Although renal replacement therapy is a clinically meaningful end point, trials must include numerous patients and follow them for long periods of time, said Kunihiro Matsushita, MD, an associate professor in the Department of Epidemiology and Division of Cardiology at Johns Hopkins University.
Although renal replacement therapy is a clinically meaningful endpoint, trials must include numerous patients and follow them for long periods of time, said Kunihiro Matsushita, MD, an associate professor in the Department of Epidemiology and Division of Cardiology at Johns Hopkins University.
Which endpoints have been most commonly used in clinical trials on kidney disease to date, and why are they inefficient or not sufficient?
Many clinicians and researchers will agree that renal replacement therapy is a hard, clinically meaningful endpoint in the field of nephrology. However, that endpoint will take time for some patients with kidney disease to reach. So if a clinical trial is designed to use renal replacement therapy as an outcome, that trial will need to include a lot of individuals and need to follow them for a long time. That's why there are data showing that the number of clinical trials in nephrology is much less, compared to the number of clinical trials in some other subspecialties like cardiology. To overcome that challenge in conducting clinical trials in nephrology, some investigators came up with the idea to use doubling of creatinine as a surrogate endpoint. Actually, many trials have used that surrogate endpoint, often in combination with the need of renal replacement therapy. However, that surrogate endpoint of doubling of creatinine is not a common outcome. So even with that surrogate endpoint, a trial needs to recruit a number of patients and needs to follow them for a long time. It was a partial solution but not a complete, or ideal solution.
Are there any alternative endpoints for kidney disease progression that ought to be considered? Should end point vary based on age?
As a part of an activity in the Chronic Kidney Disease Prognosis Consortium, we conducted a meta-analysis to quantify the association between changes in estimated glomerular filtration rate and the risk of reaching the need of renal replacement therapy. Based on that meta-analysis, we found that the association between 40% decline in estimated glomerular filtration rate and need of renal replacement therapy was higher than 5-fold. It's a very strong association. In combination with some other data from a variation of clinical trials or some simulations, we were quite comfortable to say that a 40% decline in estimated glomerular filtration rate can be a robust surrogate endpoint. In fact, at Kidney Week 2020, in the sessions of high impact clinical trials, I found a few trials incorporating a 40% decline in estimated glomerular filtration rate as a part of their endpoints.
I'm not aware that there are robust data supporting the need of age specific outcomes, but that's certainly something that the field needs to explore more in the future.