Is ESRD (End Stage Renal Disease) a precise enough hard renal endpoint?

Abstract

Abstract Background: Renoprotective therapies are aimed at slowing renal function decline and are registered for preventing End-Stage-Renal-Disease (ESRD). ESRD (renal replacement therapy [RRT]: dialysis or renal transplantation) is considered an objective and clinically relevant hard endpoint in nephrology trials since it reflects the failure of proper kidney function. However, the initiation of RRT may be based on many factors beyond kidney function alone such as patient wellbeing, (changing) doctor habits, and (changing) local guidelines. We assessed the contribution of changes in serum creatinine and other factors in the ESRD/RRT decision making in a international trial setting. Methods: We performed a post-hoc analysis of the Reduction of Endpoints in non insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) and Irebesartan Diabetes Nephropathy (IDNT) trials. We used within linear regression to calculate the duration to reach eGFR 11 ml/min/1.73m2 for each individual separately, and compared this duration with the actual time to reach RRT for that patient, as recorded by the physician. Logistic regression analysis was performed to identify factors that were associated with RRT onset before or after reaching eGFR 11. Results: In the RENAAL trial 341 patients started RRT. Of these patients, 100 subjects started RRT before and 241 after they had reached eGFR 11 Independent determinants of RRT initiation before eGFR 11 were female gender [OR: 3.13, 95% CI, 1.15 – 8.53], serum hemoglobin [OR: 0.72, 95% CI, 0.54 – 0.96], and eGFR slope [OR: 1.18, 95% CI, 1.05 – 1.32]. A large variability was observed between the time to reach eGFR 11 and the corresponding time to the actual RRT decision: only 33.7% and 61% of subjects reached eGFR 11 within 90 or 180 days of the actual ESRD decision, respectively. An analysis in a similar trial, the IDNT trial, produced comparable results. Conclusion: This study shows that the initiation of ESRD is driven by many parameters beyond serum creatinine only. These factors can vary among doctors and patients. This implies that when using ESRD as clinical trial endpoint we may be testing drug effects beyond the drug’s ability to prevent GFR decline. Thus, we need to properly define patient who have to go to RRT.