Renoprotective effects of febuxostat in hyperuricemic patients with chronic kidney disease: a parallel-group, randomized, controlled trial

Tanaka, Kenichi; Nakayama, Masaaki; Kanno, Makoto; Kimura, Hiroshi; Watanabe, Kimio; Tani, Yasuhiro; Hayashi, Yoshimitsu; Asahi, Koichi; Terawaki, Hiroyuki; Watanabe, Tsuyoshi

doi:10.1007/s10157-015-1095-1

Cited by 84 publications

(102 citation statements)

References 36 publications

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“…Previous studies have reported that febuxostat reduces uric acid more effectively than allopurinol in patients with CKD. 2,[20][21][22][23] In addition, the febuxostattreated groups showed better renal function than the allopurinol-treated groups in some of these earlier reports. [21][22][23] Tanaka and associates 2 performed a prospective, randomized, open-label, parallel-group trial in hyperuricemic patients with stage 3 CKD.…”

Section: Discussionmentioning

confidence: 71%

“…1 In addition, febuxostat is excreted by both the urinary and fecal pathways after being metabolized to acyl glucuronide metabolites in the liver. 2 A small portion of the parent compound undergoes oxidative metabolism by cytochrome P450 enzymes. 3 Allopurinol is a xanthine oxidase inhibitor, and both allopurinol and its metabolites are excreted in the urine.…”

Section: Introductionmentioning

confidence: 99%

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Baek

Kim²,

Yang³

et al. 2018

Exp Clin Transplant

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Objectives: Febuxostat, a nonpurine xanthine oxidase, is known to be effective and safe, even in patients with chronic kidney disease. However, there are insufficient data about the efficacy and safety of febuxostat in kidney transplant patients. Key words: Renal transplantation, Uric acid, Xanthine oxidase inhibitor IntroductionFebuxostat is a nonpurine xanthine oxidase inhibitor that was approved by the European Medicines Agency in 2008 and by the US Food and Drug Administration in 2009. Febuxostat is selective for the enzyme xanthine oxidase, unlike allopurinol, which inhibits other enzymes involved in purine and pyrimidine metabolism. 1 In addition, febuxostat is excreted by both the urinary and fecal pathways after being metabolized to acyl glucuronide metabolites in the liver. 2 A small portion of the parent compound undergoes oxidative metabolism by cytochrome P450 enzymes. 3 Allopurinol is a xanthine oxidase inhibitor, and both allopurinol and its metabolites are excreted in the urine. 4 Therefore, dose reduction is necessary in patients with renal impairments. 5 Benzbromarone increases the urinary excretion of uric acid and may have limited effects in patients with chronic kidney disease (CKD). 4 As shown in several previous phase 3 clinical trials, febuxostat doses at 80 and 120 mg/day were found to be significantly more effective than allopurinol at 100 to 300 mg/day in lowering serum uric acid levels in patients with hyperuricemia and gout. 6 Febuxostat was also generally well tolerated, with the most frequent adverse events reported to be abnormal liver function tests and gastrointestinal symptoms. 3,6 Some trials excluded patients with renal impairment, 7,8 whereas others included patients with mild to moderate renal dysfunction. 9,10 In the studies that included patients with renal impairment, febuxostat was reported to be more efficacious than allopurinol and equally safe.The influence of hyperuricemia on renal function and graft survival in kidney transplant recipients is controversial. 11 Although some studies have found

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Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Untitled

Baek

Kim²,

Yang³

et al. 2018

Exp Clin Transplant

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“…Among the six studies included, participants in five trials were of Asian ethnicity (14,19–22) and of Caucasian ethnicity in one trial (18). The studies all compared the efficacy of febuxostat with control agents (placebo or allopurinol), and four were randomized controlled trials (14,18,20,21). More importantly, one trial focused on the effect and safety of febuxostat in renal transplant recipients (19).…”

Section: Resultsmentioning

confidence: 99%

Efficacy and safety of febuxostat for treating hyperuricemia in patients with chronic kidney disease and in renal transplant recipients: A systematic review and meta‑analysis

Liu

Sun

et al. 2018

Exp Ther Med

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Febuxostat is potent and well-tolerated in the management of chronic gout. However, its clinical efficacy and safety in the treatment of hyperuricemia in patients with chronic kidney disease (CKD) and in renal transplant recipients have remained to be fully determined. The MEDLINE, EMBASE and Cochrane Library databases were searched for relevant articles. Data were extracted and pooled results were estimated from the standard mean difference (SMD) with 95% confidence intervals (95% CIs). The quality of the studies included was assessed, and their publication bias was examined. Four prospective randomized controlled trials and two retrospective observational studies were included in the systematic review and meta-analysis. Febuxostat administration significantly reduced the serum uric acid concentration in patients with CKD and in renal transplant recipients when compared with allopurinol or placebo in the short-term (1 month: SMD, −2.24; 95% CI, −3.59 to −0.89; P-value of SMD=0.001; I2, 92.4%; 3 months: SMD, −1.20; 95% CI, −2.04 to −0.36; P-value of SMD=0.005; I2, 88.9%; 6 months: SMD, −1.49; 95% CI, −2.68 to −0.30; P-value of SMD=0.014; I2, 92.9%). Furthermore, the increase in the estimated glomerular filtration rate in the febuxostat group was significantly higher than that in the control group (SMD, 0.30; 95% CI, 0.031 to 0.58; P-value of SMD=0.029; I2, 0.0%). No significant difference in the changes in serum creatinine (Scr), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) was identified between the two groups (Scr: SMD, −0.17; 95% CI, −0.97 to 0.63; P-value of SMD=0.67; I2, 79.2%; LDL: SMD, −0.21; 95% CI, −0.49 to 0.07; P-value of SMD=0.13; I2, 34.1%; HDL: SMD, −0.05; 95% CI, −0.70 to 0.61; P-value of SMD=0.89; I2, 69.2%). In conclusion, febuxostat is a potent and well-tolerated agent for the short-term management of hyperuricemia in patients with CKD and in renal transplant recipients. However, these data should be interpreted with caution due to the varied design of the studies included in the present meta-analysis.

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“…These results might support the heterogeneousness of the inpatients with albuminuria examined in this study. Several studies suggest that hyperuricemia may be a factor of the progress of albuminuria in diabetic nephropathy [14,15] and that XOR inhibitors may reduce albuminuria [16][17][18]. On the other hand, there were few studies that showed uricosuric agents without XOR inhibitory potency may reduce albuminuria.…”

Section: Discussionmentioning

confidence: 99%

Uric acid-lowering and renoprotective effects of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia: a randomized, double-blind, placebo-controlled, parallel-group study (UPWARD study)

et al. 2018

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Background Hyperuricemia is supposed to be an independent risk factor for kidney dysfunction in diabetic patients. We attempted to examine the uric acid-lowering effect and the renoprotective effect of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia in this pilot study. Methods The study design was randomized, double-blind, placebo-controlled, parallel-group study. A total of 65 patients with hyperuricemia and diabetic nephropathy with microalbuminuria were enrolled and assigned to either the topiroxostat group or the placebo group. Topiroxostat (stepwise dosing from 40 to 160 mg/day) or matching placebo was administered BID for 28 weeks. The primary endpoint was a change in the urinary albumin-to-creatinine ratio in the first-morning-void urine sample. Secondary endpoints were changes in the estimated glomerular filtration rate and the serum uric acid level. Results At 28 weeks, there was no significant difference in the percent change from baseline in the urinary albumin-tocreatinine ratio between the two groups (topiroxostat: 0 vs. placebo: 17%, p = 0.3206), but the changes in the estimated glomerular filtration rate (− 0.2 vs. − 4.0 mL/min/1.73 m 2 , p = 0.0303) and the serum uric acid level (− 2.94 vs. − 0.20 mg/ dL, p < 0.0001) were significantly different between the topiroxostat and placebo groups. Gouty arthritis occurred in 1 patient in the placebo group and no patients in the topiroxostat group. Conclusion These findings support that diabetic nephropathy combined with hyperuricemia may be associated with kidney dysfunctions. Topiroxostat provides strict control of the serum uric acid level preventing decline of eGFR in these patients.

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Renoprotective effects of febuxostat in hyperuricemic patients with chronic kidney disease: a parallel-group, randomized, controlled trial

Abstract: Febuxostat reduced serum UA levels more effectively than conventional therapy and might have a renoprotective effect in hyperuricemic patients with CKD. Further studies should clarify whether febuxostat prevents the progression of renal disease and improves the prognosis of CKD.

Cited by 84 publications

References 36 publications

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Efficacy and safety of febuxostat for treating hyperuricemia in patients with chronic kidney disease and in renal transplant recipients: A systematic review and meta‑analysis

Uric acid-lowering and renoprotective effects of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia: a randomized, double-blind, placebo-controlled, parallel-group study (UPWARD study)

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