Development and validation of continuous cardiovascular-kidney-metabolic syndrome severity score (cCKMS-S)...

Cardiovascular-kidney-metabolic (CKM) syndrome integrates metabolic, renal, and cardiovascular dysregulation into a unified construct. Current CKM staging systems rely on categorical thresholds that can obscure within-stage heterogeneity, leading to misclassification due to population-specific cut-offs. This study aimed to develop and validate a continuous CKM severity score (cCKMS-S) to mitigate these limitations of categorical staging as a continuous adjunct severity index.

Using data from 7,343 adults aged 20-80 years in phase III (2005-2008) of Tehran Lipid and Glucose Study (TLGS), confirmatory factor analysis (CFA) was applied to derive age- and sex-specific latent CKM constructs. Temporal validation was performed in TLGS VI, and independent external validation in National Health and Nutrition Examination Survey (NHANES) 1999-2018. Within-stage heterogeneity was assessed by stratifying Stage 2 into tertiles. Discrimination was evaluated using receiver operating characteristic (ROC) curves and mortality associations using Cox models.

In temporal external validation, area under the curves (AUCs) for stage classification were ≥ 0.83 for identifying CKM stage ≥ 2 and ≥ 0.90 for stage ≥ 3, across population subgroups. Similar discriminative performance was observed in NHANES (AUC 0.90 for stage ≥ 2 and 0.84 for stage ≥ 3). Each 1-SD increase in cCKMS-S was associated with a higher risk of all-cause (HR = 3.2;95%CI:2.7-3.9) and cardiovascular (CVD) mortality (HR = 4.7;95%CI:3.6-6.2). In NHANES, cCKMS-S also demonstrated consistent associations with mortality outcomes, with each 1-SD increase associated with a higher risk of all-cause (HR = 1.2;95%CI:1.2-1.3) and CVD mortality (HR = 1.4;95%CI:1.3-1.5), with adjusted C-indices for all-cause and CVD mortality (0.83 and 0.86, respectively) comparable to those observed in the TLGS cohort. Within Stage 2, cCKMS-S identified a marked gradient in all-cause mortality risk across tertiles (HR = 2.16, 3.33, and 9.43). Time-dependent ROC analysis for all-cause mortality in TLGS showed AUCs of 0.71 and 0.77 for cCKMS-S versus 0.66 and 0.69 for CKM staging at 10 and 18 years, improving to 0.85 and 0.84 after adjustment.

cCKMS-S introduces a continuous severity score that complements CKM staging by capturing within-stage heterogeneity and demonstrating generalizability across populations. It provides a practical tool for longitudinal monitoring and assessment of intervention efficacy, and preventive risk stratification in clinical practice. The developed online calculator of cCKMS-S is available at safdar-masoumi.github.io/ckm-calc.