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

ABSTRACT 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.