Time-updated anion gap and cardiovascular events in advanced chronic kidney disease: a cohort study

Background Studies examining associations between metabolic acidosis and cardiovascular events in chronic kidney disease (CKD) have shown conflicting results and have not differentiated between normal anion gap (hyperchloremic) acidosis and high anion gap acidosis. We aimed to examine the impact of normal and high anion gap acidosis, separately, on the risk of cardiovascular events among patients with CKD. Methods This retrospective cohort study included 1168 patients with an estimated glomerular filtration rate (eGFR) of 10-60 mL/min/1.73 m(2) and available data on anion gap. We analyzed the association of time-updated high anion gap (anion gap >= 9.2) with the rate of cardiovascular events using marginal structural models (MSMs) to account for time-dependent confounding. We also analyzed the association between time-updated normal anion gap acidosis (anion-gap-adjusted bicarbonate level <= 22.8 mEq/L) and cardiovascular events. Results The mean baseline eGFR of the cohort was 28 mL/min/1.73 m(2). The prevalence rates of high anion gap in CKD stages G3a, G3b, G4 and G5 were 20%, 16%, 27% and 46%, respectively. During a median follow-up period of 2.9 years, 132 patients developed cardiovascular events (3.3/100 patient-years). In MSMs, high anion gap was associated with a higher rate of cardiovascular events [hazard ratio (HR) 1.87; 95% confidence interval (95% CI) 1.13-3.09; P = 0.02] and the composite of cardiovascular events or all-cause death (HR 3.28; 95% CI 2.19-4.91; P < 0.001). Normal anion gap acidosis was not associated with cardiovascular events (HR 0.74; 95% CI, 0.47-1.17; P = 0.2). Conclusions Among patients with advanced CKD, high anion gap was associated with an increased risk of cardiovascular events.