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

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 ( 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 ULT, 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.