What are the non-chloride-related causes of metabolic alkalosis?

Updated: Dec 10, 2020
  • Author: Christie P Thomas, MBBS, FRCP, FASN, FAHA; Chief Editor: Vecihi Batuman, MD, FASN  more...
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The kidneys are able to excrete any excess alkali load, whether it is exogenous (eg, infusion of sodium bicarbonate) or endogenous (eg, metabolism of lactate to bicarbonate in lactic acidosis). However, in renal failure or in any condition that maintains the alkalosis, this natural ability of the kidneys to excrete the excess bicarbonate is impaired. Examples include the following:

  • Alkali-loading alkalosis
  • Hypercalcemia
  • Intravenous penicillin
  • Hypoproteinemic alkalosis

Milk-alkali syndrome comprises hypercalcemia, renal insufficiency, and metabolic alkalosis. Before the advent of H2-receptor antagonists, milk-alkali syndrome was observed in patients who ingested large amounts of milk and antacids as treatment for peptic ulcers. Currently, the syndrome is observed mainly in people who chronically ingest large doses of calcium carbonate, with or without vitamin D (typically for osteoporosis prevention). [7]

The hypercalcemia that develops in some of these persons increases renal bicarbonate reabsorption. Renal insufficiency can occur secondary to nephrocalcinosis or hypercalcemia and contributes to maintaining the metabolic alkalosis.

Patients with end-stage renal disease (ESRD) are dialyzed with a high concentration of bicarbonate in the dialysate to reverse metabolic acidosis (ie, hemodialysis using high bicarbonate dialysate). Sometimes, this high bicarbonate exceeds the amount needed to buffer the acidosis. Because the ability of the kidneys to excrete the excess bicarbonate is absent or severely diminished, the alkalosis persists temporarily. The degree of alkalosis might be severe if the patient also has vomiting.

Metabolic alkalosis has been reported after regional citrate anticoagulation in hemodialysis or in continuous renal replacement therapies. Citrate is infused in the blood inflow line in the hemodialysis circuit, where it prevents clotting by binding calcium. Because the dialyzer does not remove citrate completely, a fraction of the infused citrate might reach the systemic circulation. Citrate in the blood is metabolized to bicarbonate in the liver. The accumulated bicarbonate may lead to metabolic alkalosis.

In an international prospective cohort study involving 17,031 patients receiving thrice-weekly hemodialysis, high dialysate bicarbonate, especially in patients with prolonged exposure, contributed to higher mortality, most likely through development of post-dialysis metabolic alkalosis. The positive association between dialysate bicarbonate concentration and mortality (adjusted hazard ratio, 1.08 per 4 mEq/L higher; 95% confidence index [CI], 1.01–1.15; adjusted hazard ratio for dialysate bicarbonate ≥38 vs. 33–37 mEq/L, 1.07 [95% CI, 0.97–1.19]) was consistent across pre-dialysis session serum bicarbonate levels and between facilities that used one dialysate bicarbonate concentration and those that prescribed different concentrations for each patient. [8]

Metabolic alkalosis may be a potential complication of plasmapheresis in patients with renal failure. The source of alkali is the citrate that is used to prevent clotting in the extracorporeal circuit and in the stored blood from which the fresh frozen plasma is prepared. Using heparin as the anticoagulant and using albumin instead of fresh frozen plasma as the replacement solution can prevent the metabolic alkalosis.

Recovery from lactic or ketoacidosis in the presence of volume depletion or renal failure typically occurs when exogenous bicarbonate is administered to correct the acidosis. When the patient recovers, the beta-hydroxybutyrate and lactate are metabolized to bicarbonate and the original bicarbonate deficit is recovered. The administered bicarbonate now becomes a surplus.

Refeeding with a carbohydrate-rich diet after prolonged fasting results in mild metabolic alkalosis because of enhanced metabolism of ketoacids to bicarbonate.

Massive blood transfusion results in mild metabolic alkalosis as the citrate in the transfused blood is converted to bicarbonate. Metabolic alkalosis is more likely to develop in the presence of renal insufficiency.

Hypercalcemia may cause metabolic alkalosis by volume depletion and enhanced bicarbonate reabsorption in the proximal tubule. However, hypercalcemia from primary hyperparathyroidism is usually associated with a metabolic acidosis.

The intravenous administration of penicillin, carbenicillin, or other semisynthetic penicillins may cause hypokalemic metabolic alkalosis. This occurs because of distal delivery of nonreabsorbable anions with an absorbable cation such as Na+.

Metabolic alkalosis has been reported in patients with hypoproteinemia. The mechanism of alkalosis is not clear, but it may be related to loss of negative charges of albumin. A decrease in plasma albumin of 1 g/dL is associated with an increase in plasma bicarbonate of 3.4 mEq/L.

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