A rare cause of chronic renal failure in a girl with elevated serum uric acid level: answer

The clinical differential diagnosis of renal failure in conjunction with hyperuricemia includes partial hypoxanthine–guanine phosphoribosyltransferase deficiency, medullary cystic kidney disease type 2 (MCKD2), and familial juvenile hyperuricemic nephropathy (FJHN) [1, 2]. Hypoxanthine–guanine phosphoribosyltransferase deficiency is an X-linked disorder that results in the overproduction of uric acid. The patient’s female gender and the absence of neurological symptoms, history of nephrolithiasis, or urate granulomas on renal biopsy argued against partial hypoxanthine–guanine phosphoribosyltransferase deficiency. On the other hand, renal ultrasound did not demonstrate renal cysts; therefore, the diagnosis of MCKD2 was ruled out. The most likely etiology of the hyperuricemic chronic renal disease could be familial juvenile hyperuricemic nephropathy. This clinical picture is an autosomal-dominant disorder characterized by hyperuricemia, low fractional renal urate excretion (FEua), progressive chronic interstitial nephritis, and chronic renal failure (CRF). Renal impairment usually appears between 15 and 40 years of age, leading to end-stage renal disease (ESRD) within 10−20 years. This syndrome was first described in 1960 in a family with gout, hyperuricemia, and renal disease. However, presentation is not always with gout, and unusually for gout, FJHN affects young men, women, and children, equally [1‐4].

FJHN is caused by mutations in the uromodulin gene (UMOD) located at 16p11.2–12 that encodes for uromodulin or Tamm–Horsfall glycoprotein, the most abundant protein in normal urine. Several mutations in the UMOD gene have been identified in some families. Thus, to achieve exact diagnosis, the patient was tested for UMOD mutations by polymerase chain reaction (PCR) amplification of genomic DNA and bidirectional automated DNA sequencing of all exons in the coding region of the UMOD gene. We detected three novel missense amino acid mutations in codon 317 (Cys to Ser), codon 125 (Thr to Arg), and codon 488 (Gly to Arg), consistent with UMOD-associated kidney disease. In addition, two single nucleotide substitutions (IVS5+50C>T and IVS9-8C>A) were also detected in the UMOD gene that did not result in amino acid changes. The parents were also tested for UMOD mutations: father (IVS9-8C>A) and mother (IVS5+50C>T) showed single nucleotide substitutions. Based on these molecular genetic findings, the diagnosis of familial juvenile hyperuricemic nephropathy was established [4‐9]. On the other hand, immunohistochemical staining for UMOD could be performed, and intracellular UMOD inclusions could be detected by light and electron microscopy. Furthermore, on electron microscopy, the inclusions may appear as abundant fibrillar or granular storage material within bundles of endoplasmic reticulum.

In FJHN, it has been suggested that the intracellular UMOD overload impairs sodium reabsorption by the thick ascending limb of Henle (TALH), leading to defective urine concentrating capacity. The resultant volume depletion may be compensated by increased proximal tubular reabsorption of sodium, which in turn may promote heightened proximal tubular urate reabsorption and reduced secretion, similar to the mechanism responsible for hyperuricemia in patients receiving loop diuretics [3, 4]. The cause of the chronic renal disease is not completely understood. UMOD mutations potentially cause disruption of the molecule’s stable tertiary structure, resulting in altered protein folding, accumulation within the endoplasmic reticulum, and impaired trafficking. Retention in the endoplasmic reticulum may lead to formation of the intracellular UMOD aggregates observed in kidney biopsies and is likely a key step in the pathogenesis of FJHN [2, 10, 11].