Timing of urate-lowering therapy and risk of kidney failure and mortality in CKD: an application of the parametric G-formula

Abstract Background The optimal timing for initiating urate-lowering therapy (ULT) in chronic kidney disease (CKD) remains uncertain. Although randomized trials have provided robust evidence, their neutral findings and limited follow-up leave questions regarding whether earlier intervention improves long-term outcomes. Methods Using two nationwide CKD cohorts in Korea (n=27 260 and 9 727), we applied the parametric g-formula to estimate simulated risks for end-stage kidney disease (ESKD) and all-cause mortality under alternative ULT thresholds. Data were divided into 6-month intervals, and six strategies were simulated: observed practice (reference), initiation when serum urate (sUA) reached ≥7, 8, 9, or 10 mg/dL, and no treatment. Models accounted for time-varying confounders affected by prior therapy, and cumulative risks were estimated over 22 years. Results Deferring ULT to higher sUA thresholds or not initiating therapy was associated with dose-dependent increases in mortality and ESKD risk. Initiating therapy at 7–8 mg/dL was associated with lower 22-year cumulative risks of mortality by –0.76%p (95% CI –0.91 to –0.59) and –0.37%p (–0.44 to –0.29), and ESKD by –1.23%p (–1.44 to –0.98) and –0.43%p (–0.55 to –0.31), estimated to correspond to 100–300 fewer deaths or kidney failure events per 10 000 patients. Conclusions Timely initiation of urate-lowering therapy, particularly before serum urate exceeds 9 mg/dL, is associated with improved long-term renal and survival outcomes in CKD. These findings, which may remain undetected in shorter randomized trials, underscore the utility of the g-formula in observational studies as a valuable complement to evidence from randomized trials.