Nephropathy of Tyrosinemia and its Longterm Outlook

Nephropathy of Type I Tyrosinemia after Liver Transplantation. Laine J, Salo MK, Krogerus L, Karkainen J, Walhroos O, Holberg C. Pediatric Research 1995;37:640-5. Summary: Liver transplantation is currently regarded as being the definitive treatment for children with hereditary type I tyrosinemia. However, renal fumarylacetoacetate hydrolase (FAH) deficiency is not corrected by orthotopic liver transplantation (OLT), and there exists the theoretical possibility that ongoing production of toxic metabolites in the kidney may be responsible for a progression of the nephropathy which is almost always present in children with this inborn error of metabolism. In the present report, Laine and colleagues undertake to determine the long-term prognosis of the tyrosinemia-associated nephropathy by investigating both renal function and histopathology at 18 and 36 months following OLT in eight children with tyrosinemia. These prospective data were then compared to pretransplantation data, obtained in retrospective fashion. The diagnosis of tyrosinemia was based upon the typical clinical presentation, high urinary excretion of succinylacetone (SA) and succinylacetoacetate (SAA), and the absence of immunoreactive FAH in fibroblasts of the affected children. The mean age at presentation was 0.4 years (range: 0.1-0.6 yr), and the mean age at OLT was 1.5 years (range: 0.4-2.7 yr). Mean urinary excretion of SA (total SA + SAA) was reduced from 169 mmol/mol creatinine before OLT to 6.8 and 8.1 mmol/mol creatinine at 18 to 36 months after OLT, respectively. No progressive kidney dysfunction was documented over the time course of the study. The mean glomerular filtration rate (GFR) was 82 ml/min/1.73 m2 before OLT, improving to 102 ml at 18 months and to 93 ml at 36 months following transplantation. All patients demonstrated some evidence of tubular dysfunction prior to OLT (8/8 had hypophosphatemia, 7/8 had glycosuria or aminoaciduria, and four had signs of rickets). At 18 months after OLT, 7/8 patients showed phosphaturia or hypercalciuria, but aminoaciduria was present in only 3/8 patients and glycosuria in one. At 36 months following OLT, only hypercalciuria was evident in four patients. Histopathology revealed mild nonspecific changes felt to be consistent with either minimal progression of the original disease process or with mild cyclosporine nephrotoxicity. Laine et al. conclude that although the GFR improves after OLT, some evidence of tubular dysfunction and histopathological deterioration remains, and therefore they recommend that both renal function and histopathology be monitored in patients after OLT for tyrosinemia type I. Comment. In this interesting report, Laine et al. address an important issue for pediatric hepatologists involved in the care of children who have undergone OLT for type I tyrosinemia. Whereas the prognosis of the renal lesion was once of little consequence due to the uniform mortality of tyrosinemia, the advent of OLT has made the presence of extrahepatic disease an important consideration in the management of these children. Renal involvement in tyrosinemia is extremely variable. Our experience has shown that 50% of affected children have nephromegaly by ultrasound examination. Tubulopathy is detected in over 80% of children with tyrosinemia, and half will develop clinical rickets despite therapy. Approximately 50% are found to have an abnormal GFR at the time of transplant evaluation at our institution, and this appears to progress with time. Histologically, as many as 25% show a variable degree of glomerulosclerosis, 50% have mild to moderate interstitial nephritis and fibrosis, and one third also have nephrocalcinosis (Gastroenterology 1994;106:A893). Although there are a number of case reports relating the improvement of kidney function in patients with tyrosinemia following OLT (J Pediatr Gastroenterol Nutr 1991;13:10-5; Pediatrics 1992;89:251-5), it is clear that, at least in some children, kidney disease progresses despite OLT (J Pediatr 1987;110:397-403). To date, the exact cause of the nephropathy associated with tyrosinemia remains unknown. It has been postulated that the ongoing production of SA and SAA in the kidney is responsible for the pathology observed. Support for this hypothesis stems from in vitro studies showing that the administration of SA causes impairment of amino acid, phosphate, and sugar uptake by rat renal proximal tubule brush border vesicles (Proc Soc Exp Biol Med 1991;194:428-31), and that maleylacetoacetate (a precursor of SA and SAA) causes an experimental Fanconi's syndrome in rats (Lab Invest 1963;12:791-801). However, in what remains the only well-documented case of its kind, when a tyrosine load was administered to a patient with tyrosinemia following OLT, no worsening of kidney function was observed (J Inherit Metab Dis 1986;9:216-24). This observation would seem to suggest that the progressive kidney dysfunction observed in some patients is a manifestation of permanent renal injury sustained prior to OLT, rather than a consequence of local toxic catabolite production. To this effect, it is not without interest that the children described by Laine et al. all underwent OLT at an extremely young age. It could be that the children in this report demonstrated fewer signs of kidney dysfunction because of the early transplantation. Certainly, the degree of renal damage appears to be greater in children with long-standing tyrosinemia who are transplanted later in time (Am J Hum Genet 1990;47:317-24). Despite the improvement in kidney function and renal histopathology reported in this paper, a few considerations are in order. Laine et al. describe eight consanguinous Finnish patients who all had the same mutation in their gene coding for FAH. Seven different disease-inducing mutations of the gene, assigned to chromosome 15q23-q25, have been described. Therefore, it is presumed that hereditary type I tyrosinemia represents a disease in which different genetic mutations may lead to different phenotypic manifestations, varying in type and severity. However, it would appear that kidney function improves following OLT for tyrosinemia, the geographic origin of the children notwithstanding. In Québec, where the highest incidence of tyrosinemia in the world is found, the mutation most often seen is IVS 12 + 5G → A, which is different from the one observed in Finland. Nonetheless, our own experience with tyrosinemia and OLT has been that the renal function of children greater than five years removed from transplantation is not significantly different than that of children transplanted for other conditions, and this despite persistent succinylacetone excretion in the urine. Furthermore, different phenotypic manifestations of tyrosinemia are quite possible despite identical genotypes, as illustrated by a French-Canadian family in which one child presented with predominantly neurologic crises, another died of liver disease, and a third has predominantly kidney involvement with minimal signs of hepatic disease at 22 years of age (Am J Hum Genet 1994;55:A80; Clin Chim Acta 1969;23:257-63). The improvement in the mean GFR observed in this study, and in particular that of one patient (from 46 to 110 ml/min/1.73 m2, leads Laine et al. to state that a combined kidney-liver transplant is not a “policy to be categorically followed” in patients with a GFR < 40 ml/min/m2. Notwithstanding that the GFR of the patient they refer to was not below the recommended limit, it has been our experience that pretransplantation GFR values vary greatly, whereas they stabilize following OLT. It is not clear if the GFR values reported by Laine et al. (pre- and post-OLT) were the mean of multiple measurements or simply measurements obtained at one point in time, which may not convey an exact GFR value. Finally, GFR measurements in this report were obtained by creatinine clearance, which is a less accurate method by which to assess GFR, than for example, DPTA (J Nucl Med 1985;26:1243; Kidney Int 1985;28:830-4). It should also be emphasized that despite the fact that the histopathological changes observed following OLT were nonspecific and possibly due to cyclosporine nephrotoxicity, one patient did develop signs of glomerulosclerosis on biopsy. It is always very difficult to separate clearly those renal lesions due to immunosuppressives and those due to the progression of the original disease. However, as glomerulosclerosis is often an intermediate station on the pathology leading to renal failure, it is of some concern that it developed despite OLT. It may be that further follow-up of this particular patient may reveal progressively serious renal dysfunction despite OLT. These observations aside, the present report supplies encouraging data regarding the beneficial consequences of OLT on renal function in patients with tyrosinemia. Recently, it appeared that with the advent of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) as an extraordinarily effective medical remedy for tyrosinemia (Lancet 1992;340:813-7), OLT would no longer have a role to play in the management of these patients. It has been our experience that urinary succinylacetone excretion falls to undetectable levels within minutes to hours of NTBC administration and that GFR values also improve quickly, usually within the first week of therapy (Clin Invest Med 1995;18:A43). Tubulopathy also often corrects within days to weeks of NTBC administration. Similarly encouraging results have also been reported by Lindstedt et al. (First International Symposium on Tyrosinemia; 13-15 October 1994: Québec, Canada). In light of these encouraging results, and those presented by Laine et al. in this report, it is now probably justified to reserve combined kidney-liver transplantation for those children with persistently abnormal renal function despite NTBC therapy, which would allow for a better estimate of true renal reserve. Unfortunately, it is now relatively certain that NTBC treatment does not eliminate progression to hepatocellular carcinoma (HCC), a frequent complication of tyrosinemia, although there is insufficient experience with children treated from the neonatal period onwards. Dysplasia has been found at the time of transplantation in patients treated with NTBC for one year, and HCC has been found at OLT after three years of treatment. Furthermore, in a newly developed murine model of hereditary tyrosinemia, treatment with NTBC from birth has been shown to correct liver and renal dysfunction, but the animals develop HCC nonetheless (Nature Genet 1995;10:453-60). These observations would suggest that OLT will continue to remain the only truly definitive therapy for tyrosinemia, or at least the only one currently available by which to completely eradicate the risk of HCC. Although it appears that renal function improves in the majority of cases following OLT alone, some evidence remains that kidney damage does not resolve in all patients. Therefore, it appears that NTBC treatment is indicated at least until the time of transplantation, for it improves renal function prior to OLT and potentially allows for better renal function following transplantation as well. Future studies evaluating long-term renal function of children transplanted for tyrosinemia and treated with NTBC from birth are eagerly awaited. Khazal Paradis; Ian D. D'Angata Pediatric Gastroenterology; Montreal, Quebec, Canada