Reconsidering Biomarker Interpretation and Clinical Applicability in High-Intensity Interval Training and Kidney Function Trials

In a recent JASN article, Hallan et al. present important randomized evidence that high-intensity interval training (HIIT) may reduce the risk of rapid eGFR decline in older adults.1 This is a meaningful contribution to the growing dialogue on nonpharmacologic strategies for preserving kidney function, especially in aging populations. The study's long-term duration, methodological rigor, and large sample size are commendable. However, we wish to highlight several considerations that may refine the interpretation and translational value of the findings. First, the use of cystatin C–based eGFR appropriately mitigates confounding from exercise-induced changes in muscle mass, a limitation of creatinine-based estimates. However, cystatin C itself is not immune to non-GFR determinants, particularly systemic inflammation and thyroid dysfunction, both of which can be modulated by high-intensity exercise. Although the authors suggest cystatin C is less susceptible to confounding, recent literature shows it can be influenced by reductions in inflammatory cytokines and alterations in thyroid hormones. A supplementary sensitivity analysis using the CKD Epidemiology Collaboration combined creatinine–cystatin C equation could have helped reduce residual measurement bias and strengthen robustness. Second, although the study demonstrates a 25% relative risk reduction in rapid eGFR decline with HIIT, the absolute risk reduction was modest (approximately 7%), and none of the participants progressed to kidney failure during the follow-up. Given the high baseline eGFR (approximately 95 ml/min per 1.73 m2), this was a low-risk population. Whether HIIT meaningfully alters the trajectory toward clinically significant CKD or hard kidney outcomes remains uncertain. We urge caution in generalizing these findings to patients with established CKD, albuminuria, or reduced functional reserve. Third, adherence to assigned interventions was moderate, and overlap in achieved activity intensities across groups may have attenuated the study's internal contrast. Although the authors supplemented with observational analyses based on actual activity, unmeasured confounding remains possible. Furthermore, such intensity crossover introduces classification ambiguity that may complicate interpretation of the true intervention effect. Finally, although the trial demonstrates safety and feasibility of HIIT in a structured setting, its scalability over 5 years in frail or multimorbid older adults in real-world practice remains unclear. Pragmatic studies examining cost-effectiveness and health system integration would complement this efficacy trial and enhance its policy relevance. Despite these caveats, the Generation 100 trial offers a vital foundation for the nascent field of nephro-preventive exercise interventions. Future studies in more diverse or high-risk populations may clarify long-term clinical benefits, optimize program adherence, and delineate the underlying mechanisms.