A blood test-derived skeletal muscle index combined with handgrip strength identifies a sarcopenia-related high-risk phenotype in non-dialysis-dependent chronic kidney disease

Abstract Background Sarcopenia is associated with adverse outcomes in CKD, but direct assessment of skeletal muscle mass is not always available. We examined whether serum creatinine- and cystatin C-derived estimated skeletal muscle index (SMI), combined with handgrip strength, identifies a sarcopenia-related high-risk phenotype in non-dialysis-dependent CKD. Methods We derived a new equation for appendicular skeletal muscle mass using bioelectrical impedance analysis as the reference in 100 patients with non-dialysis-dependent CKD. In an independent multicenter cohort of 1,403 patients, SMI was estimated using this equation and a published creatinine-cystatin C-based formula. The sarcopenia-related high-risk phenotype was defined as low handgrip strength plus low estimated SMI using sex-specific cutoffs. Outcomes were all-cause, cardiovascular, and non-cardiovascular mortality. Results During 5 years, 173 patients died, including 43 from cardiovascular causes. Low estimated SMI was identified in 218 patients (15.5%) with the published formula and 312 (22.2%) with the new equation; the corresponding phenotype prevalences were 11.9% and 11.7%. The phenotype was independently associated with all-cause mortality using either formula: adjusted hazard ratios were 1.54 (95% confidence interval [CI], 1.07-2.21) for the published formula and 2.14 (95% CI, 1.52-3.00) for the new equation. Four-category and sensitivity analyses yielded consistent findings. Conclusions Combining handgrip strength with creatinine- and cystatin C-derived estimated SMI identifies a sarcopenia-related high-risk phenotype and stratifies mortality risk in non-dialysis-dependent CKD. This approach may support screening when direct muscle mass assessment is unavailable but requires further validation before use as a diagnostic substitute.