Urine Anion Gap to Predict Urine Ammonium and Related Outcomes in Kidney Disease

Abstract

Background and objectives: Low urine ammonium excretion is associated with ESRD in CKD. Few laboratories measure urine ammonium, limiting clinical application. We determined correlations between urine ammonium, the standard urine anion gap, and a modified urine anion gap that includes sulfate and phosphate and compared risks of ESRD or death between these ammonium estimates and directly measured ammonium.

Design, setting, participants, & measurements: We measured ammonium, sodium, potassium, chloride, phosphate, and sulfate from baseline 24-hour urine collections in 1044 African-American Study of Kidney Disease and Hypertension participants. We evaluated the cross-sectional correlations between urine ammonium, the standard urine anion gap (sodium + potassium - chloride), and a modified urine anion gap that includes urine phosphate and sulfate in the calculation. Multivariable-adjusted Cox models determined the associations of the standard urine anion gap and the modified urine anion gap with the composite end point of death or ESRD; these results were compared with results using urine ammonium as the predictor of interest.

Results: The standard urine anion gap had a weak and direct correlation with urine ammonium (r=0.18), whereas the modified urine anion gap had a modest inverse relationship with urine ammonium (r=-0.58). Compared with the highest tertile of urine ammonium, those in the lowest urine ammonium tertile had higher risk of ESRD or death (hazard ratio, 1.46; 95% confidence interval, 1.13 to 1.87) after adjusting for demographics, GFR, proteinuria, and other confounders. In comparison, participants in the corresponding standard urine anion gap tertile did not have higher risk of ESRD or death (hazard ratio, 0.82; 95% confidence interval, 0.64 to 1.07), whereas the risk for those in the corresponding modified urine anion gap tertile (hazard ratio, 1.32; 95% confidence interval, 1.03 to 1.68) approximated that of directly measured urine ammonium.

Conclusions: Urine anion gap is a poor surrogate of urine ammonium in CKD unless phosphate and sulfate are included in the calculation. Because the modified urine anion gap merely estimates urine ammonium and requires five measurements, direct measurements of urine ammonium are preferable in CKD.

Keywords: AASK (African American Study of Kidney Disease and Hypertension); Acid-Base Equilibrium; Ammonium Compounds; Body Fluids; ESRD; Kidney Diseases; ammonium; chronic kidney disease; chronic metabolic acidosis; mortality; outcomes; urine anion gap.

Graphical abstract

Figure 1.

Whereas UAG was higher with higher urine ammonium, UAG_SO4, UAG_PO4, and UAG_PLUS were lower with higher urine ammonium. Pairwise correlation between measured urine ammonium (abscissa) and the estimates of urine ammonium (1) urine anion gap (UAG), (2) urine anion gap with inclusion of urine phosphate (UAG_PO4), (3) urine anion gap with inclusion of urine sulfate (UAG_SO4), and (4) urine anion gap with inclusion of urine phosphate and sulfate (UAG_PLUS) in (A) the total cohort and (B) the subgroup with acidosis at baseline.

Figure 2.

The limits of agreement between urine ammonium and the additive inverse of UAG_PLUS were broad. Bland–Altman plots showing mean difference and limits of agreement between urine ammonium and the additive inverse of urine anion gap with inclusion of urine phosphate and sulfate (UAG_PLUS) in (A) the total cohort and (B) the acidosis subgroup. In each case, there is positive bias. That is, mean urine ammonium is higher than the additive inverse of UAG_PLUS. (A) Mean difference =13 mEq/d, limits of agreement =−18, 43 mEq/d. (B) Mean difference =11 mEq/d, limits of agreement =−18, 39 mEq/d.