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

Abstract

It is well known that uremia causes an increase in the serum anion gap (AG); however, whether changes in the AG occur earlier in the course of chronic kidney disease is not known. Here we investigated whether different measures of the AG, 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 AG using the traditional method, or one that was albumin-adjusted, as well as a full AG reflecting other electrolytes. A significant elevation in the traditional AG was seen only with an estimated glomerular filtration rate (eGFR) <45 ml/min per 1.73 m(2), whereas increases in the albumin-adjusted and full AG were found with eGFRs <60 or 90 ml/min per 1.73 m(2), respectively. Higher levels of each AG 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 AG were associated with mortality (relative hazard for the highest compared with the lowest quartile were 1.62 and 1.64, respectively). Thus, higher levels of AG 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 physiological significance.

Figure 1

Graphical depiction of components of the anion gap (AG) in each version of the calculation. Anion gap = Unmeasured anions (UA) – Unmeasured cations (UC). UA and UC are determined by the anions and cations that are accounted for in the calculation. Each panel depicts the components included in each AG calculation. The following definitions were used: Traditional AG=serum sodium(mEq/L) − (serum chloride(mEq/L) + serum bicarbonate(mEq/L)); Albumin-adjusted AG=Traditional AG − (2.5 × serum albumin(g/dL)); Full AG=Albumin-adjusted AG + serum potassium(mEq/L) + ionized calcium(mEq/L) − serum phosphate(mEq/L). The traditional AG calculation includes only Na⁺, Cl⁻, and HCO₃⁻. As additional anions and cations are accounted for in the calculation of the albumin-adjusted and full AG, the unmeasured components (UA and UC) become smaller.

Figure 2

Mean age-standardized anion gap by categories of creatinine-based Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate in 11,957 participants (upper panel) and cystatin C-based estimated glomerular filtration rate in 4,132 participants (lower panel) of NHANES 1999–2004.

Figure 3

Unadjusted relative hazard of all-cause mortality per one standard deviation higher full anion gap (SD = 2.49 mEq/L) within quartiles of serum phosphate (upper panel) and albumin (lower panel) in 11,957 participants of NHANES 1999–2004.