Interpreting Rapid eGFR Decline in the Generation 100 Study

We read with interest the recent JASN publication by Hallan et al.1 examining the effects of high-intensity interval training on kidney function in older adults. The trial adds meaningful data to a field where robust evidence has long been limited. However, one of the study's key findings—the high prevalence of rapid eGFR decline—raises concerns that warrant further discussion. According to the authors, 30% of participants in the control group experienced a cystatin C–based eGFR decline >5 ml/min per 1.73 m2/yr. This rate appears unusually high. In the Cardiovascular Health Study (CHS), a cohort of similarly aged adults showed a mean annual decline of −1.85 ml/min per 1.73 m2 with a SD of 2.4, suggesting that fewer than 10% would be expected to cross the −5 ml/yr threshold.2 The Generation 100 cohort, by contrast, had higher baseline kidney function, lower comorbidity, and better functional status—all factors typically associated with slower decline. Using the CHS variability as a reference, a 30% prevalence of rapid decline in Generation 100 would imply an average population slope near −3.6 ml/min per 1.73 m2/yr—almost twice that of CHS. This discrepancy is hard to reconcile and raises the possibility that random variation or measurement noise in cystatin C may have played a significant role in outcome classification. Another issue is the lack of reporting on mean or median eGFR slopes. Presenting only dichotomous outcomes limits the ability to judge whether the observed changes fall within the range of expected aging or suggest underlying pathology. Including the full distribution of slopes would provide much-needed context. Clarifying these points would strengthen the study's impact and help clinicians and researchers better understand the magnitude—and mechanisms—of exercise-related preservation of kidney function.