (Snl /ell.7~e2): 4 patients (~,4~). ge investigated the association betneen several variables of the acute stage and the long-term evolution, Fro| those uhich did nuL required peritoneal dyalisis (PO) (n=48)s 91.7~ recovered coapletely~ shale from42 children nho here under PD for 1-10 dave and 28 dyalized far more than 10 days~ complete recovery has achieved in 54.7Z and 32.1Z respectively (Chi Square for lineal trend p(O.O00Ol). Only 2 patienLs #ho did not requiredPD developed CRF, and one of thes was transplanLed. Free the cases eith significanL PR at 12 monthscontrol, 86.4Z had either CC1 (80~1 /e/l,73e2, and/or significant PN and/or hipertension in the last conLrol #bile only 2SZ of those nithout PR aL [2 aonths shoned Lhose findings (Ohi square p(O,OOOl). Ne did not found association betueen ]on CC] aL 1 year and functional renal sequelae at the end of follon-up (p=O.tb~). CONCLUSION: Ne determined that after more than 10 years of fallon-up of 118 patients nith classical HUR~43 (~6,44%) developed permanent functional sequelae~ 21 of thn CHF and 4 ESRF, fi close association was found hetueen the percentage of patients nith pereanenL functional renal sequelae at the end of follon-up~ the days that PO has reguired and the presence of PR at 12 uonths control afLer the acute episode, These appear to be prognostic parameters, ! RENOLUNIT - HOSPITALOE NIRUS - LA PLATA(ARGENTINA) 10

1)223

P224

LONG-TERM PROGNOSIS OF CHILDHOOD HAEMOLYTICUREMIC SYNDROME (HUS) Sieniawska M., Krzemiefl G., Grzesiowski P., Roszkowska-Blaim D.

IS "ERE0UTCOME0F HNM~YIE~ S I M H I E pIu@INCHLONENwlnf ~ I~IML ERIUJI~ p l ~ Blrr ~t~1t SloNBtoNI~ A Z O ~ G000 F 0WYSIS IS w n g I B ~ ? ED. THOMSON AND K.E.C. MEYER& DIVISION OF PAEDIATRIC NEPHROLOGY,UNIVERSITYOF THE WI1WATERSRANOAND JOHANNESBURGHOSPITAL, SOUTHAFRICA.

The aim of the study was to identify prognostic factors which have the most important significance for a long-term outcome of childhood HUS. Fifty three children with HUS, aged 1 month to 11 years were observed. Seven children had end-stage renal failure (ESRF) after the acute stage of the illness. Among 6 children who developed chronic renal failure (CRF) after the acute phase o f H U S 1 died of CRF aRer 1 year, 2 reached ESRF after 6 months and 5 years respectively, 2 have been observed for 18 months and 5 years without progression to ESRF, 1 has been lost to follow up. The remaining 40 patients have been followed for 4 to 19 years, mean 10 years 7 months. Poor renal outcome was seen in 10 (25%) children: 4 developed CRF and 2 hypertension (TIT) after 4 to 14 years of observation, and in 4 children HT and/or proteinuria have been lasting aRer the acute stage of the illness. All patients were divided into 2 groups: group I (n=30, 56.6%) was classified as having a good outcome: recovery without renal sequele; group II (n=23, 43.4%) as having a poor outcome i.e. ESRF (n--9), CRF (n=8), HT and/or proteinuria in patients with normal renal function (n=6). Eleven prognostic factors analysed in the short-term outcome (Pediatr. Nephrol. 1990, 4,213), were evaluated for a long-term prognosis. For statistical analysis multiple regresion was used, according to the logistic discrimination. Chi-square test was used to analyse the appropriateress of the fit in the model. Among 11 evaluated factors the most unfavourable significances were: HT persisted after resolution of fluid overload (p=0.009), anuria longer than 10 days (p=0.014) and age >12 months (p=0.134). After excluding 7 patients with ESRF after the acute stage of the illness only anuria longer than 10 days was significant. Prolonged anuria which had no prognostic significance in the short-term prognosis of the HUB in children, is a poor prognostic factor in the longterm outcome.

When 194 paediatricnephrobgistswere asked about their managementof HUB, the prime indicationto start dblyds was azotzemie,folkwed by hypertensionand anurie (S.L Schulmanand B.S. K|pien, Red. Res. Vol 33 No__Part2 April 1993 pg 365A). The same unit treated 4 HUB patients with N-ORF and profound azotaemia, who ware not dJalysed, but d~l well (9.L. Sclzu~mn et di. Unpublisheddata). We retrospectively analysed95 chikhenwith HU3 at our hospital from 1979 to March 1993. Twenty-five ware n~ldlyaffected re. renal function (scram cratiem (Cr) < 200 urno~ and were not die,rued. One other girl had recurrent HUS. The reminder, 69, dil bad significant renal thiiere (seem Cr. > 200wolff) and were grouped as follows: N Pa"ie9 > lm~g/nr of ume, or dialyzedbecauseof eliguM (< 0.3m~g/hd for B) <7 days (usuafly anurie for > 24 hours)or Q > 7 days (usually ununc for > 5 deW). The results of these 3 groups after at least 6 months follow up, are given in the fogowieg table:

University Children's Hospital, Warsaw, Poland

MEANS + $.D.

NUMBER MAXIMITM VALI~%$ FOR BLOOD LrREA (zz~ncl/]) S ~ U M C R E A T [ Z ~ (~mal~) LENGHT OF TI~E FOLLOW UP (YEARS) M O S T RECENT "qALrj~s: CALC. CRBAT, C L E A R A N C E (~t~n,l,73m~) BLOOD SYSTOUC pP,ESStr~ DIASTOLIC CHRO~C End-Jta~ RENAL FAILtrRE

OYg 9 2~ BUr < 7 ~ t ~ l , 7 3 m

2-TA~L.ED STUDE~ T 2-TAILED F~HER EXACT

A) NON-OLIGUR[C w r r H I~NAL FAILURE(SERUM CIREATINI~ > zee UMOIJL) B u r NOT DIALYZED

B) DIALYZF~D FOR LESS THAN 7 DAYS

C) DIALYZED FOR MORE TIIAN 7 DAYS

11 34.3+_.10.2 431,3 +~213,5

28 33.9+_.14~1 496_+215,9

30 32.14"i4.2 48t.1 ~1174,3

2,54+3,Q6

3.26+251

4.48+__3,64

ST,t+24,~

SO.O+2&1*

e4.6+_31.7'

97.1+7.6

101.4+_11,3

57.~+9.9"

6~,0+6,7'

0

0

10B,3+119,5

6S,2+_t3,~ 4 (tU k~t e ~ y

~

, C~B #A~C

< 0.009 < 0.037:

# A ~ B/C <0.035 B~C < 0.04~

Of the 25 mildly affected patients, aft recovered fully ucept for one patient who devdiopadmembmlmproliferative GN, The gadwith recurrent HUB died after the 4th reiepu. In the 69 pathmts,the usa of FFP, IV methylprednisilone,homo nor peritomml dialysis, did not mere to alter the outcome. Conclusion:Patientswith HUB causingsignificant azotaemb can be reneged without dialysis,as long as they are not oliguric, if dialysis is only required for < 7 days, the outcome is glen good.

Clll P225 DESIGN AND METHODOLOGY OF A RANDOMIZED TRIAL OF SYNSORB PK FOR THE PREVENTION OF HEMOLYTIC UREMIC SYNDROME (HUS). Rowe PC, Orrbine E, Armstrong GD, George A. Wells, McLaine PN, and the Canadian Pediatric Kidney Disease Research Centre (CPKDRC) - Synsorb Study Group, U. of Ottawa, Ottawa, Ontario. SYNSORB Pk, which consists of synthetic P blood group oligosaccharides attached to diatomaceous earth,binds with high affinity to Verotoxin-1 (VT-1) and VT-2 (GD Armstrong, J Inf Dis 1991; 164:1160-7). This randomized double blind placebo controlled trial was designed to determine whether SYNSORB Pk can prevent HUS in those with suspected verotoxin-producing E.coli (VI'EC) infection, or reduce the degree of renal injury in those with early HUS. Between 1 April and 30 November 1994, patients 6 months to 6 years with confirmed or suspected V'I'EC gastroenteritis were randomized to receive either SYNSORB Pk or a look alike, taste alike placebo. Both were mixed in baby food and doses were administered dependent upon body weight. Treatment was given BID for 7 days. Blood and urine samples were obtained at the time of enrollment, and on day 8-10 after enrollment to measure the percent with HUS or hemolytic anemia. After the first season of study, 135 patients had been enrolled at 12 centres from across Canada. In 48 patients, alternate (nonVTEC). pathogens were identified as the cause of the bloody or crampy diarrhea. Of the remaining 87 patients, 15% developed hemolytic anemia or HUS (2 HA, 11 HUS). The medication was well tolerated and the assignment to treatment remains blihded. The

estimated sample size for the trial is 300 pts, with interim analyses planned after each 75 patients enrolled.

P227 COLLABORATIVE COHORT STUDY OF THE RISK OF HEMOLYTIC UREMIC SYNDROME (HUS) AFTERE.COLI 0157:H7 INFECTION. PeterC. Rowe, Elaine Orrbine, George A. Wells, Hermy Lior, Peter N. McLaine and the Canadian Pediatric Kidney Disease Research Centre (CPKDRC), U. of Ottawa, Ottawa, 9Canada. The risk of HUS following E.coli 0157:H7 (EC)gastroenteritishas been reported to range from 3-26%. To better define the risk of HUS following EC gastroenteritis, we began a 3 year prospectivestudy in June 1991 at 18 medical centres in Canada. We enrolled all children < 15 years of age with HUS or EC at the participatingsites. To evaluatereferralbias, we enrolled all Alberta children <15 years with EC gastrointestinal illness reported by the Microbiology Departmentof the Alberta Children's Hospital and the two Provincial Laboratories in I:hat province where reporting of EC is mandatory. After 28 months, we had enrolled 296 Alberta children with EC documented by stool culture (80% of all with reportedEC),and 365 children at the referralcentres in the rest of Canada. Blood was drawn between days 8 and 12 after onset to ascertain for incomplete HUS. Overall there were 173 patients with HUS; 103 (60%) had stool cuffures positive for EC. Evidence of HUS was present in 26/296 (8.8%; 95% CI, 5.8-12.6%) of all Alberta patients with documented EC, and in 77/365 (21%;95% CI, 17-25%) of patients seen at referral centres in the rest of Canada (P <0.0001). A further 9 Alberta children had HUS but stool cultures were negative for EC. If these children are assumed to have had EC infection, and the 20% with reported EC who did not participateare included in the denominator, then the risk of HUS in the Alberta cohort increasesto 9.2% (CI,6.5-12.6). Among HUS patients, 42% in Alberta and 29% outside Alberta had stool cultures positive for EC prior to the diagnosis of HUS. Of the 103 with HUS, 93 (90%) had seen a physician in the 2 weeks before diagnosis, but only 72 (70%) had a stool culture sent before the HUS was recognized.The data from the completed 3 year study will be presented at IPNA. Thesedata suggestthat the risk of H US in a largecohort of Alberta children with EC gastroenteritisis approximately 9%. Higher rates reported from tertiary care centres likely reflect a greaterproportion of sicker children. Theseresults should be useful for estimatingthe risk of HUS after EC gastroenteritis in various clinical settings and should help in the design of clinical trials for the prevention of HUS.

P2,26 MICROBIOLOGY OF HEMOLYTIC UREMIC SYNDROME (HUS) IN CANADA. Hermy Lior, Peter C. Rowe, Elaine Orrbine, George A. Wells and the Canadian Pediatric Kidney Disease Research Centre (CPKDRC) U. of Ottawa, Ottawa, Ontario. This CPKDRC-HUS study was initiated in 1991 at 18 medical centres in Canada and was designed to evaluate host, organism and environmental risk factors for childhood HUS. For the microbiologic phase of the study, all children, < 15 years with HUS had stool specimens screened at the referring hospitals for E.coli 0157:H 7 (EC) using SorbitoI-MacConkey media. Stools from all patients and isolates of EC were forwarded to the National Laboratory for Enteric Pathogens, Laboratory Centre for Disease Control in Ottawa for further investigation. The following were performed: free fecal verotoxin (VT) assay, phage typing, determination of the VT gene profile using PCR techniques and culturing for non-015~z VTEC (methods in Epidemiol. Infect.(1993); 110: 1-7). Serum was obtained from all HUS patients at diagnosis and 2 months after discharge and was examined using a passive hemagglutination assay (PHA) for the 0157 LPS (Journal Clin Micro 1992; 30:1174-8). PHA titres _> 1:500 were considered positive for exposure to EC. After 31 months of study we had enrolled 176 patients with HUS. Stool samples were forwarded for analysis in 90% and at least I serum sample was available in 95%. Of the 176 patients with HUS, 112 (64%) had EC identified from stool. A further 42 (24%) with negative stool cultures had evidence of EC exposure confirmed serologically (median PHA titre 1:2000). Five patients (2.8%) had other VTEC serotypes cultured and 3 more had evidence of free fecal VT. The remaining 14 (8%) had negative stool cultures, negative fecal VT assays, and negative PHA assays. 70% of EC isolates had evidence of VTI and VT2 toxin genes and 30% had only VT2 toxin genes identified by PCR. This unique study has confirmed evidence of exposure to V l in 92% of children with HUS. The data from the completed 3 year study will be presented at IPNA.

P228 COMPLEMENT STUDIES IN FAMILIAL HEMOLYTIC UREMIC SYNqgROME M. Ohali*, H. Shalev**, D. Landau**, R. Carrel**, M. Schlesinger* HemoIytic uremic syndrome (HUS) is a clinical syndrome due to different etiologies. Atypical HUS is characterized by no antecedent diarrhea, tendency to relapse, and poor outcome. Some of the patients in this subgroup have a familial disposition in which low C3 levels have been described. Recently we treated a large kindred with familial HUS in whom a striking depression in various complement (C) components were found. Therefore, we screened the complement system in the whole family, which included patients and asymptomatic siblings and patients. Results: Three patients and ten asymptomatic family members were screened. All asymptomatic family members had normal serum urea and creatinine. Patients had normal C levels. Two of the asymptomatic siblings also had low complement levels (C2, C3). All affected patients had low C3 during and between relapses. This deficiency could not be normalized by recurrent plasma transfusions in two cases. Assessment of all of the other complement components in three patients revealed a generalized low C level (CH50, C2, C3, FB, P). In summary, a striking decrease of complement component level was found in all the symptomatic patients, but also (though less severely) in 2/10 asymptomatic family members. A follow-up of the asymptomatic siblings and their renal function in the future is warranted. *Department of Pediatrics, Barzilai Medical Center, Ashkelon, Israel ** Department of Pediatrics, Soroka Medical Center, Beer Sheva, Israel

C 112 P230

P229 HEMOLYTIC UREMIC SYNDROME: COMPARISON OF CLINICAL AND LABORATORY PARAMETERS BETWEEN TWO PERIODS SEPARATED TEN YEARS. F. Cavagnaro, E. Lagomarslno, C Gonr.alez,I. Garc~-Huidobro, and lll. Cerd~ The Hemolytic Uremic Syndrome tHUS) is a well defined disease with the classical triad of acute renal failure, microanginpatie hemolytic anemia and trombecytopouin. It is nmaily recognized as the main cause of oligerie acute renal failure among infants and preschool children in m a n y countries. O u r purpose was to evalnate, comparatively, the clinical and laboratory f'mdings of patients with lIES hospitalized in our Pediatric Service in two periods of five years separated ten years each other: Group A (1979-1983) and Group B (1989-1993). In both period the discharge diagnosis of HILTSwas done in 14 patients each (2.8 pts/year), witha similar age at presentation (group A: x 12.3 -~ 6.3 mouths, range 5-23 vs. group B: 19.6 4-12.8 months, range 4-59; p: NS). No differances were fmmd in sex distribution ( M/F ~1), clinieol findings on admission ( anemia, edema, oligounuria, bemorraglc phenomena) and rate of complications during hospitaiizatiom Diarrhea was the most frequent prodromic event (12/14, 86%) in both groups, being enterocolic in two third of them. The diagnosis of HUS was correctly made on admission in 6/14 (43%) in group A and 9/14 (65%) in group B, difference not reaching statistical significanc~ Both groups required peritoneal dialysis in 36 % (5/14) of the patients, and the rate of RBC transfusions were 71% in group A and 57 % in group B (p: NS). Interestingly enough, the hospitalization period decreased from x : 30 4-17 days, range 9-60 in group A to x : 16 4-16 days, range 3-62 in group B (p: 0.03). No fatalities doe to HUS were found in either group. In a six months follow up, no patients presented progressive renal failure, neureiagic sequelae or HUS relapse. In conclusion, the present study shows that HUS remained very similar in clinical and laboratory presentation and evolution between beth periods. Its treatment remains basically based on supportive therapy pins dialysis (1/3 of the cases), with an excellent survival and few long term sequelae. Differences in the accuracy of diagnosis on admission may be related to a better knowledge of this disease by general pediatricians. The difference of in-hospital stay is multifactorial, and apparently not related to diagnostic accuracy. Department of Pediatrics, Cathofic University, Santiago Chile.

HEMOLYTIC-UREMIC SYNDROME tHUS) DUE TO PROLACTIN ACTIVITY ? J.Janda, E.~imkowi, V.Rambousek, J.Kreisinger

HUS has repeatedly been reported in adults in association with the use of contraceptives or with both pregnancy and delivery in young women. Case report: A 15 year-old gift with a negative history developed abdominal pain, diarrhea, recurrent vomitus and fever. On admission moderate dehydration, leukocytes count of 10 000, thrombocytopenia 40 000, hemoglobine level of 98 g/1 and oliguria was noted. The urine was not examined on the 1st day because of menstrual bleeding. Total anuria d e v e l o p e d o n t h e 2 n d d a y w i t h the S e r o f 6 9 0 u m o l / l a n d u r e a o f 2 7

mmol/l. The most interesting clinical finding was heavy galaktorrhea. The girl was treated by hemodialysis (4 sessions). Examination of the hormonal status revealed extremely high levels of plasmatic prolactin (ca 20x higher t h a n n o r m a l ) . F S H , T 3 , T 4 , S T H a n d testosteron levels w e r e n o r m a l . S i n c e t h e day 4 s u f f i c i e n t u r i n e o u t p u t w a s o b s e r v e d a n d the g i r l ' s c l i n i c a l status

improved very quickly. Nevertheless, the marked galaktorrhea lasted for further 3 weeks. CT and NMR exams showed a microadenome in the hypophysis. Bromocriptin (Parlodel) therapy was used to block the secretion of prolactine. The patient recovered very well and had normal renal function more than 1.5 years after acute episode. Levels of hormones including prolactin were normal. Seven years ago we treated a 16 year-old gid with a typical thrombotic thrombocytopenic purpura (TTP). Her status (mainly central nervous system damage) improved dramatically after plasmapheresis. Menstrual bleeding started after 6 weeks of secondary amenorrhea. Rapid deterioration of clinical status resulted into severe brain hemorrhage and death. At the autopsy bilateral overfilled breast milk ducts were found. The level of prolactin was not examined, the galaktorrhea was not apparent. The possible r o l e o f p r o l a c t i n in t h e p a t h o g e n e s i s o f H U S a n d "I'TP is d i s c u s s e d . Ist D e p t m . o f P e d i a t r i c s , U n i v . H o s p i t a l M o t o l , P r a g u e , C z e c h R e p u b l i c

P O S T E R S E S S I O N - (P) - Transplantation P232

1)231 EFR~CTOFRIMUNO~d.II~EI~eN1EDRUas;ONTNEMONOCWgFUN~FIOtqSOFTHP-1CELLS. L ReL~men', L Roherfi', H. Addn' We have been studying the effects of imnaunosuppressivedrogs on rncnncyte functions using as a model system, THP-1. calls, an established human leukemic call line with monocytic proper~ea, including immune functions. The ability of the imrnunasuppreaelvedn~s; dexamethasuna, cyclcaporine, FK506, and rapamydn, alone and in combination, to suppress interleukin-lp secreSon in vitro by THP-1 cells when stimulated by Ilpopelysacchande (LPS) was evaluated. All four drugs, when added to cell culture medium at ~'wrepeutic conoontra~ns, significantly decreased seore~on d the munokine to well below control levels. However, only dexarnathasone completely suppresses intedeukin-ll~ secretion in a ddse dependent fashion. Cyslospodne, FKS06, and repamycin only parlJally suppress secretion of intedeuldn-lp at concen~tians within their therapeutic ranges and inoreadng concentrations of the drags do not result in furbher suppression of secretion. Ukewica, the combination of any two of 6qeae three drugs does not provide any additional suppressive affect. Dexamethasuno, however, when added in increasing concentral~ons in cornbination with any of the other drugs, results in further suppression of intedsuldn-ll], secretion in a dose dependent fashion. Using techniques of cytofluorometry, the ability of these immunosuppreasive drugs, to suppress expression of activation antigons on THP-t cells was examined. THP-1 cells were incubated with one of the study drugs or in medium alone and than activated with either r in~rferon or LPS. Results of mean fluorescent intensity are tabulated below: CD64 CD32 CD11a CD54 FcR I FcR II LFA-1 ICAM1 DR 15.1 53,4 114.1 68.2 Control 84.8 DEX 70.6,+ 7.7*+ 48.8 81.2 *+ 48.6 `'+ 16.5 53.5 111.9 72.7 CsA 106 t4.3 49.3 87.8' 70.1 FK 90.2 12.7. 51,4 84.4" 59.4* RAP 91.3 *p~.001 vs. control §162 vs other agents C,j~ospodno and FK506 easentially have no suppressive effect on the call surfaca antigens studied. Rapamycin has a small ~ t significant effect on CD11a, 54, and 64. Dexamethasone causes a significant d~creaca in the intensity of each of these antigens as compared to the controls and to the other drugs. * Depar'~tent of Pediathcs, Mount Sinai Medical Center, Now York, NY, USA

19

COMPARISON OF NEORAL AND SANDIMMUN PHARMACOKINETIC PROFILES IN YOUNG RENAL TRANSPLANT RECIPIENTS SC Kabasakul*, M Clarke*, H Kane**, J Karsten**, G Clark* Whole blood ttxmgh levels of cyclosporin A (CYA) usiug Sandinnnun| (SIM) in young renal transplant recipients are highly variable. A major factor determining CYA levels is variation in the absorptinu o f S I M Neoral | (NEO) is a new formulation of CYA with more predictable gut absorption in adults. AIM. Wc compared the pharmacokinetic profiles and trough levels of S[M and NEO in young children who had stable renal allografls lhnetion lbr >3 months. METHOD. Five cltil&'en aged <11 y (median 9.8y. range 4.9-10,9y) with cadaver allografts (Per range 38- 114 p.mol/L) had CYA whole blood levels determined at 0, 0.25, 0.5, I, 1.5, 2.5.5, 7 and 12 hours after receiving their usual SIM dose ( 1.75-3.2mg/kg. or 49-93mg/m~ BSA, 12 hourly) on Day 0. NEO was then c~snrnenecd at the same dose taken twice daily; CYA trough levels were checked on days 1,3, 7.14 mM 28. Another 9 point pharmacokinetic profile was obtained on day 7. CYA was assayed using the monoclonal antibtxly / Abbot TDx method. Using Siphor Win software, median initial baseline (C Oh) and 12h tC 12h) trough concentrations, Cmax, Tmax, mean ~'ea I Jnder Culwe ('l'0-TtNr.tnrrv) and total clearance (Cl.r..r) for the profiles and enefiieient of variant of trough levels for NL:O (I) 1 to 1728) and SIM (5 previous results) were analysed. RESULTS C Oh ~g/L

C 12tl p~.,

C max p/i,

TV2 h

T max h

CITo~ L/hr

AUCINv ~$/L.h"

C.V. troughs

NEO

71

81

992

2.36

1.5

0.021

3670

I1%

SIM

91

64

475

2.41

1.5

0.031

2476

14%

No child showed increa:~l tremor, hypertansion or persistant ranal dysfunction. Tlu'ee children had their NEO dose reduced by 10mg/dose aller their Pcr increased by 12%, 24% and 31% Their ereatinines rctunacd to baseline, t)ne boy had his dose increased by 10nlg/dose to maintain his CYA mmgh levels. NEO was well tolerated in 4 children; I child convclled to SIM after 20 days because of headache, persistent oausea and malaise" she was taking the highest NEO dose (I 87 mg/m~/d). Neoral produced greater CYA Cmax and AUCs titan SIM; the average increase in AUCo,r~Fwas 48 percent. Mild reversible renaI dyst~nution may be seen within the tirst week of N'EO and was sueces,,~fulty treated with NEO dose reduction. CONCLUSIONS. Further studies and long-term lbllow-up are on-going to assess whether CYA profiles and trough lords are more predictable with Neoral than with S[M. * Dept of Paediatric Ncphrolo~,_,'y,t/MDS, Guy's I Iospital, 1,ondon IlK ** Sandtlz Pharmaceuticals, Frin~lcy, I.JK

Cl13 P233

P234

IMPACT OF CYCLOSPORINE A BLOOD LEVEL ON ERYTHROPOIETIN PRODUCTION IN RENAL TRANSPLANT CHILDREN A Mahrnoud, N Pozet, G Lardet, M Vial, P Cochat Unit6 de N6phrologie P&liatrique, H6pital E Herriot, Lyon, France

HOW TO PRESCRIBE CYCLOSPORINE A IN CHILDREN: DATA FROM A PHARMACOKINETIC MODEL IN A SINGLE CENTRE MH Said, MD Cabiac, H Humbert, I Liponski, L David, P Cochat Unit6 de N6phrologie P6diatrique, h6pital E Herriot, Lyon, and Sandoz Pharma, Ltd, Rueil-.Malmaison, France

After renal transplantation (RT) the development of graft function leads to reticulocytosis and improves the anemia of CRF. It has been shown that endogenous erythropoietin (]EPO) level increases before reticulocytosis has begun, that might be due to intrarenal vasoconstriction induced by cyclosporine A (CyA). However, there is no available data on the relationship between CyA and EPO level on the long term following RT. In 30 RT children (9 girls, mean age 11.4+5.4 years), CyA trough blood level (HPLC) and EPO level (immuno-enzyme assay, Biom6rieux, France) were studied concomitantly. According to CyA blood level, RT children were divided into 2 groups: group 1 (CyA<100 mg/L, n= 14, EPO level= 9.3+4.9 mU/rnl) and group 2 (CyA>100 mg/L, n= 16, EPO level= 28.9-+27.9 mU/ml). Values were expressed as mean + SD. A positive correlation (r=- 0.46, p<0.005) was found between CyA and EPO levels. In relation to the time since RT, the mean duration in group 1 was 4.8+3.9 years and 1.9+1.6 years in group 2 (p= 0.0009). When assessed by inulin clearance (ml/min/1.73 m2), the GFR in group 1 was 70.1+30.3 while it was 61.3+25.8 in group B, that is not significantly different. In conclusion 1) there is a positive correlation between cyclosporine trough blood level and erythropoietin level, 2) changes of cyclosporine level during the years following RT parallel to erythropoietin level, 3) the level of glomerular filtration rate does not inluence erythropoietin production in renal transplant children.

In order to determine the optimal prescription of cyclosporine A (CsA) i.e. mg/kg body weight (bw), mg/m2 body surface or mg independently from bw - we analyzed retrospectively the data of 33 renal transplant children under triple immunosuppression. The population studied (mean age + SD 9.7+4.9 years, range 2.0-17.3; mean bw 29.7+15.8 kg, range 10.9-93.4) included 6 children less than 15 kg (group I: mean bw 12.9-2_1.6kg, median 13, range 10.9-14.6), 7 children with bw 15.0-24.9 kg (group 2, mean bw 19.1+_2.8, median 18.4), 14 children with bw 25.0-39.9 kg (group 3, mean bw 32.4-1"3.9 kg, median 32.1) and 6 children with bw >40 kg (group 4, mean bw 52.7+__20.0 kg, median 45.8). All the patients received initially oral CsA adapted for square meter body surface. Steady state whole blood levels of CsA were measured by HPLC. From a pharrnacokinetic model, we adapted daily individual dose (in mg, mg/kg and mg/m2) aiming at reaching a theoretical standard trough blood level of 200 ng/mL for each patient. When the dose was expressed in mg indenpendenfly from bw, there was a significant difference between group 1 and 3 (p<0.005), between group 2 and 3 (p<0.04), between group 1 and 4 (p<0.002). On the other hand, the dose required for each group was not significantly different when expressed in mg/kg or mg/m2. In conclusion, this study suggests that cyclosporine A prescription in children should be optimally expressed according to body weight or body surface. This is different from recent studies in children (Humbert, Transplant Proc 1994; 26: 2791) and adults (Book, Transplantation 1994; 57: 1484) who recommend prescription in mg whatever bw or body surface.

P235

P236

OKT3 MONOCLONAL ANTIBODY IN THE TREATMENT OF ACUTE REJECTION IN CHILDREN WITH CADAVER KIDNEY GRAFt frx) M.~ikut, J.Janda, J.Kulichovd, J.Feber

LACK OF RENAL HEMODYNAMIC EFFECT OF L-ARGININE INFUSION IN RENAL ALLOGRAFT RECIPIENTS XZ. Zhang, GL. Ardissino,L. Ghio, AS. Tirelli, V. Dacc~ F. Marchesi, A. Claris-Appiani

In the period 1989-1994 eleven patients (pts) with Tx received monoclonal antibody (OKT3) as a treatment of acute steroid-resistant graft rejection. Mean age atthe time of Tx was 10.5 years (range 2.8-17.2). OKT3 therapy was started 0.5-26 months (mean 7.4) after Tx. Administration of antithymocyte globulin preceded OKT3 treatment in only 2 pts. OKT3 was administered during 1-10 days in a daily absolute dose ranging from 1-2.5 mg accompanied by the administration of furosemide and corticosteroids. In 3 pts OKT3 therapy was interrupted due to severe leucopenia and in 2 of them restarted after 11-15 days. In 3 pts with a rapid drop of Scr the OKT3 was stopped already after 3 injections. Fever and hypertension were observed in 7 pts and septic fever was noted in only 2 pts. No patient developed life threatening illness~ The number of total lymphocytes and their subpopulations (CD3, CD4, CDS) decreased during the first week of OKT3 treatment (p<0.01) with significant rebound increase of CD3 (p<0.01) and CD4 (p<0.04) lymphoeytes in the 2nd week. The therapy was regarded as successful in 7 out of 11 pts with a prompt decrease of Scr levels after a few days. Two cases required a longer period to obtain the prerejeetion Scr levels. Renal function deteriorated in two further pts who required dialysis treatment after 2 months. In coficlusion, OKT3 can be used successfully in the treatment of steroid-resistant rejection, but close immunologicalmonitoring with the use of cytoflowmetry is recommended. Late sequalae of this treatment are to be evaluated including the risk of lymphoproliferativedisease.

9 It has been recently suggested that L-arginine, a precusor of nitric oxide(NO), might ameliate cyclosporine nephrotoxicity and have beneficial effect on hypertension and renal function. We have assessed effects of L-arginine infusion on systemic and renal hemodynamics in cyctosporineA-treated renal allograft recipients with mild-to-moderate renal insufficiency9 11 patients (6M 5F), range of age 11-21 yrs, CRC1(30-73 ml/min/1.73 m2), post-transplantation time 2-7 yrs, underwent an infusion of L-arginine at the rate of 290 mg/min/1.73m2 bsa for 70 minuts. Before and during the infusion mean arterial blood pressure (MAP), GFR(Inutest Clearance), RPF (PAH Clearance) and cGMP urinary excretion have been determined. Data are presented as mean_+sd. Statistical analysis: t-test for paired data. Before During p MAP (mmHg) 115 _+15 112 _+12 NS GFR (mVmin/1.73m2) 37 _+ 12 40 _+13 NS RPF ( ml/min/1.73m2) 181 _+70 200 _+69 NS cGMP (nmol/100mlGF) 2.0 _+0.9 1.8 _+0.9 NS In renal allograft recipients, L-Arginine infusion did not affect both systemic and renal hemodynamics. The fact that urinary cGMP excretion during L-arginine infusion did not increase is consistent with the hypothesis that NO synthesis is not enhanced by L-arginine, and this might account for the observed lack of hemodynamic effect.

Ist Deptm. of Pediatrics, University Hospital Prague-Motol, Czech Republic Dept. of Pediatrics, University of Milan, Milan, Italy

C 114 P237 RENAL FUNCTION AFTER LONG TERM CYCLOSPORIN A AND FK506 FOR ORTHOTOPIC LIVER TRANSPLANTATION IN CHILDHOOD B. Rodeck, M. Melter, P.F. Hoyer, R, Kardorff, S. Rdmaamg J. Brodehi Orthotopic fiver transplantation (OLT) is well established in the treatment of end-stage liver diseases in children. However, the impact of long-term immunosuppressivetreatment with Cyclosporin A (CsA) or FK506 (in steroid resistant rejection) on renal function in growing children is debated. The aim of the study was to assess renal function after OLT and to compare CsA- and FK506-treated chi/dren in long-term follow-up. Patients and methods: 128 consecutive transplanted children were studied. Children suffering from combined liver and renal diseases prior to OLT were excluded. At time o f OLT 60 patients were severely malnourished with a Standard Deviation Score (Z-SPore) for weight below -1. Glomemlar filtration rate (GFR) was calculated from plasma creatinine and body length (Schwartz formula) at time and up to 5 years after OLT in the remaining 68 children (59 CsA, 9 FK506) with Z-Score above -1, because the Schwartz formular is not applicable to children with reduced muscle mass and therefore low plasma creatinine. Median age at time of OLT was 4.26 years (0.15-16.8 years). Results: GFR (mean, SD, ml/min/1.73 m 2) was 1598 (73.6) at time of OLT and 123.8 (31.6), 119.4 (41.8), 111.2 (22.4), 112.8 (25.9), 114.6 (26.7) lethe following years. Matched paired T-tests showed a signifieartt deterioration of GFR in the first year (p=0.015), but no further deterioration in the following years. There was no difference in GFR at time, one or two years after OLT in the CsA- group compared to the FK506-group. However, all 9 FK506-treated patients developed a metabolic acidosis (bicarbonate < 20 retool/l). This was not the ease in CsA-treated children. Conclusions: Calculated GFR up to 5 years after OLT remains in the normal range, however declines in the first year. FK506-treated patients developed renal acidosis, otherwise there was no difference between FKS06 and CsA. Dept. of Pediatric Nephrology, Medical School Hannover, Germany

P239 FULMINANT CALCIPHYLAXI8 IN A 5-YEAR-OLD BOY TWO MONTHS AFTER UNSUCCESSFUL PRE-EMPTIVE TRANSPLANTATION OF A MATERNAL KIDNEY Th. Lennert*, U. Gillert*, W. Ramdohr**, A. Schwarz**, H. Versmold* The phenomenon of calciphylaxis still is only partially understood, after it was described by Selye 1962 in animal experiments. It is a rare condition, mostly seen in patients in chronic renal failure or after renal replacement therapy. The clinical picture includes rapid calcification of soft tissue, blood vessels and lungs, followed by severe, sometimes gangrenous, ischemic necrosis of digits or extremities. "Sensitizing" factors can be Vitamin D, PTH, elevated calcium-phosphate product or renal failure. Local trauma, steroids and immunosuppressives are discussed as "challenging" factors. Morbidity and mortality are high, treatment consists of lowering the Ca-P-product, which in most cases can be reached by urgent total parathyroidectomy only. We saw fulminant calciphylaxis in a 5-year-old boy, who was born with bilateral hypoplastic kidneys. Progressive renal failure started in the 3rd year of life, and the boy needed calcitriol and phosphate binders to control the rising PTH and P. He got his mother's kidney transplanted at the age of 5 112 without prior dialysis (creafinine 700 pmo[/{, Ca 2,57 mmoIll, P 3,07 mmoltl, PTH 682 ng/I (normal 10-65)). Unfortunately the transplant did not show any function. By biopsy acute ,rejection could be ruled out, but cortical necrosis was found. The boy was hemodialyzed, the transplant removed 7 weeks later, when CAPD was started. 2 weeks later with rising Ca (max. 3,35 mmol/I) and P (max. 3,54 mmol/I) the boy showed a spotty red discoloration of his left lower leg, which was first misdiagnosed as hematoma. As he had suffered from an episode of pneumocystis carinti pneumonia earlier, increased density of the lungs first was taken as symptom of interstitial pneumonia. Only when deep cutaneous necrosis developed in the leg and PTH was found elevated (388 and 485 ng/I) inspite of high Ca levels, the diagnosis of acute calciphylaxis with tertiary hyperparathyroidism was made. As Ca and P could not be controlled by phosphate binders and calc[ton{n, total parathyroidectomy had to be performed, showing 3 of 4 glands hyperplastic. 6 weeks later pulmonary and vascular calcifications appear unchanged, but the necrotic areas in the leg start to heal. Ca and P are controlled by mild oral substitution of Ca and calcitriol. This case shows that the rare complication of acute calciphyiaxis can be found in chitdren, too, even after pre-emptive transplantation and a subsequer~t period of dialysis as short as two months. Whether a better control of Ca, P and PTH prior to transplantation could have prevented this comp]ication, remains an open quest)on. *Paediatric and **Medical Department, Klinikum Benjamin Franklin, Freie Universitw iBerlin, Germany.

P238 MECHANISMS OF CYCLOSPORINE-1NDUCED HYPERKALEM1A IN RENAL TRANSPLANTED CHILDREN J. Laine and C.Holmberg

Purpose: To investigate pathogenesis of cyclosporine A (CsA) associated hyperkalemia after renal transplantation. Methods/materiah 24 renal transplanted children (mean age 5.8 years at Tx) were studied 6 months after transplantation. Only patients without concurrent complications were accepted. 51Cr-EDTA-, PAl-l-, lithium and sodium clearances, 24h urinary creatinine and potassium excretions, plasma renin activity and aldosterone concentrations were measured. Transtubular potassium concentration gradient (TrKG) was calculated. An ACTH-test was performed to document adrenal function. Hyperkalemia was defined as serum potassium>5.3 mmol/L. Results: Eleven patients had hyperkalemia. The TTKGs were low normal or reduced in both normo- and hyperkalemic patients implying inhibition of K+ secretion. The hyperkalemic patients received more CsA (mean dose 21.3 vs 9.7 mg/kg/d,p=0.01), and had lower lithium clearances (mean 9.9 vs 17.0 ml/min/1.73m2,p<0.05). Adrenal function had no clear effect. There were no differences in plasma renin activity or aldosterone. Serum potassium concentration correlated with CsA dose (r=0.773,p<0.001) and inversely with lithium clearance (r=0.568,p<0.01). Conclusion: CsA induced decrease in distal tubular flow rate reduced tubular K+ excretion. Extrarenal mechanisms may also have a role. The type of treatment of CsA-induced hyperkalemia (i.e. potassium-binding resins, mineralocorticoid substitution, loop-acting diuretic) should b e chosen on an individual basis. Children's Hospital, University of Helsinld - Helsinki -Finland

P240 ~(Y#rH POST RENAL ~ P ~ A ~ O N

~

CHI'LDR]~.

P i n t o V.*, P e f a u r J.',~*, Morales J .*~*, Hocarquer A. ~',+, Carranza C.*. a~ Depar~ament o f P e d i a t r i c s ~ Exequie I C~nz5] ez Cort~s Hospital. * * Departament o f Nephrology,Barros Luco-Trudeau H o s p i t a l . S a n t i a g o de C h i l e . For c h i l d r e n a s u c c e s s f u l t r a n s p l a n t (TX) i s t h e uZtimate l o n g term g o a l t o a c h i e v e t h e b e s t p o s s i b l e r e h a b i I i t a t i o n ; n e v e r t h e l e s s , growth r a t e does n o t always improve a f t e r transplantation. This s t u d y was u n d e r t a k e n t o analyse some os t h e f a c t o r s Maich a f f e c t p a t t e r n s o f growth p o s t transplantation. Betva~n J a n u a r y 1990 and December 1993, 14 p a e d i a t r i c s p a t i e n t s with ESRD underwent t h e i r F i r s t Renal TX. The median age a t t h e t i m e o f TX was 11.2 y e a r s ; sex ratio: 7/7; LR/CD, 11/3; P r i o r D i a l y s i s t r e a t m e n t : .1.1/4 and normal r e n a l f u n c t i o n w i t h a median follow-up o f one y e a r : 13/14. All p a t i e n t s were managed on Cyclospor i n a (CYA), A z a t h i o p r i n e and P r e d n i s o l o n e . Growth was e x p r e s s e d a s increment i n l e n g t h (cm/year), as height s t a n d a r d d e v i a t i o n s c o r e ($DB) and growth v e l o c i t y (GV). The GV i n prepubeWcal c h i l d r e n was ~ 50 t h Pc i n 4/7 and l e s s 3rd Pc i n 3/7. On t h e pubeval c h i l d r e n GV was ~ 50th Pc i n 1/7; between 25th - .~Oth Pc in l / 7 ; 3rd- lOth Pc i n 1/7; and ~ 3 r d Pc in 4/7. The h e i g h t a c c o r d i n g t o SDS d u r i n g t h e f i r s t 12 month o f f o l l o w - u p showed improvement in 57.2% and 28.5% of p r e p u b e r a l and p u b e r a l p a t i e n t s r e s p e c t i v e l y . The median dose of Prednisolone

was : 0 . 7 2 ;

0.47,

0.34

and

0.22

mg/kg/

day a t 1 , 3 , 6 and 12 month p o s t TX. Pvepubera[ p a t i e n t s ~n whom c a t c h - u p ~ r o ~ h does n o t occ~P, were g i v e n h i g h dose o f s t e r o i d s . Kn c o n c l u s i o n : i t may be s a i d t h a t r e n a l TX i n c r e a s e s t h e growth r a t e p r i n c i p a l l y a t younger age. The a d v e r s e ~ f f e c t s of s t e r o i d s on growth i s r e c o g n i z e d .

Cl15 P241 INFECTIONS COINCIDENT WITH REJECTION EPISODES IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS. P. Acott*, S. Lee*, B. Kennedy*, H. Bitter-Suermann*, J. Lawen*, J. Crocker* Renal transplant rejection has a higher incidence in children. Pediatric patients also are more prone to intercurrent febrile illnesses. The role of infection with rejection was investigated in a prospective fashion. Over 24 months, rejection was seen in 6 of 36 (14%) patients less than 18 years of age foH0wed in our center. Assessment included blood serology for Human Herpes Virus type 6 (H]BV-6),

Epstein Burr Vires (EBV), Cytmnegalovirus (CMV), Varicella (VZ), Hepatitis B & C, and Human lmmunodeficicney Virus (HIV) pre-transplant, and subsequently with rejection or intereurrent illnesses. Nasopharyngeal aspirates were obtained for Respiratory Syncytiai Virus, Influenza, Parainflnenza, and Adenovirus. Perioral or cutaneous ulcerations were scraped for virus isolation and identification. Blood, throat, and urine cultures were obtained for bacterial and viral pathogens with periodicity and febrile events. Five eellniar and one vascular acute rejection were confirmed by renal biopsy during this two year period. All episodes were reversed with high dose pulse prednisone. Reactivation of HHV-6 was shown with elevation of specific IgM antibody despite the presence of lgG antibody in 4 of the 6 rejections. Acute EBV infection coincided with one rejection event based on IgM antibody to EBV capsid antigen. The other rejection occurred coincident with E. coI~ pyalonephritts. This study confirmed coincident infection in all 6 rejection episodes with a comprehensive infection monitoring program. I]HV-6 reactivation was confirmed hi the pediatric patient post renal transplant and was associated with a rejection event in all 4 patients. Yoshikawa (year) reported reactivation of HHV-6 viremia and a significant rise of antibody ti~e to HHV-6 in 55% of adult traaspiant patients within 3 months following transplantation. HHV-6 infection in pediatric transplant patients can occur after 3 months post transplant (2, 4, 17, 39 months respectively) and was coincident with rejection in all 4 patients. HHV.6 reactivation was not seen in post transplant patients with non-rejeclion febrile events. HHV-6 reactivation post renal transplant is coincident and possibly a causative event during rejection in the pediatric renal transplant patient. *IWK Children's Hospital, Dalhousie University, Halifax, Nova Scotia.

1'242 DYNAMICS OF THE REGULATION OF URAEMIC CALCIUM-PHOSPHATE METABOLISM DISTURBANCES AND BONE CHANGES (EXPRESSED AS TOTAL BODY BONE MINERAL DENSITY- BMD) IN CHILDREN DURING FIRST 12 MONTHS AFTER RENAL TRANSPLANTATION B. Materna, R.Grenda, R. Lorenc The aim of this study was to evaluate the dynamics of regulation of uraemic calcinmphosphate metabolism disturbances and bone changes expressed as TB BMD and spine L2-L4 BMD in children during first 12 months after kidney transplantation. Methods: Group of 25 uraemic children (12 boys, 13 girls) of 11.7+42 years (1.75-17.5), were observed during fwst 12 months after renal transplantation. All received triple therapy zA+AZA+Pred). In 12 patients acute graft rejection episodes were treated with i.v. methylprednisolone (10 mg/kg b.w.). Control group included healthy, age and sex-matched (n=1612) children. Serum level of creatinine, phosphate, calcium, ionised Ca, 1.25OH2D3, 25OH D3, PTH (C-terminal) and alkaline phosphatase activity and urine concentration of creatinine, phosphate and calcium were evaluated in 1,2, 3, 4 weeks and 3, 6,12 months after transplantation. Bone mineral density (DEXA) was measured in 0, 3,6 and after 12 months. Results: 1) There were no significant differences in age, PTH level, BMD total and spineL2L4 between males and females at the beginning and end of the study, 2) S-creatinine, s-PTH significantly decreased in the first month of the observation (t- test, p<0.00Ol)in all cases and remained normal during observation period, 3)The average levels of serum calcium remained within normal limits (2.25-2.75 mmol/l), while serum innised calcium level was (1.30 vs 1.27 mmol/t) close to upper normal limit (0.95-1.3 mmol/1)over the study period, 4) 1.25 OH2D3 level significantly increased (t-test, p<095) despite of reduction or withdrawing of vit. D supplementation, 5) S-phosphate levels significantly decreased in the first 3 month, which was accompanied by low TRP values (70.9_+17.7%).After 6th month of the study period correction of hipophosphatemia was observed due to statistically significant increase of TRP (t-test, p<0 95), 6) S-alkaline phosphatase activity significantly increased over the study period (t-test p<0.001), and correlated with a SD spine L2-L4 BlVlDvalue (r---0.59;p<0.05), 7) SD TB BMD significantly increased over the study period (t-test p<0.05), although there s no significant changes in SD spine BMD [ASD spine BMD correlated with patients age ~,=0.78;p<0.01 )], 8)Teudency to decrease of SD spine BMD was observed in la-ansplant recipients treated with high-dose steroids (> 051 mg/kg b.wJday) Conelusious: SuccessfuU renal transplantation corrects rapidly disturbed calcium-phosphate metabolism and markedly increases bone mineralisatinn. Renal gral~recipients treated with high-dose steroids (especially younger children) are at risk of osteoporosis. Simoultaneous administration of vit. D with steroids should be considered in these cases. Nephrology, Dialysis and Transplantation Dpt., Child Health Center, Warsaw, Poland

P243

ESTIMATION OF LIPID ABNORMALITIES IN CHILDREN AFTER RENAL TRANSPLANTATION (rTx). J.Latoszy~ska, A.Boguszewska, R.Grenda. An aim of research was to estimate lipid abnormalities in pediatric patients (pts) after rTx, with stable graft function (s=creatinine<2.2 mg%). Patients and methods: lipid parameters levels (total cholesterol - TC, triglicerides - TG, phospholipids- PL, HDL, VLDL, LDL, apolipoproteine B- apoB) were men sured every 3 months in 49 pts (27 girls, 22 boys, mean age 14.6 ys). Pts were divided into groups depending on: I) time after rTx (Sys), 2) serum creatinine (10mg/ma/day). Additionally we separeted 2 groups of pts with hypertension in relation to antihypertensive treatment: nifedipine (2Opts) or acebutolol (1Opts). Results: I) only average values of TO and VLDL were higher than upper limit standarts in all groups, 2) we did not find any statistically significant differences between groups in relation to time after rTx, s-creatinine, immunosuppressive therapy and hypertensive therapy 3) we found statistically significant higher values of TC, PL LDL and apoB in pts who received more than 10mg/mZ/day of prednisone. Department of Nephrology, Dialysis and Transplantation; Child Health Center; 04-736Warsaw, Poland.

P244 PHARMACOKINETICS OF THE NEW MICROEMULSlON FORMULATION OF CSA IN RENAL TRANSPLANT RECIPIENTS UNDER SIX YEARS A. BOkenkamp, G. Offner, P.F. Hoyer, U.Vester, J. Brodehl Background: Absorption of the Sandimmun| preparation of CsA is greatly influenced by concomitant food intake. Recently Neoral| a new microemulsion formulation of CsA with a more predictable pattern of absorption was introduced. Both in adults and adolescents accelerated absorption with peak levels found 1 hour post ingestion has been demonstrated with Neoral| Small children are known to have higher clearance rates of CsA than adults. Aim of the study was to characterize the pharmacoldnetlcs of Neoral| in children under 6 years of age. Patients and methods: 10 renal transplant recipients with a median age of 4.8 yrs [1.8 to 5.8] are switched fromSandimmun| to Neoral| at a conversion ratio of 1:0.9. One week after conversion a pharmacokinetic profile of CsA is performed. CsA levels are measured in hemolyzed whole blood by a monoelonal assay. Results: Preliminary results are availble from 5 patients. Median peak CsA concentration was 852 1400-r ng/ml [496 to 1342], it was found 1 hr [0.5 to 2] post ingestion. The area under the concentrationlime curve (AUC) was 3761 ngohr/ml [2190 to 4381 ] and correlated with the trough level at 12hrs (r=0.88, p<0.05). The trough level was 72 0 1 2 3 4 5 6 7 8 9 101112 ng/ml [42 to 152]. time post ingestion [hrs] Conclusion: These data resemble the profiles recorded in adult and adolescent patients. Therefore a modification of dosage intervals does not appear to be necessary when switching young children to the Neoral| formulation of CsA. KinderkUnik. MedizinischeHochschuleHannover,0-30623 Hannover,FRG

Cl16

P245

P246

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MYELODYSPLASTIC SYNDROME ( MDS ) WITH MONOSOMY 7 IN A RENAL TRANSPLANT RECIPIENT. F. JANSSEN, B. RENNEBOOG, V. HANSEN, M HALL, P. HEIMANN, A.FERSTER, Th. SCHURMANS, P. KINNAERT. Hopital universitaire des enfants - Reine Fabiola. Universit6 libre de Bruxelles - BELGIUM. Cytogenetic abnormalities have been described after chronic Azathioprine ( AZA ) treatment. We report a case of monosomy 7, a preleukemic state, in a 19 years old transplant recipient which was reversible after cessation of AZA administration..The patient was suffering of congenital spine bifida with a neurogenic bladder. Hemodialysis was started at the age of 9 and a first renal transplantation was performed at the age of 12. The kidney functioned for 15 months and the child was taken back to hemodialysis. The second transplant is still functioning after 5 years and before the present episode, the patient received 2 mg / kg / day of AZA and 10mg / day prednisolone. She was admitted 4 months ago.for anemia and presented with the following results : Hb 4.6 g/dl, Hematocrit 14.2%, MCV 96.6 fl, WBC 4200 / mm ~, Plat 307000 / m m ~, negative Coombs test, normal erythrocytic enzymes, Vit. B12 and folicacid were increased, viral serology was not contributive. 8one marrow ( BM ) aspiration showed a hypocellutar marrow, dyserythropoiesis and dysgranulopoiesis consistent with refractory anemia with ring sideroblasts, a type of myelodysplastic syndrome ( MDS ). Cytogenetic studies on BM cells showed a 45 XX,-7 kariotype in 3 mitoses. Fluorescent in situ hybridization revealed several other BM cells with monosomy 7 confirming the existence of a myelodysplastic cells clone. The patient received a single blood transfusion, AZA was stopped and replaced by ciclosporine. Two weeks later, the hematologic values had improved : Hb 103 g/dl, Hematocrit 33%, reticulocyte count 1.1%. A new BM examination was performed 4 months after cessation of AZA treatment, it showed a normal erythropoiesis and a 46 XX karyotype without monosomy 7 suggesting the cure of a preleukemic state.

....... F~I

venal ~an~plan~,.

P247

P248

BODY COMPOSITION IN CHILDREN AFTER RENAL TRANSPLANTATION J Feber, P BraiUon, MH Said, L David, P Cochat Unit6 de N6phrologie P6diatdque, HSpital E Herriot, Lyon, France and l.st Pediatric Clinic, University Hospital Motol, Prague, Czech Republic

PROTEINURIA AND ENZYMURIA AFTER TRANSPLANTATION J.HH.Ehrich*, G. Filler*,U. Wurster**,N.Kehring**

Dual energy X-ray absorptiometry (DEXA) can be used to measure whole body bone mineral content, lean body mass (LBM) and fat body mass (FBM). Using this technique we have foUowed the evolntion of LBM and FBM in children after renal transplantation (Tx) treated with prednisone, azathioprine and cyclosporine A. We studied 15 children aged 9.4_+5.4 years at the time o f ' I x who were enrolled into a prospective longitudinal study. DEXA was performed within 6 months preceding Tx (M0) and repeated 3, 6 and 12 months after Tx (M3, M6 and M12, respectively). LBM and FBM are expressed in percentages of total body mass measured by DEXA. Body mass index (BMI) was calculated for all time periods and transformed into SDS for normal children population (RollandCachera, A m J Clin Nutr 1982; 36: 178-84). Statistics used non parametric Wilcoxon test to compare median values. Individual FBM increased by a median of 8.2% (p<0.05) in the first 3 months after Tx, but did not change significantly in the periods M0-M6 and M0-M12 (6.1% and 5.4%, respectively). Similarly, LBM diminished by a median of 7.9% in the period M0-M3 (p<0.05); the decrease was not significant in the periods M0-M6 and M0-M12 (5.6% and 5.5%, respectively). Median increase of BMI was 1.27 SDS in M0-M3 (p<0,01), 2.03 SDS in M0-M6 (p<0.01) and 1.60 SDS in M0-M12 (p<0.01). In conclusion, significant increase of BMI was observed in children during the first year after renal transplantation. Maximal changes were observed during the first three months after transplantation as documented by a marked increase of FBM and decrease of LBM, most probably due to the corticosteroid therapy.

RENAL

Glomerularand tubular proteinuriawere studied in 86 patients (5-26 years) with a stable renal graft function and without infection,rejeetiort, recurrence or denovo glomerulonephritis.Mean proteinuria(total urinary protein, albumin,c~-lmicroglobulin)and enzymuria(N-acetyl-~-D-glugosaminidase)were signific~fly higher than in healthy controls (Table). Ninety-one percent of patients had a pathological proteinuriaor enzymuria.The extent of proteinuriacorrelated with serum creatinineand with the number of antihypertensivesrequired to control medal hypertension. Patients treated with cyelosporine A had an elevated enzymuria and showed more frequently a tubular pattern of proteinuria than patients treated with azathioprine. Four out of eight patients with proteinuria over 1.7g/day/1.73m2 lost their graft within the next year. In summasy,there was a high proportion of childrenwith a pathologicalproteinuriaand enzymuriaafer renal transplantation which correlated with the graf GFR and arterial hypertension.A massiveproteinuriaindicateda poor graft survival. Table. Proteinuriaand enzymuriain 86 patientsafter kidneytransplantation. (c~-l -M = cs 1-mieroglobulin;NAG = N-acetyl-B-D-glucosaminidase).

Transplanted

patients

Healthy

controls Mean (:kSD) Median Range 95th Perc. 431 (4-541) 233 42-3320 160 3-2220 30 48 Albumin (mg/g erea3 182 (• 3-182 15 31 (*37) 21 (z-I-M (m~/gere~ 0.4-4.1 1.2 1.5 ( ~ . 8 ) 1.s INAG (U/mmolerea.) *Departmentof PediatricNephrology- HumboldtUniversity- Berlin - German **Departmentof PediatricNephrology- MedicalSchool- Harmover- Germany iProtein (mg/g erea.)

C 117 P249 R E N A L F U N C T I O N IN R E L A T I O N TO D O N O R A N D RECIPIENT SEX AND A G E IN C H I L D R E N AFFER KIDNEY TRANSPLANTATION (TX) U. Berg*, A-B. Bohtin* and G. Tyd6n** The aim o f the study was to evaluate the influence o f donor and recipient sex and age on renal function in children following kidney tx. Renal function was evaluated 3 months after kidney tx and thereafter yearly in 71 grafts from 66 children and adolescents (34 boys) aged 0.4-19.6 (median 7.2) years at tx. T i m e of follow-up varied between 1.0 and 12.8 years. 54 grafts were received from living related donors (LD, 30 males) aged 22-67 (median 39) years and 17 from cadaveric donors (CD, 9 males) 3-63 (median 25) years. Renal function was evaluated as glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) determined by the clearances of inulin and P A H . P a t i e n t s w e r e treated w i t h c y c l o s p o r i n e , a z a t h i o p r i n e and prednisolone. GFR and ERPF in absolute values (ml/min) were stable during the first 6 years after tx but when related to body surface area (BSA) decreased from the first to the later investigations. GFR of L D and CD kidneys did not differ significantly but ERPF of the LD grafts was higher during the ftrst 3 years after tx. During the ftrst 3 years GFR and ERPF were higher in children not having experienced any rejection episodes than in those having had rejections. Children with grafts from male donors had significantly (around 10 ml/min per 1.73 m2) higher GFR during the first 2 years after tx and significantly higher ERPF 1-4 years after tx than those with grafts from female donors. Children with grafts from donors >40 years of age had lower GFR than those with grafts from y o u n g e r donors. One and 3 years after tx there was a significant inverse correlation between GFR related to BSA and donor age. There was no difference in renal function between male an female recipients. In recipients <12 years o f age GFR decreased with time, whereas in those > 12 years GFR remained stable. In conclusion, GFR in children after k i d n e y tx was highest in children receiving grafts from male donors <40 years of age and in those not having experienced any rejection episodes. Deps of Pediatrics* and Transplantation Surgery**, H u d d i n g e Hospital, Sweden

P251 RENAL EFFECTS OF l:1 CONVERSION FROM SANDIMMUN | TO SANDIMMUN NEORAL | AFFER LIVER TRANSPLANTATION IN CHILDREN : ADMINISTRATION IN TWO OR THREE DAILY DOSES ? C. Holmberg, J.Laine, K.Hoppu, H.Jalanko and K.ROnnholm Purpose: In comparison to the "old" cyclosporine (Sandimmun| Sandimmun Neoral| is more rapidly absorbed from the GI-tmct, and there is less variation in the absorption. Better absorption leads to earlier and higher peak trough blood drug concentrations. Administration of Neoral| in 3 daily doses results in more stable 24-h, and lower maximum concentrations than administration in 2 doses when the same target concentrations are used. Avoidance of very high peak concentrations might be beneficial in reducing side-effects. The purpose of the study was to investigate the renal effects of a 1:1 conversion to Sandimmun Neoral| after liver transplantation in children and to determine the role of drag dosing. Methods/materiah 1:1 switch from Sandimmun| to Sandimmun Neoral| was performed in 22 liver transplanted children. 11 received cyclosporine in 2 and 11 in 3 daily doses. Graft and renal function was investigated before the switch and after 6 months. 51Cr-EDTA- and PAH-clearances and renal handling of potassium and arate were studied. Currently 10 recipients (mean age at transplantation 9.3 yrs, mean time between tx and the switch 2 yrs) have been studied at 6 months (the rest within next 2 rot). 6 received cyclospotine in 2, and 4 in 3 daily doses. Results: The mean trough blood cyclosporine concentration was 118 ng/L at baseline and 103 at 6 mo (p=ns). The mean dose (mg/kg/d) was 5.2 at baseline (Sandimman| and 5.4 at 6 mo (Sandimmun Neoral| Graft function was stable in all patients. Mean serum alanine aminotransferase was 41 IU/L at baseline and 45 at 6 rot. The mean GFR was stable: 103 (range 72-147) at baseline, 98 (68-154) ml/min/1.73m2 at 6 mo (p=ns). However, 4 of the 6 patients receiving cyclosporine in 2 daily doses showed a 15-38% reduction in GFR with the mean (all 6 pts) decreasing from 109 to 93 (p=0.17). In 3/4 patients on 3 daily doses GFR showed slight increase. Significant changes in PAil-clearances were not seen. Serum urate increased in 7 patients, but more in the patients on 2 daily doses (mean 307p.mo|IL at baseline and 363 at 6 rot, p=0.06). Hyperariceima (serum urate >330~mol/L) was seen in 4 patients at 6 mo (3 on 2 doses). Serum potassium concentration increased in 5 of the 6 patients on 2 daily doses and in 2 on 3 daily doses. Conclusion: Renal function was good after conversion. However, so far 4 of 6 patients receiving Sandimmun Neural| in 2 daily doses presented with reduced GFR 6 months after the switch. Our data suggest that Sandimman Neoral| should be administered in 3 daily doses in children in order to ensure optimal kidney function. Children's Hospital, University of Helsinki - Helsinki - Finland

P250 SIMULTANEOUS HEART AND KIDNEY TRANSPLANT IN A CHILD. I. Elshihabi, G. Halff, J. Calhoon, D. Kaspar. We present the very interesting case history of a young girl who underwent combined cadaveric orthotopic heart and renal transplant. By literature review, she is the youngest combined cardiac and ranal transplant recipient to date. J.M. is a 13 year old hispanic female who presented at age 11 with a two week history of fatigue, edema, and hypertension. U/A: 2+ protein, 3+ blood. I-lb 8.3 gm/dl, Hot 24.4%. BUN 41 mg/dl, creatinine 4.7 mg/dl, albumin 2.1 g/dl. C3, C4, and CH50 were all low. ANA was negative. Biopsy revealed membranoproliferative glomerulonephritis (MPGN), Type II dense deposit disease (D.D.D.) with cresents. She was declared ESRD and hemodialysis (HD) was initiated. After several ER visits for puhnonary edema despite recent HIg, a cardiac consultation and echocardiogrmn showed left atrial and ventricular enlargement with a shortening fraction of 20%. She underwent hemodialysis for one year and was re-evaluated by Cardiology via cardiac catheterization and a cardiac muscle biopsy. It showed idiopathic terminal congestive cardiomyopathy with a shortening fraction of 8% and reversible pulmonary hypertension. She was placed on the waiting list for a combined heart/kidney transplant. Within 18 months she received a cadaveric orthotopic cardiac and renal transplant. Cardiac transplantation occurred first with a pump time of two hours, 3 minutes and cold ischemic time of one hour, fifteen minutes. Renal transplantation started once the patient was stabilized. The kidney allograft made 453 cc of urine in the first hour post transplantation and 650 cc in the second hour. Fre-op she received Imuran 2.5 m g / k g / d a y . Intraoperatively she received Solu-Medrol 15 m g / k g / d a y , and OKT3 10 mg. Cyclosporin was initiated at 15 m g / k g / d a y on post-op day #2. She was extubated within 24 hours. Her creatinine returned to baseline of 0.7 within 72 hours. Fourteen months post transplant laboratory was significant for a creatinine of 1.5 rising to 2.8/63. She underwent percutaneous renal biopsy which showed recurrence of MPGN, Type II (D.D.D.). Pulse steroids were initiated (Solu-Medrol 500 mg IV at four doses). Her urine output picked up and creatinine decreased. She was discharged on hospital day #9 with a creatinine of 1.2. Conclusion: We report an association of end stage renal disease secondary to membranoproliferative glomerulonephritis with terminal idiopathic congestive cardiomyopathy. Recurrence of membranoproliferative glomerulonephritis is usually slow, but in this case it was rapid. This patient is the youngest living recipient of a combined heart and kidney transplant.

P252 RENAL REPLACEMENTTHERAPY IN CHILDREN J. Martinez.* Grupo de transplantes, Facultad de Medicina Universidad de Antioquia- Hospital San Vicente de Paul. Through a 10 year period until June 1994 we have performed 42 kidney transplants and 22 patients have been treated with continuous ambulatory peritoneal dialysis (CAPD). Urological abnormalities and pyelonephritis were the most frequent causes of end stage renal disease. Mean age for CAPD patients was 10.3 (range 8 months to 13 years), Mean time on dialysis was 16 months/patient. Catheters survival was 95.5% and 91% after I and 2 years and only 3 patients died during d i a l y t i c therapy. P e r i t o n i t i s rate was one for 8.5 patient-months. Thirteen of these patients have received kidney transplants, 37 of 42 were l i v i n g related donor transplants; 26 patients had pretransplant dialysis, 21 of them with CAPD and 5 with hemodialysis. Twelve of 37 l i v i n g donors recipients were treated with donor specific transfusions, AZA and prednisone and 25 received t r i p l e therapy including Cyclosporine, 8mg/kg, tapered to 3mg/kg by 2 months. Cadaverrecipients received t r i p l e therapy. Patient survival was 92% after the second post-transplant year and graft survival was 84, 74, 68, 64 and 55% from one to five years. Low Cyclosporine doses can explain the absence of s i g n i f i c a t i v e difference in graft survival in the two treatment groups. *Servicio de Pediatria. Facultad de Medicina, Universidad de Antioquia. Medellin, Colombia.

C 118 P254

1'253

CUMULATIVE EXPERIENCE WITH RENAL TRANSPLANTATION CHILDREN IN BANGALORE, INDIA. ~r S~ BallalL Dr S. S u n d a r , D r N. T a l w a l k a r , D r K. P h a d k e ~ Bangalore Nephrology Study M.S. Ramalah ~nstltute of Nephro-Urology, B a n g a l o r e 560 054, India.

IN

group,

O v e r l a s t s i x years, t h i r t y - s e v e n renal transplantations were performed in children below 18 y e a r s o f age, o u t o f w h i c h t w o w e r e s e c o n d

transplants. TWenty-six were males, eleven were females. Five were below 5 years of age, eleven between 5-10 years, 21 between 10-18 years. Ten c h i l d r e n w e r e b e t w e e n 1 0 - 1 5 kg, 23 were b e t w e e n 1 5 - 2 5 kg, 4 c h i l d r e n > 2 5 kg. K i d n e y d o n o r w a s mother (11 c a s e s ) ~ f a t h e r ( 6 ) , b r o t h e r ( 2 ) , a u n t (I), llve unrelated (17), S e v e n c h i l d r e n u n d e r w e n t preemptive renal transplantation. 23 children had u n d e r l y i n g g l o m e r u l a r d i s e a s e as t h e c a u s e f o r e n d stage renal disease (ESRD). F o u r t e e n c h i l d r e n h a d tubulolnterstltial d i s e a s e as t h e c a u s e o f E S R D . TTiple immunosuppression w a s u s e d in all e x c e p t t w c cases w h o d i d n o t r e c e i v e c y c l o s p o r i n e . F o l l o w u p

period ranged between 6 months to 68 months with mean followup 23.8 m o n t h s . N i n e e p i s o d e s o f a c u t e rejection were encountered includingone hyperacute rejection, 3 did not respond to methylprednisolone 9h l c h was u s e d as a n t i r e j e c t i o n d r u g . F o u r p a t i e n t s ~ e v e l o p e d c h r o n i c r e j e c t i o n r e s u l t i n g in g r a f t loss. D n e y e a r g r a f t & p a t i e n t s u r v i v a l w a s 83%. 2 y e a r s graft & patient survival was 70%. Poor linear growth was identified as a p r o b l e m e s p e c i a l l y i n c h i l d r e n >8 years. E x c e l l e n t r e h a b i l i t a t i o n w a s o b t a i n e d i n

most children with functioning grafts.

P255

OUTCOME OF~ P E D I A T R I C DURING

LAST

RENAL

TRANSPLANTS

11 Y E A R S

W. Mizushima*' ***, H. Kawaguchi*, IvL Hattori *, Y. Komatsu*, Y.Takeda*r K. Ito*~ K. Sonda*r K. Tanabe*r K. Ota*r K. Takaha~** We used cielosporin(CyA )as a major immunosupressant in pediatric renal transplantation, aad in some cases FK506 was used due to CyA nephrotoxicity. The purpose of this study is to evaluate long-term outcome of renal transplantation(RTx) in children treated with new immunosupressants in our institute. Ninty-seven renal transplantations (51 boys and 42 girls, 4 children received second RTx) were performed from Apr. 1983 to Dec. 1994. Eighty one grafts were given from living related and 16 from cadaveric donors. These included 3 preemptive, 7 ABe blood type incompatible, and 17 low body weight children less than 15Kg. The original renal diseases were congenital in 35 children (renal hypo-dysplasea: 17 etc.) and acquired in 58 children (focal glomerulosclerosis: 14 etc.). Total patient survival rate was 96.7% at 10 years after RTx and the graft survival rams ware 85.3%, 78.2%, 67.5% and 55.7 % at 1, 3, 5, 10 years, respectively. Glaft survial rotes between children over 15Kg and those under 15Kg were not significantly different. Immediate recurrence of focal glomerulosclerosis following RTx was observed in 7 out of 15 cases of the disease. Among those patients, two showed rapid decline in graft renal function. Evaluation of cardiac functions by echocardiography and water loading test, were useful in determing an indication of RTx. * Depts. of Padiattic Nephrology, Surgery lit, and Urology, Kidney Center, Tokyo Women's Medical College **Niigata University Department of Urology ***Musashisakai Ekimae Clinic

P256

REI'IAL TRAN.qPI.ANTATION I N CHII.DREN WITIiOtlT PI~EVIOUS D I A L Y T I C TIIERAPY . Pofialoza J . T u l . ' c o n l A . D I i I z M.Adl'/l~Jna M. Bl~JorleS L.Mondi.lahorT.U F.Dolflnclo N.

ETHICAL AND PSYCHOLOGICAL ASPECTS OF PEDIATRIC LIVING-DONOR-KIDNEY-TRANSPLANTATION G. We]if*, J. H. H. Elmch**, J. Brodehl*

P.eI]~ ~_ t L-~llS[31~llt~ t iOl] i-~lil~i :'~S t h e t ]?0-~ t IIIGDt of c h o i c e for end-stag§ [enr ,JJ ~elw;~, I13 the last y@aFs l:her~ W<'~ al~I ]nc!rm,~9:~l"lr[I IqllD~b~l- Of l i v e - r e ] a t e d d o n o r kldn,~y I:r,~inspltult::: in chl ] dren whithout dialytic therapy prior ~

Currently, there is a highly controver,:ial discussion about the standards and modes of organ transplantation and about the reliability, of braindeath diagnosis in several European countries. This discussion reflects multiple insecurities and sceptical attitudes in the public as well as among health care providers, It seems to seriously aggravate the shortage of transplantable organs. Among other factors, tl~s shortage is likely to increase the pressure on parents of children with end-stage renal failure towards living organ donation. In some families living organ donation can lead to psycliosocial problems, such as dependency conflicts, or serious sequelae of non-compliance. There arise several ethical indications for a pre-transplantation psychosocial assessment, for instance, pre-existing dysfunctional family patterns, clarification of undue pressure towards organ donation, or the anticipatory prevention and reduction of possible risks of non-compliance. Careful consideration of systemic and intercommunicative treatment conditions, comprehensive information, and the establishment of trust are inalienable prerequirements in order to ensure the involved persons' autonomy, adherence, and consequently optimal treatment resul~ Potential ethical conflict constellations can be elucidated if clarified along basic ethical guidelines like "to put the patient's welfare in first place', "to preserve life', "not to do any harm to the patient', "to respect the human dignity', and "to be and to remain trustworthy". However, whereas the medical examination of the potential donor and the recipient is mandatory and ethical, a psychological inquiry could be unethical in case it is pursued without sufficient clarification of the patients' and / or families" motivation for such an inquiry.

tz'aDsplentation

Between decembmr ]988 alad decen~ber 1994 . 163 children r e c e iv,9,J 169 l<.i dn~y t YO n,'7:I-,[ an t a, 82 c]]ildren(48Z)frum cadaveric d o n o r s e n d 87[529{ from l i v i n g r e l a t e d d o n e r s We r_mtro~pective]y evaluated 21 chil,-[ren w h o did not recelv~,J a n y d i a l y t i c therapy prior transplantation t.,'i t h a l i v i n g r ela t~:,J d o n o r ]
/',. ] 2".,~.':? . .,~ 7"..2",~.%,! t ]'y2~,~

*Working Group of Pediatric Psychology, Dept_ of Pediatric Nephrology and Metabolic Diseases (Head: ? r o f Dr. L Brodehl), Kinderklinik, Medizinlsche Hochschule, 30623 Haunover; ~-*Depr_ of Pediatric Nephrology, Charite, 10098 Berlin. FRG.

C 119 P257 RESPONSE TO DIPHTHERIA- AND TETANUS TOXOID VACCINATION IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS A. BOkenkamp, B. Enke, G. Offner, P. Bartmann', J. Brodehl Background: Little is known about the effectiveness of diphtheria and tetanus vaccination in pediatric renal transplant recipients. Patients and methods: 39 children (age 12.9 _+3.4 yrs, time post transplan. tation 3.5 -+ 2.1 yrs) had recieved a complete primary immunization 8.9 _+4.1 years before transplantation. Immunosuppressive therapy consisted of CsA/ prednisone in 15 (39%), CsNprednisonelazathiopdne in 22 (56%) and FK 506/prednisone in 2 (5%). After informed consent a booster of 0.5 ml Tdtoxoid (Behring, Marburg, FRG) was administered. Antibody levels against diphtheria and tetanus toxin were measured by ELISA before and 4 to 8 weeks after booster immunization. Antibody levels greater than 0.1 U/ml were considered protective. Results: Prior to the booster immunization, 16 children (41%) had protective antibody levels against diphtheria and 33 (85%) against tetanus. After the booster vaccination protective levels were found in 37 patients (95%) against diphtheria and all the children against tetanus Antibody levels before and after booster vaccination are shown in the table: Diphtheria (U/ml) Tetanus (U/ml) pre post pre post geometr, mean 0,09 1,72 0,54 9,12 25th centile 0,02 0,98 0,23 4,87 i75th centile 0,31 3,91 2,00 20,30 Comparing the different immunosuppressive regimens there was no significant difference in the antibody response following booster vaccination. No severe side effects or acute rejection episodes were observed. Conclusion: After renal transplantation a diphtheria-tetanus booster vaccina[ion is effective. The study is being extended to analyse antibody levels at 6 months after the booster in order to assess whether the duration of immunity is comparable with healthy children. Kinderklinik, Medizinische Hochschule Hannover, D-30623 Hannover,FRG * Universit,~tskinderklinik Bonn, D-53113 Bonn, FRG

POSTER

SESSION

- (P) - M i n e r a l M e t a b o l i s m P259

P258 EFFECT OF HYDROCHLOROTHIAZID (HOT) AND INDOMETHACIN (IM) ON THE CALCIUM (CA)-EXCRETION IN CHILDREN WITH NEPHROCALCINO61S(NO) G. R6nnefarth 1, H...J. Seyberth 2, J. Mlaselwitz 1 To prevent progression of NC the achievement of normocalciuria is aimed at. In 12 children (9 boys) suffering from idiopathic hypercalciuria (IHC) and NC, Ca and prostaglandin E2 (PGE2) in the urine, 1,25-(OH)2 D and PTH in the serum were investigated before therapy as well as during HCT-and IM-therepies under the condition of a defined diet. The excretion of PGE2 was normal in 7 children (group 1) and increased In 5 children (group 2). There was a significant difference with respect to the CaJCrea ratio (rag/rag) between both groups under fasting (o,20 + 0,08 to 0,40 + 0,23; p 9 0,05) and under Ca-loading (0,35 + 0,07 to 0,56 + 0,24; p < 0,05). Between Ca/Crea ratio and urinary PGE 2 was a positive correlation (r = 0,73; p < 0,01). The PGE2 (ng/h/1,73 m2) and Ca-exckretion (mmol/kg/d) during HCT- and IM-theraplas are shown in the table. The Ca-excretion declined significantly during the HCT-therepie in goup 1 only. In spite of PGE2-reduotion dudng the HCT- as well as the IM-therapias the oalcluda remained unchanged in group 2. 1,25-(OH)2 D showed values in the upperlimit of normal range without significant differences between the two groups and the difference therapies. PTH levels were normal except in 2 children with moderate decrease of GFR.

withhouttherapy HCT ~otm I tvoun2 =nmm1 ~rOLm2 PGE2 8.3 + 3,0 62,8+31,9 7,2+2,5 28,9• Ca 0.13+0,05a 0,17+0,05 0,06~.0,02ab 0,16-+.0.06b a: p < 0,05; b: p 9 0,01

IM ~rou~t ~rouu 2 14.2+11,1 8,7+7,8 0,14-+-0,08 0.13-+-0,04

Conclualone: 1. On the basis of the determination of the udnary PGE2 children with IHC can be divided into 2 groups, such with elevated and such with normal exkretlon. 2. The determination of the urinyry PGE2 is recommended, if treatment of IHC is indicated. 3. Only in patients with normal udnary PGE2 C a excretion can be normalized by means of HCT-, but not by means of IM-therapies.

t Klinik for Kinder. und Jugendmedizin "J. Ibrahim' KochstraSe 2, D-07740 Jena 2 Universit~tskinderklinik, DeutschhausstraSe 12, D-35033 Marburg

THE CALCIUM TO CREATININE AND URIC ACID TO CREATININE CONCENTRATION RATIOS OF A SINGLE VOIDED UIRNE SPECIMEN IN CHILDREN M.G.M.G, Penido, J.S.S. Diniz, M.L.S.F. Moreira, M.M.M. Guimaries, R. Barbosa. Hypercalciuria a n d Hyperuricosuria are common metabolic abnormalities frequently present in children with nephrolithiasis. The conventional diagnostic criterion for theses diagnosis is absolute quantity of calcium and uric acid found in 24h urine collection. It has 9 therefore been suggested the measurement of the calcium to creatlnine and uric acid to creatinine concentrations ratios in a morning urine samples. W e measured calcium-creatinine(UCa/Cr) a n d uric acidcreatinine(UA/Cr) ratios in urine samples collected from 114 children. The m e a n was 0.12(mg/I per rag/l) for UCa/Cr a n d the mean was 0.78(mg/! per rag/l) for UAJCr. The 95th percentile value was 0.36 for UCa/Cr and 1.34 for UAJCr. Significant positive correlation between 24h urinary calcium excretion and uric acid excretion with UCa/Cr and UA/Cr ratios was found.(r: 0.2088, p: 0.03 and r: 0.3937, p: 0.01) This study d a t a provides additional reference values for urinary excretion of calcium and uric acid.

UnMade de Nefralogia Pediitrica do Hospital das Cllnicas da U F M G Belo Horizonte - Minas Gerais - BrasH.

C 120 P260

P261

AN UNUSUAL CASE OF HYPERCALCEMIA, NORMAL L O W CALCIURIA, WITH LOW PARATHYROID HORMONE AND HIGH 1,25(OII)2D 3 SECRETION. M.G. Brunette*, R. Kremer**, J. Laehapelle*, J. Saintonge*

A seven day old male baby was hospitalized for a syndrome associating a left ecehimotic testis, left kidney enlargement, gross hematuria, hypoplaquettosis (71 000 pl) and leucoeytosis (69 000 WBC). Two eomecutive ultrasound echos showed enlarged left kidney with zones of hyperechogenicity suggestive of small calcifications. A doppler examination after a seven day evolution failed to show a left renal vein thrombosis. During the subsequent twenty months, the child showed an hyperealeemia (plasma Ca from 2.6 to 2.9 raM) despite a normal protein concentration, (73 g/l) a normal phosphatemia (plasma Pi 1.87 raM), a normal-low calcinria (Ca/creat rag/rag 0.9). Parathyroid hormone (intact molecule), measured in two occasions was low: < 1.8 and 1.9 pM (N 1.4 to 5.7). Whereas the 25 OH D~ was within the normal range: 41 and 83 nM (N: 30-115 ruM) the 1,25(OH)2D3 was above the two standard deviation values: 121 pM (N: 72-120 pM). Finally, plasma calcitonin concentrations were low in two occasions: < 10 and 3,8 ng/l (N: 3-26). Follow up showed a consistent hyperealeemia, and revealed after few months, bilateral kidney calcifications, as well as salx oerebri calcification. The child is slightly mentally retarded but does not have peculiar facies. Caleemia was measured in 10 immediate family members and did not show any abnormal value. We suggest that this syndrome reflects an abnormal sensing of let 25 OH I)3 hydroxylase to calcium. *Maisonneuve-Rosemont Hospital, University of Montreal. **Royal Victoria Hospital, McGill University, Montreal, Canada.

P262

UROI.IIIqIAS]S IN CHILDHOOD. CLINICAL PRESENTATION AND' METABOLIC STUDY. Michelle IVI. I..bpez*, Lyssis A. Castillo*, Juan B. ChtWez*, Carmen I. R a m o n e s * Urolithinsis has been increaginEin frequency among children. We describe the clinicad and m ~ aspects of this entity in 242 dailthen (126 girls and 116 boys), aged between 1 month and 12 years, and whom were followed at the outpatient clinic from January 93 to December 93. The most frequent clinical present~ions were microscopic hematuria (72 %), urinary lmet infection (49 %), gross henmtutia (39 %), and 8])domirml~ (40%). Forty children had passed one or more stones. In 114 children (47 %) there was a family history,of urolithiasis. Diag~sis was confirraed by. renal ultrasound in 92% of the cases and by intravenous pyelography in 19 %. Renal functional assessment included: urina~ calcium excretion (urinary calcium/crealinine ratio or 24 hour urinary caldum excretion), uric acid fractional excretion, blood add base status, sernm creafinine and electrolytes, urinary-blood pCOZ with alkaline urine, urinary net acid excretion with amonium chloride loading. Results were as follows: Mean SD Min Max C~JCr u 0.32 0.2 0.01 1.8 Ca u (rag/K/d) 4.64 2.62 0.3 13.8 Uric add FE(%) 1029 7.99 0.3 50 U-B pep2 ( ~ 12.02 11.98 -18 52 UVH (ME/sin/1.73) 68.63 33.63 6.4 192 The following abnormalities were found: hypercalciuria (urinary calcium/creatinine ratio > 0.11 or 24 hour urinal, calcium excretion > 2 mg/gg/day ), 231 children (95%); hyperuricosutia (uric acid frsctinnsl excretion > 14%) 53 children (22%); complete distal tubular acidosis, 98 children (40%); incomplete distal tubular acidosis, 99 children (41%). Fifty six percent of the patients, had radiological findings consistent with medullary sponge kidn~. Therapeutical aplnV~h consisted in dietary' modifications (78 %), potassium cilrate (63%).. thiszides,(56%) and citric acid + sodium citrate (13%). During follow-up (6 months - 13 years), there was improvement or tolal remission of clinical manifestations in 94 % of the patients. We conclude that in most children with urofithiasis it is possible to identhqya metabolic disturbance a~ an etiologic factor and that long lasting clinical improvement can be achieved with appmpiate treatment * Dept. of Nephrology. Hospital de Nifios J. M. de los Rips. Caracas. Venezuela_

P263 UROLITHIASIG IN ARGENTINEAN CHILDREN R.C.Rahsan, F.D,Spizzirri $ No are presenting the clinical features of % children with urolithiaaie evaluated and treated in our Unit from 1972 to 1993. There were 64 boys and 32 girls. In all cases the stones were documented either radiographicall/, by ulLrasonogrmphy or were seen when eliminated, Age ranged from 2 months to 19 years (mean8.7 years). R family history of lithiasis wan present in 42.3% of the casss, The most commonpresenting features were abdominal or flank pain, gross heeaturia, urinary tract infection (UTI} and lower urinary tract symptoms. UTI at presentation or during evolution was recorded in 57.8% of the cases, Metabolic studies shosed abnormal findings in 4& out of G3 cases (55.4%). Hypercalciuria (43.4X) and hyperuricosuria(25.32), alone o in combination were the most commonmetabolic abnormalities. Calcium salts were the most commoncomponents of the calculi, being more frecuently localized to the kidneys (55~) than in the ureters (23%)~ bladder (II,2X) or urethra (8,4~). Only in 14 cases the lithiasis was associated with malformations of the urinary tract. The calculi were spontaneously eliminated in 33 children while 31 were operated and 10 underwent extracorporeal shock wave lithotripsy. CONCLUGIQNG:I) A family history of lithiasis was pre~ent in ~2.3~ of the patients. 21 UTI was found to be present, before or during the recognition of the urolithiasis in 57.8~ of the patients, 3] More than half (55.4X) showed meLhabolic abnormalities, 43,3X were hypercalciuric. 4) Calcium salts were the most frequent calculi components. A complet evaluation of the metabolic abnormalities or the conditions that lead to the developement of urinary calculi~ are essential for a rational treatment of this pathology in childhood, and, of most importance, for its prevention. IRENAL U N I T 14

-

HOSPITALDE NIROS - LA PLATA(ARGENTINA)

URINARY CALCIUMOXALATE SATURATION IN HEALTHY INFANTS AND CHILDREN B. Hoppel, 2, Andrea Jahnen2, D. Bach2, A. Hesse2 A number of factors influence the development of renal calculi. Increased urinary excretion of a single lithogenie, or decreased excretion of an inhibitory parameter may explain why patients formed renal calculi. But taken all the urinary lithogenic and inhibitory parameters into account, a more specific prediction about the risk of (recurrent) stone disease will be possible. It is essential for a growing calculi that the urine will be supersaturated with respect to the precipitating (= lithogenie) parameter. In a previous work we determined normal age related values for urinary lithogenic and inhibitory substances in infants and children. All these parameters, the urinary volume, pH and specific weight were later included in a computed programs (EQUIL 2) to calculate urinary saturation for ealciumoxalate. This equilibration program may give a clue about the risk for ealeiumoxalate precipitation and crystallization. Results [mean (+/- SEM), total n = 473 ]: Age / years 0 -1 2 -3 4-6 7-9 10 - 12 13 - 15 mean

n= boys gifts 34 16 29 22 72 34 60 31 82 35 43 15 320 153

Urinary calcium- oxalate saturatior boys girls 5.22 (2.86) 2.03 (1.27) 6.51 (3.04) 4.36 (1,71) 6.23 (1.11) 4.15 (lAD 8.84 (3.38) 5.47 (1.55) 7.03 (1.38) 5.49 (1.44) 5.29 (1.37) 3.35 (1.99) 6.72 (0.89) 4.46 (0.64)

Urinary CaOx saturation was always higher in boys than in girls. The saturation increased until age 7-9 in both boys and girls and decreased then ~ain until adolescent values were comparable with infancy. University Children's Hospital, D-50924 Cologne, Germany 2Experimental Urology, Department of Urology, University of D-53127 Bonn, Germany

C 121 P265

P264 RETROSPECTIVE STUDY OF PEDIATRIC UROLITHIASIS (92 C A S E S ) A. Oner*, G. Demircin*, H. Ipek~jio~lu*, M. Biilbiil*, O. (~akmak*, N. Ecin*

Ninety two children with urolithiasis were studied retrospectively according to the clinical pattern and etiological factors between January 1990 and January 1995. Their ages ranged fi'om 2 months to 14 years with a mean age of 6,9 yeats and 56 (60.9%) of them were males, 36 (39.1%) were females. The stones were localised at upper urinary system in 68.5%, at lower urinary system in 14.1% and in both in I2% of the patients while 5 cases were presented after passing the stones. Chemical analysis of the stones was performed to 21 patients showing calcium oxalate (10/21) as the most fl'equent type of stone. Recurrence rate was 15.2% in all patients. Anatomical defect was found in 30.4%, infection in 31.5%, metabolic disot'der in 8.6% of patients as an etiological factor and 27(29.3%) of them were classified as idiopathic. All the patients with anatomical defect had hydronephrosis and pelviureteral junction obstruction (4/28) was the most common defect. Infection slones were most commonly in renal localisation (75.8%) with E. Coil as the pi~cdominant microorganism (57.6%). Earliest presentation (avarage age: 2.7) was seen in metabolic stones all of which were in renal Iocalisation and they had the highest recurrence rate (37.5%). Metabolic defects that were diagnosed were hyperoxaluria (3/8), cystinuria (2/8), purine metabolism defects (2/8) and cystinosis (1/8). Hypercalciuria was present in 16 patients. Lithotomy was performed on 38 (41.3%) patients, nephrcctotny on 2 and ext!'acorporeal shock wave lithotripsy (ESWL) on 3 patients. Medical management and diet therapy according to the etiological factors were applied to some patients. By this study we wanted to show once more that pediatric urolithiasis is not rare in our country and to emphasise that nephrectomy can be prevented by a good man:lgement and fol/ow up of the patients. * Dr. Sami Ulus Children's Hospital, Departments of Nephrology, Pediatric Surgery and Radiology-Ankara-Turkey.

P266

BONE MINERAL DENSITY IN HYPERCALCIURIC CHILDREN: A 5 YEAR FOLLOW-UP H,C. Perrone*, M.M.S. Marone *, A.C. Bianco*, J. Toporovski*, L.F. Malvestiti*, N. Schor** Bone mineral density (BMD) was prospectively evaluated in 46 children with idiopathic hypercalciuria (IH) during a period of 18 to 60 months. Nineteen children presented nephrolithiasis and 27 hematuria in association with IH. Lumbar spine (L2-L4),femoral neck and total body BMD as well as 24h urinary calcium were performed every 6 months. The children were divided into 3 groups: Hypercalciuric controlled children (C, n=22) (those who presented only one hypercalciuric urinary episode); Irregularly Controlled (IC, n=16). (Children who presented normocalciuric and hypercalciuri 9 periods), and Not Controlled (NC, n=8). (Children always hypercalciuric). The results of BMD (1..2-L4)showed for groups C and IC high values compared to NC group (p<0.029 and p<0.025). There were no significant differences between the groups in femoral neck and total body BMD. However, expressing the results as "z" score, groups C and IC had a significant increase in (L2-L4) BMD compared to NC children (p<0.034 and p<0.002). Femoral neck presented significant differences between C and NC groups (p<0.034). Moreover, when it was analyzed for the children who presented (I) nephrolithiasis or (11)hematuria or (111)hematuric children who developed kidney stone, significant differences were observed in total body BMD between groups I and III (p=0.0006) as well as in the "z" score (p=0.056). In summary: 1. Not controlled IH children presented low BMD. 2. It is necessary to do a careful eyaluation of IH children regarding bone status and calcium metabolism in order to prevent bone loss. *Pediatric/Nephrology Department of Santa Casa of S.P. **NeDhroloev Division of Escola Paulista de Medicina.

Pediatric Urolithiasis (PU) in Southern Israel D. Landau1, IL Shalev1. Past works2 have described the epidemiology of pediatric urolithiasis (PU) in Israel, based on analysis of surgically extracted stones. These studies found different prevalences of PU among patients of Arab and Jewish ancestry. Many of the stones in Arab children were located in the bladder, a typical finding for "endemic" stones. Since then, new technologies have changed the therapeutic and diagnostic approach to PU. We summarized our experience with PU during the past 4 years, based on data from patients seen in our clinic, located in the only referral center for southern Israel. It covers a semiarid and hot area, and serves two pediatric populations: Jewish (J) (63%) who are mostly settled in urban conditions and Bedouin (13) (37%), who are Arabs in ancestry, undergoing an urbanization process in the past 20 years. Only cases with well docunaented U were included, and cases with only microhematuria or nephrocalcinosis without stones were excluded. Biochemical analysis of serum and urine was undertaken in most of these children. Stone location and size were assessed by sonography. Results: 53 cases were reviewed, only 41 qualified for analysis (nephrocalcinosis, n=5; incomplete data and other, n=7). [Data in ( ) = SD] Bedo~mn Jewish Total n 32 9 41 Rate (cases/103 at risk) 0.47* 0.08 0.24 Age Onset [months] 46(47) 50(59) 47(49)" % males 61 78 65 Family History of UL [%] 35 22 33 Underlying Disease [%] 48 22 43 Symptomatic onset [%] 69 78 71 Ur-Ca/Creat > 0.25 15/25 5/7 20/32 Ur-UA Excr. Index >0.6 3 13/21 3/6 16/27 Number of Stones 2(2) 1.2(0.4) 1.85(1.87) Stone Diameter[mm]

17.4(22)

10(6)

16.1(20.5)

Bladder stone only 0 0 Ur: urinary; UA: uric acid; * p
P267

BRAZILIAN MULTICENTRIC STUDY OF PEDIATRIC NEPHROLITHIASIS (MULTIPED) Cooperative Group of Nephrologic Centers. Pediatric Department of the Brazilian Society of Nephrology. To be presented by H.C. Perrone In order to evaluate the characteristics of the lithiasic disease among the population of Brazilian children, a cooperative study was organized, unifying the work of 13 medical centers in several states of Brazil. In the present phase the characterization of some clinical aspects of nephrolithiasis was done. Presently 7 medical centers have accepted to participate and we have studied 323 children. Among them, 199 (64%) are male and 124 (36%) female. The age at which the disease was detected ranged from 3 months to 17 years old. Only 3% of this population was asymptomatic. The initial prevailing symptoms were hematuria in 110 patients (34%); abdominal and/or lumbar pain in 90 (28%); hematuria associated with pain in 87 (27%) but only 28 (10%) had lumbar pain (in ; association or not with hematuria). Some other less frequerit symptoms were dysuria in 21 patients (8%); recurring infection of urinary tract in 15 (6%); elimination of calculi in 3 (1%); others symptoms in 1%. Kidney malformations were fqund in a small group of patients (26/323). This multicentric study provides the clinical profile of nephrolithiasis in Brazilian children and also stimulate other centers to study the management of this pathology.

C 122 P268

1'269 METHYL MALON[C ACIDURIA IN ASSOCIATION WITH DISTAL RENAL TUBULAR ACIDOSIS AND NEPHROCALCINOSIS. &Dudley,J. Allen, M E McGraw.

DIETARY EVALUATION IN NEPHROLITHIASIS CHILDREN H.C.Perrone*, D.C.Thomr*, F.Sehor*, L.A.Martini**, J.Toporovski*, N.Schor**

Case report An infant born to consanguineous parents presented at 3 weeks of

Evidence suggests that high intake of animal protein, calcium and dairy products may represent a risk for calcium nepbrolithiasis. Furthermore, dietary patterns have been implicated as major contributors to the high prevalence of urinary stones in several countries. The aim of the present study is to compare the dietary intake of nephrolithiasic and hematuric plus hypercalciuric children with a age matched control group. Dietary intake data for 3 days during the week (except Sunday) were obtained from all patients and controls. Nutrition intake was calculated using a computer program developed in Escola Paulista of Medicina. Results are presented as mean + SE: *p<0.05 vs, CONT

CONT (n=l 1) HEM (n=8) LIT (n=24)

Calories Kcal/kg 63.2+_4.6 52.1+4.1 64.3+6.2

Protein (g/kg) 2.3+-0.2 2.0+_0.2 2.3+0.2

Calcium (mg/24h) 766+-98 398+30* 519+-42

age withfailure to thrive, lnitial inves#gatians revealed a systemic acidosis with impairment of urinary acidification. An ammonium chloride loading test confirmed a distal renal tubular acidosis. There was also evidence of hypercalcaemia (max. serum calcium 3,31mmol/L) and hypercalciuria (urinary Ca:creatinine 2.17). Profound nephrocalcinosis with a medullary distribution was shown on renal ultrasound at the age of six weeks. Urinary organic acid profile revealed the presence of high levels of methylmalonic acid (7601anol/mmol creatinine), which persisted after admim~tral~on of vitamin B12.There was no incease in the other metabolites of propionyl CoA. Plasma MMA values were shown to be raised when the infant was 12 months of age, however, MMA mutase activity in cultured skin fibroblcfts was normal and no defect in propionate incorporation couM be demonstrated. Furthermore an isoleucine load did not increase excretion of urinary MMA and had no effect on plasma levels. Urinary excretion of MMA has remained constant, however, significant improvement of acidosis, hypercalcaemia & hypercalciuria has been observed following administration of citrate supplements and at 14 months the infant is thriving on 75% ile for weight and height and development is normal. Transient neonatal and benign MMA have been describedpreviously but to our knowledge the association of nephrocalcinosis, distal renal tubular acidosis and methylmalonic aciduria has not been observed.

Purine (mg/24h) 89.4+-16.5 105.9+-18.3 1 3 4 6 + 10.5"

CONT=comrol group; HEM=hematuria plus hy0ercalciuria group and LlT=lithiasis group.

Paediatric department, Southmead Hospital Bristol UK.

In this series it was observed that calcium intake for nephrolithiasic and hematuric children was 60% lower than the suggested RDA (1200mg/day). On the basis of these findings we can suggest that prior to prescribe a severe calcium restriction a careful evaluation of all nutrients intake must be done in order to adequatethe individual needs. *Pediatric/Nephrology Department of Santa Casa of S.P **Nephrology Division of Escola Paulista de Medieina.

P270

P271

A NEW PATHOGENESIS OF HYPERCALCIURIA. G.Lama, A.M.Aurino, G.Avino, M.Majorana, L.Valentino and M.Pedull&.

In the 1985 Nakagawa e coll. identified in human urine a glycoprotein (GCI) that inhibitis calcium oxalate crystal growth stronghy. They isolated GCI molecules from the urine of normal subjects and patients with calcium oxalate stones, and reasoned that patiems who form stones could produce GCI molecules that are less inhibitory than normal, or excrete normal GCI in small quantities. GCI may have four different molecular form, which differ in their primary aminoacid sequence or in the contain of gamma carboxyglutamic acid (Gla). Protein eontaing Gla occurs in blood-clotting (II, IX and X), and in bone matrix.The Gla molecules can hind calcium and appear essential for the activity of prothrombin.lt was demonstrated that, like osteocalein, also the urinary Gla protein ihibitis the precipitation of various calcium salts from supersaturated solutions. The concentration of the urinary Gta protein, which inhihitis the calcium precipitation is 16 mg/l. The convertion of glutamil acid residues into gamma carboxyglutamil acid is Vitamin K dependent reaction.We have supposed that deficit Vitamin K can play a role in the genesis of the stones in hyperealciuric children, reducing carboxilation of glutamic acid residues of urinary GCI. Case summary: M.V. (10 years old) was admitted for recurrent abdominal pain. Pathologic case history: numerous episodes of epistaxis. At 11 years old, renal colic with urinary elimination of black material, elastic consistency, lamellar appearance, of about 3 ram: organic calculi. Blood biochemistry, urinalysis and instrumental examinations were normal, except for a reduction of PT and PIT activity(PT 59.4%;aPTT 34.3") and an increase of serum osteocalcin. Renal colics are always more frequent and after 12 months, ultrasound showed bilateral microlithiasis. Epistaxis, persistent reduction of PT and aPTT activity (PT 69.1%; aPTT 36.8"), elevated values of serum osteocalcin (256,7ng/ml;n,v.85-a:16) normality of the laboratory examination induced us to a deficit carboxylyase of Gla proteins for a probabile deficit of Vitamin K. Therefore, we have measured: PT, PIT, blood coagulation factors II, VII, IX, X activity, Prot.C and ProLS, before and post oral somministmtion of Vitamin K(10 mg x 3/die)for three days. The oral load demostmted an increase of 10% about of the basic activity and a reduction of osteocalcin values (120.4 nglm| dosed at 52 ~ hour from the load). It was prescrived oral therapy with Vitamin K 10 mg/day per os for one month. At its interruption, values of the hemocoagulativ tests were: PT 84% aPTT 31.6" and osteocalcin 107.2:ng/ml. Recently his daugheter shows also epistaxis, low PT and aPTT values and on ultrasound bilateral microlithyasis. D e p a r t m e n t o f Pediatrics. II University

Naples

Italy

C H A N G I N G P A T T E R N OF P R I M A R Y H Y P E R O X A L U R I A (PH) E. L e u m a n n , N. K o p p

Prognosis of PH (type i) is considered to be very poor w i t h half of the patients dying before the age of 15 years. However, previous studies were biased in favour of younger and seriously affected patients. We therefore studied all patients with PH t r e a t e d during the last 15 years and residing in Switzerland (pop. 7 mill.), based on a survey. Of the 25 patients observed, 18 were alive in 1994 - 14 (all with type i) on conservative t r e a t m e n t and 4 on renal replacement therapy (RRT). This suggests a prevalence of 2 per mill. population. Diagnosis was usually much delayed (median 8 yrs. after first symptom) except in infants. Eight patients were >20 yrs. old and six already required RRT at the time of diagnosis. Seven p a t i e n t s were detected by chance, 6 by family screening and 1 by abdominal echography. Six patients w e r e p y r i d o x i n sensitive. Diagnosis of PH was made less often during the first half of the o b s e r v a t i o n p e r i o d (A; 7) than during the second part (B; 12). Prognosis has improved over the years: 5 of 13 patients died during p, riod A as opposed to 2 of 20 during period B. Less than one fourth of patients is expected to require RRT before age 15. Conclusions: PH (type I) is underestimated and p r o g n o s i s appears better than hitherto believed. Greater awareness of PH is needed to improve prognosis further both by early diagnosis and intervention. Univ.

Children's

Hospital

- Zurich - Switzerland.

C 123 F272

P273

H Y P O C I T R A T U R I A IN C Y S T I C F I B R O S I S (CF) V.Garc~a-Nieto*, M.Monge*, JL.Fern~ndez-Gonz~lez*, M . S u a r e z * , L.Ortigosa*, C.Oliva*, M.Muros*, H A r m a s * *

A high incidence of nephrocalcinosis has been r e p o r t e d in p a t i e n t s s u f f e r i n g of CF (Bodian 1952; Katz et al. 1988). Although hyperuricosuria, h y p e r c a l c i u r i a and h y p e r o x a l u r i a have been r e p o r t e d in some p a t i e n t s w i t h CF, the p a t h o g e n e s i s of c a l c i c d e p o s i t s at the renal p a r e n c h i m a is not well known. We did not o b s e r v e d i f f e r e n c e s in u r i n a r y e x c r e t i o n of calcium, m a g n e s i u m or o x a l a t e in a g r o u p of c h i l d r e n w i t h CF (n=25; 14V,11M; 9.1• years; 27.7• Kg) in r e l a t i o n to a control g r o u p (C) (n=18; 7 . 6 • years; 31.3• Kg). C h i l d r e n on CF s h o w e d s i g n i f i c a n t d e c r e a s e d levels of uric a c i d c l e a r a n c e (7.6• vs 10.9• ml/min/1.73mZ; p<0.01) and c i t r a t u r i a (454.7 • vs 8 7 6 . 1 • mg/day/ 1.73m2; p<0.001). C i t r a t e / c r e a t i n i n e u r i n a r y r a t i o m e a s u r e d in the first m o r n i n g v o i d i n g was i n v e r s e l y c o r r e l a t e d w i t h w e i g h t (r=-0.53; p<0.05) and w i t h b a s a l fat stool e x c r e t i o n (r=-0.67; p<0.05) and it was d i r e c t l y c o r r e l a t e d w i t h folate p l a s m a t i c levels (r=0.60; p<0.05). H y p o c i t r a t u r i a a s s o c i a t e d to a d i s t a l a c i d i f i c a t i o n d e f e c t was r u l e d out b e c a u s e there w e r e no d i f f e r e n c e s in m a x i m u m pCO 2 in a l k a l i n e u r i n e a f t e r a c e t a z o l a m i d e s t i m u l u s (1000 mg/1 73m 2) in r e l a t i o n to C g r o u p (88.1• vs 8 2 . 0 • mmHg). In summary, some CF p a t i e n t s s h o w e d h y p o c i t r a t u r i a (10/25; 40%). T h i s may favour long term a p p e a r e n c e of n e p h r o c a l c i n o s i s . The o r i g i n may be a b s o r t i v e in r e l a t i o n to p a n c r e a t i c d y s f u n c t i o n of CF, p r o b a b l y by d e c r e a s e d b i c a r b o n a t e c o n c e n t r a t i o n of the p a n c r e a t i c secretion. * H o s p i t a l Ntra. Sra. de la C a n d e l a r i a - T e n e r i f e Canary Islands-Spain ** H o s p i t a l U n i v e r s i t a r i o de C a n a r i a s

P274 URINE CITRATE LEVELS IN HYPERCALCIURIC CHILDREN

N.Caviedes~,L.Torres*,B.Barillas*,A.Bercowsky~,E.Bercowsky*j R.Medrano* and Q.Torres*. The urine citrate is a very important inhibitor of cristalization of calcium salts. It was been reported that the citrate excretion is lower in hypercalciuric than normal patients. 60 hyperealeiuric children (M:35;F:25) divided in two groups (GI:25years;G I~7-12years) were evaluated in terms of: renal funotio~ 24hrs. urine citrate excretion and urine acidification capacity. Children with renal tubular acidosis (RTA) were analized separately. Our results showed: - Renal function was normal in all the patients. - RTA was found in 18 children (30%) and 12 of them (66,6%) coursed with nephrolitiasis. - There was not difference in citrate excretion between both groups, neither normal children. Urine citrate excretion in hyperoaleiuric and RTA patients was signifieately lower than hyperealeiuric group without RTA. URINE CITRATE EXCRETION (mgs/24hra.) Hypercalciuric Group I ( n = 1 9 ) 130.84T67 Group I I ( n = 4 1 ) 141.30•

Hypercalciuric and RTA 60.50• p
Ours re~ults showed than patients with hypercalciuria and RTA coursed with hypoeitraturia and the nephrolitiasis is a more common risk. In eonclution oral citrate salts must be added to conventional treatment. (*) IVSS Hospital "Miguel Perez Carre~o", Servicio de Nefrologia Caracas, Venezuela.

NORMAL VALUES CHILDREN

OF

URINARY

CITRATE

LEVELS

IN

HEALTHY

A. Loreto*,B. Zambrano*,L. Torres*, A. Bercowsky*, E. Bercowsky*, G. Torres*, B. Barillas*, N. C a v i e d e s * The aim of this study was to d e t e r m i n e the normal values of urinary citrate in children. One h u n d r e d and twenty h e a l t h y c h i l d r e n (60 males and 60 females), aged 2-14 years ( 4 = 6 • who came from different social levels were s t u d i e d . They were d i v i d e d into 2 groups:2-7 years, and 8-14 years. Twenty four hours u r i n a r y citrate excretion, creatinine and citrate in f a s t i n g sample urine were measured. The citrate was d e t e r m i n e d by the c i t r a t e - l y a s e technique; and the c r e a t i n i n e by the usual c h o l o r i m e t r i c method. These are the results: 2-7 years: 0.60 +~34 m M o l / 2 4 h ( l 1 9 • mg/24h) 8-14 years: 0.85 • mMol/24h(168.8• mg/24h) w i t h a m e a n value for b o t h groups of : 0.72• 0.42 m M o l / 2 4 h (143• mg/24h i r r e s p e c t i v e to the sex of the c h i l d r e n studied. The 24-hours u r i n a r y citrate was s i g n i f i c a n t l y lower in c h i l d r e n than in adults:( 0.72• vs 1.5• 0.75 mMol/24h( adult values found in V e n e z u e l a by others investigators)). A n d this s h o u l d be taken into account at time of m a k i n g such m e a s u r e m e n t s in children. We found that the value of c i t r a t e - c r e a t i n i n e ratio was 0.44• a l t h o u g h no linear c o r r e l a t i o n was found b e t w e e n this value and the 24h citrate excretion.

* Hospital Fediatricd'-~Jias Toro" Caracas,Venezuela.

C 124 POSTER

S E S S I O N - (P) - H y p e r t e n s i o n

~75

P276

A COMPARISON OF THREE DIFFERENT METHODS OF ESTIMATING GLOMERULAR FILTRATION RATE IN CHILDREN POST RENAL TRANSPLANT. N. AI-Harbi. MD, Department of Child Health, College of Medicine, King Saud University, Abha Saudi Arabia and Prof. D. Lireman MD, Division of Nephrology, Department of Pediatrics, University of British Columbia, B.C. Children's Hospital, Vancouver, BC V6H 3V4 Abstract In 48 renal t r a n s p l a n t e d c h i l d r e n aged 3 - 19 years (33 male and 15 female), g l o m e r u l a r f i l t r a t i o n rate estimated from creatinine clearance involving urine collection over 4 hours in hospital under direct supervision and creatinine clearance predicted from plasma creatinine concentrations and height were compared to glomerular filtration rate (GFK) estimated by 99mTc DTPA clearance. There was a good correlation between the three methods (r=0.8). Measured creatinine clearance and formula creatinine clearance overestimated GFR as measured by 99~ Tc DTPA by an average of 19.7(+SD 21.2) ml/min/l.73m 2 and 21.9(~22.9) ml/min/l.73m-~ respectively. So they should be used with caution to estimate true GFR. In trying to assess the influence of cyclosporine on creatinine secretion by renal tubules, we compared two groups of patients with similar GFR as measured by 9~Tc DTPA; ther~ was no significant difference between the means of creatinine clearance (p<0.54) between the group on cyclosporine and azathioprine and the other on azathioprine alone. It seems therefore that cyclosperine did not cause increased tubular secretion of creatinine leading to overestimation of GFR.

P277

EFFECTS OF THE NOVEL CALCIUM BL O CKER AMLODIPINE GIVEN O N C E - D A I L Y IN RENAL AND P O S T - T R A N S P L A N T H Y P E R T E N S I O N M.G. Bianchetti, R. Laux-End Background and methods: Although the calcium-channel antagonist nifedipine has been used successfully to treat hypertension in children, the short duration of action limits its usefulness as a long-term agent. The novel antagonist amlodpinine, structurally related to nifedipine, has a high oral bioavailability and a long elimination half-time. In adults with chronic hypertension amlodipine given once-daily markedly reduces blood pressure (Murdoch D: Drugs 41: 478-505, 1991). Since no data are available in childhood, amledipine was given for 12 weeks in 12 patients (8 boys and 4 girls, aged 2.8-18 years) with renal (N=8) or pest-transplant (N=4) hypertension. Results: The initial dosage of 5 mg once-daily was adjusted to 10 mg once-daily if necessary (at the end of the study: 5 mg in 2, 10 mg in 9 subjects). Amledipine was withdrawn in a boy who experienced edema and flushing. N Before study Amlodipine for1 week for 3 weeks for 6 weeks for12weeks

Supine Blood Pressure Supine Hart Rate Body Weight mm Hg% BeatsJMinr kg$

12 139-152-173/82-93-101

74-81-96

17.3-24.5-79.3

12 11 11 11

60-82-96 64-82-93 69-80-95 70-81-93

17.5-24.7-79.0 17.2-24.6-79.5 18.0-24.3-79.3 17.7-24.4-80.0

137-150-164/81-90-100 131-144"-166 / 76-90a-96 125-139"-160 / 74-88*-96 119-132"-152/69-85"-89

A P
I~78

ECHOCARDIOGRAPHIC ASSESSMENT OF LEFT VENTRICLE STRUCTURE AND FUNCTION IN ADOLESCENTS WITH SIGNIFICANT ESSENTIAL HYPERTENSION (SEH), Cichocka E. Litwin M., Kawalec W. (intr. T. Wyszyflska )

SUCCESSFUL IMMUNO SUPPRESSIVE TREATMENT IN A CHILD WITH TAKAYASU'S ARTERITIS: A SEVENYEARFOLLOW-UP.

The aim of the study was to evaluate cardiovascular changes in adolescents with significant essential hypertension (SEH) Material: Thirty untreated (mean systolic blood pressure-SBP- 156+8.0, diastolicDBP-88+7.0, MAP-106.1• mmHg, heart rate-HR-93.6+17.9 beats/min), pts (5 girls+25 boys) aged 14 to 16 years (mean age 14.2+1.9 yrs), mean duration of hypertension 2.3_+0.6 yrs and 17 age matched healthy controls (7girls+10 boys, mean age 13.9+1.7 yrs, SBP-122.5_+12.1, DBP-67.8• MAP-86.81+5.6 mmHg) entered and completed the study. Methods: The study protocol included ECHO M-mode, 2D and Doppler measurements: left ventricular dimensions: LVIDd, IVSd, LVPWd, IVSd/LVPWd, RWT; SV, CI, %SF; left ventricular mass index (LVMI); transmitral Doppler flow (diastolic filling parameters- E and A velocities, E/A ratio; total peripheral resistance index (TPRD. Results: ECHO examination in adolescents with SEH in comparison with healthy controls demonstrated significantly* higher IVSd (10.8+1.4 vs 4.74+_0.7 ram), LVPWd (9.3+1.4 vs 4.6• mm), IVSd/LVPWd (1.11+0.29 vs 1.0• RWT (1.14• vs 0.35+0.07), LVMI (68.6_+15.9 vs 51.3_+15.3 G/m2). Concentric cardiac hypertrophy was recognized in 9.7%, IVSd hypertrophy in 19.4%, LVPW hypertrophy in 12.9% of hypertensives. Cardiac index (4.57+_2.5 vs 3.53_+1.0 L/min/m2) and percentage of LV fractional shortening (46.4_+8.0 vs 42.5_+9.0%) were significantly higher than in controls. TPRI and Doppler parameters didn't differ. Conclusions: 1. Left ventricular hypertrophy in adolescents with SEH in early stage is not accopanied by increased TPRI. 2. Systolic and diastolic function of left ventricle in adolescents with SEH in early stage is normal despite of marked hyperkinetic hypertrophic disease. (* p
A 7 year o l d c h i l d presented w i t h a severe form o f Takayasu a r t e r i t i s w i t h two c o n s e c u t i v e episodes i n v o l v i n g the r i g h t t e s t i s and then the l e f t k i d n e y f o u r months l a t e r . The renal a r t e r y o b s t r u c t i o n was accompanied by lumbar and l o i n p a i n , hematuria and h y p e r t e n s i o n . An a o r t o g r a p h y showed a complete o b s t r u c t i o n o f the renal a r t e r y and a narrowing o f the r i g h t s u b c l a v i a n a r t e r y . Plasma r a n i n a c t i v i t y was e x t r e m e l y high. D e s p i t e a f o u r month t r e a t m e n t w i t h ant i h y p e r t e n s i v e drugs, predni sone, procytox and a n t i c o a g u l a n t , the blood p r e s s u r e never r e t u r n e d t o normal and the l e f t renal f u n c t i o n remained c o m p l e t e l y absent, A nephrectomy was performed which immedi a t e l y normal i zed pl asma renin activity and blood p r e s s u r e . The c h i l d was subsequently t r e a t e d w i t h Prednisone 1 mg/Kg/day e v e r y second day f o r p e r i o d s o f t h r e e months, a l t e r n a n t w i t h t h r e e months o f Imuran. P e r s a n t i n and a c e t y l s a l i c y l i c a c i d ( ~ A ) was continuously administered. The r i g h t r a d i a l p u l s e r e t u r n e d t o normal w i t h i n t h r e e y e a r s . A seven year f o l l o w - u p f a i l e d t o d e t e c t any new episode o f a r t e r i t i s . Growth was e n t i r e l y normal, The r i g h t kidney showed s i g n s o f compensatory h y p e r t r o p h y . F i n a l l y , a recent a r t e r i o g r a p h y showed not o n l y a normal renal a r t e r y blood f l o w but the almost t o t a l disappearance o f the r i g h t s u b c l a v i a n a r t e r y o b s t r u c t i o n . It i s hoped t h a t the encouraging r e s u l t s o b t a i n e d w i t h t h i s case will stimulate further investigation i n t o the use o f immunosuppressive t h e r a p y i n Takayasu d i s e a s e .

J

M.G. B r u n e t t e ,

$

.

Y. Bonny, L. S p l g e l b l a t t

$

, G. B a r r e t t e

*Department of pediatrics, **Department Mai sonneuve-Rosemont H o s p i t a l , University M o n t r e a l , Quebec,

$$

.

of Radiology, of Montreal,

C 125 P280

P279

INFLUENCE OF ARTERIAL HYPERTENSION ON ENDOGENOUS ERYTHROPOIETIN PRODUCTION A Mahmoud, N Pozet, A Hadj-Aissa, M Vial, P Cochat Unit~ de N6phrolo[~ie P&liatrique, H6pital E Herriot, Lyon, France Recent studies have suggested a relationship between reninangiotensin system (RAS) and erythropoietin (EPO) production. This can explain high EPO in special forms of hypertension - e.g. renal or renovascular. This study was designed to study EPO level in hypertensive children irrespective to the cause of hypertension; the role of RAS was estimated by fraction excretion of sodium (FENa). EPO was assessed in 60 ehildren by immuno-enzyme assay (Biom6rieux, France): 30 had a functioning renal transplant (RT) and 30 had CRF i.e. GFR (inulin clearance) < 80 ml/min/1.73 m2- on conservative treatment. In RT children, 14 were hypertensive and 16 were normotensive while in CRF children they were 13 and 17, respectively. Results were expressed as mean + SD and statistics used paired t test. In the hypertensive RT children, EPO level was 25.3_+.27.7 mU/ml, GFR was 61.8+31.0 ml/min/1.73 m2 and FeNa was 2.05:2.2%; in hypertensive CRF children EPO level was 20.5+19.2 mU/ml, GFR was 46.0-228.6 ml/min/1.73 m 2 and FENa was 2.1+_3.2%. In the normotensive RT children, EPO level was 9.9+_5.8 mU/ml, GFR was 73.~_27.4 ml/min/1.73m2 and FeNa was 1.5+1.3% while in normotensive CRF children EPO level was 9.8.-h3.3 mU/ml, GFR was 54.3_+_20.9 mllnfin/1.73 m 2 and FENa was 1.1+0.8%. Among RT and CRF children there was no significant difference between GFR nor FeNa in hypertensive and normotensive patients while EPO level was significantly higher in both RT or CRF hypertensive children (p<0.05). In conclusion 1) there is a significant relationship between medal hypertension and erythropoietin level in renal transplant and chronic renal failure children, 2) the stimulatory effect on erythropoietin production in medal hypertension is possibly variable and not entirely dependent on renin-angiotensin system in children.

P281 A RISK FACTOR H Y P E R T E N S I V E

FROM

IN C H I L D R E N PARENTS_

DR. SAIEH ANDONIE,C., ENRIQUEZ G.,ZUBAREW T. AND BERTIN L.

During the last years normal individuals with a high blood pressure family background have shown early cardiac deterioration, with left ventricular hypertrophy. Researches have evidence that growth factors can increase the proliferation of cardiac muscle cell; they have been characterized as growth hormone, insulin, noradrenaline and angiotensine II. We studied 26 normotensive children (Ii males and 15 females], with aged fluctuating between 7 and 19 years, born to hypertensive parents. This group showed pressure around 111/70 compared to a normal control group of similar ages and sex. A bidimensional echocardiogram (Bruce protocol) showed left ventricular hypertrophy in 2 out of 26, and 8 had increase in the antero-posterior aortic diameter. In spite of our small number of patients we suggest investigate children of high blood pressure for parents.

to

Beside blood pressure control, heart cavities evaluated with bidimensional echocardiagram.

be

Depto. Pediatrfa.Unidad Santiago, Chile. Salvecor.Santiago,

de

Nefrolog~a

Cl~nica

should

Las

Chile

Dpto.Salud P6blica. Facultad Medicina,Sede 0riente Universidad de Chile.

Condes.

RENAL DISTAL FIBROMUSCULAR D Y S P L A S I A : AN UNUSUAL CASE. A. C e p e r o - A k s e l r a d * , F. R a m i r e z - S e i j a s * , V. P a r d o * *

An 8 y e a r old b l a c k h a i t i a n boy w a s admitted with h e a r t f a i l u r e . B / P w a s 170/130. P a t i e n t was t r e a t ed w i t h n i f e d i p i n e , hydralazine, Lasix, A l t a c e and D i g o x i n . U / A d i s c l o s e d 2 to 5 RBC's. C3, C4, ANCA, PPD and r e n a l U/S were normal. R e n i ~ level w a s 343.7ng/ml. B U N w a s 34 m g / d l and s e r u m c r e a t i n i n e 2 . 3 m g / d l ; 5 d a y s l a t e r w a s 3 . 0 mg/dl. Renal b i o p s y showed extensive capillary c o l l a p s e and wrinkled capillary walls consistent with ischemia. Glomer u l a r and i n t e r l o b u l a r a r t e r i e s exhibited narrowing of luminae and t h i c k e n i n g of the media with muscle cells in t h e w a l l s r e p l a c e d by l a y e r s of c u b o i d a l cells. A large i n t r a r e n a l b r a n c h of the renal artery proximal to the interlobar area showed a narrow t o r t u o u s lumen. E.M. s h o w e d the arteriolar walls replaced by e p i t h e l i o i d cells containing numerous renin g~anules in d i f f e r e n t s t a g e s of s e c r e t i o n and a m a r k e d l y dilated rough endoplasmic reticulum and juxtaglomerular apparatus (JGA>. A o r t o g r a m s h o w e d normal extra renal arteries but d i f f u s e a r t e r i o l a r d i s e a s e w i t h p o o r nephrogram bilaterally. Fibromuscular dysplasia involving distal r e n a l v e s s e l s may m i m i c a v a s c u litis and can p r e s e n t as a nephritic syndrome. E.M. f i n d i n g s w i t h the n u m e r o u s r e n i n g r a n u l e s in t h e a r t e r i o l a r w a l l s and the m a r k e d l y d i l a t e d JGA is very unusual. Severe ischemia resulted in chronic renal failure. * Pediatric Nephrology, Miami Children's Miami, F l o r i d a , U S A **Dept. of P a t h o l o g y V.A. H o s p i t a l - M i a m i ,

Hospital, FI.

USA