Rethinking clinical endpoints in kidney transplant trials.

Abstract

Clinical trials testing novel kidney transplant therapies are challenged by low rates of long-term clinical outcomes such as death and graft loss. Herein, we critically review traditional and more recent strategies to expedite new therapies by minimizing sample size and follow-up duration using surrogates (alone or in the context of composite endpoints), or using different clinical endpoints. Multiple surrogate endpoints are increasingly important for organ transplantation trial design: glomerular filtration rate slope, albuminuria, donor-specific alloantibodies, and histological score at graft protocol biopsies. However, surrogate endpoint use is limited by bias when data are missing. Hierarchical multiple primary endpoints - that are successfully used in other settings and frequently utilize surrogate endpoints - have not yet been integrated into kidney transplant studies. New clinical endpoints, focusing on treatment safety and patient quality of life have been recently standardized and should be reported regardless of the primary endpoint of any randomized controlled trial. Defining surrogates, standards for outcome reporting, and statistical strategies to appropriately analyze them are critical to effectively testing and implementing novel therapeutic strategies to improve long-term clinical outcomes in kidney transplantation.