Combined liver-kidney transplantation in primary hyperoxaluria type 1

Abstract

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder characterised by an increased urinary excretion of calcium oxalate, leading to recurrent urolithiasis, nephrocalcinosis and accumulation of insoluble oxalate throughout the body (oxalosis) when the glomerular filtration rate falls to below 40-20 mL/min per 1.73 m(2). The disease is due to a functional defect of the liver-specific peroxisomal enzyme alanine: glyoxylate aminotransferase (AGT), the gene of which is located on chromosome 2q37.3. The diagnosis is based on increased urinary oxalate and glycollate, increased plasma oxalate and AGT measurement in a liver biopsy. AGT mistargeting may be investigated by immuno-electron microscopy and DNA analysis. End-stage renal failure is reached by the age of 15 years in 50% of PH1 patients and the overall death rate approximates 30%. The conservative treatment includes high fluid intake, pyridoxine and crystallisation inhibitors. Since the kidney is the main target of the disease, isolated kidney transplantation (Tx) has been proposed in association with vigorous peri-operative haemodialysis in an attempt to clear plasma oxalate at the time of Tx. However, because of a 100% recurrence rate, the average 3-year graft survival is 15%-25% in Europe, with a 5-10-year patient survival rate ranging from 10% to 50%. Since the liver is the only organ responsible for the detoxification of glyoxylate by AGT, deficient host liver removal is the first rationale for enzyme replacement therapy. Subsequent orthotopic liver Tx aims to supply the missing enzyme in its normal cellular and subcellular location and thus can be regarded as a form of gene therapy. Because of the usual spectrum of the disease, isolated liver Tx is limited to selected patients prior to having reached an advanced stage of chronic renal failure. Combined liver-kidney Tx has therefore become a conventional treatment for most PH1 patients: according to the European experience, patient survival approximates 80% at 5 years and 70% at 10 years. In addition, the renal function of survivors remains stable over time, between 40 and 60 mL/min per 1.73 m(2) after 5 to 10 years. In addition, liver Tx may allow the reversal of systemic storage disease (i.e. bone, heart, vessels, nerves) and provide valuable quality of life. Whatever the transplant strategy, the outcome is improved when patients are transplanted early in order to limit systemic oxalosis. According to the European experience, it appears that combined liver-kidney Tx is performed in PH1 patients with encouraging results, renal Tx alone has little role in the treatment of this disease, and liver Tx reverses the underlying metabolic defect and its clinical consequences.

Regressive course of oxalate deposition in primary hyperoxaluria after kidney transplantation

“…7,8 Early kidney transplantation is evidently sufficient to eliminate oxalate deposits at least partially and has the effectiveness to improve patient's condition without liver transplantation. 9 This option should be considered in pyridoxine-sensitive patients even in the existence of systemic oxalosis because of the good results of isolated kidney graft. 10,11 Allen et al identified a patient with clinical and biochemical existence of residual AGT activity and with a perfect renal function without the formation of a new calculus 1 year after renal transplantation from a live donor.…”

“…The aim of this approach is not only to cease kidney involvement but also to prevent the progressive nature of oxalate deposition in other organ and soft tissues. 8,9,13,14 In this respect retinal examination gives opportunity to evaluate oxalate deposition. Small et al presented 24 patients with ocular involvement.…”

Paediatric liver transplantation-a review based on 20 years of personal experience

“…If the liver is normal but for the absence of an enzyme, the indications for liver replacement are based on poor quality of life, e.g. in Crigler-Najjar's disease, where phototherapy becomes excessively constrainingin the growing child [60], or on extrahepatic complications, as in primary hyperoxaluria type I (indication for combined liver-kidney transplantation, in order to avoid systemic oxalosis, when GFR falls to < 50 ml/min) [61]. When the enzyme deficit leads to liver cirrhosis (alpha-I antitrypsin deficiency, tyrosinaemia, Wilson's disease..…”

The Evaluation of the Renal Transplant Candidates: Clinical Practice Guidelines

“…Kasiske et al (383). Although liver transplantation is potentially curative, there is no consensus regarding the timing of liver transplantation and the role of isolated kidney transplantation in treating patients with PH1 (384).…”

“…However, the authors concluded that because kidney/liver transplantation can still follow a failed kidney transplant, isolated, living-related donor, kidney transplantation is a reasonable first option for patients with PH1 (389). Aggressive hemodialysis should be used to reduce the oxalate load pretransplant (383). Isolated kidney transplant should also be accompanied by intensive medical management to prevent recurrent renal disease (390,391).…”