What is the pathophysiology of metabolic alkalosis maintenance?

Updated: Dec 10, 2020
  • Author: Christie P Thomas, MBBS, FRCP, FASN, FAHA; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Decreased perfusion to the kidneys, caused by either volume depletion or a reduction in effective circulating blood volume (eg, edematous states such as heart failure or cirrhosis) stimulates the renin-angiotensin-aldosterone system. This increases renal sodium ion reabsorption throughout the nephron, including the principal cells of the collecting duct, and results in enhanced hydrogen ion secretion via the apical proton pump H+ adenosine triphosphatase (ATPase) in the adjacent A-type intercalated cells.

Aldosterone may also independently increase the activity of the apical proton pump in the collecting duct. Whenever a hydrogen ion is secreted into the tubular lumen, a bicarbonate ion is gained into the systemic circulation via the basolateral Cl-/HCO3- exchanger.

Chloride depletion may occur through the GI tract by loss of gastric secretions, which are rich in chloride ions, or through the kidneys with loop diuretics or thiazides. Chloride depletion, even without volume depletion, enhances bicarbonate reabsorption by different mechanisms as discussed below.

In the late thick ascending limb (TAL) and early distal tubule, specialized cells called the macula densa are present. These cells have an Na+/K+/2Cl- cotransporter in the apical membrane, which is mainly regulated by chloride ions. When fewer chloride ions reach this transporter (eg, chloride depletion), the macula densa signals the juxtaglomerular apparatus (ie, specialized cells in the wall of the adjacent afferent arteriole) to secrete renin, which increases aldosterone secretion via angiotensin II.

In alkalemia, the kidneys secrete the excess bicarbonate via the apical chloride/bicarbonate exchanger, pendrin, in the B-type intercalated cells of the collecting duct. In this way, protons are gained to the systemic circulation via the basolateral H+ ATPase. In chloride depletion, fewer chloride ions are available to be exchanged with bicarbonate, and the ability of the kidneys to excrete the excess bicarbonate is impaired.

Many of the causes of metabolic alkalosis are also associated with hypokalemia. In turn, hypokalemia maintains metabolic alkalosis by five different mechanisms.

First, hypokalemia results in the shift of hydrogen ions intracellularly. The resulting intracellular acidosis enhances bicarbonate reabsorption in the collecting duct.

Second, hypokalemia stimulates the apical H+/K+ ATPase in the collecting duct. Increased activity of this ATPase leads to teleologically appropriate potassium ion reabsorption but a corresponding hydrogen ion secretion. This leads to a net gain of bicarbonate, maintaining systemic alkalosis.

Third, hypokalemia stimulates renal ammonia genesis, reabsorption, and secretion. Ammonium ions (NH4+) are produced in the proximal tubule from the metabolism of glutamine. During this process, alpha-ketoglutarate is produced, the metabolism of which generates bicarbonate that is returned to the systemic circulation. Hypokalemia stimulates NH4+ uptake via the Na+/K+/2Cl- cotransporter of TAL because NH4+ competes with K+ for the transporter. Hypokalemia increases the expression of the ammonia transporter RhBG, which increases NH3 excretion in the collecting duct.

Fourth, it leads to impaired chloride ion reabsorption in the distal nephron. This results in an increase in luminal electronegativity, with subsequent enhancement of hydrogen ion secretion.

Fifth, it reduces the glomerular filtration rate (GFR). Animal studies have shown that hypokalemia, by unknown mechanisms, decreases GFR, which decreases the filtered load of bicarbonate. In the presence of volume depletion, this impairs renal excretion of the excess bicarbonate.

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