Serum Chloride and Mortality in Cardiovascular-Kidney-Metabolic Syndrome

Background: Serum chloride, though routinely measured, remains an underexplored marker of risk in individuals with cardiovascular-kidney-metabolic (CKM) syndrome. Methods: We analyzed data from 32,259 adults with CKM syndrome (stages 1–4) participating in the National Health and Nutrition Examination Survey (1999–2018). Associations between baseline serum chloride levels and all-cause, cardiovascular, and non-cardiovascular mortality were assessed using restricted cubic spline models and Cox proportional hazards regression. We also examined the joint impact of serum chloride and CKM stage on mortality risk. Results: Over a median follow-up of 107.0 months, 5,641 participants died, including 1,557 from cardiovascular causes. Serum chloride showed a U-shaped association with all mortality outcomes, with the lowest risk observed near 104.5 mmol/L. Markedly low chloride levels (<96.5 mmol/L) were associated with the highest all-cause mortality (HR, 2.21; 95% CI, 1.91–2.56). The association became progressively stronger with advancing CKM stage; in stage 4 CKM, hypochloremia (<100.4 mmol/L) conferred a four-fold increase in all-cause mortality (HR, 4.01; 95% CI, 3.09–5.20) and a nearly seven-fold increase in cardiovascular mortality. These U-shaped relationships remained consistent across sensitivity and subgroup analyses, with more pronounced inverse associations in participants aged <65 years and those with chloride <=104.5 mmol/L. Conclusion: In adults with CKM syndrome, serum chloride was independently associated with mortality in a U-shaped manner. These findings position serum chloride as a simple yet informative biomarker that may enhance risk stratification in this vulnerable population.