The serum anion gap is altered in early kidney disease and associates with mortality

It is well known that uremia causes an increase in the serum anion gap; however, whether changes in the anion gap occur earlier in the course of chronic kidney disease is not known. Here we investigated whether different measures of the anion gap, as a marker of kidney function, are associated with mortality. To do this we analyzed the available laboratory data of 11,957 adults in the National Health and Nutrition Examination Survey 1999–2004 to calculate anion gap using the traditional method, or one that was albumin-adjusted, as well as a full anion gap reflecting other electrolytes. A significant elevation in the traditional anion gap was seen only with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73m(2), whereas increases in the albumin-adjusted and full anion gap were found with eGFRs less than 60 or 90mL/min/1.73m(2), respectively. Higher levels of each anion gap were associated with an increased risk of all-cause mortality after adjustment for age, gender, race/ethnicity, and eGFR. After adjustment for additional covariates including body-mass index and comorbidities, higher levels of the albumin-adjusted and full anion gap were associated with mortality (relative hazard for highest compared to the lowest quartile were 1.62 and 1.64, respectively). Thus, higher levels of anion gap are present in individuals with less advanced kidney disease than previously recognized, and are associated with increased risk of mortality. Further study is needed to identify the unmeasured anions and to determine their physiologic significance.