Pediatr Radiol (1999) 29: 104±108 Ó Springer-Verlag 1999

The kidney in children with tyrosinemia: sonographic, CT and biochemical findings

Sylviane Forget Heidi B. Patriquin JosØe Dubois Maud Lafortune Aicha Merouani Khazal Paradis Pierre Russo

Received: 27 October 1997 Accepted: 4 June 1998

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S. Forget × H. B. Patriquin ( ) × J. Dubois × M. Lafortune Department of Medical Imaging Hôpital Sainte-Justine 3175 Côte-Sainte-Catherine MontrØal, QuØbec Canada H3T 1C5 A. Merouani Department of Nephrology Hôpital Sainte-Justine MontrØal, QuØbec, Canada K. Paradis Department of Gastroenterology Hôpital Sainte-Justine MontrØal, QuØbec, Canada P. Russo Department of Pathology Hôpital Sainte-Justine MontrØal, QuØbec, Canada

Abstract Background. Tyrosinemia relates to a deficiency of fumarylacetoacetate hydrolase and presents early in life with central nervous system and liver abnormalities. Renal function is often impaired. Little is known about the architecture and function of the kidneys. Objective. Imaging changes on US and CT are compared to the function of the kidneys in children with tyrosinemia, and followed after liver transplantation. Materials and methods. Renal sonography, CT and renal function tests in 32 children were reviewed. Renal length, volume, echogenicity and nephrocalcinosis were evaluated. Renal function was assessed by glomerular filtration rate, and the presence of aminoaciduria, acidosis and calciuria. Seventeen children had open renal biopsy during time of liver transplantation. Histology was reviewed. Statistical analyses relating renal structure to function were performed, and repeated after transplantation.

Introduction Tyrosinemia is a recessively inherited deficiency of the enzyme fumarylacetoacetate hydrolase (FAH), the last enzyme in tyrosine degradation. Accumulation of the final compounds in tyrosine metabolism is accompanied chiefly by liver damage, renal tubular dysfunction and neurologic crises [1, 2]. The disease is rare (1/ 100 000 live births). The Saguenay-Lac-St-Jean region

Results. The kidneys were enlarged (47 %), hyperechogenic (47 %) and showed nephrocalcinosis (16 %). There was delayed excretion of contrast medium at CT in 64 %. Aminoaciduria was present in 82 % of children, hypercalciuria in 67 %, tubular acidosis in 59 %, and low GFR in 48 %. Delayed excretion of contrast was associated with low GFR (P < 0.05). Renal biopsies showed dilated tubules (81 %), interstitial fibrosis (56 %), glomerulosclerosis (56 %) and tubular atrophy (56 %). During a mean observation period of 3 years following liver transplantation, GFR improved in 50 %, tubular acidosis in 50 % and hypercalciuria in 70 %. No change was noted in renal size or sonographic architecture. Conclusion. Renal architecture and function are abnormal in the majority of children with tyrosinemia. Liver transplantation improves renal function in about 50 % of patients, but abnormal renal size and architecture persist.

of Quebec has the highest incidence of tyrosinemia in the world (1/1800 live births) and affected children generally receive liver transplantation. We wished to determine renal architecture and function in these children, both before and after liver transplantation.

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Fig. 1 Increased size and cortical echogenicity of the kidneys. a All dimensions of the kidney are enlarged in this 3-monthold boy: the length is 7.9 cm and the kidney appears globular, reflecting its increased thickness (4.6 cm). b The renal cortex is hyperechogenic, simulating the echogenicity of the spleen. (Normally, the renal cortex is less echogenic than the spleen.)

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Materials and methods We retrospectively reviewed the records of 32 children with tyrosinemia diagnosed within one month of birth. The children had been treated with an appropriate diet low in phenylalanine and tyrosine [3]. Renal architecture was assessed by sonography and CT. Function was studied by biochemical tests and also by excretion of intravenous contrast at CT. The sonographic examination of the kidneys included renal volume and architecture. Renal volume was calculated as that of an ellipsoid: L ” W ” D ” 0.523 where L = length, W = width and D = depth. Renal volume was compared to normal standards [4] and classified as normal, increased or small if it was beyond the 95 % or 5 % of N standards. Renal length alone was not used as a standard because the thickness (AP diameter) of these kidneys is often increased. Cortical echogenicity was classified as normal or increased, using the spleen as reference (Fig. 1). The liver, the usual standard of comparison, was not used because it is often abnormal in these children. The spleen is not directly affected by the disease and remains homogeneous, although it may enlarge with portal hypertension. Kidneys were judged to be hyperechogenic if their echogenicity exceeded that of the spleen. Patterns of calcium deposition within the pyramids were noted, as described in the literature [5]. Computed tomography was performed during manual injection of 1.5 cc/kg of intravenous contrast material (Omnipaque 300). Fifty percent of the bolus was injected before, and the rest at the beginning of acquisition of images. Uptake and intrarenal circulation of contrast material were observed and compared to normal patterns: rapid, homogeneous uptake of contrast by the renal cortex and excretion into the collecting system at the time of appearance of contrast in the IVC [6] (Fig. 2). Both uptake and excretion of contrast were classified as normal or delayed, with delayed excretion manifested as a persistent cortical or medullary nephrogram (Fig. 3). The following parameters of renal function were recorded: glomerular filtration rate (GFR), measured by DPTA clearance and defined as abnormal if below 80 ml/min/1.73 m2; aminoaciduria (defined as the presence of any aminoacid in the urine, above the limits of normal); acidosis (serum bicarbonate K 20 meq/l) of tubular origin if urine pH was > 6; and hypercalciuria (> 5 mg/kg/ 24 h or Ca++/creatinine > 0.2). Biochemical tests and imaging of the kidneys were performed within a maximum delay of 2 weeks. Seventeen children had open renal biopsies at the time of liver transplantation. Descriptions of histologic findings were reviewed. Renal sonography and function tests were performed at 4- to 6-

b month intervals, 4 months to 5 years after transplantation, with a mean follow-up period of 3 years. Statistical analyses, relating renal structure (assessed radiologically and pathologically) and function (GFR), were performed. Two stepwise multiple regression models were designed, using GFR as the dependent variable, to identify structural variables predictive of glomerular filtration. Independent variables tested included (a) renal volume, cortical hyperechogenicity and contrast retention at CT; and (b) presence of glomerular sclerosis and tubular atrophy at biopsy. Analysis was adjusted for age. The Alpha level was set at 0.05.

Results The most common architectural abnormalities were hyperechogenicity of the cortex (15/32 = 47 %) (Fig. 1), nephromegaly (15/32 = 47 %) (Fig. 1) and nephrocalcinosis involving the pyramids (5/32 = 16 %) (Fig. 4). Two children with renal failure had small kidneys. The affected kidneys had smooth contours, and there was no hydronephrosis. The pyramids either stood out in sharp contrast to the hyperechogenic cortex or, in older children, were sometimes poorly defined (Fig. 5). Nephrocalcinosis was seen as small sharply defined hyperechogenic foci, usually without acoustic shadowing, within the pyramids (Fig. 4) [5]. Renal CT was performed in 28 children. The uptake of intravenous contrast material by the kidneys was nor-

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Fig. 2 Normal excretion of intravenous contrast medium by the kidneys in a child with tyrosinemia: while the aorta and inferior venae cava (IVC) are opacified, contrast medium has reached the collecting systems of the kidneys Fig. 3 a Delayed excretion of contrast medium in a child with tyrosinemia. Cortical nephrogram: although contrast medium has reached the IVC, no excretion into the collecting system is outlined. Instead, the contrast medium appears to stagnate in the cortex. b In another child, the contrast medium stagnates at the level of the medulla: while the inferior vena cava is opacified, no medium is noted in the collecting system but instead stagnates in the pyramids

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3a mal in all. In 18 (64 %) children, excretion of contrast material by the kidneys was delayed and seen as a prolonged cortical (3/28 = 11 %) or medullary (7/ 28 = 25 %) nephrogram or a combination of the two (8/ 28 = 29 %) (Fig. 3). The following tests of renal function were abnormal: GFR was low in 13 of 27 (48 %) children tested. There was aminoaciduria in 18/22 (82 %), tubular acidosis in 19/32 (59 %) and hypercalciuria in 16/24 (67 %). Four children (13 %) had a complete Fanconi syndrome (renal glycosuria, generalized aminoaciduria, hypophosphatemia and chronic acidosis resulting from impairment of the proximal renal tubule). Statistical studies of two regression models showed a negative correlation between GFR and contrast retention at CT. Delayed excretion was associated with low GFR (P < 0.05). Patients with hyperechoic kidneys had higher GFR than those with normal cortical echogenicity (P < 0.05). Seventeen children received a liver transplant, 2 a concurrent renal transplant. GFR was measured in 16/ 17 patients 7 to 100 months post-transplantation, and improved (to > 80 ml/min/m2) in half of the patients. Using only cases for which complete data was available, tubular acidosis, present in 10/17 cases pre-transplant, resolved in 5/10 post-transplant. Hypercalciuria, present in 7/9 patients pre-transplant, improved in 5/7 within

3b 3 months of transplantation. In 6 children, cortical hyperechogenicity decreased. We could detect no other change in size or architecture of the kidneys 4 months to 5 years after liver transplantation (mean follow-up period 3 years). All 17 transplant patients had renal biopsies performed at the time of transplantation, 16 had sufficient tissue for diagnosis. The most common findings were: dilated tubules, mainly proximal (13/16 = 81 %), interstitial fibrosis (9/16 = 56 %), tubular atrophy (9/ 16 = 56 %) and vascular sclerosis (3/16 = 19 %). Calcium deposition was noted in 2 cortical biopsy specimens. Significant glomerulosclerosis was present in 9/16 (56 %) of the specimens, while the mesangial matrix was slightly increased in 7/16 (44 %) cases. Tubular atrophy and glomerulosclerosis were associated with a lower GFR. However, this association was not statistically significant, perhaps because of the smaller sample size (16 rather than 32).

Discussion Renal tubular defects, including Fanconi syndrome and hypophosphatemic rickets, are considered hallmark features of tyrosinemia [7, 8], although cases of chronic tyrosinemia without these features have been described

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4a

4b

4c

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Fig. 4 Nephrocalcinosis: 3 patterns are outlined in 3 different patients. a Almost the entire pyramid is filled with echogenic material. b The edges of the pyramids are hyperechogenic. c Accumulation of hyperechogenic material at the tip of the pyramids; detailed view of the cortex and 3 pyramids in a 6-month-old patient. (Note also the sharp distinction between the hyperechogenic cortex and the pyramids.) Fig. 5 Loss of corticomedullary differentiation in a 4-year-old child. The kidney is enlarged (8.5 cm). The pyramids can no longer be distinguished from the hyperechogenic cortex

[9]. The toxic liver metabolites upstream of the enzyme FAH are accumulated and are thought to mediate the tubular injury [10, 11]. The majority of our patients had biochemical evidence of tubular dysfunction, and at biopsy there was dilatation of proximal tubules accompanied by vacuolization and/or atrophy of tubular cells. (Interstitial fibrosis and glomerulosclerosis were also noted.) The in vivo architecture of these kidneys consisted of generalized enlargement, hyperechogenic cortex and nephrocalcinosis. Intravenously injected contrast material stagnated in the cortex and/or medulla. Why are the kidneys in tyrosinemia enlarged? It is clearly not because of the deposition of any foreign sub-

stance within the kidney or because of edema. Neither interstitial fibrosis nor glomerular sclerosis is related to enlargement of the kidney. It is not known whether there is an increased number of nephrons in the tyrosinemic kidney; however, since the number of nephrons is established at 36 weeks' gestation, it is unlikely that this is so. The only structural, microscopic abnormality that can explain renal enlargement is the dilatation of the proximal tubules. Since the substance of the cortex is largely composed of tubules, their dilatation probably results in significant increase in volume. Cortical hyperechogenicity has been reported in a number of diseases associated with decreased renal filtration function and/or glomerular hypoperfusion [12, 13]. In the absence of vascular lesion in our patients, it is unlikely that the hyperechogenicity is related to glomerular hypoperfusion. Perhaps the cortical hyperechogenicity can be explained by tubular dilatation. Dilated tubules, by creating many small ªcystic spacesº increase the number of tissue interfaces that meet the ultrasound beam. The echogenicity of the renal cortex is thereby increased, by a similar mechanism as in recessive polycystic disease in which the collecting ducts are dilated [14]. The delay in excretion of intravenously injected contrast medium at CT may relate to stasis in dilatated

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proximal tubules. A similar but much more severe delay in excretion is noted in recessive polycystic kidney disease, where the collecting ducts are dilated and contrast medium pools at this site [15]. Decreased GFR is unlikely to be explained by glomerular hypoperfusion, since our results show a perfectly normal glomerular uptake of the intravenous contrast medium on CT. Given the observed association between delayed contrast excretion and low GFR, and given that the delayed contrast excretion can be related to tubular dilatation, it is likely that the tubules are the cause of the low GFR in these patients. Liver transplantation has become the treatment of choice for children with tyrosinemia, to correct the basic metabolic defect and to prevent the development of hepatocellular carcinoma [16, 17, 18]. However, it is not known to what extent the persistence of the enzyme defect within the kidney continues to cause local tissue in-

jury [18, 19, 20]. After transplantation, there was improvement of renal tubular function in most of our patients, as in those reported by Shoemaker et al. [21]. However, GFR remained low in half of our patients. The sonographic architecture of the kidneys did not change significantly. In summary, the majority of children with tyrosinemia have reduced renal function, despite adequate dietary treatment. Aminoaciduria and low glomerular filtration rate are the principal abnormalities. The kidneys are enlarged. Cortical hyperechogenicity and medullary nephrocalcinosis are seen with ultrasound and delayed excretion of intravenous contrast medium is noted on CT scans. Liver transplantation results in partial improvement of tubular dysfunction, but reduced GFR persists in half of the patients. The size and architecture of the kidneys are essentially unchanged within the first 3 years following liver transplantation.

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