Reframing kidney outcomes in CKD trials: eGFR slopes, competing risks, and pragmatic trial design

In both clinical research and study design, the definition of outcomes for chronic kidney disease (CKD) is changing. New molecules available for testing in humans, and the fact that kidney diseases are best treated earlier in their course, make the duration of studies requiring 'hard endpoints' longer than is feasible for registration purposes and funding agencies. Improved mathematical modelling and statistical analyses, and the availability of electronic medical records and registries have also impacted nephrology clinical research. Thus, eGFR slopes have been promoted as surrogate endpoints for kidney failure, competing-risk methods have exposed the limitations of standard survival analysis in high-mortality CKD and dialysis populations, and pragmatic, registry-based trials enroll patients who resemble those seen in daily practice. This review suggests that eGFR slopes, time to kidney failure, and competing risk factors must be considered in their totality, so that CKD and cardiovascular (CV) evidence can be understood in clinical practice by patients and clinicians. We propose that eGFR slopes may provide a clinically intuitive summary of 'kidney time', showing how, under appropriate conditions, chronic slope differences may be translated into approximate 'years of dialysis delayed' at the population level. We frame competing risks as a clinical, not only statistical, issue, and we examine how pragmatic CKD trials can and should integrate slope-based endpoints and competing-risk analyses into their design and reporting. To advance nephrology research, we must embrace these changes in study design and methodology to ensure that clinicians and patients understand them, and thus are more prepared to implement trial results.