To investigate the clinical significance of urine anion gap and urine osmolal gap as indirect markers of urine acidification in chronic metabolic acidosis, we evaluated urine ammonium (NH4+), net acid excretion (NAE), urine anion gap (Na(+) + K(+) - Cl-), and urine osmolal gap (urine osmolality - [2(Na(+) + K(+)) + urea]) in 24 patients with chronic renal failure (CRF), eight patients with classic distal renal tubular acidosis (dRTA), and eight NH4Cl-loaded normal controls (NCs). Urine NH4+ excretion was lower (P < 0.001) in the CRF (5.4 +/- 0.6 mmol/d) and dRTA (19.2 +/- 2.7 mmol/d) patients than in the NCs (52.6 +/- 3.7 mmol/d); NAE was also lower (P < 0.001) in the CRF (9.8 +/- 1.6 mmol/d) and dRTA (16.7 +/- 4.7 mmol/d) patients than in the NCs (79.4 +/- 4.7 mmol/d). Urine anion gap was higher (P < 0.001) in the CRF (24.7 +/- 2.2 mmol/L) and dRTA (36.7 +/- 7.7 mmol/L) patients than in the NCs (-16.2 +/- 5.5 mmol/L). Urine osmolal gap was lower (P < 0.05) in the dRTA patients (129.7 +/- 17.0 mmol/L) than in the NCs (319.7 +/- 58.4 mmol/L). When the data from all subjects were pooled, urine anion gap correlated inversely with urine NH4+ (r = -0.70, P < 0.001) and with NAE (r = -0.83, P < 0.001), and urine osmolal gap correlated positively with urine NH4+ (r = 0.69, P < 0.01) and with NAE (r = 0.71, P < 0.05). We conclude that impaired urine acidification in CRF and dRTA patients is associated with an increase in urine anion gap and a decrease in urine osmolal gap, and that both urine anion gap and urine osmolal gap correlate well with NAE as well as with urine NH4+.