The difference between cystatin C- and creatinine-based estimated glomerular filtration rate and all-cause and cardiovascular mortality in populations with cardiovascular-kidney-metabolic syndrome stages 0–3: a prospective cohort study

Introduction: Cardiovascular-kidney-metabolic (CKM) syndrome represents an integrated pathophysiological framework encompassing CVD, kidney dysfunction, and metabolic disorders. The difference between cystatin C-based and creatinine-based estimated glomerular filtration rate (eGFRdiff) may reflect pathophysiological processes beyond kidney function, yet its prognostic significance across CKM syndrome stages remains poorly understood. Methods: We examined records from 4382 adult participants diagnosed with CKM syndrome (stages 0-3) extracted from the National Health and Nutrition Examination Survey database (1999-2004), with mortality surveillance continuing through December 2019. eGFRdiff was calculated using both absolute difference (eGFRabdiff) and the ratio (eGFRrediff) between cystatin C- and creatinine-based calculations. To investigate associations with overall and cardiovascular mortality outcomes, we employed Cox proportional hazard regression models with adjustments for demographic factors, clinical parameters, and biochemical indicators. Results: Throughout a median surveillance period spanning 201.8 months, we documented 1,034 fatalities (15.69% of the cohort), with cardiovascular events accounting for 230 deaths (22.2% of all deaths, representing 3.24% of the entire cohort). After comprehensive adjustment in our statistical models, participants exhibiting a negative absolute eGFRdiff (eGFRabdiff <-15 mL/min/1.73 m2) demonstrated significantly elevated all-cause mortality risk (HR 1.75, 95% CI 1.34-2.29) compared to those with intermediate eGFRabdiff values (-15 to 15 mL/min/1.73 m2). Conversely, subjects with positive eGFRabdiff (≥15 mL/min/1.73 m2) showed a protective association (HR 0.65, 95% CI 0.54-0.80). Quantitatively, each standard deviation reduction in eGFRabdiff corresponded to a 42% mortality risk increase (HR 1.42, 95% CI 1.28-1.59) and 57% higher cardiovascular mortality (HR 1.57, 95% CI 1.36-1.82). The relative difference metric yielded similar patterns, with eGFRrediff <1 associated with elevated risks for both all-cause (HR 1.79, 95% CI 1.48-2.17) and cardiovascular mortality (HR 1.71, 95% CI 1.23-2.38) versus eGFRrediff ≥1. Notably, these associations were significant in CKM syndrome stages 2-3 but not in stages 0-1. Conclusion: eGFRdiff is inversely associated with all-cause and cardiovascular mortality in populations with CKM syndrome stages 0-3, with stronger associations in more advanced stages. eGFRdiff may serve as a valuable prognostic marker in CKM syndrome, potentially reflecting underlying inflammatory, oxidative stress, and endothelial dysfunction processes that contribute to adverse outcomes.