Miho Hikita

Clinical and Molecular Analysis of Patients with Renal Hypouricemia in Japan-Influence of URAT1 Gene on Urinary Urate Excretion

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.

SERUM URIC ACID AND RENAL PROGNOSIS IN PATIENTS WITH IGA NEPHROPATHY

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.

Analysis of urolithiasis in patients with gout and hyperuricemia using ultrasonography

The number of patients with gout and hyperuricemia is increasing in Japan. Urolithiasis is one of the important complications in this disease and early diagnosis of urolithiasis is necessary in disease management. Therefore, we expected to find an exact incidence of urolithiasis in Japanese gouty and hyperuricemic patients in our study. We examined 208 patients using ultrasonography (US) of the abdomen at our hospital (171 primary gout and 37 asymptomatic hyperuricemia). We examined the incidence of urolithiasis in US of the abdomen, past history and urine occult blood reaction in gouty and hyperuricemic patients. We also examined the duration of the current illness. The total number of ‘positive findings’ in US of the abdomen was 64 among 208 cases (30.8%). For these 64 with ‘positive findings’, 51.6% had ‘calcification’ or ‘stone formation’ in bilateral kidneys and 48.4% showed ‘positive findings’ before the onset of gouty arthritis. Among the 208 cases, 16.3% had a history of urolithiasis. Of the 59 cases with ‘stone formation’ among the 64 with ‘positive findings’ in US of the abdomen, 10.2% showed a positive urine occult blood reaction. The frequency of detecting a ‘positive findings’ was evidently proportional to the detection of this illness. In conclusion, the incidence of urolithiasis in gouty and hyperuricemic patients was examined by US of the abdomen. The value of this diagnostic modality was highly appreciated in this instance. The following were suggested as important approaches for the management of gouty or hyperuricemic patients: correction of the serum uric acid levels, early diagnoses of urolithiasis by US of the abdomen, proper alkalization of urine and sufficient diuresis.

Clinical characteristics of nateglinide response as assessed by insulinogenic indices: Preliminary study to determine an optimal indication for nateglinide

Insulin secretion dynamics and response to nateglinide were studied in patients with type 2 diabetes and reduced early-phase insulin secretion. On day 1, 24 patients underwent a 75-g oral glucose tolerance test without taking nateglinide. On day 2, they were given oral nateglinide 90 mg immediately before the oral glucose tolerance test. After glucose loading, insulin levels increased significantly at 30, 60, 90, and 120 minutes after the patients took nateglinide, along with insulinogenic indices, the total area under the insulin curve, the area under the 0- to 90-minute insulin curve, and the area under the 90- to 180-minute insulin curve. Both the plasma glucose level at 60, 90, 120, and 180 minutes and the total area under the glucose curve were significantly reduced following nateglinide administration. Compared with the low responders (n=13), the high responders (n=11) had a significantly shorter duration of disease, significantly higher insulinogenic indices in the absence of nateglinide administration, and a higher homeostasis model assessment-β cell performance. Nateglinide demonstrated a rapid-onset and rapidoffset insulin secretion-stimulating effect in this study population. A single dose of nateglinide may be indicated for patients with a relatively high homeostasis model assessment-β cell performance, a short duration of disease, and relatively high insulinogenic indices prior to nateglinide administration.

An epidemiologic study on pathogenesis of uric acid urolithiasis

Recently, the number of patients with gout and hyperuricemia has increased in Japan; therefore, we expected to find an increase in the number of uric acid stones in our study. We examined the frequency of uric acid stones and its relationship with the number of patients with gout and hyperuricemia or their nutritional state. We reviewed the records of 5477 patients with urolithiasis who visited our hospital between 1975 and 1993. During this period, the incidence of calcium-containing stones remained at 86%. The percentage incidence of uric acid and urate stones during the same period showed a steady increase to 7.2%. This increase was computed to be 3-fold that of 1975. The male gender dominates among the patients with uric acid and urate stones. We believe that the increases in the incidence of gout and hyperuricemia and alcohol consumption are responsible for this trend.