JMIR Publications

ABSTRACT

Background:

As the most abundant anion, serum chloride plays a crucial role in maintaining homeostasis. However, the importance of serum chloride is often overlooked in clinical practice, and the association of variances of serum chloride with long-term mortality risk in general populations has been rarely investigated.

Objective:

The aim of this study was to assess the association of serum chloride with all-cause and cause-specific mortality in the general U.S. adult population.

Methods:

A total of 51060 adult participants from the National Health and Nutrition Examination Survey (1999-2018) were recruited. Mortality status was obtained by linkage to the National Death Index through 31 December 2019. After adjustment of extensive covariates, weighted Cox proportional risk models were constructed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality and cause-specific mortality.

Results:

During a median follow-up of 111 months, 7582 deaths were documented, 2388 of cardiovascular disease (CVD), 1639 of cancer, and 567 of respiratory disease. The weighted Kaplan-Meier survival analyses showed consistent highest mortality risk in individuals with the lowest quartiles of serum chloride. The multivariate-adjusted HRs (95% CIs) from lowest to highest quartiles of serum chloride, (≤ 101.2, 101.3-103.2, 103.2-105.0, ≥ 105.1 mmol/L) were 1.00 (reference), 0.77 (0.67-0.89), 0.72 (0.63-0.82), and 0.77 (0.65-0.90), respectively for all-cause mortality (Ptrend < .001); 1.00 (reference), 0.65 (0.54-0.79), 0.59 (0.47-0.74), and 0.69 (0.55-0.86) for CVD mortality (Ptrend = .004); 1.00 (reference), 0.67 (0.54-0.84), 0.65 (0.50-0.85), and 0.65 (0.48-0.87) for cancer mortality (Ptrend = .004); and 1.00 (reference), 0.68 (0.41-1.13), 0.59 (0.40-0.88), and 0.51 (0.31-0.84) for respiratory disease mortality (Ptrend = .004). The restricted cubic spline analyses revealed the nonlinear and L-shaped associations of serum chloride with all-cause and cause-specific mortality (all P for nonlinearity < .05), in which lower serum chloride was prominently associated with higher mortality risk. The associations were robust and no significant additional interaction effect was detected (P for interaction > .05).

Conclusions:

In general US adults, decreased serum chloride concentrations were independently associated with increased all-cause mortality, CVD mortality, cancer mortality, and respiratory disease mortality. Further studies to explore the potential pathophysiological mechanisms for the associations of serum chloride and mortality are warranted.