The Evolving Role of High‐Sensitivity C‐Reactive Protein for Mortality Prediction Across the Spectrum of Cardiovascular–Kidney–Metabolic Syndrome

AIMS: High-sensitivity C-reactive protein (hsCRP) is central to cardiovascular-kidney-metabolic (CKM) syndrome pathogenesis, but its prognostic value across progressive CKM stages remains uncertain. We aimed to evaluate the stage-specific associations between hsCRP and mortality in CKM syndrome. MATERIALS AND METHODS: In this prospective analysis of 86 829 participants from the Kailuan Study, we evaluated hsCRP's association with all-cause mortality stratified by AHA-defined CKM stages (0-4). Multivariable Cox models assessed hazard ratios (HRs) for mortality per unit increase in ln(hsCRP) and by dichotomised hsCRP (< 2 vs. ≥ 2 mg/L). RESULTS: Over a median follow-up of 16.01 years, 13 960 deaths occurred. HsCRP levels were associated with higher mortality across all stages, but the association progressively attenuated with advancing CKM stages. Adjusted HRs per ln(hsCRP) were 1.11 (95% CI: 1.03-1.20) in Stage 0, 1.14 (1.07-1.21) in Stage 1, 1.08 (1.06-1.10) in Stage 2, 1.05 (1.03-1.07) in Stage 3 and 1.04 (1.00-1.08) in Stage 4 (p for interaction < 0.001). Similarly, dichotomised hsCRP showed declining mortality risks from Stage 0 (HR: 1.51, 1.15-1.98) to Stage 4 (HR: 1.07, 0.97-1.19). Restricted cubic splines confirmed this gradient, with early stages displaying steep risk curves that plateaued in advanced stages. Sensitivity analyses supported robustness. CONCLUSIONS: The association of hsCRP with mortality diminishes with CKM syndrome progression, suggesting a shift from inflammation-driven risk in early stages to complex multiorgan dysfunction in late stages. These findings advocate for stage-specific risk assessment, with hsCRP retaining utility in early CKM management but requiring integrated approaches in advanced disease.