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Maintenance of Metabolic Alkalosis
The various mechanisms responsible for the maintanence of metabolic alkalosis are shown in Table 3. If metabolic alkalosis develops and the GFR is not markedly reduced, correction of the alkalosis should be relatively straightforward: merely excrete a large fraction of the filtered HCO3− (which should be supranormal because of the higher serum/filtered [HCO3−]). A brisk HCO3− diuresis would then reduce the [HCO3−] and restore normal acid-base status. This obviously has not occurred when metabolic alkalosis persists. Why does the kidney not excrete HCO3− and rapidly restore normal acid-base status? The answer to this question varies, depending on the underlying cause, and the precise explanations continue to be refined and debated.
Normal individuals ingesting up to 1000 meq/d of NaHCO3 for several weeks are able to efficiently excrete this load with a minimal increase in their serum [HCO3−] (24). Consequently, when metabolic alkalosis develops and persists despite a relatively normal GFR, this indicates the kidney is reclaiming HCO3− at a supranormal rate.
Most patients with metabolic alkalosis have developed increased proximal HCO3− reabsorption. The major stimulatory factors responsible are reduced intravascular, or effective arterial, blood volume, and hypokalemia (12). Metabolic acidosis and chronic respiratory acidosis also increase proximal tubule HCO3− reabsorption, but these disorders are not relevant to the current discussion.
Metabolic alkalosis is also usually associated with accelerated distal HCO3− reabsorption and generation. Generous distal Na+ delivery, combined with avid distal Na+ reabsorption (for example, because of high aldosterone levels), accelerates distal H+ and K+ secretion. This occurs, in part, because distal Na+ reabsorption, mainly via the epithelial sodium channel (ENaC) in principal cells, generates a lumen negative electric potential (potential difference [PD]=−40 mv), which drives paracellular and transcellular anion (mostly Cl−) reabsorption and enhances the secretion of H+ and K+. Also, many neurohormonal stimuli of distal Na+ absorption increase type A intercalated cell activity (25) (Figure 4).
Figure 5 shows three types of intercalated cells. The type B intercalated cell secretes HCO3− in exchange for Cl−, and can therefore contribute to the correction of metabolic alkalosis. However, generous distal delivery of Cl− is required to enable this cell to secrete major quantities of HCO3−. Recent studies show that intercalated cells also play an important role in NaCl reabsorption and volume regulation (25–31) (discussed in the legend for Figure 5).
When the GFR is markedly reduced, metabolic acidosis usually develops. However, occasionally, metabolic alkalosis occurs and then the HCO3− load cannot be excreted because of the reduced GFR. Kidney dysfunction contributes to the maintenance of metabolic alkalosis in several syndromes, including milk-alkali or calcium-alkali syndrome (35) and bicarbonate ingestion or vomiting by patients with severe kidney dysfunction (36).