Uric Acid Lowering and Biomarkers of Kidney Damage in CKD Stage 3: A Post Hoc Analysis of a Randomized Clinical Trial

Abstract

Rationale & Objective: Hyperuricemia is associated with chronic kidney disease (CKD) progression. We evaluated whether lowering serum uric acid levels improves levels of biomarkers of kidney damage. Study Design: Post hoc analysis of clinical trial participants. Setting & Participants: A double-blind randomized placebo-controlled study designed to lower serum uric acid levels. 80 patients with stage 3 CKD and asymptomatic hyperuricemia were randomly assigned to allopurinol treatment or placebo (300 mg/d) for 12 weeks. Exposure/Predictor: Allopurinol treatment versus placebo. Outcomes & Measures: We evaluated the change from baseline for the following urinary biomarkers of kidney damage: albumin-creatinine ratio (ACR), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), and transforming growth factor β1 (TGF-β1). Additionally, we evaluated CKD Epidemiology Collaboration (CKD-EPI)-estimated glomerular filtration rate (eGFR) and cystatin C eGFR. Analytical Approach: Generalized linear mixed modeling was used. Results: After 12 weeks, allopurinol (compared to placebo) significantly lowered serum uric acid levels with an estimate of −3.3 mg/dL (95% CI, −4.1 to −2.5 mg/dL; P < 0.001). Estimates for the change for allopurinol versus placebo over time were 1.09 (95% CI, 0.77-1.54) for ACR, 0.77 (95% CI, 0.36-1.63) for NGAL, and 2.36 (95% CI, 0.97-5.70) for TGF-β1. The model did not converge for KIM-1, but Wilcoxon signed rank test showed no significant difference in change from baseline between study groups. There was no significant change observed in CKD-EPI eGFR or cystatin C eGFR. Limitations: Post hoc analysis and short duration of the study. Conclusions: Uric acid–lowering with allopurinol is not associated with improvement in levels of biomarkers of kidney damage in patients with asymptomatic hyperuricemia and stage 3 CKD. Funding: The study was funded by the National Institutes of Health through a career development award, K23DK088833, and the Clinical and Translational Science Award UL1TR002537. Trial Registration: NCT01228903. Index Words: Chronic kidney disease, allopurinol, uric acid, kidney function, kidney damage