Abstract. Renal hypouricemia is an inherited and heterogeneous disorder characterized by increased urate clearance (CUA). The authors recently established that urate was reabsorbed via URAT1 on the tubular apical membrane and that mutations in SLC22A12 encoding URAT1 cause renal hypouricemia. This study was undertaken to elucidate and correlate clinical and genetic features of renal hypouricemia. The SLC22A12 gene was sequenced in 32 unrelated idiopathic renal hypouricemia patients, and the relationships of serum urate levels, and CUA/creatinine clearance (Ccr) to SLC22A12 genotype were examined. Uricosuric (probenecid and benzbromarone) and anti-uricosuric drug (pyrazinamide) loading tests were also performed in some patients. Three patients had exercise-induced acute renal failure (9.4%), and four patients had urolithiasis (12.5%). The authors identified eight new mutations and two previously reported mutations that result in loss of function. Thirty patients had SLC22A12 mutations; 24 homozygotes and compound heterozygotes, and 6 heterozygotes. Mutation G774A dominated SLC22A12 mutations (74.1% in 54 alleles). Serum urate levels were significantly lower and CUA/Ccr was significantly higher in heterozygotes compared with healthy subjects; these changes were even more significant in homozygotes and compound heterozygotes. These CUA/Ccr relations demonstrated a gene dosage effect that corresponds with the difference in serum urate levels. In contrast to healthy subjects, the CUA/Ccr of patients with homozygous and compound heterozygous SLC22A12 mutations was unaffected by pyrazinamide, benzbromarone, and probenecid. The findings indicate that SLC22A12 was responsible for most renal hypouricemia and that URAT1 is the primary reabsorptive urate transporter, targeted by pyrazinamide, benzbromarone, and probenecid in vivo.Approximately 90% of all urate that is filtered through the glomerulus is eventually reabsorbed. A four-component hypothesis has been proposed to explain the renal urate transport mechanisms; it includes glomerular filtration, presecretory reabsorption, secretion, and postsecretory reabsorption (1,2). Renal hypouricemia is a common inherited and heterogeneous disorder characterized by impaired tubular urate transport (3). The incidence of renal hypouricemia has been reported to be 0.12 to 0.72% (4,5), and exercise-induced acute renal failure and nephrolithiasis have been reported as complications (6).Renal hypouricemia has been classified into the following five types according to responses to the anti-uricosuric drug pyrazinamide, and the uricosuric drug, probenecid: (a) a presecretory reabsorptive defect with an attenuated response to both pyrazinamide and probenecid (3); (b) a post-secretory reabsorptive defect when pyrazinamide suppressible urate clearance (CUA) is not influenced by probenecid (7); (c) total inhibition of urate reabsorption when pyrazinamide induces elimination of CUA exceeding the rate of glomerular filtration (8); (d) enhanced secretion when the pyrazinamide suppressible CUA ...

Background/Aims: This study was designed to elucidate the clinical significance of serum uric acid (SUA) and the relationship between hyperuricemia and renal prognosis in IgA nepropathy. Methods: The correlation between SUA and other clinical parameters were examined in 748 IgA nephropathy patients (432 males and 316 females). Among these patients, 226 (144 males and 82 females) who were followed for more than 5 years were examined for the relationship between hyperuricemia and renal prognosis. Results: In IgA nephropathy, SUA correlated negatively with creatinine clearance (Ccr), and positively with urinary protein and tubulointerstitial damage. SUA was higher in patients with hypertension or diffuse proliferative glomerulonephritis. Hyperuricemia was a risk factor for renal prognosis, both in terms of serum creatinine (p = 0.0025) and Ccr (p = 0.0057). In 56 patients with normal Ccr at renal biopsy, the change of Ccr after more than 8 years was –22.3 ± 20.8% in 13 patients with hyperuricemia, compared with +2.6 ± 39.4% in 43 patients without hyperuricemia (p = 0.0238). Hyperuricemia was related independently to deterioration of Ccr (p = 0.0461). Conclusion: Hyperuricemia in IgA nephropathy is derived from both glomerular and tubulointerstitial damage, and correlated with hypertension. Hyperuricemia is a risk factor for renal prognosis in IgA nephropathy.

Objective We investigated the relationship between serum uric acid (SUA)

Objective The purpose of this study was to investigate gouty arthritis in Japanese patients with end-stage renal disease (ESRD).Methods Questionnaires plus patient interviews and reviews of medical records were used to investigate gouty arthritis in 493 Japanese patients with ESRD receiving maintenance dialysis.Results The frequency of gouty arthritis was 4.1% for female patients and 15.4% for male patients greater than 2 years before the start of dialysis, and 0.6% for female patients and 7.7% for male patients less than 2 years before the start of dialysis. After the start of dialysis the frequency was 3.4% for the first 2 years and 1.2% thereafter in male patients, but no gouty arthritis appeared in female patients. Although the annual number of gouty attacks was 2.0±4.2 greater than 2 years before the start of dialysis, and 1.9±6.6 less than 2 years before the start of dialysis, the annual number of attacks decreased significantly after the start of dialysis to 0.2±0.7 in the first 2 years and 0.1±0.6 thereafter.Conclusions The frequency of gouty arthritis in Japanese patients with ESRD is similar to that of patients with hyperuricemia in the general population and it is decreased slightly before dialysis; however, the frequency decreases markedly after dialysis.

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