The CALLY index for risk stratification of advanced cardiovascular-kidney-metabolic syndrome and mortality: a dual-cohort study from NHANES and a real-world clinical setting.

BACKGROUND

Cardiovascular Kidney Metabolic (CKM) syndrome is a complex systemic condition, but identifying patients at advanced stages (Stages 3 or 4) remains a clinical challenge due to the lack of readily available markers. The C-reactive Protein-Albumin-Lymphocyte (CALLY) index is a composite measure reflecting the axis of inflammation, nutrition, and immunity. However, its role across integrated advanced CKM risk stratification and all-cause mortality assessment, particularly with cross-population validation, remains insufficiently clarified.

METHODS

This study used a dual-cohort design. We analyzed a nationally representative population from the United States (NHANES, N = 11,690) and an independent clinical cohort from a Chinese hospital (N = 1,056) for external validation. The associations between the CALLY index and advanced CKM or all-cause mortality were assessed using survey-weighted logistic regression and Cox proportional hazards models. Non-linear dose-response relationships were evaluated using restricted cubic splines (RCS). We further measured the incremental value of the CALLY index over standard models through the Net Reclassification Improvement (NRI), Integrated Discrimination Improvement (IDI), and Decision Curve Analysis (DCA).

RESULTS

In the NHANES cohort, a higher CALLY index was associated with a lower risk of advanced CKM (Q4 vs. Q1: OR 0.70, 95% CI 0.54-0.90) and all-cause mortality (Q4 vs. Q1: HR 0.64, 95% CI 0.55-0.76). In the external validation cohort, participants in the highest CALLY quartile had lower odds of advanced CKM (Q4 vs. Q1: OR 0.41, 95% CI 0.28-0.62). Both cohorts showed a clear L-shaped non-linear association. Adding the CALLY index to conventional models significantly improved risk reclassification (NRI 0.1968 in NHANES and 0.4134 in the validation cohort, both P < 0.001). DCA also indicated that the CALLY-integrated model provided greater model-based net benefit across a range of threshold probabilities, despite relatively small changes in the area under the curve (AUC).

CONCLUSION

The CALLY index is a simple, routinely available composite indicator that may support advanced CKM risk stratification and mortality risk assessment. It provided incremental risk-stratification information in this study and may help identify individuals at higher risk across the CKM spectrum.