BACKGROUND AND OBJECTIVES: RRT and doubling of serum creatinine are considered the objective hard end points in nephrology intervention trials. Because both are assumed to reflect changes in the filtration capacity of the kidney, drug effects, if present, are attributed to kidney protection. However, decisions to start RRT are not only on the basis of filtration capacity of the kidney, but also on other factors. We therefore compared the time to RRT with the time to a fixed eGFR threshold and assessed the effect of the renoprotective drug irbesartan on both components. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: analysis of two clinical trials, the Irbesartan Diabetic Nephropathy Trial (IDNT) and Reduction of End points in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan Trial, in patients with type 2 diabetes and nephropathy. The time to a predefined eGFR level of 11 ml/min per 1.73 m (eGFR), calculated by within-patient linear regression, was compared with the time to RRT or sustained serum creatinine ≥6 mg/dl. RESULTS: A large difference was observed in the median time to RRT (779 days) compared with eGFR (678 days; =0.01). We also observed a large variation in the difference between the time to RRT and eGFR. In IDNT, the hazard ratio for the effect of irbesartan on the serum creatinine ≥6.0 mg/dl end point was 0.60 (95% confidence interval, 0.39 to 0.91; =0.02), whereas it was smaller for the RRT end point (hazard ratio, 0.78; 95% confidence interval, 0.58 to 1.07; =0.12). CONCLUSIONS: This study shows a difference in the time to RRT and a fixed eGFR threshold, and shows that the effect of an angiotensin receptor blocker on a filtration-based end point versus RRT varies. This implies that evaluating renoprotective effects of drugs with a combined RRT and doubling of serum creatinine end point may result in evaluating other effects beyond renoprotection alone. Future trials should consider registering all parameters that lead to RRT decisions.