Abstract: Objective To investigate frailty index (FI), edema, and depression in the genetic causal relationship between chronic kidney disease (CKD) and appendicular lean mass (ALM), in order to provide references for the prevention of CKD-related sarcopenia.  Methods  Summary data for FI, edema, depression, CKD, and ALM were obtained from publicly available genome-wide association study (GWAS) databases. A two-step Mendelian randomization (MR) approach was first applied to evaluate potential mediators between CKD and ALM. Subsequently, multivariable Mendelian randomization (MVMR) analysis was conducted to identify causal factors independently associated with ALM. Finally, a mediation MR model was constructed, with CKD as the exposure, ALM as the outcome, and the identified independent causal factors as mediators to explore potential mediation pathways.  Results  Two-step MR, MVMR, and mediation MR analyses revealed that FI is a potential independent mediator between CKD and ALM (OR=0.458, 95% CI: 0.411～0.511, P=0.021). Further mediation analysis indicated a significant indirect causal effect of CKD on ALM through FI (βmediation effect=-0.24, OR=0.787, 95% CI: 0.67～0.978, P=0.019).  Conclusion  The effect of CKD on ALM is primarily mediated indirectly through frailty. Frailty serves as a key mediator of CKD-related sarcopenia, providing a genetic basis for clinical intervention of sarcopenia.

Key words: Chronic kidney disease, Frailty, Edema, Depression, Appendicular lean mass, Two-step Mendelian randomization, Multivariable Mendelian randomization, Mediation Mendelian randomization