Lower urinary ammonia excretion, a marker of an impaired ability of the kidneys to excrete the daily acid load, is independently associated with an increased risk of end-stage renal disease (ESRD) in patients with chronic kidney disease (CKD), according to French researchers.

In a study of 1,065 adult CKD patients, investigators found that patients in the lowest tertile of fasting urinary ammonia excretion had a significant 82% increased risk of progressing to ESRD and 84% increased risk of a fast decline in measured glomerular filtration rate (mGFR) compared with those in the highest tertile, after adjusting for confounders. Each 10 mEq/L decrease in fasting ammonia concentration was associated with a significant 43% increase in ESRD risk.

In addition, patients in the lowest tertile of baseline plasma total CO2 had a significantly increased risk of a fast decline in mGFR, but not ESRD. The investigators defined a fast decline as greater than 10% per year.

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The researchers, led by Pascal Houillier, MD, of Hôpital Européen Georges Pompidou in Paris, concluded that urinary ammonia and net acid excretion decrease with glomerular filtration rate, whereas net endogenous acid production (NEAP) does not. “Therefore, patients with CKD develop a positive acid balance as CKD worsens,” the researchers wrote in Kidney International (2015;88:137-145).

The investigators stated that, to their knowledge, their study is the first to show that a low urinary ammonia excretion is associated with a higher risk of ESRD.

“Detecting patients with a defect in ammonia excretion in early CKD stages may help physicians to select those patients who may benefit from oral alkali supplementation,” the authors concluded.

Study subjects were participants in the NephroTest Cohort Study group. All had their GFR measured by 51Cr-EDTA renal clearance. The cohort’s median measured GFR was 37.6 mL/min/1.73 m2.

After a median follow-up period of 4.3 years, 201 patients reached ESRD and 114 died before reaching ESRD.

Dr. Houillier’s group found that the relationship between 24-hour ammonia/creatinine ratio and renal outcomes differs slightly from that observed for fasting ammonia concentration. ESRD risk associated with 24-hourammonia/creatinine ratio is not linear. The lowest risk was observed among patients in the middle tertile.

Unlike fasting ammonia, 24-hour ammonia excretion depends on basal acid production as well as dietary acid load and, conceivably, by changes in plasma potassium concentration. “The fact that the association with renal outcomes is strongest with fasting ammonia concentration supports our hypothesis that the inability of the kidney to excrete the acid load rather than the daily acid load itself is deleterious to the course of renal disease,” the researchers wrote.

In an accompanying editorial, Julia J. Scialla, MD, of Duke University School of Medicine in Durham, N.C., questioned the usefulness of urinary ammonia excretion in guiding therapy. In the new study, both venous total CO2 and urinary ammonia appear to decrease with mGFR in a similar fashion, Dr. Scialla pointed out. “The use of urinary ammonia as a guide for alkali therapy is limited by the fact that in any individual CKD patient low urinary ammonia excretion could represent either impaired acid excretion or low acid load, in which addition of alkali is unnecessary, or worse, inappropriate,” she wrote.