Harnessing Exercise for Chronic Kidney Disease: Integrating Molecular Pathways, Epigenetics, and Gene-Environment Interactions

Chronic kidney disease (CKD) affects a significant fraction of the global population and is closely associated with elevated cardiovascular risk and poor clinical outcomes. Its pathophysiology entails complex molecular and cellular disturbances, including reduced nitric oxide bioavailability, persistent low-grade inflammation, oxidative stress, endothelial dysfunction, altered mineral metabolism, genetic predispositions, and uremic toxin accumulation. As current pharmacological treatments provide only partial risk reduction, complementary approaches are imperative. Exercise training, both aerobic and resistance, has emerged as a potent non-pharmacological intervention targeting these underlying molecular pathways. Regular exercise can enhance nitric oxide signaling, improve antioxidant defenses, attenuate inflammation, facilitate endothelial repair via endothelial progenitor cells, and stabilize muscle metabolism. Additionally, accumulating evidence points to a genetic dimension in CKD susceptibility and progression. Variants in genes such as APOL1, PKD1, PKD2, UMOD, and COL4A3–5 shape disease onset and severity, and may modulate response to interventions. Exercise may help buffer these genetic risks by inducing epigenetic changes, improving mitochondrial function, and optimizing crosstalk between muscle, adipose tissue, and the vasculature. This review synthesizes how exercise training can ameliorate key molecular mediators in CKD, emphasizing the interplay with genetic and epigenetic factors. We integrate evidence from clinical and experimental studies, discussing how personalized exercise prescriptions, informed by patients’ genetic backgrounds and nutritional strategies (such as adequate protein intake), could enhance outcomes. Although large-scale trials linking molecular adaptations to long-term endpoints are needed, current knowledge strongly supports incorporating exercise as a cornerstone in CKD management to counteract pervasive molecular derangements and leverage genetic insights for individualized care.