Effect of fenofibrate on uric acid metabolism and urate transporter 1.

OBJECTIVE: To examine the effects of fenofibrate, an antilipotropic drug, on uric acid metabolism in healthy male subjects and on urate transporter 1 (URAT1). METHODS: Fenofibrate was administered to nine male volunteers at a dose of 300 mg (corresponding to 200 mg of micronized fenofibrate), and the metabolic parameters of uric acid were investigated for more than 12 hours. In addition, the effect of fenofibrate on URAT1-expressing cells was examined. RESULTS: After the administration of fenofibrate, the concentration of serum uric acid had significantly decreased from 5.8+/-0.4 mg/dL to 4.3+/-0.3 mg/dL at 10 h. Uric acid clearance and the fractional excretion of uric acid increased. Fenofibric acid, a fenofibrate metabolite, inhibited URAT1 to an extent similar to that observed with benzbromarone and losartan. CONCLUSION: Fenofibrate decreased serum uric acid levels by increasing its urinary excretion, most likely through the inhibition of URAT1 by fenofibric acid, its major metabolite.

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.

[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.

[Current management of renal anemia in patients with chronic kidney disease at the predialysis stage].

OBJECTIVE: Patients with chronic kidney disease (CKD) are frequently complicated by renal anemia as renal function declines. However, clinical guidelines on erythrocyte stimulating agents (erythropoietin : EPO) for such patients have not been established. Current clinical practice for EPO administration is based on the recommendations of the Japanese health insurance regulations, which have not always been supported by clinical evidence. MATERIALS & METHODS: The study subjects were 49 patients with CKD staged above 3 who had developed renal anemia requiring EPO. These patients were treated with EPO S. C. at the dose of 6,000 IU/week together with iron supplementation as deemed necessary for more than 24 weeks. RESULTS: The hemoglobin (Hb) value was 9.2 +/- 1.0 g/dL at the start, 10.9 +/- 1.6 g/dL at the peak (n = 49, p < 0.001 the start vs. the peak), and 9.0 +/- 1.6 g/dL at the commencement of dialysis (n = 49, p < 0.001 the peak vs. the commencement of dialysis). Seventy-one percent (35/49) of the patients achieved Hb levels over 10 g/dL, and 51% (25/49) achieved Hb levels over 11 g/dL. Conversely, 28% (14/49) of the patients failed to reach an Hb level over 10 g/dL. Factors explaining the good response to EPO (good responders were defined as those achieving Hb levels over 11 g/dL) had shown high Hb levels at the start (Logistic multiple regression analysis, p = 0.03) along with low creatinine concentration at the start (Cox's proportional hazard models, p = 0.015). Transferrin saturation (TSAT) at the start was 33.6 +/- 13.6%, 34.0 +/- 19.9% at the peak, and 24.7 +/- 11.6% at the commencement of dialysis, showing a significant reduction in TSAT at the commencement of dialysis compared to that at the start (n = 49, p = 0.0383, the start vs. the commencement of dialysis). Serum ferritin concentration was 140.7 +/- 139.5 pg/mL at the start, 107.9 +/- 110.8 pg/mL at the peak, and 131.9 +/- 112.4 pg/mL at the commencement of dialysis, indicating an absence of significant differences among the three time points. CONCLUSION: The current health insurance regulations in Japan seem to be inappropriate in that the permitted EPO dosage of 6,000 IU/week might not be sufficient to achieve the target Hb level of more than 11 g/dL in most patients with CKD. To more efficiently achieve renoprotection, both early and timely initiation of EPO and reconsideration of the recommended EPO dosage appear to be warranted.

[Regression of cardiac hypertrophy using angiotensin II receptor blocker in patients with chronic kidney diseases].

OBJECTIVE: Cardiovascular complications proportionally increase as chronic kidney diseases (CKD) progress into chronic renal insufficiency or failure. The present study addressed whether the long-term use of angiotensin II receptor blocker (ARB) exerts a cardio-protective effect in CKD patients with mild to moderate renal damage. MATERIAL AND METHODS: Fifteen patients with CKD above stage 3 were enrolled in the study. While their previous antihypertensive therapy remained unchanged, the ARB candesartan, was newly added to the concurrent therapy and the patients were followed for 12-24 months thereafter. RESULTS: The main results were as follows: 1) The use of ARB improved the status of BP control classifications, shifting them to the better control categories where there was less morning hypertension. 2) ARB significantly reduced the left ventricular (LV) mass index(LVMI), the relative wall thickness (RWT), the LV intra-dimension in diastole(LVIDd), and as a result, the LV ejection fraction(LVEF) improved. In parallel, the LV mass category shifted to lower categories, indicating a significant improvement. 3) The levels of BNP decreased significantly from 135.2 +/- 136.0 to 85.0 +/- 80.3 pg/mL. 4) ARB reduced urinary protein excretion in all cases. Regardless of an inevitable increase in the serum creatinine(Cr) concentration, the slope of reciprocal serum Cr concentration (l/Cr) in the treatment period with ARB was significantly less steep compared to that in the run-in period. 5) Throughout the observation period, no serious side effects were found in any of the patients. CONCLUSION: The present study indicated that the long-term use of ARB exerts both cardio-, and renoprotective effects in patients with advanced CKD. This agent could be especially indicative and useful not only for patients with CKD, but also for patients of CKD with cardiac hypertrophy.

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.