Crosstalk in the kidney-muscle axis: myokines and muscle-relevant mediators in chronic kidney disease-associated sarcopenia.

Chronic kidney disease (CKD) is a systemic disorder in which sarcopenia serves as a critical driver of frailty and mortality. However, the "kidney-muscle axis" remains conceptually fragmented, often confounded by the overlapping definitions of protein-energy wasting (PEW) and cachexia. This review argues that CKD-associated sarcopenia is not driven by isolated myokines, but rather by a clearance-distorted, inflammation-coupled signaling network. We first disambiguate sarcopenia from PEW and cachexia, distinguishing canonical myokines from mediators whose interpretive value is altered by uremia. We then propose a framework organized around four pillars: hypercatabolism, anabolic resistance, mitochondrial dysfunction and bioenergetic remodeling, and context-dependent inflammatory signaling. Within this context, we reinterpret key mediators, including myostatin, growth differentiation factor 15 (GDF-15), insulin-like growth factor 1 (IGF-1), irisin, and interleukin-6 (IL-6), emphasizing that their circulating levels reflect a complex entanglement of altered secretion, impaired renal clearance, and tissue-specific resistance. While the kidney-to-muscle vector is well-supported, direct muscle-to-kidney feedback remains less established. By framing myokine dysregulation as a mechanistic interface, this review aims to refine causal inference and support the development of targeted therapies for muscle wasting in CKD.