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

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.