[Usefulness of combination treatment using allopurinol and benzbromarone for gout and hyperuricemia accompanying renal dysfunction: kinetic analysis of oxypurinol].

A study was conducted to determine whether combination treatment using allopurinol and benzbromarone was more useful than single allopurinol treatment for the gout and hyperuricemia accompanying renal dysfunction. The subjects were 45 male patients who received urate-lowering treatment and showed a stable serum urate level. The patients were divided into four groups according to the urate-lowering treatment and creatinine clearance (Ccr) (A group: single treatment, normofunction, B group: single treatment, hypofunction, C group: combined treatment, normofunction, D group: combined treatment, hypofunction). There were no differences in serum urate levels among the four groups. Urate clearance (CUA)and daily urinary urate excretion (UUAV) showed significantly high values in the C group, but no difference was seen in the fractional excretion of urate (FEUA) among the four groups. The dosage of allopurinol in the D group was significantly lower than in the A and B groups. Serum oxypurinol concentration in the C group was lower than that in the B group. Oxypurinol clearance (C oxypurinol) in the C group was significantly high compared with the B and D groups. There was a close correlation between C oxypurinol, Ccr, and CUA, with an especially strong correlation between C oxypurinol and CUA. There were no differences in the serum concentration and clearance of xanthine and hypoxanthine among the four groups. Results of the study suggested that combination treatment using allopurinol and benzbromarone for the gout and hyperuricemia accompanying renal dysfunction is more useful, because a lower dose of allopurinol can be used and the serum oxypurinol concentration is reduced compared with single allopurinol treatment.

Frequency of gouty arthritis in patients with end-stage renal disease in Japan.

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.

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-beta cell performance. Nateglinide demonstrated a rapid-onset and rapid-offset 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-beta cell performance, a short duration of disease, and relatively high insulinogenic indices prior to nateglinide administration.

Sevelamer decreases serum uric acid concentration through adsorption of uric acid in maintenance hemodialysis patients.

BACKGROUND: Sevelamer, a nonabsorbed hydrogel that binds phosphate, is reported to reduce the serum urate concentration in maintenance hemodialysis patients, however the urate-lowering mechanism remains obscure. In this study we verify the urate-lowering effect of sevelamer in Japan in which the hemodialysis environment is different from that of western countries, and we also clarify the urate-lowering mechanism of sevelamer. METHODS: A total of 127 Japanese patients undergoing maintenance hemodialysis were investigated. These patients consisted of 93 males and 34 females, and their mean age was 58.4+/-12.4 years (range, 25-88 years). The mean duration of hemodialysis was 8.7+/-6.1 years (range, 0.5-27.5 years). Sevelamer was added to each patient's former prescription for the treatment of hyperphosphatemia, and the changes in laboratory data before and after administration of sevelamer were compared. In order to clarify the mechanism of urate-lowering effect by sevelamer, a urate adsorption experiment was carried out in vitro. RESULTS: Sevelamer significantly decreased serum phosphate value three and six months after administration. Sevelamer showed a significant reduction in serum urate values in maintenance hemodialysis patients with hyperuricemia, but not in patients with normouricemia. The change rate of serum urate correlated with the change rate of serum phosphate and the change rate of serum calcium x phosphate product, but did not correlate with that of serum calcium. Sevelamer hydrochloride adsorbed urate in vitro. CONCLUSION: Sevelamer decreases serum urate possibly by adsorbing urate in hemodialysis patients.

Relationship between hyperuricemia and body fat distribution.

OBJECTIVE: We investigated the relationship between serum uric acid (SUA) and body fat area, serum lipid level, insulin resistance, and metabolic syndrome in Japanese men. METHOD: We studied 508 Japanese man industrial workers who underwent an annual medical examination and agreed to participate in the CT scanning examination. Body fat area was measured at the umbilical level. Metabolic syndrome was defined by the presence of visceral fat Accumulation (> or = 100 cm2) accompanied by two or more disorders; dyslipidemia, hypertension, and hyperglycemia. RESULTS: SUA was positively correlated with visceral fat area, subcutaneous fat area, serum total cholesterol level, serum triglyceride level, the Homeostasis Model Assessment index, and was negatively correlated with the high-density lipoprotein cholesterol level. In multiple regression analysis, the most influential factor for SUA was visceral fat area (p=0.0027), followed by the serum triglyceride level (p=0.0245). We clarified a higher SUA in the metabolic syndrome group as compared with the non-metabolic syndrome group: 6.67+/-1.14 mg, 6.09+/-1.14 mg, respectively (p<0.0001). The median SUA was elevated with increasing metabolic syndrome factors (p<0.0001). CONCLUSION: The present study indicated that SUA is related to visceral fat accumulation. Patients with metabolic syndrome revealed a higher SUA.

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.