Urine Ammonium Predicts Clinical Outcomes in Hypertensive Kidney Disease

Abstract

Metabolic acidosis is associated with poor outcomes in CKD. Because impaired renal ammonium excretion is important in the pathogenesis of acidosis, urine ammonium excretion might be a better and perhaps earlier acid-base indicator of risk than serum bicarbonate, particularly in patients without acidosis. We evaluated the association between baseline ammonium excretion and clinical outcomes in African American Study of Kidney Disease and Hypertension participants (n=1044). Median daily ammonium excretion was 19.5 (95% confidence interval [95% CI], 6.5 to 43.2) mEq. In Cox regression models (adjusted for demographics, measured GFR, proteinuria, body mass index, net endogenous acid production, and serum potassium and bicarbonate), hazard ratios of the composite outcome of death or dialysis were 1.46 (95% CI, 1.13 to 1.87) in the low tertile and 1.14 (95% CI, 0.89 to 1.46) in the middle tertile of daily ammonium excretion compared with the high tertile. Among participants without acidosis at baseline, the adjusted hazard ratio for those with ammonium excretion <20 mEq/d was 1.36 (95% CI, 1.09 to 1.71) compared with those with ammonium excretion ≥20 mEq/d. Additionally, compared with participants in the high ammonium tertile, those in the low ammonium tertile had higher adjusted odds of incident acidosis at 1 year (adjusted odds ratio, 2.56; 95% CI, 1.04 to 6.27). In conclusion, low ammonium excretion is associated with death and renal failure in hypertensive kidney disease, even among those without acidosis. Low ammonium excretion could identify patients with CKD and normal bicarbonate levels who might benefit from alkali before acidosis develops.

Keywords: AASK (African American Study of Kidney Disease and Hypertension); acidosis.; chronic kidney disease; dialysis; mortality.

Figure 1.

Daily uNH₄⁺ excretion decreases with lower mGFR. P<0.001 for trend.

Figure 2.

Daily uNH₄⁺ excretion is modestly correlated with protein intake, and there is little to no correlation with mGFR, total CO₂, and NEAP. Correlations of uNH₄⁺ with (A) mGFR, (B) serum total CO₂, (C) protein intake, and (D) NEAP at baseline.

Figure 3.

Participants with lower daily uNH₄⁺ excretion had higher unadjusted likelihood of death or ESRD during follow-up.

Figure 4.

The risks of death or ESRD increase below uNH₄⁺ 30 mEq/d. Shown is the cubic spline regression plot of the association between baseline uNH₄⁺ excretion and the composite outcome of death or ESRD. The median value of uNH₄⁺ excretion (19.5 mEq/d) served as the reference point. The solid line represents the mean HR and the dashed lines represent the 95% CIs. Adjusted for age, sex, randomized group, mGFR, proteinuria, NEAP, serum potassium, and serum tCO₂. Stratified by BMI.

Figure 5.

Low uNH₄⁺ predicts death or ESRD in participants without acidosis. Shown are HRs with 95% CIs of the composite outcome of death or ESRD according to uNH₄⁺ excretion and serum tCO₂. Adjusted for age, sex, randomized group, mGFR, proteinuria, NEAP, and serum potassium. Stratified by BMI. REF, reference group.