The serum anion gap (AG) is a time-honored tool in nephrology. As discussed in Chapter 6, the AG is the difference between the plasma concentration of sodium, the major extracellular cation, and the sum of the concentrations of the major extracellular anions chloride and bicarbonate, that is, [Na⁺] – ([Cl^–]+ [HCO₃^–]). Stated differently, the AG occurs due to a higher concentration of unmeasured anions (i.e., not chloride or bicarbonate) than unmeasured cations (i.e., not sodium). The normal AG is about 10 to 14 mEq/L (see Fig. 6.1). Note that AG is usually expressed as milliequivalents per liter because it is a difference in charge.

The urine AG (UAG) is the difference between measured cations and anions in the urine (or the flip side, unmeasured anions and cations). However, as opposed to plasma, urine contains high concentrations of potassium and generally very small amounts of bicarbonate. Therefore, the UAG is ([Na⁺] + [K⁺]) – [Cl^–].

How is this helpful? It was initially postulated by Halperin and colleagues (Goldstein et al., 1986) that the UAG is a rough indicator of the amount of ammonium ion (NH₄⁺) excreted in the urine. This is because in the absence of bicarbonate or another anion, NH4+ must be excreted with Cl-. Thus, as urinary NH₄⁺ increases, so will urinary Cl-. Therefore, the lower (or more negative) the UAG, the more ammonium is in the urine. A bit of renal physiology must be reviewed. Bicarbonate is freely filtered by the glomerulus and then almost completely reabsorbed (reclaimed) by the proximal tubule. Normally, there is little or no bicarbonate in the urine. So far, this seems like a “wash,” that is, no gain or loss of
bicarbonate. However, most of us eat what is called an “acid-ash” diet, which generates “nonvolatile” acid, which must be excreted by the kidneys. Such diets consist largely of meat or fish, eggs, and cereals with a lesser quantity of milk, fruit, and vegetables. Animal product consumption produces acid when catabolized due to the formation of sulfuric acid from an abundance of sulfur-containing amino acids (cysteine, cystine, and methionine) in animal proteins.

The role of the diet and its influence on the acidity of urine have been studied for decades. The French biologist Claude Bernard made the classical observation that changing the diet of rabbits from an herbivore to a carnivore diet changed the urine from more alkaline to more acid. Subsequent investigations focused on the chemical properties and acidity of constituents of the remains of foods combusted in a bomb calorimeter, described as ash. The “dietary ash hypothesis” proposed that foods, when metabolized, would leave a similar “acid ash” or “alkaline ash” in the body as those formed when the foods were oxidized in combustion (Dwyer et al., 1985).

It is generally stated that about 1 mEq/kg (mmol/kg) of “nonvolatile” acid is formed per day due to metabolism. This acid will consume an equal amount of body bicarbonate; this bicarbonate then must be regenerated by the distal nephron via renal acid excretion by one of the following three mechanisms:

1. Excretion of free H⁺, thus lowering urine pH. This is minor mechanism; as even with a maximally acidic urine, the pH is only about 4.5, a [H⁺] of less than 0.04 mEq/L.

2. Excretion of H+ in conjunction with an anion. This is predominantly phosphate via the reaction:

HPO₄^2- + H⁺ → H₂PO₄^–

3. Excretion of H⁺ in conjunction with ammonia (NH₃). The main adaptive renal response to metabolic acidosis is to increase H⁺ excretion in the form of NH₄^+. In patients with severe metabolic acidosis and normal renal function, NH4+ excretion can increase from the normal value of 30 to 40 mmol/day to as much as 200 to 300 mmol/day (Clarke et al., 1955).

Ammonium is usually excreted with chloride but is sometimes excreted with other anions such as ketoacid anions, hippurate, or bicarbonate. Since measurement of urinary NH₄⁺ is not available in most clinical laboratories, the urinary [NH₄⁺] is generally estimated by its effects on the excretion of its accompanying anion (generally Cl-). This led to the concept of the UAG, since there is a linear relationship between the UAG and
urine [NH₄⁺]. In response to an acid load, the UAG is normally -20 to -50 mEq/L in healthy subjects. Later, the terminology urine net charge instead of UAG was used, with the normal response to acidosis being a negative net charge.

Metabolic acidosis of renal origin in the absence of renal failure, called renal tubular acidosis (RTA), can result from the failure of proximal bicarbonate reabsorption or distal acid excretion (Table 9.1).