Abstract
BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome involves interconnected cardiovascular, renal, and metabolic dysfunctions. While rapid kidney function decline (RKFD) portends poor prognosis in CKM patients, reliable early predictors remain limited. The triglyceride-glucose (TyG) index and atherogenic index of plasma (AIP) have recently emerged as promising indicators of metabolic dysregulation, but their predictive value for RKFD in CKM syndrome requires further investigation. METHODS: We conducted a prospective cohort analysis of 2763 participants aged ≥ 45 years with CKM syndrome using data from the China Health and Retirement Longitudinal Study (CHARLS). The main outcome measured was the occurrence of RKFD, characterized by an annual estimated glomerular filtration rate decline at least 3 mL/min/1.73 m(2) during follow-up. Multivariable logistic regression was employed to examine associations between the TyG index, AIP and RKFD, with dose-response relationships assessed using restricted cubic splines. Subgroup analyses evaluated effect modifications by key covariates, with multiplicity adjustment. A mediation analysis was conducted to explore potential mediators. RESULTS: During 4-year follow-up, 278 cases (10.1%) of RKFD were identified. In the fully adjusted model, each one-unit increase in the TyG index and AIP was associated with 1.80-fold and 3.01-fold higher risks of RKFD, respectively. Restricted cubic spline analysis confirmed nearly linear dose-response relationships (both p-nonlinear > 0.05). Inclusion of the TyG index or AIP enhanced both discrimination and reclassification beyond conventional markers. No significant interactions were observed in subgroup analyses (all P for interaction > 0.05). Uric acid significantly mediated the associations of baseline TyG index and AIP with RKFD, accounting for 17.59% and 17.69% of the total effects, respectively. CONCLUSIONS: Our findings demonstrate the utility of the TyG index and AIP as effective biomarkers for stratifying the risk of RKFD in the clinical management of CKM syndrome. Furthermore, uric acid plays a significant partial mediating role in this relationship.