Mechanisms by which metabolic alkaloses develop and persist

What are the mechanisms by which metabolic alkaloses develop and persist?

Traditionally, the factors responsible for a rise in [HCO ₃ ⁻ ] have been classified as those that directly raise [HCO ₃ ⁻ ] and those that account for the failure of the kidneys to excrete the excess bicarbonate anions.

Six broad mechanisms are recognized. A and B are processes that generate metabolic alkalosis; C to E are contributors to the maintenance of metabolic alkalosis.

Generation:

• A. The loss of a nonvolatile acid from the extracellular fluid (ECF) compartment (e.g., vomiting)
• B. Addition of exogenous alkali (e.g., ingestion of NaHCO ₃ )
• C. Loss of NaCl-rich fluid, leading to reabsorption of NaHCO ₃ (e.g., loop and thiazide diuretics)

Maintenance:

• D. Increased reabsorption of bicarbonate within the proximal tubule
• E. Increased regeneration of bicarbonate at the distal nephron
• F. Increased bicarbonate produced from the bicarbonate buffer system

With respect to A, the most common clinical example is vomiting or nasogastric suction causing loss of HCl. These are common generators of metabolic alkalosis. Addition of base (B) is also a possible underlying mechanism but a relatively infrequent event, such as ingestion of NaHCO ₃ . A large input of NaHCO ₃ cannot maintain metabolic alkalosis because the kidneys will readily excrete sodium (Na ⁺ ) and HCO _3 − or potential HCO ₃ ⁻ (citrate) very quickly, unless reduced kidney function is present. Milk-alkali syndrome is an example in which base administration occurs, and reduced glomerular filtration rate (GFR) accounts for a reduction in the kidney’s ability to excrete the excess base.

The secrets surrounding direct HCl loss are elaborated in much more detail later.

In the metabolic alkalosis frequently seen with the use of both loop and thiazide diuretics, the urine produced contains mostly NaCl and KCl, removing a portion of plasma that will lead to a higher [HCO ₃ ]. This initial generating phase is termed “contraction” alkalosis. The failure of the kidney to correct the [HCO ₃ ] is due to the ensuing deficiency of both Cl and K, leading to maintenance of the contraction-initiated alkalosis.

Augmentation of proximal bicarbonate reabsorption (D) is considered a perpetuator of alkalosis rather than a trigger. Bicarbonate reabsorption at the proximal convoluted tubule (PCT) is driven largely by angiotensin II and hypokalemia, both of which favor PCT proton excretion, which captures filtered bicarbonate for reabsorption. These processes, which help maintain metabolic alkalosis, are important mediators in states of extracellular volume depletion, or reduced effective arterial blood volume, which stimulate renin and angiotensin II production. When there is a reduction in effective arterial blood volume, reabsorption of sodium predominates over the kidney’s ability to maintain acid-base balance. Angiotensin directly stimulates proximal Na ⁺ /H ⁺ exchange (NHE3), leading to reabsorption of NaHCO ₃ regardless of [HCO ₃ ⁻ ]. Because loss of gastric acid, or the action of diuretics, causes loss of Cl, the reabsorption of Na ⁺ in the PCT must be accompanied by HCO ₃ . Potassium depletion with both vomiting and diuretic effects also contribute to the maintenance process.

Distal bicarbonate regeneration (E) occurs in response to distal sodium delivery and the action of aldosterone. These two prerequisites allow for sodium-proton exchange; the excreted proton leaves the urine as ammonium chloride. Thus hyperaldosteronism is a potential generator of alkalosis. A secret here is that aldosterone promotes the action of the distal proton-ATPase (H ⁺ -ATPase); this protein lies on the luminal side of the distal convoluted tubule and excretes hydrogen ions into the lumen such that bicarbonate is reclaimed. In addition, hypokalemia enhances distal proton-potassium-ATPase (H ⁺ /K ⁺ -ATPase)—a luminal facing hydrogen ion, potassium antiporter—which also leads to bicarbonate absorption. Thus hypokalemia and hyperaldosteronism independently potentiate the magnitude of renal proton excretion (or distal bicarbonate regeneration). Another secret is that chronic elevations of arterial carbon dioxide tension (PaCO ₂ ) up-regulate the expression of distal H ⁺ -ATPase and H ⁺ /K ⁺ -ATPase—the basis for metabolic compensation for chronic respiratory acidosis; note that these processes most appropriately are considered “compensation” rather than “primary metabolic alkalosis.” Stimulation of both distal H ⁺ -ATPase and H ⁺ /K ⁺ -ATPase are associated with enhanced appearance of bicarbonate in the blood as long as the generated protons appear in the urine.

Lastly, bicarbonate can come from underperfused muscle (F). In states with a low effective arterial blood volume and diminished blood flow to muscles, PCO ₂ in capillary blood rises. Because CO ₂ must diffuse from cells to capillaries, it follows that the intracellular PCO ₂ must also be high. This high PCO ₂ will drive its conversion to H ⁺ and HCO ₃ ⁻ within skeletal muscle. The H ⁺ binds to proteins in cells while the HCO ₃ ⁻ . exits via the Cl-/HCO ₃ ⁻ anion exchanger. This condition will persist as long as the blood flow rate to muscles remains low.