Pediatr Nephrol (2011) 26:675–692 DOI 10.1007/s00467-010-1656-1
EDUCATIONAL REVIEW
Diagnosis and management of childhood polycystic kidney disease William E. Sweeney Jr & Ellis D. Avner
Received: 9 February 2010 / Revised: 17 August 2010 / Accepted: 27 August 2010 / Published online: 29 October 2010 # IPNA 2010
Abstract A number of syndromic disorders have renal cysts as a component of their phenotypes. These disorders can generally be distinguished from autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) by imaging studies of their characteristic, predominantly non-renal associated abnormalities. Therefore, a major distinction in the differential diagnosis of enlarge echogenic kidneys is delineating ARPKD from ADPKD. ADPKD and ARPKD can be diagnosed by imaging the kidney with ultrasound, computed tomography, or magnetic resonance imaging (MRI), although ultrasound is still the method of choice for diagnosis in utero and in young children due to ease of use, cost, and safety. Differences in ultrasound characteristics, the presence or absence of associated extrarenal abnormalities, and the screening of the parents >40 years of age usually allow the clinician to make an accurate
diagnosis. Early diagnosis of ADPKD and ARPKD affords the opportunity for maximal anticipatory care (i.e. blood pressure control) and in the not-too-distant future, the opportunity to benefit from new therapies currently being developed. If results are equivocal, genetic testing is available for both ARPKD and ADPKD. Specialized centers are now offering preimplantation genetic diagnosis and in vitro fertilization for parents who have previously had a child with ARPKD. For ADPKD patients, a number of therapeutic interventions are currently in clinical trial and may soon be available.
W. E. Sweeney Jr : E. D. Avner Department of Pediatrics, Research Center of Excellence in Pediatric Nephrology, Children’s Research Institute, Children’s Hospital Health System of Wisconsin and Medical College of Wisconsin, Milwaukee, WI, USA
Introduction
E. D. Avner Department of Physiology, Research Center of Excellence in Pediatric Nephrology, Children’s Research Institute, Children’s Hospital Health System of Wisconsin and Medical College of Wisconsin, Milwaukee, WI, USA E. D. Avner (*) Children’s Research Institute, Children’s Hospital Health System of Wisconsin, Children’s Corporate Center, Suite C-730, 999 North 92nd Street, Wauwatosa, WI 53226, USA e-mail:
[email protected]
Keywords Autosomal recessive polycystic kidney disease . Autosomal dominant polycystic kidney disease . Childhood PKD . Ultrasound . Differential diagnosis . Management . Therapy
Many pediatric disorders demonstrate renal cysts or cystic dysplasia as a component of their clinical pleiotropic phenotypes (Table 1) [1]. The disorders noted in Table 1 can generally be distinguished from autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) by a detailed history, physical examination, basic laboratory and imaging studies and, in particular, by their characteristic, predominantly non-renal clinical features. However, in most clinical settings, the major distinction in the differential diagnosis of enlarged cystic, echogenic kidneys in the pediatric patient is clearly delineating ARPKD from ADPKD. Exceptions to this general principle are glomerulocystic kidney disease (GCKD) [2, 3] and, rarely, the tuberous
676 Table 1 Miscellaneous causes of cystic and/or enlarged echogenic kidneys [21]
Pediatr Nephrol (2011) 26:675–692 Disease
References
Polycystic kidney diseases (PKD) Autosomal recessive polycystic kidney disease (ARPKD) Autosomal dominant polycystic kidney disease (ADPKD) Glomerulocystic kidney disease Tuberous sclerosis complex (TSC) Von-Hippel-Lindau syndrome (VHL) Inherited disorders associated with polycystic kidneys Bardet-Biedl syndrome Beckwith-Wiedemann syndrome Hajdu-Cheney syndrome Ivemark syndrome Jeune syndrome and other chondrodysplasia syndromes Juvenile nephronophthisis (JN)/medullary cystic disease (MCD) complex Meckel-Gruber syndrome Oro-facial-digital syndrome Type 1 Trisomy 9 and 13 Zellweger cerebrohepatorenal syndrome Sporadic disorders associated with cystic kidneys Caliceal diverticula Isolated cystic dysplasia Multicystic dysplastic kidney (MCDK) Unilateral/localized cystic kidney disease
sclerosis complex (TSC) and von Hippel-Lindau disease (VHL) [4]. In order to clinically differentiate GCKD, TSC, or VHL from ARPKD and ADPKD, a detailed family history, physical examination, and close clinical follow-up are necessary. The interested reader is referred to excellent recent reviews which describe these disorders as well as the many syndromes and malformation complexes which include renal cystic lesions [3–7]. This review will focus in detail on the monogenic polycystic kidney diseases: ARPKD and ADPKD.
[7, 21, 58] [46, 58] [2, 3, 133] [4, 134, 135] [4] [136] [137] [138] [110] [139] [136, 140, 141] [7] [136] [142] [143] [144, 145] [136] [146] [147]
ADPKD (OMIM 173900; 173910) is the most common inherited human kidney disease and is a major cause of end-stage renal disease (ESRD) in adults. However, onset and morbidity in children can and does occur [13]. ADPKD occurs in one in every 400 live births and is usually caused by mutations in one of two genes, PKD1 or PKD2 [13, 14]. There is, however, a small percentage of families that do not link to either of the two known loci, and some researchers have suggested that these may represent a third locus (?PKD3) [15–17]. Recent confirmation of a third ADPKD locus is lacking, and possible alternatives will be discussed below.
Polycystic kidney disease: ARPKD and ADPKD Current convention generally restricts the use of the term “polycystic kidney disease” (PKD) to two genetically distinct conditions: ARPKD and ADPKD. In most clinical settings, the major distinction in the differential diagnosis of enlarged cystic kidneys in the pediatric patient is discriminating ARPKD from ADPKD. In fact, ADPKD presenting in the neonatal period may be clinically indistinguishable from ARPKD [8, 9]. ARPKD (OMIM 263200) occurs less frequently (1:20,000 live births) than ADPKD, is generally diagnosed in utero or at birth, and occurs as a result of mutations in a single gene, Polycystic Kidney and Hepatic Disease 1 (PKHD1) [10–12].
Autosomal recessive PKD ARPKD—epidemiology and genetics ARPKD belongs to a group of congenital hepatorenal fibrocystic syndromes and is a significant cause of renaland liver-related morbidity and mortality in children. It is characterized by non-obstructive fusiform dilatation of the renal collecting tubules and a ductal plate malformation of the liver, ultimately resulting in congenital hepatic fibrosis (CHF). Estimates of ARPKD prevalence vary widely, but an overall frequency of one in 20,000 live births and a carrier level of up to 1:70 have been proposed [18]. The
Pediatr Nephrol (2011) 26:675–692
phenotype of ARPKD is highly variable with a broad clinical spectrum of disease. Despite this variability, genetic linkage studies indicate that mutations at a single locus are responsible for all phenotypes of ARPKD [10]. The ARPKD disease gene, PKHD1, is a large gene located on chromosome 6p21.1–p12 that encodes a multidomain integral membrane protein of unknown function called fibrocystin [12] or polyductin [11]. Notwithstanding the variable clinical spectrum of ARPKD [19], the majority of patients are identified either in utero or at birth [20, 21]. The most severely affected fetuses have enlarged echogenic kidneys and oligohydramnios caused by poor fetal urine output. These signs are potentially detectable in utero, but may not manifest until late in the third trimester [22]. Improved neonatal intensive care and enhanced disease recognition have increased survival of the newborns, but death still occurs in 25–30% of affected neonates due to respiratory insufficiency [9, 23, 24]. Nearly 50% of affected individuals surviving the neonatal period progress to ESRD within the first decade of life [23, 25]. The 10-year survival of patients surviving the first year of life is estimated to be 82%, and the 15-year survival is projected to be 67–79% [21]. For surviving patients, a wide range of associated morbidities can develop, including systemic hypertension, renal failure, portal hypertension, and renal and hepatic fibrosis [21, 26, 27]. A minority of individuals present as older children, adolescents, or even adults with hepatosplenomegaly as the predominant presenting feature. A recent study revealed that nearly one-third of patients with mutations in PKHD1 and substantial hepatic involvement were 20 years or older at the time of initial presentation, suggesting that the clinical spectrum of ARPKD is considerably broader than previously recognized [19]. These patients typically exhibit less renal enlargement and more variability in renal cyst size [19, 28]. In general, there is a reciprocal relationship between the degree of renal and hepatic involvement in individual patients [19, 28]. Hepatic involvement in ARPKD patients can range from mild to severe, ultimately resulting in CHF and Caroli disease, a dilatation of the intrahepatic bile ducts. Patients with significant hepatic involvement are more likely to develop complications of CHF, including an increased risk of ascending cholangitis and benign and malignant liver tumors, especially cholangiocarcinoma [29]. Patients with severe Caroli disease may require porto-systemic shunting [7]. ARPKD—clinical features Due to the routine use of antenatal ultrasound, the majority of ARPKD patients are identified late in pregnancy or at birth. Severely affected fetuses display a “Potter-like”
677
oligohydramnios phenotype with pulmonary hypoplasia, and massively enlarged echogenic kidneys that can compromise normal delivery [18, 20, 30]. Infants with true pulmonary hypoplasia often die soon after birth. Although the complete lack of amniotic fluid production during the third trimester occurs in other pathological states and generally leads to neonatal demise, cases of ARPKD with third trimester oligohydramnios may produce viable newborns with minimal pulmonary disease [21]. Whether this is a unique, disease-specific feature of ARPKD is unknown. Although a discussion of the complex process and consequences of oligohydramnios is beyond the scope of the article, severe cases of oligohydramnios have been treated with amnioinfusion during labor. Since the mother’s fluid status has a major effect on amniotic fluid volume, maternal hydration has been used in an attempt to increase amniotic fluid volume, but with limited success [31]. At birth, ARPKD patients usually have large, palpable flank masses, and most patients (70–80%) have evidence of impaired renal function in the newborn period [9, 30]. Initial management of the most severely affected neonates focuses on the stabilization of respiratory function by mechanical ventilation and occasionally unilateral or bilateral nephrectomy. Neonates with oliguria or anuria may require peritoneal dialysis within the first days of life. Hypertension is treated with angiotensin-converting enzyme (ACE) or angiotensin II receptor inhibitors. Supplemental feedings via nasogastric or gastrostomy tubes are often required. Affected children with significant chronic kidney disease and growth failure may benefit from treatment with growth hormone. As previously noted, 70–75% of newborns with ARPKD survive the neonatal period. Transient hyponatremia is often present, but usually resolves over time [21, 30]. Most patients have a urinary concentrating defect, and symptoms of polyuria and polydipsia develop quickly [9, 24, 32]. The somewhat paradoxical change from low fetal urinary output (which contributes to oligohydramnios) to extrauterine polyuria is largely a consequence of postnatal circulatory and hemodynamic maturation. While the fetal kidney receives 3% of cardiac output during the third trimester, the newborn kidney undergoes an 18-fold increase in renal blood flow due to increased cardiac output and a series of complex vasoregulatory changes in the transition from fetal to extrauterine life [33]. Death from renal insufficiency is uncommon, and infants with ARPKD will usually have a transient improvement in their glomerular filtration rate (GFR), probably due to some degree of the normal renal maturation that occurs during the first 6 months of life [30]. Thereafter, a progressive but highly variable decrease in renal function occurs. Renal manifestations include cystic dilatation and ectasia of renal collecting tubules. Dilated ectatic cysts in the
678
collecting tubules in ARPKD, unlike ADPKD cysts, retain both their afferent and efferent tubular connections [34, 35]. In addition, kidney size or volume in ARPKD stabilizes over time and does not show the progressive macrocystic enlargement classically seen in ADPKD. Liver disease is invariably present in all ARPKD patients. All patients with ARPKD have biliary ductal abnormalities at birth, ranging from asymptomatic microscopic abnormalities to CHF [29]. A subset of patients with ARPKD may present as older infants with congenital hepatic fibrosis and mild-to-moderate renal disease [18, 20, 29]. The chief pathologic hallmarks of ARPKD liver disease are biliary dysgenesis due to a primary ductal plate malformation with associated periportal fibrosis, resulting in CHF and dilatation of intrahepatic bile ducts (Caroli disease). Liver manifestations may present the major symptomatic disease complications in older patients [19, 21, 28]. In such patients, especially in those following treatment of ESRD with dialysis or transplantation, complications of CHF and Caroli disease can result in portal hypertension (PH) and an increased risk of ascending cholangitis. Such patients demonstrate splenomegaly, hypersplenism with low platelet counts, and gastroesophageal varices with attendant risks of acute bleeding, and they are at risk for bacteremic infections from both splenic dysfunction and cholangitis [20, 23, 29]. Patients with significant PH may require porto-systemic shunting. In addition, ARPKD patients are at increased risk of benign and malignant liver tumors, especially cholangiocarcinoma [29]. Systemic hypertension, which may be severe, is common in both infants and children [21, 25] even in patients with normal renal function. The majority of children with ARPKD are eventually affected with systemic hypertension [9, 20, 30]. ARPKD—imaging and diagnosis Early diagnosis of at-risk individuals for ARPKD (infants born to parents with a previously affected child) affords the opportunity for maximal anticipatory care (i.e. blood pressure control), and the future opportunity to benefit from new therapies (i.e. early treatment with therapies currently under pre-clinical and clinical development to arrest disease progression, as noted in the final section of this review Pathophysiology and translational implications). Imaging modalities used for the diagnosis of ARPKD include ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI). US can detect cysts ranging in size from 1 to 1.5 cm and is a widely available and inexpensive imaging modality. CT is more sensitive than US, with detection limits as low as 0.5 cm. It is more expensive than US and involves the use of
Pediatr Nephrol (2011) 26:675–692
radiation, which limits its utility for routine diagnostic studies, particularly in children. CT studies may be used in cases where US imaging is equivocal or when more complicated issues are suspected, such as the possibility of a tumor. MRI is more sensitive than either US or CT and may be the best imaging modality to monitor volume changes in different compartments (cystic, microcystic, normal parenchyma, or fibrosis). This imaging modality is particularly valuable in studying the natural history of changes in ARPKD kidneys and livers. More importantly, if such compartment changes can be standardized, MRI may provide, in the future, a non-invasive tool to evaluate the effectiveness of therapeutic interventions aimed at arresting or ameliorating disease. Despite the limited resolution of US compared to CT or MRI, its ease of use, wide availability, and low cost make US the most widely used imaging technique for diagnosing ARPKD. The typical ultrasonographic appearance of ARPKD is large echogenic kidneys with poor corticomedullary differentiation (CMD) (Fig. 1a). Macrocysts, a feature of ADPKD, are not generally present at birth, but they are not uncommon as the disease progresses [36]. Definitive diagnostic criteria for ARPKD have yet to be established. However, criteria proposed by Zerres et al., with modifications [30], are the most widely used by pediatric nephrologists and include: 1. Ultrasonographic features typical of ARPKD, including enlarged, echogenic kidneys, with poor corticomedullary differentiation (see Fig. 1a); and 2. One or more of the following: a) absence of renal cysts by sonography in both parents, particularly if they are >40 years old, b) clinical, laboratory, or radiographic evidence of hepatic fibrosis, c) hepatic pathology demonstrating characteristic ductal plate abnormalities, d) previous affected sibling with pathologically confirmed disease, e) parental consanguinity suggestive of autosomal recessive inheritance. As noted above, renal US may be less diagnostic in children who present later in childhood. Furthermore, in patients who present as older children and adolescents, hepatic abnormalities are often the prominent presenting feature. Although renal biopsy will clearly differentiate the isolated fusiform collecting tubule cysts of ARPKD from the heterogeneous cystic nephron involvement of ADPKD [37], renal biopsies are generally not indicated for patients who fulfill the classic criteria for ARPKD and/or those for whom genetic testing is definitive [21]. In certain instances,
Pediatr Nephrol (2011) 26:675–692
679
ARPKD kidneys may be markedly enlarged at birth, over time, the majority of the kidneys have been found to stabilize or decrease in size [29, 40, 41]. Ultrasonographic findings in the liver include hepatomegaly, increased echogenicity, poor visualization of the peripheral portal veins, and splenomegaly. Reversal of normal venous flow can be seen by Doppler study and, when associated with splenomegaly, is highly suggestive of portal hypertension and, consequently, ARPKD. Hypertrophy of the left lateral segment of the liver is also occasionally observed [42], and a subset of patients have overt evidence of biliary ductal dilatation (Caroli disease) when examined by MRI or endoscopic retrograde cholangiopancreatography (ERCP) [42]. MRI of ARPKD patients demonstrate enlarged kidneys with hyperintense T2-weighted signals [43]. Kern et al. reported that ARPKD kidneys have a characteristic hyperintense, linear radial pattern in the cortex and medulla by RARE-MR urography that reflects the microcystic dilatation seen histologically [43, 44]. In a National Institutes of Health (NIH)-supported natural history study, over 75% of ARPKD patients demonstrated intra- and extra-hepatic biliary dilatations. High-resolution ultrasound findings included dilated common bile ducts and enlarged gall bladders [29]. Macroscopic liver cysts are uncommon in ARPKD [45]. A listing of the most useful differential clinical features to differentiate between ADPKD from ARPKD in children are presented in Table 2.
Fig. 1 a Ultrasound scan of an autosomal recessive polycystic kidney disease (ARPKD) kidney. Both kidneys are markedly enlarged (only right kidney is shown) and demonstrate poor corticomedullary differentiation. The right kidney measures 8.34 cm in length, which is approximately 2.5-fold the normal length for a patient of this age. Note the dilated cortical collecting ducts just under the cortex which are visible with high-frequency ultrasonagraphy. b Ultrasound scan of autosomal dominant PKD (ADPKD) kidney. The left kidney measures 14.9 cm compared to a normal kidney of 10.5 cm±0.29 cm for a patient this age. There are multiple hypoechoic cysts with the largest cyst in the left kidney measuring 3.5 cm on the lateral aspect. The echogenicity of the kidneys is normal
liver biopsy may provide additional information and reveal the characteristic biliary dysgenesis of ARPKD. In a study of renal sonographic features of adult patients with ARPKD, the presence of multiple small cysts in relatively normal-sized kidneys, increased cortical echogenicity, and loss of CMD were common features [38]. Stein-Wexler and Jain [39] proposed that ultrasonographic findings of “focal rosettes”, corresponding to the macroscopic appearance of radially oriented collecting tubule cysts, are specific for ARPKD. This finding has not yet been confirmed in additional studies. In addition, although
ARPKD—molecular diagnosis and prenatal diagnosis Although molecular diagnostic testing is available for ARPKD and, as of 2010, can be used to establish a diagnosis with 85% certainty, the diagnosis usually relies on imaging studies, a complete family history, clinical findings and, rarely, biopsy findings. Molecular testing for PKD either by linkage analysis or direct sequencing is not recommended for patients in whom a diagnosis can be obtained by imaging analysis alone. Molecular diagnostics is a relatively expensive approach and does not always provide usable data. There are, however, instances where molecular diagnosis is warranted [46–48]. Counseling should always be provided before molecular testing is undertaken, especially in an asymptomatic patient. The passage in 2008 of the Genetic Information Nondiscrimination Act (GINA) into law has reduced the possibility of employment and insurability discrimination. GINA provides a baseline level of protection against genetic discrimination for all Americans. Many states already have laws that protect against genetic discrimination in health insurance and employment situations. However, the degree
680 Table 2 Clinical features which can help differentiate between ARPKD and ADPKD, although no single finding is diagnostic [21] Major clinical features of both ARPKD and ADPKD Enlarged kidneys Hypertension Concentrating defect Sterile pyuria Clinical features suggesting ARPKD rather than ADPKD Neonatal presentation Progression to end-stage renal disease as a child Hepatosplenomegaly Portal hypertension and esophageal varices Bacterial cholangitis Negative family history (parents, grandparents –no renal cysts on imaging studies) Clinical features suggesting ADPKD rather than ARPKD Positive family history (parents, aunts and uncle≥40 and/or grandparents positive for cysts) Extrarenal cysts (liver, and/or pancreas) Cerebral aneurysms Asymptomatic presentation Unilateral renal presentation Hematuria Urinary tract infection
of protection they provide varies widely, and while most provisions are less protective than GINA, some are more protective. GINA, however, applies only to asymptomatic individuals and does not extend to life insurance, disability insurance, or long-term care insurance. Further, it does not prohibit insurance underwriting based on information about current health status and does not apply to employers with fewer than 15 families [47, 48]. However, once a specific mutation has been identified in a family, presymptomatic diagnosis in other at-risk family members can be made relatively inexpensively by screening for the known mutation. Sequencing screening for the specific family mutation may be particularly useful in providing definitive PKD disease status of a nonsymptomatic family member being assessed as a potential donor. PKHD1 is a large, complex gene, with a complicated transcription profile that likely generates multiple protein isoforms [11, 12]. Mutations are distributed throughout the gene, and polymorphisms are common [49, 50]. The roles of the various splice forms in determining disease severity have yet to be determined. A locus-specific database for ARPKD that catalogs published mutations in the PKHD1 gene can be found at http://www.humgen.rwth-aachen.de. Although improved methodologies have resulted in detection rates as high as
Pediatr Nephrol (2011) 26:675–692
85%, the ability to definitively assess the likelihood of mutations being pathogenic is still lacking [49–53]. Due to the significant morbidity and mortality of ARPKD, many parents of ARPKD children seek prenatal genetic diagnosis (PGD). The two methods of mutation detection for single-gene disorders include direct sequencing and linkage analysis. Direct mutation testing is generally used when the genetic disorder is the result of a single mutation that occurs in most affected families. ARPKD, however, is the result of many different mutations, and most families harbor private mutations [54]. As a result, a customized assay must be developed for each family. Due to the large number of mutations, the development of mutation-specific protocols for PGD testing in ARPKD is very expensive, labor intensive, and time consuming. Prenatal diagnoses of ARPKD based on PKHD1 mutation analysis have been successful [55], and clinical gene-based testing as well as preimplantation genetic diagnosis/in vitro fertilization (PGD/IVF) are available in highly specialized centers. In families with diagnostic uncertainties, the detection of PKHD1 mutations by direct sequencing has been the only option for accurate genetic counseling and prenatal diagnosis until recently. A novel, reliable linkage-based protocol for preimplantation genetic diagnosis of ARPKD using single-cell multiple displacement amplification (MDA) products for PKHD1 haplotyping has been developed that significantly decreases the problem of allelic dropout [56]. This unique protocol uses whole-genome amplification of single blastomeres, MDA, and haplotype analysis with 20 novel polymorphic short tandem repeat (STR) markers from the PKHD1 gene and flanking sequences. This method enables unambiguous identification of the PKHD1 haplotypes of embryos produced by at-risk couples [56]. Further details on the molecular diagnosis of ARPKD can be found at GeneClinics: Clinical Genetic Information Resource (database online) at http://www.geneclinics.org [57].
Autosomal-dominant PKD ADPKD—epidemiology and genetics ADPKD is generally a late-onset, systemic disease characterized by bilateral, progressive enlargement of focal cysts occurring in all nephron segments with variable extrarenal manifestations. Although all races and both sexes are equally affected, the renal phenotype may be more severe in males, with liver manifestations more severe in females. ADPKD affects approximately 600,000 individuals in the USA and 13 million individuals worldwide and is respon-
Pediatr Nephrol (2011) 26:675–692
sible for 4.4% of the population with ESRD. Direct medical costs for dialysis and transplantation alone are estimated at 1.5 billion U.S. dollars per year [58]. ADPKD is usually asymptomatic until the middle decades of life; however, 2–5% of ADPKD patients present with an early and severe neonatal course, with significant morbidity and mortality [25, 32, 59]. Such early clinical manifestations of ADPKD may be identical to those of ARPKD and can be differentiated only by histological or genetic analysis. There is a familial incidence of childhood presentation, as siblings of affected children have a greater risk of early disease. However, this relationship within families is not absolute [59]. Genetic studies have indicated that most, if not all cases of ADPKD are caused by mutations in two genes: PKD1 and PKD2. An analysis of linkage in European families characterized by ADPKD estimated that nearly 85% of affected individuals had mutations in the PKD1 gene (on chromosome 16p13.3), whereas nearly 15% demonstrated mutations of the PKD2 gene (on chromosome 4q21) [60– 62]. Recent studies of specific cohorts have documented the prevalence of PKD2 to be as high 36%, suggesting that PKD2 may have been under-detected before the widespread use of imaging [63]. The existence of a small fraction of ADPKD families that is not characterized by a link to either the PKD1 or PKD2 loci had led to speculation that there may be at least one additional disease-causing gene [16, 17, 64]. However, confirmation of a third disease-causing locus has so far been futile, and recent findings that PKD can result from two independently segregating PKD1 and PKD2 mutations [65] and that gene dosage may play a role in development of PKD [66] make the existence of a third gene for ADPKD questionable at this time. Although mutations in PKD1 and PKD2 produce similar phenotypes, the phenotype of PKD1 [67] is significantly more severe than that of PKD2, with the average age of ESRD onset occurring 20 years earlier in PKD1 patients than in PKD2 patients (54 vs. 74 years, respectively) [67, 68]. The comparative severity of PKD1 mutations has been shown to be due to an increased number of cysts forming at an earlier time point in PKD1 patients and not to differences in the rate of growth of PKD2 cysts [69]. PKD1, a large and complex gene [70], has been mapped to chromosome 16p13.3 [71]. PKD1 contains 46 exons, with a large 14-kb mRNA containing 12,909 bp. The 33 exons of the PKD1 5′ region are duplicated elsewhere on chromosome 16, complicating diagnostic mutation screening [13]. The 33 exons of the PKD1 5′ region are encoded by a genomic region that has been duplicated six times upstream of PKD1 on the short arm of chromosome 16. These six duplicated regions represent six pseudogenes that appear to have some expression but encode early stop codons,
681
signifying they do not express large protein products. The PKD1 pseudogenes are 99% identical to PKD1 in homologous areas but harbor unique deletions and additional rearrangements. Anchored and locus-specific long-range PCR protocols have been developed to leverage these unique sequence differences between the pseudogenes and PKD1 in order to specifically amplify the PKD1 gene for mutational screening [67, 72, 73]. The PKD1 gene encodes a large complex glycoprotein (polycystin 1) with 4,303 amino acids and a molecular weight of 467 kDa [70]. Polycystin 1 is predicted to be an integral membrane protein containing a large N-terminal extracellular domain with multiple transmembrane domains. It is also predicted to be involved cell–cell-matrix interactions and may also play a role in calcium homeostasis through its physical interaction with polycystin 2, the protein product of PKD2 [74]. PKD2 has been mapped to chromosome 4q13-q23 [75, 76] and encodes a 968-amino acid polypeptide, polycystin-2 (PC-2) [75]. Polycystin-2, also called TRPP2, is a calcium permeable, non-selective cation channel [77, 78] that increases membrane permeability to Ca2+ and plays an essential role in polycystin-1 localization and function [13, 79]. ADPKD is an autosomal dominant disorder with 100% penetrance [47]. Despite the presence of an inherited (germline) mutation in the PKD1 or PKD2 gene in every renal epithelial cell, cysts occur in only 3–5% of nephrons. This fact, as well as the wide variability in disease spectrum even among family members, has led to the proposal of the “two-hit hypothesis”, which states that an inherited germline mutation must be followed by an acquired somatic mutation in the normal allele in order to initiate cyst formation [80]. Subsequent analysis has provided confirmation of the two-hit hypothesis [81]. ADPKD, therefore, has an autosomal dominant pattern of inheritance but is a recessive disease at the molecular level [80, 82]. ADPKD is genetically heterogeneous, and the disease gene is a major determinant of severity; as mentioned above, PKD1, on average, is associated with the development of ESRD 20 years earlier than PKD2. Recent studies in experimental models [83–85] and molecular screening of two consanguineous families indicate that some mutated alleles retain partial activity (hypomorphs). These data demonstrate that level of gene expression may also play a significant role in disease progression [66] and that PKD1 and PKD2 alleles may be hypomorphic or incompletely penetrant. ADPKD—clinical features ADPKD is a systemic, progressive disorder that usually presents in the third or fourth decade of life and is characterized by bilateral renal cysts in progressively
682
enlarging kidneys with sporadic presentation of extra-renal manifestations. Cystic lesions may occur in liver, pancreas, spleen, and seminal vesicles. Other extra-renal presentations may consist of vascular abnormalities, including cerebral aneurysms, dilatation of the aortic root, dissection of the thoracic aorta, mitral valve prolapse, abdominal and inguinal hernias, and early onset hypertension [58, 86–88]. The renal manifestations of ADPKD include hypertension, gross or microscopic hematuria, flank pain, pyelonephritis, nephrolithiasis, and renal insufficiency. Cystic liver disease is the most common extra-renal feature of ADPKD, although liver cysts are usually benign and normally do not affect hepatic function. MRI studies [89] have revealed that hepatic cysts are present in 83% of individuals between 15 and 46 years of age and in 55% of patients between the ages of 15 and 25 years [90]. These data suggest that hepatic cysts may be common in children with ADPKD, and like pancreatic cysts, when present, may clearly differentiate ADPKD from ARPKD. The prevalence of hepatic cysts in ADPKD patients is similar in men and women, although women may develop cysts at an earlier age and extreme hepatic cystic disease occurs almost exclusively in women [89, 91]. Severe hepatic cystic disease can also be seen in autosomal dominant polycystic liver disease (PCLD: OMIM #174075), which is a separate genetic entity that is not associated with any renal involvement. ADPKD is characterized by progressive nephromegaly, with renal volumes reaching volumes >1,500 ml compared to the normal adult volumes of 202±36 ml per kidney [92]. Despite the presence of numerous cysts in both kidneys, the GFR is well preserved in most patients until the age of 30– 40 years [93]. Between the ages of 40 and 70 years, however, renal function usually declines rapidly. ESRD affects approximately 50% of the patients with ADPKD by age 60 years. Hypertension occurs at a much earlier age in ADPKD patients than in the general population [94] and occurs in 50–70% of ADPKD patients before any substantial reduction in GFR is detected. The incidence of hypertension is significantly greater when the affected parent is or was hypertensive [95]. Hypertension is associated with a rapid progression to ESRD and increased cardiovascular complications [96]. Left ventricular hypertrophy (LVH), an important risk factor for premature cardiovascular death, occurs in up to 44% of ADPKD patients [97], Patients with ADPKD are usually diagnosed and become symptomatic in adulthood, but 2–5% present in childhood or in utero with an early-manifesting clinical course of significant morbidity. Early manifestation of ADPKD is defined as symptomatic disease (systemic hypertension, proteinuria, and impaired renal function) occurring before
Pediatr Nephrol (2011) 26:675–692
the age of 15 years. Families with early-manifesting offspring have a high recurrent risk that subsequent siblings will follow a similar early-manifesting clinical course. The clinical spectrum of pediatric ADPKD ranges from severe neonatal presentation indistinguishable from ARPKD to renal cysts noted on an ultrasound scan in asymptomatic adolescents to disease that remains clinically silent well into adulthood. A unilateral presentation of renal cysts with renal enlargement is not uncommon in children. Hypertension can present during the newborn or infant periods and is common in pediatric and young adult ADPKD patients, despite normal renal function [32, 59, 90, 94, 98]. Young hypertensive children with ADPKD may present with acute congestive heart failure [21]. Hypertension shows a direct correlation with the severity of structural renal damage and renal volumes [99]. Ambulatory blood pressure monitoring has demonstrated that a significant proportion of normotensive young adults with ADPKD have “prehypertension” and blunted “nocturnal dipping” [100]. Intracerebral/intracranial aneurysms (ICAs) occur in approximately 8% of ADPKD patients and tend to cluster in families. Although ruptured cerebral aneurysms in children with ADPKD are rare, they have been reported [101]. Screening for ICAs is recommended at the age of 20 years in high-risk patients with follow-ups at 10-year intervals, especially for patients with a family history of ruptured ICAs [90, 102]. Many pediatric nephrologists will study “at-risk” patients at ages 5–10 years, given the devastating consequences of a ruptured aneurysm in the pediatric population. In addition to ICAs, the vascular phenotype of ADPKD includes early reductions in renal blood flow, mitral valve prolapse, and left ventricular hypertrophy [103]. At the mean age of 44 years, 48% of hypertensive ADPKD adults have LVH [103, 104]. ADPKD—imaging and diagnosis Early diagnosis of asymptomatic individuals with ADPKD affords the opportunity for maximal anticipatory care (i.e. blood pressure control), and the future opportunity to benefit from new therapies as outlined in the final section of this review (Pathophysiology and translational implications). Imaging modalities used for the diagnosis of ADPKD include US, which can detect cysts as small as 1 cm, CT, which has a resolution of 0.5 cm, and MRI, which has a much greater resolution but at greater expense. As noted in the discussion of imaging for ARPKD, CT studies may be used in complicated cases where issues such as a suspected tumor may be present. MRI is the best imaging tool to monitor renal size or volume and may be the method of choice for monitoring the efficacy of
Pediatr Nephrol (2011) 26:675–692
clinical trials in ADPKD [105]. However, as previously noted, its ease of use, wide availability, and low cost make US the most widely used imaging technique for diagnosing ADPKD. Age-dependant ultrasound diagnostic criteria for patients at risk for PKD1 [106] were developed based in part on the principle that simple renal cysts do not occur in children or adolescents but occur with increasing frequency as patients age. The Ravine criteria, although designed for diagnosing asymptomatic patients at risk for PKD1, are widely used for genetic counseling and for the evaluation of at-risk individuals for living-related kidney donation. Recognizing the milder phenotype of PKD2, Pei and his colleagues examined the validity of the Ravine criteria applied to patients at risk for either PKD1 or PKD2 [107]. The results of their study demonstrated that the Ravine criteria did not perform well when applied to PKD2, primarily because of a higher risk for false-negative results, which reduced test sensitivity. Due to a milder presentation and slower disease course in PKD2 patients, the diagnostic use of the Ravine criteria to patients with unknown PKD genotype was inappropriate. These results led to the development of the “Unified Criteria for Ultrasonographic Diagnosis” for the diagnosis of PKD in families of unknown genotype, as outlined below [107]. The criteria for a positive PKD diagnosis by ultrasound based on age for: 15–39 years old requires three or more unilateral or bilateral cysts; 40–59 years old requires two or more cysts in each kidney; ≥60 years old requires four or more cysts in each kidney. This revision determined that US could not be used to exclude the diagnosis of PKD in asymptomatic patients under 40 years of age. This is an important consideration when evaluating a potential kidney donor from a family at risk for PKD. Thus, the use of more sensitive imaging modalities, such as MRI, may be warranted in asymptomatic potential donors under 40 years. There are no specific clinical diagnostic criteria for children with suspected ADPKD, although Gabow et al. found that the presence of a single cyst by US was diagnostic in at-risk children [108]. As previously noted, ADPKD can present in any age group, including fetuses and neonates. The diagnosis of ADPKD has been made in utero by ultrasound, and affected newborns can present with a “Potter-like” phenotype and die from pulmonary hypoplasia. Affected infants can be born with large hyperechoic kidneys with or without macrocysts, increased corticomedullary differentiation [109], and varying degrees of renal insufficiency.
683
Kidney echogenicity is diagnosed after 17 weeks of gestation, when the kidneys inappropriately appear more echoic than the liver or spleen [41]. Echogenic kidneys accompany many renal diseases that have very different prognoses and outcomes (Table 1). A study of fetal ultrasounds with findings of echogenic kidneys found that location, size, and number of cysts were not specific to a particular diagnosis but that ultrasound was particularly useful in finding associated malformations [110]. The demonstration of an associated malformation, along with a comprehensive family history, was essential to an accurate diagnosis [110]. When no associated malformations are found, the main diagnosis is either ADPKD or ARPKD. A study of prenatal sonographic patterns in ADPKD found moderately enlarged [1–2 standard deviations (SD) > mean] kidneys with increased CMD (an echogenic cortex and hypoechogenic medulla) presenting in the third trimester [109]. A fetal ultrasound with an echogenic cortex and increased CMD, although not specific to ADPKD, should trigger the screening of siblings, parents and, if possible, grandparents (see Fig. 1b). Interestingly, in children with ADPKD, renal involvement may be asymmetric and even unilateral in early stages of the disease, as previously noted [111]. The extrarenal cysts commonly seen in adults with ADPKD [86] are uncommon in pediatric patients, with the possible exception of hepatic cysts in adolescents. Although liver cysts were originally thought to be uncommon in children, a recent MRI study suggests that liver cysts may be present in up to 55% of adolescents and young adults [89]. Liver cysts in children, when present, are not generally associated with the pain, infection, or hepatomegaly that often occurs in adult patients. Pancreatic cysts are found exclusively in PKD1 patients but do not appear to contribute to morbidity or mortality [112]. Pancreatic cysts, when found, can differentiate ADPKD and ARPKD. The Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease (CRISP), a longitudinal prospective study of adult ADPKD patients, used highresolution MRI to image the kidneys of a well-defined cohort [113]. These studies demonstrated that individual cysts are visible by MRI and that total cyst and kidney volumes can be accurately determined [105]. MRI can also be used to monitor individual cysts and changes in overall renal growth or volume as well as changes in renal blood flow [114, 115]. Many pediatric nephrologists agree that the most useful examination in the assessment of a child with early-onset renal cystic disease of unknown underlying disease entity is US of the parents [116]. The absence of cystic disease in family members makes the diagnosis of ARPKD more likely. It does not, however, exclude the diagnosis of
684
ADPKD, since approximately 8–10% of all ADPKD cases are the result of new gene mutations. The characteristic ultrasound pattern seen in ADPKD differs significantly from that observed in cases of ARPKD (which remains the main differential diagnosis), i.e. very large kidneys (4–12 SD>mean), absent or decreased CMD, cysts, and frequently reduced amniotic fluid [117]. Severe oligohydramnios can interfere with sonographic imaging. Again, the presence of an associated malformation and the presence or absence of renal cysts in parents over 40 years old are very useful for diagnostic accuracy. ADPKD—molecular diagnosis and prenatal diagnosis Molecular genetic testing for both ADPKD (PKD1 and PKD2) is currently available (www.genetests.org). As of 2010 molecular diagnostic testing is available for ADPKD and can be used to establish a diagnosis with >90% certainty; however, the diagnosis usually relies on imaging (including imaging of parents), a complete family history, and clinical findings. Although not necessary in every case, mutation-based diagnostics are increasingly used in individuals who are at risk of ADPKD, and they are especially helpful in cases where imaging studies are equivocal and a definite diagnosis is required. These include:
Pediatr Nephrol (2011) 26:675–692
Linkage analysis is particularly helpful for screening embryos before implantation (preimplantation genetic diagnostics), where the typing of several markers is required to ensure against problems associated with screening a very small amount of DNA, such as allele dropout [119]. Although various indirect methods have been used for screening for mutations associated with ADPKD [73, 120], direct sequencing of exonic and flanking intronic regions from genomic DNA is possible. Numerous studies have demonstrated a high degree of allelic heterogeneity in PKD1 and PKD2, with no single mutation accounting for more than 2% of affected families; in the majority of families, ADPKD is caused by a unique mutation. Consequently, diagnostic screening of a new family requires sequencing of all PKD1 and PKD2 exons, which significantly increases the cost. However, once a mutation has been identified in a family, diagnosis in asymptomatic at-risk family members can be made by simply screening only for the known mutation, which dramatically reduces the cost of such testing. There are considerable limitations and complexities associated with the molecular diagnosis of ADPKD, and interested readers are referred to three excellent, comprehensive reviews on the subject of molecular diagnosis of ADPKD [47, 48, 121].
Pathophysiology and translational implications 1. Identification of potential living related donors in families affected by ADPKD; 2. Individuals with a negative family history of ADPKD, because of potential phenotypic overlap of ADPKD with several other disorders; 3. Family planning concerns or utilization of PGD-IVF in an at-risk pregnancy. 4. Screening of at risk patients with a familial clustering of ICAs, especially in families with a history of rupture. As noted in the discussion of ARPKD molecular diagnostics, genetic counseling and an understanding of the limitations of the GINA legislation are a pre-requisite for genetic testing for any indication. Linkage analysis for the diagnosis of ADPKD has been possible since the mapping of PKD1 and PKD2. Multiple flanking and intragenic markers are now available for the analysis of these two genes [118]. However, because of the genetic heterogeneity of ADPKD, several affected members of a family are required in order to identify which gene is affected; consequently, only a minority of families are of the appropriate size to be informative for linkage-based diagnostics. Other genetic complexities mean that linkage analyses need to be applied with caution and are best used in families in whom the mutation has been characterized [118].
Despite the identification of the genes responsible for ADPKD and ARPKD, the precise function of these genes and their protein products is unknown and remains an area of intense study. Since the discovery and cloning of the genes responsible for ADPKD and ARPKD, extensive studies over the past decade have defined a unique “cystic phenotype”, which provides a number of potential targets for future genetic and pharmacological therapy. Multiple studies have demonstrated that the protein products of the ADPKD and PKHD1 genes as well as other proteins involved in renal cyst formation (“cystoproteins”) exist in large multimeric protein complexes at various intracellular locations. These sites include the apical cell membrane (particularly in, on, or adjacent to the primary cilium), adherins junctions, desmosomes, and focal adhesions. These multimeric protein complexes participate in signaling pathways that are critical in maintaining normal tubular growth and differentiation. Thus, the gene products of PKD1, PKD2, and PKHD1 are components (factors) of novel multifunctional signaling pathways. Alterations in the structure and function of these complexes can occur if any of the individual protein components are altered. Mutations that alter an individual components structure, function and/or stoichiometric relationship to other protein components can result in an
Pediatr Nephrol (2011) 26:675–692
685
&
aberrant integration of complex signaling events. In PKD, this leads to increased cellular proliferation, secretory abnormalities, and epithelial dedifferentiation, resulting in cyst formation and growth. A number of signal-transduction cascades have been implicated in the pathogenesis of both ADPKD and ARPKD and are depicted in Fig. 2. Common abnormalities have been identified in vitro and in vivo in both experimental models and in human PKD and are thought to be pathogenic in both ARPKD and ADPKD. These include but are not limited to: & & & &
Recent significant advances have occurred in our understanding of the molecular and cellular pathogenesis of PKD, and these have been recently reviewed in detail [21, 58, 122–124]. The enhanced understanding of complex signaling pathways and cellular changes associated with PKD has led to the development of targeted therapies, validated in experimental models of PKD, which directly inhibit the development or growth of cysts. The experimental rationale of targeted therapies based upon the current understanding of the pathophysiology of PKD is shown in Fig. 2. For example, in PKD epithelia from either ARPKD or ADPKD kidneys, low Ca2+ levels and cSrc-dependant phosphorylation of β-Raf result in an increased expression of cAMP as well as a switch in cAMP from an antiproliferative signaling molecule to a pro-mitogenic stimuli that subsequently activates MAPK and promotes cellular
Abnormal structure and/or function of the primary cilia. Abnormalities of expression and function of the epidermal growth factor (EGFR)-family of receptors and ligands (EGFR-axis). Decreased intracellular calcium with aberrant intracellular cAMP signaling. Alterations in planar cell polarity (PCP).
1
PI3K AKT
heterro
homo o
T J
3 MMP’s
HB-EGF TGF TGF-α Amphiregulin
Ligand g
ER
c--Src S Shc
2
Grb2
S Sos
Ras *
6 TSC1 ------TSC2
Alterations in cell–cell and cell–matrix interactions.
R f1 Raf-1
4
T J
5 Normal Renal Epithelia
7
( ) (+)
MEK1/2
cAMP AMP
PKA
() (-)
mTOR
PDE Ca2+
PKD Epithelia
β-Raf Raf 10 P
8 ARPKD ENaC Mediated Fluid Secretion ?
ADPKD CFTR Mediated Cl- Secretion
Erk1/2
11
9
X β-catenin catenin
Wnt
Proliferatio P lif tion Angiogenessis
Fig. 2 Cystic phenotype and therapeutic interventions. This figure depicts a simplified cartoon of the primary signaling pathways which have been implicated in mediating progressive cyst formation and enlargement in ARPKD and ADPKD. Abnormal expression of the epidermal growth factor receptor (EGFR)-axis and adenylate cyclase activating receptor activity leading to increased cAMP in a decreased intracellular calcium environment lead to increased proliferation, secretory abnormalities, and altered cell–cell and cell–matrix interactions. Superimposed on the figure are key sites of therapeutic targeting based on empirical data obtained from non-orthologous and orthologous models of PKD. To illustrate, the EGFR axis can be targeted at a number of critical points shown in Fig. 2. Arrow 1 refers to the use of antibodies to the ligand binding site of the receptor
X AC-activating receptor t
ATP
12
13 R
Gi
Gs
V2R
preventing the binding of the EGFR ligand and thus prevention of receptor activation. Arrow 2 illustrates the use of small inhibitor inhibitors that prevent EGFR family receptors from dimerizing, a necessary step for activation. Arrow 3 refers to the use of enzyme inhibitors (matrix metalloproteinases, MMPs) that are necessary to cleave pre-pro ligands to their mature state and thus activate the receptor. Arrow 4 represents the activation of Src which, when phosphorylated at pY418, acts in a reciprocal fashion to phosphorylate and thus activate EGFR. The interested reader is referred to recent comprehensive reviews which provide much more detail regarding recent advances on our understanding of the pathophysiology of PKD and hence the rationale behind the proposed therapies shown in Fig. 2 [21, 46, 58, 122–124]
686
proliferation [125–127]. Our understanding this pathway and the relationship of the multiple players suggest that therapies that prevent increases in cAMP may be effective therapeutic targets for the amelioration of cyst formation and growth. In the case of cAMP, these targets, as shown by the arrows in Fig. 2, may include (1) a decrease in c-Src activity (arrow 4) and the prevention of β-Raf activation (arrow 5); (2) prevention of decreases in intracellular calcium (arrow 10); (3) blocking of β-Raf phosphorylation directly (arrow 5); (4) prevention of the stimulation of AC-activating receptor and subsequent increases in cAMP with either somatostatin (arrow 12) or tolvaptan (arrow 13). These compounds may be given as a single therapy or used in combination. These data suggest that the PKD proteins (PC1, PC2, and fibrocystin) play a role in maintaining Ca2+ homeostasis. Mutations in any of the PKD proteins may lead to a reduction in intracellular Ca2+ and activate the cAMP mitogenic pathway through activation of the MEK/ERK pathway. Detailed reviews that provide detailed descriptions of the molecular and cellular pathophysiology of PKD have recently been published [21, 58, 122–124]. Given the complex intracellular cascades activated in both ADPKD, and ARPKD, the “holy grail” of future therapy is to identify key cellular signaling “checkpoints” where diffuse processes and signaling pathways are integrated, resulting in the cystic phenotype. Examples of such checkpoints illustrated in Fig. 2 include Src (arrow 4) and the AC-activating receptor (arrows 12 and 13). There are currently no specific therapies which unequivocally arrest the progression of ARPKD or ADPKD. Therefore, management of all patients with PKD includes aggressive control of blood pressure, anticipatory management of the known complications specific to ARPKD and ADPKD detailed above, and avoidance of any additional nephrotoxic insults (including drugs—legal, illicit, or naturopathic but of unknown safety). Dialysis and transplantation remain the ultimate therapy for PKD with ESRD. On the basis of preclinical experimental studies, avoidance of cAMP agonists, such as caffeine, theophylline-like drugs, estrogens, and calcium channel blocking drugs (used as anti-hypertensives), has been recommended by many experts in the field. The prospects for therapeutic interventions in PKD are clearly improving, and new therapies are entering clinical trials yearly. Even now, early clinical trials on various experimental therapies are currently taking place (see Appendix 1). However, despite the impressive improvements in our understanding of the pathophysiology of PKD, many hurdles still remain. Recent reports of early results of clinical trials of mTOR inhibitors have been disappointing [128, 129], despite the extensive experimental literature implicating mTOR in PKD [130–132]. Until successful trials are available, patients with PKD should to be advised to follow the current management
Pediatr Nephrol (2011) 26:675–692
recommendations noted above. Foundations devoted to PKD which provide important patient and family information, as well as ongoing clinical and research updates including listings of clinical trials currently recruiting patients, include the PKD Foundation (www.pkdcure.org) and the ARPKD-CHF Alliance (www.arpkdchf.org). Excellent, more general webbased resources for renal disease are listed in Appendix 2.
Appendix 1: Current clinical trails for PKD Polycystic Kidney Disease (PKD) Foundation. Available at: http://www.pkdcure.org/research/clinicalTrials. http://clinicaltrials.gov (search for PKD trials)
Appendix 2: Web-based resources for information on renal cystic disease Polycystic Kidney Disease (PKD) Foundation. Available at: http://www.pkdcure.org. GeneTests. Available at: http://www.genetests.org NIH/National Kidney and Urologic Diseases Information Clearinghouse. Available at: http://kidney.niddk.nih.gov ARPKD/CHF Alliance. Available at: http://www.arpkdchf.org March of Dimes. Available at: http://www.marchofdimes.com. American Kidney Fund. Available at: http://www.kidney fund.org. National Kidney Foundation. Available at: http://www. kidney.org. The Kidney Foundation of Canada. Available at: http:// www.kidney.on.ca American Urological Association. Available at: http://www. afud.org. National Center for Biotechnology Information. Available at: http://www.ncbi.nlm.nih.gov/. Online Mendelian Inheritance in Man (OMIM). Available at: http://www.ncbi.nlm.nih.gov/entrez/ National Organization for Rare Disorders (NORD). Available at: http://www.rarediseases.org. Tuberous Sclerosis Alliance. Available at: http://www. tsalliance.or Questions Answers appear following the reference list. 1) Childhood ADPKD a) When present, liver and/or pancreatic cysts may help differentiate early-onset ADPKD from ARPKD. a. True b. False
Pediatr Nephrol (2011) 26:675–692
687
b) Unilateral disease presentations in children are unique to ADPKD (as compared to ARPKD).
and have a variety of extracellular and intracellular motifs.
a. True b. False c) If both biological parents of a patient with PKD are older than 30 years and demonstrate no renal cysts, the diagnosis of ADPKD can be eliminated.
a. True b. False
a, True b. False d) Most children with ADPKD are asymptomatic, and their major clinical manifestation of disease is hypertension and associated cardiac co-morbidities. a. True b. False 2) ARPKD a) The mortality of patients presenting with prenatal oligohydramnios and postnatal severe renal disease is 70%. a. True b. False b) Given the incidence of pulmonary hypoplasia in patients presenting with severe neonatal disease, intubation and ventilation in the neonatal period should be deferred in favor of a conservative clinical approach. a. True b. False c) Patients with ARPKD who survive the first month of life have a 10-year survival of >75%. a. True b. False d) Because a serious and potentially lethal complication of ARPKD is ascending cholangitis, fever and/ or elevation of liver function test results mandate prompt diagnosis and treatment. a. True b. False 3) Molecular aspects of PKD a) In standard practice ARPKD and ADPKD are diagnosed by identifications of mutations in PKD1, PKD2, and PKHD1. a. True b. False b) The proteins encoded by PKD1 (polycystin 1) and PKHD1 (fibrocystin) comprise >4,000 amino acids
c) Gene therapy for ADPKD is not promising given the size of the PKD1 gene and the fact that both increased and decreased expression of PKD1 lead to ADPKD in experimental models. a. True b. False d) Despite the many differences in the molecular biology of ADPKD and ARPKD, clinical differentiation of these diseases in a newborn with enlarged kidneys and hypertension can be difficult in many cases a. True b. False 4) ADPKD vs. ARPKD: therapeutics a) Given the current understanding of the pathophysiology of cyst formation and progressive growth in ADPKD and ARPKD, caffeine, theophylline-like agents, and particularly calcium channel antagonists (for hypertension) should be avoided. a. True b. False b) Vasopressin antagonists are potentially useful agents to reduce biliary lesions in ARPKD. a. True b. False c) Ignoring the possibility of spontaneous mutations, PGD coupled with IVF has the potential to eliminate the familial risk of ADPKD in subsequent generations a. True b. False d) Promising future therapies for treatment of both ADPKD and ARPKD include: EGFR-axis inhibitors, Src inhibitors, mTor inhibitors, cystic fibrosis transmembrane conductance regulator (CFTR) inhibitors, and somatostatin analogs. a. True b. False
References 1. Fliegauf M, Benzing T, Omran H (2007) When cilia go bad: cilia defects and ciliopathies. Nat Rev Mol Cell Biol 8:880–893
688 2. Bernstein J (1993) Glomerulocystic kidney disease—nosological considerations. Pediatr Nephrol 7:464–470 3. Lennerz JK, Spence DC, Iskandar SS, Dehner LP, Liapis H (2010) Glomerulocystic kidney: one hundred-year perspective. Arch Pathol Lab Med 134:583–605 4. Siroky BJ, Czyzyk-Krzeska MF, Bissler JJ (2009) Renal involvement in tuberous sclerosis complex and von HippelLindau disease: shared disease mechanisms? Nat Clin Pract Nephrol 5:143–156 5. Deltas C, Papagregoriou G (2010) Cystic diseases of the kidney: molecular biology and genetics. Arch Pathol Lab Med 134:569– 582 6. Parisi MA (2009) Clinical and molecular features of Joubert syndrome and related disorders. Am J Med Genet C Semin Med Genet 151C:326–340 7. Gunay-Aygun M (2009) Liver and kidney disease in ciliopathies. Am J Med Genet C Semin Med Genet 151C:296–306 8. Guay-Woodford LM, Galliani CA, Musulman-Mroczek E, Spear GS, Guillot AP, Bernstein J (1998) Diffuse renal cystic disease in children: morphologic and genetic correlations. Pediatr Nephrol 12:173–182 9. Kaariainen H, Koskimies O, Norio R (1988) Dominant and recessive polycystic kidney disease in children: evaluation of clinical features and laboratory data. Pediatr Nephrol 2:296–302 10. Guay-Woodford LM, Muecher G, Hopkins SD, Avner ED, Germino GG, Guillot AP, Herrin J, Holleman R, Irons DA, Primack W, Thompson PD, Waldo FB, Lunt PW, Zerres K (1995) The severe perinatal form of autosomal recessive polycystic kidney disease maps to chromosome 6p21.1-p12: Implications for genetic counseling. Am J Hum Genet 56:1101–1107 11. Onuchic LF, Furu L, Nagasawa Y, Hou X, Eggermann T, Ren Z, Bergmann C, Senderek J, Esquivel E, Zeltner R, RudnikSchoneborn S, Mrug M, Sweeney W, Avner ED, Zerres K, Guay-Woodford LM, Somlo S, Germino GG (2002) PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexintranscription-factor domains and parallel beta-helix 1 repeats. Am J Hum Genet 70:1305–1317 12. Ward CJ, Hogan MC, Rossetti S, Walker D, Sneddon T, Wang X, Kubly V, Cunningham JM, Bacallao R, Ishibashi M, Milliner DS, Torres VE, Harris PC (2002) The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet 30:259–269 13. Ong AC, Harris PC (2005) Molecular pathogenesis of ADPKD: the polycystin complex gets complex. Kidney Int 67:1234–1247 14. Gabow PA (1993) Autosomal dominant polycystic kidney disease. N Engl J Med 329:332–342 15. Ariza M, Alvarez V, Marin R, Aguado S, Lopez-Larrea C, Alvarez J, Menendez MJ, Coto E (1997) A family with a milder form of adult dominant polycystic kidney disease not linked to the PKD1 (16p) or PKD2 (4q) genes. J Med Genet 34:587–589 16. de Almeida S, de Almeida E, Peters D, Pinto JR, Tavora I, Lavinha J, Breuning M, Prata MM (1995) Autosomal dominant polycystic kidney disease: evidence for the existence of a third locus in a Portuguese family. Hum Genet 96:83–88 17. Daoust MC, Reynolds DM, Bichet DG (1995) Evidence for a third genetic locus for autosomal dominant polycystic kidney disease. Genomics 25:733–737 18. Zerres K, Mucher G, Becker J, Steinkamm C, RudnikSchoneborn S, Heikkila P, Rapola J, Salonen R, Germino GG, Onuchic L, Somlo S, Avner ED, Harman LA, Stockwin JM, Guay-Woodford LM (1998) Prenatal diagnosis of autosomal recessive polycystic kidney disease (ARPKD): molecular genetics, clinical experience, and fetal morphology. Am J Med Genet 76:137–144
Pediatr Nephrol (2011) 26:675–692 19. Adeva M, El-Youssef M, Rosetti S, Kamath PS, Kubly V, Consugar MB, Milliner DM, King BF, Torres VE, Harris PC (2006) Clinical and molecular characterizations defines a broadened spectrum of autosomal recessive polycystic kidney disease (ARPKD). Medicine 85:1–21 20. Guay-Woodford LM, Desmond RA (2003) Autosomal recessive polycystic kidney disease: the clinical experience in North America. Pediatrics 111:1072–1080 21. Dell KM, Sweeney WE, Avner ED (2009) Polycystic kidney disease. In: Avner ED, Harmon WE, Niaudet P, Yoshikawa N (eds) Pediatric nephrology. Vol. 1. Springer, Berlin, Heidelberg, pp 849–887 22. Zerres K, Hansmann M, Knopfle G, Stephan M (1985) Prenatal diagnosis of genetically determined early manifestation of autosomal dominant polycystic kidney disease? Hum Genet 71:368–389 23. Roy S, Dillon MJ, Trompeter RS, Barratt TM (1997) Autosomal recessive polycystic kidney disease: long-term outcome of neonatal survivors. Pediatr Nephrol 11:302–306 24. Kaplan BS, Kaplan P, Rosenberg HK, Lamothe E, Rosenblatt DS (1989) Polycystic kidney diseases in childhood. J Pediatr 115:867–880 25. Cole BR, Conley SB, Stapleton FB (1987) Polycystic kidney disease in the first year of life. J Pediatr 111:693–699 26. Guay-Woodford L (1996) Autosomal recessive polycystic kidney disease: clinical and genetic profiles. In: Watson ML, Torres VH (eds) Polycystic kidney disease. Oxford University Press, New York, pp 237–266 27. Davis ID, Ho M, Hupertz V, Avner ED (2003) Survival of childhood polycystic kidney disease following renal transplantation: the impact of advanced hepatobiliary disease. Pediatr Transplant 7:364–369 28. Blyth H, Ockenden BG (1971) Polycystic disease of kidney and liver presenting in childhood. J Med Genet 8:257–284 29. Turkbey B, Ocak I, Daryanani K, Font-Montgomery E, Lukose L, Bryant J, Tuchman M, Mohan P, Heller T, Gahl WA, Choyke PL, Gunay-Aygun M (2009) Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD/CHF). Pediatr Radiol 39:100–111 30. Zerres K, Rudnik-Schoneborn S, Deget F, Holtkamp U, Brodehl J, Geisert J, Scharer K (1996) Autosomal recessive polycystic kidney disease in 115 children: clinical presentation, course and influence of gender. Arbeitsgemeinschaft für Pädiatrische, Nephrologie. Acta Paediatr 85:437–445 31. Hofmeyr GJ, Gulmezoglu AM (2000) Maternal hydration for increasing amniotic fluid volume in oligohydramnios and normal amniotic fluid volume. Cochrane Database Syst Rev CD000134 32. Gagnadoux MF, Habib R, Levy M, Brunelle F, Broyer M (1989) Cystic renal diseases in children. Adv Nephrol Necker Hosp 18:33–57 33. Hunley TE, Kon V, Ichikawa I (2009) Glomerular circulation and function. In: Avner ED, Harmon WE, Niaudet P (eds) Pediatric nephrology, vol 1. Springer, Berlin, Heidelberg, pp 31–64 34. Osathanondh V, Potter EL (1964) Pathogenesis of polycystic kidneys. Type 1 due to hyperplasia of interstitial portions of collecting tubules. Arch Pathol 77:466–473 35. Bernstein J, Slovis TL (1992) Polycystic diseases of the kidney. In: Edelmann C (ed) Pediatric kidney diseases, vol 2. Little, Brown, Boston, pp 1139–1157 36. Traubici J, Daneman A (2005) High-resolution renal sonography in children with autosomal recessive polycystic kidney disease. AJR Am J Roentgenol 184:1630–1633 37. Holthofer H, Kumpulainer T, Rapola J (1990) Polycystic disease of the kidney: evaluation and classification based on nephron segment and cell-type specific markers. Lab Invest 62:363–369
Pediatr Nephrol (2011) 26:675–692 38. Nicolau C, Torra R, Badenas C, Perez L, Oliver JA, Darnell A, Bru C (2000) Sonographic pattern of recessive polycystic kidney disease in young adults. Differences from the dominant form. Nephrol Dial Transplant 15:1373–1378 39. Stein-Wexler R, Jain K (2003) Sonography of macrocysts in infantile polycystic kidney disease. J Ultrasound Med 22:105– 117 40. Blickman JG, Bramson RT, Herrin JT (1995) Autosomal recessive polycystic kidney disease: long-term sonographic findings in patients surviving the neonatal period. AJR Am J Roentgenol 164:1247–1250 41. Avni FE, Guissard G, Hall M, Janssen F, DeMaertelaer V, Rypens F (2002) Hereditary polycystic kidney diseases in children: changing sonographic patterns through childhood. Pediatr Radiol 32:169–174 42. Akhan O, Karaosmanoglu AD, Ergen B (2007) Imaging findings in congenital hepatic fibrosis. Eur J Radiol 61:18–24 43. Kern S, Zimmerhackl LB, Hildebrandt F, Ermisch-Omran B, Uhl M (2000) Appearance of autosomal recessive polycystic kidney disease in magnetic resonance imaging and RARE-MRurography. Pediatr Radiol 30:156–160 44. Kern S, Zimmerhackl LB, Hildebrandt F, Uhl M (1999) RareMR-urography—a new diagnostic method in autosomal recessive polycystic kidney disease. Acta Radiol 40:543–554 45. Boal DK, Teele RL (1980) Sonography of infantile polycystic kidney disease. Am J Radiol 135:575–580 46. Torres VE, Harris PC (2009) Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int 76:149–168 47. Harris PC, Rossetti S (2010) Determinants of renal disease variability in ADPKD. Adv Chronic Kidney Dis 17:131–139 48. Harris PC, Rossetti S (2010) Molecular diagnostics for autosomal dominant polycystic kidney disease. Nat Rev Nephrol 6:197–206 49. Bergmann C, Senderek J, Windelen E, Kupper F, Middeldorf I, Schneider F, Dornia C, Rudnik-Schoneborn S, Konrad M, Schmitt CP, Seeman T, Neuhaus TJ, Vester U, Kirfel J, Buttner R, Zerres K (2005) Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD). Kidney Int 67:829–848 50. Sharp AM, Messiaen LM, Page G, Antignac C, Gubler MC, Onuchic LF, Somlo S, Germino GG, Guay-Woodford LM (2005) Comprehensive genomic analysis of PKHD1 mutations in ARPKD cohorts. J Med Genet 42:336–349 51. Losekoot M, Haarloo C, Ruivenkamp C, White SJ, Breuning MH, Peters DJ (2005) Analysis of missense variants in the PKHD1-gene in patients with autosomal recessive polycystic kidney disease (ARPKD). Hum Genet 118:185–206 52. Bergmann C, Kupper F, Dornia C, Schneider F, Senderek J, Zerres K (2005) Algorithm for efficient PKHD1 mutation screening in autosomal recessive polycystic kidney disease (ARPKD). Hum Mutat 25:225–231 53. Rossetti S, Torra R, Coto E, Consugar M, Kubly V, Malaga S, Navarro M, El-Youssef M, Torres VE, Harris PC (2003) A complete mutation screen of PKHD1 in autosomal-recessive polycystic kidney disease (ARPKD) pedigrees. Kidney Int 64:391–403 54. Consugar MB, Anderson SA, Rossetti S, Pankratz VS, Ward CJ, Torra R, Coto E, El-Youssef M, Kantarci S, Utsch B, Hildebrandt F, Sweeney WE, Avner ED, Torres VE, Cunningham JM, Harris PC (2005) Haplotype analysis improves molecular diagnostics of autosomal recessive polycystic kidney disease. Am J Kidney Dis 45:77–87 55. Zerres K, Senderek J, Rudnik-Schoneborn S, Eggermann T, Kunze J, Mononen T, Kaariainen H, Kirfel J, Moser M, Buettner R, Bergmann C (2004) New options for prenatal diagnosis in
689
56.
57.
58. 59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
autosomal recessive polycystic kidney disease by mutation analysis of the PKHD1 gene. Clin Genet 66:53–57 Lau EC, Janson MM, Roesler MR, Avner ED, Strawn EY, Bick DP (2010) Birth of a healthy infant following preimplantation PKHD1 haplotyping for autosomal recessive polycystic kidney disease using multiple displacement amplification. J Assist Reprod Genet 27:297–407 Dell KM, Avner ED (2008) Autosomal recessive polycystic kidney disease. In: GeneClinics: Clinical Genetic Information Resource (database online). Copyright, University of Washington, Seattle. Available at http://www.geneclinics.org. Initial posting July 2001, updated August 2008 Harris PC, Torres VE (2009) Polycystic kidney disease. Annu Rev Med 60:321–337 Sedman A, Bell P, Manco-Johnson M, Schrier R, Warady BA, Heard ED, Butler-Simon N, Gabow P (1987) Autosomal dominant polycystic kidney disease in childhood: a longitudinal study. Kidney Int 31:1000–1005 Parfrey PS, Bear JC, Morgan J, Cramer BC, McManamon PJ, Gault MH, Churchill DN, Singh M, Hewitt R (1990) The diagnosis and prognosis of autosomal dominant polycystic kidney disease. N Engl J Med 323:1085–1090 Peters DJ, Sandkuijl LA (1992) Genetic heterogeneity of polycystic kidney disease in Europe. Contrib Nephrol 97:128– 134 Dobin A, Kimberling WJ, Pettinger W, Bailey-Wilson JE, Shugart YY, Gabow P (1993) Segregation analysis of autosomal dominant polycystic kidney disease. Genet Epidemiol [Suppl 10]:189–200 Barua M, Cil O, Paterson AD, Wang K, He N, Dicks E, Parfrey P, Pei Y (2009) Family history of renal disease severity predicts the mutated gene in ADPKD. J Am Soc Nephrol 20:1833–1838 Turco AE, Clementi M, Rossetti S, Tenconi R, Pignatti PF (1996) An Italian family with autosomal dominant polycystic kidney disease unlinked to either the PKD1 or PKD2 gene. Am J Kidney Dis 28:759–761 >Pei Y, Paterson AD, Wang KR, He N, Hefferton D, Watnick T, Germino GG, Parfrey P, Somlo S, St George-Hyslop P (2001) Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease. Am J Hum Genet 68:355– 363 Rossetti S, Kubly VJ, Consugar MB, Hopp K, Roy S, Horsley SW, Chauveau D, Rees L, Barratt TM, van't Hoff WG, Niaudet WP, Torres VE, Harris PC (2009) Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease. Kidney Int 75:848–855 Rossetti S, Consugar MB, Chapman AB, Torres VE, GuayWoodford LM, Grantham JJ, Bennett WM, Meyers CM, Walker DL, Bae K, Zhang QJ, Thompson PA, Miller JP, Harris PC (2007) Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 18:2143–2160 Hateboer N, van Dijk MA, Bogdanova N, Coto E, SaggarMalik AK, San Millan JL, Torra R, Breuning M, Ravine D (1999) Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1–PKD2 Study Group. Lancet 353:103–107 Harris PC, Bae KT, Rossetti S, Torres VE, Grantham JJ, Chapman AB, Guay-Woodford LM, King BF, Wetzel LH, Baumgarten DA, Kenney PJ, Consugar M, Klahr S, Bennett WM, Meyers CM, Zhang QJ, Thompson PA, Zhu F, Miller JP (2006) Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 17:3013–3019
690 70. Consortium TIPKD (1995) Polycystic kidney disease: the complete structure of the PKD1 gene and its protein. Cell 81:289–298 71. Reeders ST, Breuning MH, Davies KE, Nicholls RD, Jarman AP, Higgs DR, Pearson PL, Weatherall DJ (1985) A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16. Nature 317:542–544 72. Phakdeekitcharoen B, Watnick TJ, Germino GG (2001) Mutation analysis of the entire replicated portion of PKD1 using genomic DNA samples. J Am Soc Nephrol 12:955–963 73. Rossetti S, Chauveau D, Walker D, Saggar-Malik A, Winearls CG, Torres VE, Harris PC (2002) A complete mutation screen of the ADPKD genes by DHPLC. Kidney Int 61:1588–1599 74. Tsoikas L, Kim E, Arnould T, Sukatme VP, Walz G (1997) Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2. Proc Natl Acad Sci USA 94:6965–6970 75. Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A, Kimberling WJ, Breuning MH, Deltas CC, Peters DJ, Somlo S (1996) PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272:1339–1342 76. Peters DJ, Spruit L, Saris JJ, Ravine D, Sandkuijl LA, Fossdal R, Boersma J, van Eijk R, Norby S, Constantinou-Deltas CD (1993) Chromosome 4 localization of a second gene for autosomal dominant polycystic kidney disease. Nat Genet 5:359–362 77. Koulen P, Cai Y, Geng L, Maeda Y, Nishimura S, Witzgall R, Ehrlich BE, Somlo S (2002) Polycystin-2 is an intracellular calcium release channel. Nat Cell Biol 4:191–197 78. Kottgen M (2007) TRPP2 and autosomal dominant polycystic kidney disease. Biochim Biophys Acta 1772:836–850 79. Witzgall R (2005) New developments in the field of cystic kidney diseases. Curr Mol Med 5:455–465 80. Ong AC, Harris PC (1997) Molecular basis of renal cyst formation—one hit or two? Lancet 349:1039–1040 81. Watnick T, Germino GG (1999) Molecular basis of autosomal dominant polycystic kidney disease. Semin Nephrol 19:327–343 82. Sutters M, Germino GG (2003) Autosomal dominant polycystic kidney disease: molecular genetics and pathophysiology. J Lab Clin Med 141:91–101 83. Qian Q, Hunter LW, Li M, Marin-Padilla M, Prakash YS, Somlo S, Harris PC, Torres VE, Sieck GC (2003) Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells. Hum Mol Genet 12:1875–1880 84. Lantinga-van Leeuwen IS, Dauwerse JG, Baelde HJ, Leonhard WN, van de Wal A, Ward CJ, Verbeek S, Deruiter MC, Breuning MH, de Heer E, Peters DJ (2004) Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease. Hum Mol Genet 13:3069–3077 85. Shannon MB, Patton BL, Harvey SJ, Miner JH (2006) A hypomorphic mutation in the mouse laminin alpha5 gene causes polycystic kidney disease. J Am Soc Nephrol 17:1913–1922 86. Gabow P (1993) Autosomal dominant polycystic kidney disease. N Engl J Med 329:332–342 87. Gabow PA (1990) Autosomal dominant polycystic kidney disease–more than a renal disease. Am J Kidney Dis 16:403–413 88. Torres VE, Harris PC (2003) Autosomal dominant polycystic kidney disease. Nefrologia 23[Suppl 1]:14–22 89. Bae KT, Zhu F, Chapman AB, Torres VE, Grantham JJ, GuayWoodford LM, Baumgarten DA, King BF Jr, Wetzel LH, Kenney PJ, Bennett BME, WM KS, Meyers CM, Zhang X, Thompson PA, Miller JP (2006) Magnetic resonance imaging evaluation of hepatic cysts in early autosomal-dominant polycystic kidney disease: the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort. Clin J Am Soc Nephrol 1:64–69
Pediatr Nephrol (2011) 26:675–692 90. Rizk D, Chapman A (2008) Treatment of autosomal dominant polycystic kidney disease (ADPKD): the new horizon for children with ADPKD. Pediatr Nephrol 23:1029–1036 91. Everson GT (1990) Hepatic cysts in autosomal dominant polycystic kidney disease. Mayo Clin Proc 65:1020–1025 92. Cheong B, Muthupillai R, Rubin MF, Flamm SD (2007) Normal values for renal length and volume as measured by magnetic resonance imaging. Clin J Am Soc Nephrol 2:38–45 93. Chapman AB, Schrier RW (1991) Pathogenesis of hypertension in autosomal dominant polycystic kidney disease. Semin Nephrol 11:653–660 94. Kelleher CL, McFann KK, Johnson AM, Schrier RW (2004) Characteristics of hypertension in young adults with autosomal dominant polycystic kidney disease compared with the general U.S. population. Am J Hypertens 17:1029–1034 95. Schrier RW, Johnson AM, McFann K, Chapman AB (2003) The role of parental hypertension in the frequency and age of diagnosis of hypertension in offspring with autosomaldominant polycystic kidney disease. Kidney Int 64:1792–1799 96. Gabow PA, Johnson AM, Kaehny WD, Kimberling WJ, Lezotte DC, Duley IT, Jones RH (1992) Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease. Kidney Int 41:1311–1319 97. Chapman AB, Johnson AM, Rainguet S, Hossack K, Gabow P, Schrier RW (1997) Left ventricular hypertrophy in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 8:1292–1297 98. MacDermot KD, Saggar-Malik AK, Economides DL, Jeffery S (1998) Prenatal diagnosis of autosomal dominant polycystic kidney disease (PKD1) presenting in utero and prognosis for very early onset disease. J Med Genet 35:13–16 99. Seeman T, Dusek J, Vondrichova H, Kyncl M, John U, Misselwitz J, Janda J (2003) Ambulatory blood pressure correlates with renal volume and number of renal cysts in children with autosomal dominant polycystic kidney disease. Blood Press Monit 8:107–110 100. de Almeida EA, de Oliveira EI, Lopes JA, Almeida AG, Lopes MG, Prata MM (2007) Ambulatory blood pressure measurement in young normotensive patients with autosomal dominant polycystic kidney disease. Rev Port Cardiol 26:235–243 101. Kubo S, Nakajima M, Fukuda K, Nobayashi M, Sakaki T, Aoki K, Hirao Y, Yoshioka A (2004) A 4-year-old girl with autosomal dominant polycystic kidney disease complicated by a ruptured intracranial aneurysm. Eur J Pediatr 163:675–677 102. Schrier RW, Belz MM, Johnson AM, Kaehny WD, Hughes RL, Rubinstein D, Gabow PA (2004) Repeat imaging for intracranial aneurysms in patients with autosomal dominant polycystic kidney disease with initially negative studies: a prospective tenyear follow-up. J Am Soc Nephrol 15:1023–1028 103. Chapman AB (2008) Approaches to testing new treatments in autosomal dominant polycystic kidney disease: insights from the CRISP and HALT-PKD studies. Clin J Am Soc Nephrol 3:1197–1204 104. Ecder T, Chapman AB, Brosnahan GM, Edelstein CL, Johnson AM, Schrier RW (2000) Effect of antihypertensive therapy on renal function and urinary albumin excretion in hypertensive patients with autosomal dominant polycystic kidney disease. Am J Kidney Dis 35:427–432 105. Grantham JJ, Torres VE, Chapman AB, Guay-Woodford LM, Bae KT, King BF Jr, Wetzel LH, Baumgarten DA, Kenney PJ, Harris PC, Klahr S, Bennett WM, Hirschman GN, Meyers CM, Zhang X, Zhu F, Miller JP (2006) Volume progression in polycystic kidney disease. N Engl J Med 354:2122–2130 106. Ravine D, Gibson RN, Walker RG, Sheffield LJ, Kincaid-Smith P, Danks DM (1994) Evaluation of ultrasonographic diagnostic
Pediatr Nephrol (2011) 26:675–692
107.
108.
109.
110.
111.
112.
113.
114.
115.
116. 117.
118.
119.
120. 121.
criteria for autosomal dominant polycystic kidney disease 1. Lancet 343:824–827 Pei Y, Obaji J, Dupuis A, Paterson AD, Magistroni R, Dicks E, Parfrey P, Cramer B, Coto E, Torra R, San Millan JL, Gibson R, Breuning M, Peters D, Ravine D (2009) Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol 20:205–212 Gabow PA, Kimberling WJ, Strain JD, Manco-Johnson ML, Johnson AM (1997) Utility of ultrasonography in the diagnosis of autosomal dominant polycystic kidney disease in children. J Am Soc Nephrol 8:105–110 Brun M, Maugey-Laulom B, Eurin D, Didier F, Avni EF (2004) Prenatal sonographic patterns in autosomal dominant polycystic kidney disease: a multicenter study. Ultrasound Obstet Gynecol 24:55–61 Chaumoitre K, Brun M, Cassart M, Maugey-Laulom B, Eurin D, Didier F, Avni EF (2006) Differential diagnosis of fetal hyperechogenic cystic kidneys unrelated to renal tract anomalies: A multicenter study. Ultrasound Obstet Gynecol 28:911– 917 Fick-Brosnahan G, Johnson AM, Strain JD, Gabow PA (1999) Renal asymmetry in children with autosomal dominant polycystic kidney disease. Am J Kidney Dis 34:639–645 Torra R, Nicolau C, Badenas C, Navarro S, Perez L, Estivill X, Darnell A (1997) Ultrasonographic study of pancreatic cysts in autosomal dominant polycystic kidney disease. Clin Nephrol 47:19–22 Chapman AB, Guay-Woodford LM, Grantham JJ, Torres VE, Bae KT, Baumgarten DA, Kenney PJ, King BF Jr, Glockner JF, Wetzel LH, Brummer ME, O'Neill WC, Robbin ML, Bennett WM, Klahr S, Hirschman GH, Kimmel PL, Thompson PA, Miller JP (2003) Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort. Kidney Int 64:1035–1045 Grantham JJ, Cook LT, Torres VE, Bost JE, Chapman AB, Harris PC, Guay-Woodford LM, Bae KT (2008) Determinants of renal volume in autosomal-dominant polycystic kidney disease. Kidney Int 73:108–116 Torres VE, King BF, Chapman AB, Brummer ME, Bae KT, Glockner JF, Arya K, Risk D, Felmlee JP, Grantham JJ, GuayWoodford LM, Bennett WM, Klahr S, Meyers CM, Zhang X, Thompson PA, Miller JP (2007) Magnetic resonance measurements of renal blood flow and disease progression in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2:112–120 Ogborn MR (1994) Polycystic kidney disease—a truly pediatric problem. Pediatr Nephrol 8:762–767 Reuss A, Wladimiroff JW, Stewart PA, Niermeijer MF (1990) Prenatal diagnosis by ultrasound in pregnancies at risk for autosomal recessive polycystic kidney disease. Ultrasound Med Biol 16:355–359 Zhao X, Paterson AD, Zahirieh A, He N, Wang K, Pei Y (2008) Molecular diagnostics in autosomal dominant polycystic kidney disease: utility and limitations. Clin J Am Soc Nephrol 3:146–152 De Rycke M, Georgiou I, Sermon K, Lissens W, Henderix P, Joris H, Platteau P, Van Steirteghem A, Liebaers I (2005) PGD for autosomal dominant polycystic kidney disease type 1. Mol Hum Reprod 11:65–71 Harris PC, Rossetti S (2008) Molecular diagnostics of ADPKD coming of age. Clin J Am Soc Nephrol 3:1–2 Pei Y, Watnick T (2010) Diagnosis and screening of autosomal dominant polycystic kidney disease. Adv Chronic Kidney Dis 17:140–152
691 122. Torres VE (2008) Role of vasopressin antagonists. Clin J Am Soc Nephrol 3:1212–1218 123. Patel V, Chowdhury R, Igarashi P (2009) Advances in the pathogenesis and treatment of polycystic kidney disease. Curr Opin Nephrol Hypertens 18:99–106 124. Zhou J (2009) Polycystins and primary cilia: primers for cell cycle progression. Annu Rev Physiol 71:83–113 125. Yamaguchi T, Nagao S, Wallace DP, Belibi FA, Cowley BD, Pelling JC, Grantham JJ (2003) Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys. Kidney Int 63:1983–1994 126. Yamaguchi T, Pelling JC, Ramaswamy NT, Eppler JW, Wallace DP, Nagao S, Rome LA, Sullivan LP, Grantham JJ (2000) cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway. Kidney Int 57:1460–1471 127. Yamaguchi T, Wallace DP, Magenheimer BS, Hempson SJ, Grantham JJ, Calvet JP (2004) Calcium restriction allows cAMP activation of the B-Raf/ERK pathway, switching cells to a cAMP-dependent growth-stimulated phenotype. J Biol Chem 279:40419–40430 128. Serra AL, Kistler AD, Poster D, Krauer F, Senn O, Raina S, Pavik I, Rentsch K, Regeniter A, Weishaupt D, Wuthrich RP (2009) Safety and tolerability of sirolimus treatment in patients with autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 24:3334–3342 129. Perico N, Antiga L, Caroli A, Ruggenenti P, Fasolini G, Cafaro M, Ondei P, Rubis N, Diadei O, Gherardi G, Prandini S, Panozo A, Bravo RF, Carminati S, De Leon FR, Gaspari F, Cortinovis M, Motterlini N, Ene-Iordache B, Remuzzi A, Remuzzi G (2010) Sirolimus therapy to halt the progression of ADPKD. J Am Soc Nephrol 21:1031–1040 130. Zafar I, Ravichandran K, Belibi FA, Doctor RB, Edelstein CL (2010) Sirolimus attenuates disease progression in an orthologous mouse model of human autosomal dominant polycystic kidney disease. Kidney Int. doi:10.1038/ki.2010.250 131. Shillingford JM, Piontek KB, Germino GG, Weimbs T (2010) Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1. J Am Soc Nephrol 21:489–497 132. Becker JU, Saez AO, Zerres K, Witzke O, Hoyer PF, Schmid KW, Kribben A, Bergmann C, Nurnberger J (2010) The mTOR pathway is activated in human autosomal-recessive polycystic kidney disease. Kidney Blood Press Res 33:129–138 133. Bissler JJ, Siroky BJ, Yin H (2010) Glomerulocystic kidney disease. Pediatr Nephrol 25:2049–2059 134. Bernstein J (1993) Renal cystic disease in the tuberous sclerosis complex. Pediatr Nephrol 7:490–495 135. Orlova KA, Crino PB (2010) The tuberous sclerosis complex. Ann N Y Acad Sci 1184:87–105 136. Rohatgi R (2008) Clinical manifestations of hereditary cystic kidney disease. Front Biosci 13:4175–4197 137. Spivey PS, Bradshaw WT (2009) Recognition and management of the infant with Beckwith-Wiedemann Syndrome. Adv Neonatal Care 9:279–284 138. Currarino G (2009) Hajdu-Cheney syndrome associated with serpentine fibulae and polycystic kidney disease. Pediatr Radiol 39:47–52 139. Johnson CA, Gissen P, Sergi C (2003) Molecular pathology and genetics of congenital hepatorenal fibrocystic syndromes. J Med Genet 40:311–319 140. Hildebrandt F, Attanasio M, Otto E (2009) Nephronophthisis: disease mechanisms of a ciliopathy. J Am Soc Nephrol 20:23–35 141. Salomon R, Saunier S, Niaudet P (2009) Nephronophthisis. Pediatr Nephrol 24:2333–2344
692 142. Raniga S, Desai PD, Parikh H (2006) Ultrasonographic soft markers of aneuploidy in second trimester: are we lost? Med Gen Med 8:9 143. Steinberg SJ, Dodt G, Raymond GV, Braverman NE, Moser AB, Moser HW (2006) Peroxisome biogenesis disorders. Biochim Biophys Acta 1763:1733–1748 144. Passerotti C, Chow JS, Silva A, Schoettler CL, Rosoklija I, Perez-Rossello J, Cendron M, Cilento BG, Lee RS, Nelson CP, Estrada CR, Bauer SB, Borer JG, Diamond DA, Retik AB, Nguyen HT (2009) Ultrasound versus computerized tomography for evaluating urolithiasis. J Urol 182:1829– 1834 145. Estrada CR, Datta S, Schneck FX, Bauer SB, Peters CA, Retik AB (2009) Caliceal diverticula in children: natural history and management. J Urol 181:1306–1311 146. Becker AM (2009) Postnatal evaluation of infants with an abnormal antenatal renal sonogram. Curr Opin Pediatr 21:207–213 147. Bisceglia M, Galliani CA, Senger C, Stallone C, Sessa A (2006) Renal cystic diseases. A review. Adv Anat Pathol 13:26–56
Pediatr Nephrol (2011) 26:675–692
Answers: 1a. 1b. 1c. 1d. 2a. 2b. 2c. 2d. 3a. 3b. 3c. 3d. 4a. 4b. 4c. 4d.
True True False True False False True True False True True True True False True True