Association of Serum Cystatin C with Stroke Morbidity and All-Cause and Cardio-Cerebrovascular Mortality: Evidence from the NHANES

Background: Serum cystatin C is a promising biomarker for vascular risk, yet its nonlinear dose–response relationships and prognostic value in general populations remain unclear, particularly for stroke-specific outcomes. Methods: This study utilized data from the National Health and Nutrition Examination Survey (NHANES) conducted in 1999–2002 cycles. A total of 11,610 participants were included in the primary analysis examining the cross-sectional association between cystatin C and stroke morbidity, using multivariate logistic regression models and odds ratios (ORs). Analyses utilized complete-case data (n = 11,610 for morbidity; n = 11,598 for mortality). Subsequently, 11,598 adults were retained for mortality endpoint analyses, which focused on the longitudinal association between cystatin C and stroke mortality, using cause-specific weighted multivariable Cox models and ratios (HRs). Restricted cubic splines identified nonlinear thresholds, and piecewise regression quantified risk gradients. Models were adjusted for sociodemographic/clinical/behavioral confounders. Results: Serum cystatin C exhibited a nonlinear dose–response relationship with stroke morbidity (p for nonlinear < 0.001), with an inflection point at 1.24 mg/L; below this threshold, each 0.1 mg/L increase conferred 13.84-fold higher odds (95% CI: 7.11–27.03, p < 0.001). For mortality, nonlinear thresholds were identified at 1.24 mg/L for all-cause/cause-specific mortality (HR = 6.73–10.60 per 0.1 mg/L increase, p < 0.001) and 1.81 mg/L for stroke-specific mortality. Conversely, cerebrovascular mortality demonstrated a linear association (HR = 1.43 per 1 mg/L increase, p = 0.008), though cystatin C independently predicted risk (HR = 1.38/continuous, p = 0.034 in fully adjusted models). Conclusions: This study identifies serum cystatin C as an independent predictor after full adjustment of stroke morbidity and all-cause and cardio-cerebrovascular mortality. Consequently, cystatin C emerges as a dual-purpose biomarker for early vascular injury detection in subclinical populations and integrated mortality risk stratification. Future research should validate these thresholds in prospective neuroimaging-confirmed cohorts and investigate interventions targeting cystatin C pathways to optimize preventive strategies.