Kenjiro Kimura1, Tatsuo Hosoya2, Shunya Uchida3, Masaaki Inaba4, Hirofumi Makino5, Shoichi Maruyama6, Sadayoshi Ito7, Tetsuya Yamamoto8, Yasuhiko Tomino9, Iwao Ohno10, Yugo Shibagaki11, Satoshi Iimuro12, Naohiko Imai13, Masanari Kuwabara14, Hiroshi Hayakawa15, Hiroshi Ohtsu16, Yasuo Ohashi17. 1. Tokyo Takanawa Hospital, Tokyo, Japan. Electronic address: kimura-kenjiro@takanawa.jcho.go.jp. 2. Division of Chronic Kidney Disease Therapeutics, The Jikei University, Tokyo, Japan. 3. Department of Internal Medicine, Teikyo University, Tokyo, Japan. 4. Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan. 5. Okayama University, Okayama, Japan. 6. Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 7. Department of Nephrology, Hypertension, and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Japan. 8. Health Evaluation Center, Osaka Gyoumeikan Hospital, Osaka, Japan. 9. Department of Nephrology, Juntendo University School of Medicine, Tokyo, Japan. 10. Division of General Medicine, Department of Internal Medicine, The Jikei University, Tokyo, Japan. 11. Division of Nephrology and Hypertension, St. Marianna University School of Medicine, Kawasaki, Japan. 12. Teikyo Academic Research Center, Teikyo University, Tokyo, Japan. 13. Division of Nephrology and Hypertension, Kawasaki Municipal Tama Hospital, Kawasaki, Japan. 14. Department of Cardiology, Toranomon Hospital, Tokyo, Japan; Division of Renal Disease and Hypertension, University of Colorado Denver School of Medicine, Denver, CO. 15. Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University, Tokyo, Japan. 16. Center for Clinical Science, National Center for Global Health and Medicine, Tokyo, Japan. 17. Department of Integrated Science and Engineering for Sustainable Society, Chuo University, Tokyo, Japan.
Abstract
RATIONALE & OBJECTIVE: Epidemiologic and clinical studies have suggested that urate-lowering therapy may slow the progression of chronic kidney disease (CKD). However, definitive evidence is lacking. STUDY DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING & PARTICIPANTS: 467 patients with stage 3 CKD and asymptomatic hyperuricemia at 55 medical institutions in Japan. INTERVENTION: Participants were randomly assigned in a 1:1 ratio to receive febuxostat or placebo for 108 weeks. OUTCOMES: The primary end point was the slope (in mL/min/1.73m2 per year) of estimated glomerular filtration rate (eGFR). Secondary end points included changes in eGFRs and serum uric acid levels at 24, 48, 72, and 108 weeks of follow-up and the event of doubling of serum creatinine level or initiation of dialysis therapy. RESULTS: Of 443 patients who were randomly assigned, 219 and 222 assigned tofebuxostat and placebo, respectively, were included in the analysis. There was no significant difference in mean eGFR slope between the febuxostat (0.23±5.26mL/min/1.73m2 per year) and placebo (-0.47±4.48mL/min/1.73m2 per year) groups (difference, 0.70; 95% CI, -0.21 to 1.62; P=0.1). Subgroup analysis demonstrated a significant benefit from febuxostat in patients without proteinuria (P=0.005) and for whom serum creatinine concentration was lower than the median (P=0.009). The incidence of gouty arthritis was significantly lower (P=0.007) in the febuxostat group (0.91%) than in the placebo group (5.86%). Adverse events specific to febuxostat were not observed. LIMITATIONS: GFR was estimated rather than measured, and patients with stages 4 and 5 CKD were excluded. CONCLUSIONS: Compared to placebo, febuxostat did not mitigate the decline in kidney function among patients with stage 3 CKD and asymptomatic hyperuricemia. FUNDING: Funded by Teijin Pharma Limited. TRIAL REGISTRATION: Registered at the UMIN (University Hospital Medical Information Network) Clinical Trials Registry with study number UMIN000008343.
RCT Entities:
RATIONALE & OBJECTIVE: Epidemiologic and clinical studies have suggested that urate-lowering therapy may slow the progression of chronic kidney disease (CKD). However, definitive evidence is lacking. STUDY DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING & PARTICIPANTS: 467 patients with stage 3 CKD and asymptomatic hyperuricemia at 55 medical institutions in Japan. INTERVENTION: Participants were randomly assigned in a 1:1 ratio to receive febuxostat or placebo for 108 weeks. OUTCOMES: The primary end point was the slope (in mL/min/1.73m2 per year) of estimated glomerular filtration rate (eGFR). Secondary end points included changes in eGFRs and serum uric acid levels at 24, 48, 72, and 108 weeks of follow-up and the event of doubling of serum creatinine level or initiation of dialysis therapy. RESULTS: Of 443 patients who were randomly assigned, 219 and 222 assigned to febuxostat and placebo, respectively, were included in the analysis. There was no significant difference in mean eGFR slope between the febuxostat (0.23±5.26mL/min/1.73m2 per year) and placebo (-0.47±4.48mL/min/1.73m2 per year) groups (difference, 0.70; 95% CI, -0.21 to 1.62; P=0.1). Subgroup analysis demonstrated a significant benefit from febuxostat in patients without proteinuria (P=0.005) and for whom serum creatinine concentration was lower than the median (P=0.009). The incidence of gouty arthritis was significantly lower (P=0.007) in the febuxostat group (0.91%) than in the placebo group (5.86%). Adverse events specific to febuxostat were not observed. LIMITATIONS: GFR was estimated rather than measured, and patients with stages 4 and 5 CKD were excluded. CONCLUSIONS: Compared to placebo, febuxostat did not mitigate the decline in kidney function among patients with stage 3 CKD and asymptomatic hyperuricemia. FUNDING: Funded by Teijin Pharma Limited. TRIAL REGISTRATION: Registered at the UMIN (University Hospital Medical Information Network) Clinical Trials Registry with study number UMIN000008343.