Frailty index and type 2 diabetes with renal complications: insights from Mendelian randomization and retrospective observational study.

OBJECTIVES: To investigate the relationship between frailty and diabetic kidney disease (DKD)-related renal complications using Mendelian randomization (MR) and complementary clinical analysis. METHODS: Two-sample MR was performed using genome-wide association study summary statistics to assess the association between genetically predicted frailty and type 2 diabetes with renal complications. Functional annotation and sensitivity analyses, including exclusion of potentially pleiotropic variants and multivariable MR, were conducted. A retrospective hemodialysis cohort (n = 100) was analyzed to characterize frailty burden in patients with DKD-related versus non-DKD end-stage renal disease. RESULTS: Genetically predicted frailty was significantly associated with increased risk of type 2 diabetes with renal complications (inverse-variance weighted odds ratio = 5.30, 95% confidence interval: 1.89-14.91, p = 0.002), without substantial pleiotropy or heterogeneity. Functional annotation suggested exploratory neuromuscular and cytoskeletal signals. In the clinical cohort, patients with DKD had higher frailty scores than those without DKD (median 2.0 vs. 1.0, p = 0.003). Exploratory machine learning analysis identified dialysis vintage, grip strength, and physical activity as major contributors to DKD classification. CONCLUSIONS: Frailty was associated with DKD-related renal complications, and forward MR suggested a potential causal contribution. Frailty may represent a clinically relevant marker of systemic vulnerability in this setting, although further validation in larger prospective cohorts is needed.