Organ Crosstalk in CKD-Associated Frailty: Mechanistic Insights, Translational Opportunities, and Clinical Implications

Frailty in chronic kidney disease (CKD) is increasingly recognized as a manifestation of accelerated biological aging, characterized by systemic impairments that extend beyond the musculoskeletal domain. A distinctive yet underappreciated feature of CKD-associated frailty is its triple burden-the co-existence of sarcopenia, bone fragility, and cognitive impairment. Rather than isolated phenomena, these deficits share convergent pathophysiological drivers, including uremic toxicity, oxidative stress, hormonal dysregulation, and chronic inflammation. Accumulating evidence highlights the role of organ crosstalk-particularly along the muscle-bone and muscle-brain axes-as a key integrative mechanism linking these outcomes. This review synthesizes current understanding of the epidemiology, diagnostic approaches, and mechanistic underpinnings of this multisystem condition, emphasizing skeletal muscle as a central node in a dynamic physiological network. Recent advances in biomarker development, imaging technologies, and therapeutic strategies point toward a shift from compartmentalized to network-informed care. By framing CKD-related frailty as a disorder of disrupted inter-organ communication resulting in a triple burden of decline, we propose a unified pathophysiological model to guide earlier recognition and personalized, multimodal interventions. Importantly, this perspective also calls for a critical re-evaluation of current treatment targets in CKD management to ensure alignment with the goals of frailty prevention and long-term functional preservation.