Revisiting the Urinary Anion Gap: A Sound Concept during Hyperchloremic Metabolic Acidosis

Background: The urine anion gap (UAG) has been used since the late 80s with the primary idea of estimating if urine ammonium (NH4+) increases appropriately ,as in patients with hyperchloremic metabolic acidosis MA of gastrointestinal etiology , or not as in patients with with distal renal tubular acidosis or chronic kidney disease in whom its excretion is markedly diminished . The use of the UAG as a marker of urinary NH4+ has been criticized because there is a very poor correlation between urine NH4+ and UAG in large databases. Here we go over the concept of the UAG measured as the difference in unmeasured anions (UA) and unmeasured cations (UA) to illustrate how in MA a robust rise in NH4+ results in a corresponding fall in the UAG. Methods: We used published data from Leman et al (JCI, 1966, many years before the UAG was introduced) where all the anions and cations were measured before and after MA induced by NH4Cl. This way, the UAG could be calculated using measured anions and compared to the the calculated by the formula UAG = (Na+ + K+) – Cl-. The following are the reported mean values (mEq/day): NH4+: Before NH4Cl = 28, NH4Cl = 171 Ca++: Before NH4Cl = 4, NH4Cl = 7 Mg++: Before NH4Cl = 11, NH4Cl =12 SO4--: Before NH4Cl = 34, NH4Cl = 38 OA: Before NH4Cl = 29, NH4Cl = 27 PO4---: Before NH4Cl = 20, NH4Cl=23 Results: Based on the principle of electroneutrality, the sum of all anions and all cations should be equal; (Cl- + HCO3-) + (UA) = (Na+ + K+) + (UC) After rearranging, = UA – UC = (SO4+P+OA) – (Ca+Mg+ NH4) = Measured UAG Before NH4Cl = (34 + 20 + 29) – (4 + 11 + 28) = 40 NH4Cl = (38 + 23 + 27) – (7 + 12 + 171) = -105 Calculated UAG = (Na+ + K+) – Cl- Before NH4Cl = (127 + 49) – 135 = 41 NH4Cl = (136 + 67) – 316 = -113 Conclusion: Ammonium chloride induced MA in normal people results in a marked decrease in the UAG , both measured and calculated , that matches perfectly the induced increase in urine NH4+ excretion . Such perfect correlation, is not seen or expected in the clinical setting where other changes in urine anions and cations take place but the UAG still roughly reflects if there is or not an increase in ammonium excretion in response to hyperchloremic MA supporting its use as an initial diagnostic tool .