Abstract
BACKGROUND: Elevated skin autofluorescence (SAF), a marker of advanced glycation end-products (AGEs), predicts cardiovascular outcomes. However, the predictive value of SAF across diabetes mellitus (DM), chronic kidney disease (CKD), and atherosclerotic cardiovascular disease (ASCVD) remains incompletely compared. This meta-analysis aimed to clarify SAF's prognostic strength across these populations, highlighting potential mechanisms and therapeutic implications. METHODS: We performed a systematic search of PubMed, Embase, and Cochrane databases through March 2025, identifying prospective observational studies evaluating associations between SAF and cardiovascular outcomes. Primary endpoints included all-cause mortality, cardiovascular death, cardiovascular disease (CVD), and stroke. Subgroup analyses compared SAF's predictive value in patients stratified by ESRD status (ESRD vs. non-ESRD), dialysis modality (hemodialysis [HD] vs. peritoneal dialysis [PD]), and diabetes type (type 1 vs. type 2 DM). RESULTS: Twenty-four studies involving 12,361 participants were included. Elevated SAF significantly predicted increased risks of all-cause mortality (hazard ratio [HR] 1.59; 95% confidence interval [CI] 1.37-1.85, I(2) = 65.4%), cardiovascular death (HR 1.42; 95% CI 1.07-1.88, I(2) = 43.9%), CVD events (HR 1.64; 95% CI 1.34-2.03, I(2) = 78.5%), and stroke (HR 2.33; 95% CI 1.49-3.32, I(2) = 0.0%). Subgroup analyses demonstrated a significantly stronger association between elevated SAF and CVD events in ESRD patients compared to non-ESRD patients (HR 3.51 vs. 1.56; P for interaction = 0.001). Although not statistically significant, PD patients tended to show a stronger SAF-CVD association than HD patients. CONCLUSIONS: Elevated SAF predicts increased cardiovascular risk, with notably stronger associations in chronic kidney disease and end-stage renal disease. These findings support the biological relevance of systemic AGE accumulation. However, further prospective validation and decision-analytic studies are required to assess SAF's incremental predictive value beyond established scores and determine its clinical utility for risk stratification.