Outcome of kidney transplantation in familial juvenile hyperuricaemic nephropathy

Familial juvenile hyperuricaemic nephropathy (FJHN) and medullary cystic kidney disease (MCKD) are rare autosomal-dominant disorders, both characterized by early hyperuricaemia due to reduced urinary excretion of urate and the development of chronic interstitial nephropathy, most often leading to end-stage renal failure (ESRF) in adulthood. Although a history of gout is more frequently reported in FJHN and corticomedullary renal cysts more frequently found in MCKD, both phenotypes overlap [1]. Two loci for MCKD (MCKD1 and MCKD2) were localized to chromosome 1q21 and 16p12, respectively [2,3]. A locus for FJHN was mapped to chromosome 16p11.2, in a region overlapping with the MCKD2 locus, raising the hypothesis that FJHN and MCKD2 were two facets of the same disease [4]. This was demonstrated by the identification of mutations in the UMOD gene encoding uromodulin (or Tamm-Horsfall protein) in three families with FJHN and one with MCKD2 [5]. Several groups soon confirmed the role of the UMOD gene as the cause of FJHN, with a cluster of mutations in exons 4 and 5 (reviewed in [1]). The cause of the onset and progression of chronic interstitial nephritis in UMOD-related disorders remains a moot point. Uromodulin is a kidney-specific protein produced in the thick ascending limb (TAL) of the loop of Henle and excreted in the urine [1]. Mutant uromodulin has been shown to accumulate in the endoplasmic reticulum of TAL cells, with only wildtype uromodulin found in the urine of affected patients [6,7]. Intratubular accumulated uromodulin is thought to induce cell death and interstitial fibrosis, through unidentified mechanisms. If this is true, the transplantation of a normal kidney producing only wild-type uromodulin should cure the disease, without fear of recurrence. The earliest manifestation of the disease is a decreased fractional urinary excretion of urate (FEur), expressed as a function of age and sex. The most likely explanation for this abnormality is an increased reabsorption of urate in the proximal tubule along with sodium, the latter thought to be a compensation for the decreased sodium uptake in the TAL related to the uromodulin defect [1]. This abnormality should be reversed after kidney transplantation. There is so far no data in the literature on the results of kidney transplantation in this condition. This prompts us to report on the outcome of kidney transplantation in six patients with FJHN due to a documented mutation in the UMOD gene, with emphasis on the post-transplant renal handling of uric acid.