Application of a Kidney Hierarchical Composite Endpoints in Trials of CKD Progression: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Despite approved therapies for chronic kidney disease (CKD), many patients experience progressive loss of kidney function, and there remains an unmet need for additional therapies. Hierarchical composite endpoints (HCEs) have emerged as candidate tools to improve the efficiency of randomized controlled trials (RCTs) by integrating multiple outcomes ranked by clinical importance. The National Kidney Foundation convened a Scientific Workshop involving a broad group of stakeholders to consider the application of HCEs to CKD. A proposed kidney HCE includes all-cause mortality, kidney failure with or without initiation of kidney replacement therapy, time to sustained declines in GFR, and GFR slope. Workshop participants concluded that a kidney HCE is a promising candidate for establishing efficacy of therapies in settings in which we typically conduct large trials that use kidney composite endpoints to establish efficacy. It was acknowledged that no endpoint is universally applicable in all situations. The ideal population for an HCE would be one at risk for progression but unlikely to yield sufficient clinical events during the trial period to permit application of the traditional time-to-event endpoint. Additional investigations are required to address key challenges in application of HCE to CKD, such as how to best assess differences in individual GFR slope.