Combined liver kidney transplantation in primary hyperoxaluria type 1

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder c haracterised by an increased urinary excretion of calcium oxalate, leading to recurrent urolithiasis, nephrocalcinosis and accumulation of insoluble o xalate throughout the body (oxalosis) when the glomerular filtration rate f alls to below 40-20 mL/min per 1.73 m(2). The disease is due to a functiona l defect of the liver-specific peroxisomal enzyme alanine: glyoxylate amino transferase (AGT), the gene of which is located on chromosome 2q37.3. The d iagnosis is based on increased urinary oxalate and glycollate, increased pl asma oxalate and AGT measurement in a liver biopsy. AGT mistargeting may be investigated by immuno-electron microscopy and DNA analysis. End-stage ren al failure is reached by the age of 15 years in 50% of PH 1 patients and th e overall death rate approximates 30%. The conservative treatment includes high fluid intake, pyridoxine and crystallisation inhibitors. Since the kid ney is the main target of the disease, isolated kidney transplantation (Tx) has been proposed in association with vigorous peri-operative haemodialysi s 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%. Si nce the liver is the only organ responsible for the detoxification of glyox ylate by AGT, deficient host liver removal is the first rationale for enzym e replacement therapy. Subsequent orthotopic liver Tx aims to supply the mi ssing enzyme in its normal cellular and subcellular location and thus can b e 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 T x has therefore become a conventional treatment for most PH1 patients: acco rding to the European experience, patient survival approximates 80% at 5 ye ars and 70% at 10 years. In addition, the renal function of survivors remai ns stable over time, between 40 and 60 ml/min per 1.73 m(2) after 5 to 10 y ears. In addition, liver Tx may allow the reversal of systemic storage dise ase (i.e. bone, heart, vessels, nerves) and provide valuable quality of lif e. Whatever the transplant strategy, the outcome is improved when patients are transplanted early in order to limit systemic oxalosis. According to th e European experience, it appears that combined liver-kidney Tx is performe d in PH 1 patients with encouraging results, renal Tx alone has little role in the treatment of this disease, and liver Tx reverses the underlying met abolic defect and its clinical consequences.