Pathogenesis of metabolic alkalosis

INTRODUCTION — Metabolic alkalosis is a relatively common disorder that is most often generated by diuretic therapy or the loss of gastric secretions due to vomiting (which may be surreptitious) or gastric suction. Metabolic alkalosis may also result from severe hypokalemia, alkali ingestion when kidney function is markedly diminished, primary aldosteronism, or disorders that mimic primary aldosteronism or persistent diuretic activity.

The pathogenesis of metabolic alkalosis will be reviewed here. The causes, evaluation, and treatment of this disorder are discussed separately. (See "Causes of metabolic alkalosis" and "Clinical manifestations and evaluation of metabolic alkalosis" and "Treatment of metabolic alkalosis".)

PATHOGENESIS — The development of metabolic alkalosis and its subsequent maintenance generally have distinct and separate explanations [1-4]:

●An elevation in the plasma bicarbonate concentration can develop due to excessive hydrogen ion loss in the urine or from the gastrointestinal tract, hydrogen ion movement into the cells, the administration of bicarbonate salts (or other alkalinizing salts such as sodium acetate or lactate), or volume contraction around a relatively constant amount of extracellular bicarbonate (called a contraction alkalosis). (See "Causes of metabolic alkalosis".)

●An elevated bicarbonate concentration is maintained by conditions that reduce kidney bicarbonate filtration, enhance kidney bicarbonate reabsorption, and/or impair kidney bicarbonate secretion, and thereby prevent excretion of the excess bicarbonate in the urine. Otherwise, bicarbonate excretion would correct the alkalosis [1,5].

Several factors are responsible for increased net renal bicarbonate reabsorption in metabolic alkalosis [1,5]. In the absence of advanced kidney failure, one or more of these factors must be present to sustain the high plasma bicarbonate concentration:

•A reduction in extracellular fluid (ECF) volume or reduced effective arterial blood volume, which exists in many edematous states such as congestive heart failure and cirrhosis. (See "Pathogenesis of ascites in patients with cirrhosis".)

•Chloride depletion and hypochloremia (which almost always is associated with reduced ECF volume).

•Hypokalemia.

•The combination of increased sodium delivery to the distal nephron together with enhanced sodium reabsorption through epithelial sodium channels. This generates excess secretion of hydrogen and potassium ions.

The clinician must understand the pathophysiology of bicarbonate generation and renal bicarbonate reabsorption in order to select the most appropriate therapy. Many forms of metabolic alkalosis can be corrected by the administration of sodium chloride and/or potassium chloride-rich intravenous fluid, which causes excess bicarbonate to be excreted in the urine (this is called salt-sensitive metabolic alkalosis). By contrast, such intervention is ineffective, or often counterproductive, in other forms of metabolic alkalosis (this is called salt-resistant metabolic alkalosis). (See "Treatment of metabolic alkalosis".)

VOLUME DEPLETION — Both true extracellular fluid (ECF) volume depletion and reduced effective arterial blood volume (as occurs in heart failure or cirrhosis) will decrease the glomerular filtration rate and also activate the renin-angiotensin-aldosterone system and the sympathetic nervous system. The decreased glomerular filtration rate reduces the filtered load of bicarbonate. Increased activity of angiotensin II, aldosterone, and the sympathetic nervous system all stimulate renal tubule sodium reabsorption, bicarbonate reclamation, and new bicarbonate generation [1,5,6]. Reclamation of bicarbonate and generation of new bicarbonate by the kidney are accomplished by secretion of hydrogen ions into the tubular lumen.

Angiotensin II and the sympathetic nervous system stimulate sodium-hydrogen exchange in the proximal tubule, while aldosterone increases hydrogen ion secretion in the distal tubule [7-12]:

●Proximal tubule – Angiotensin II stimulates apical (luminal) sodium-hydrogen exchange via a sodium-hydrogen exchange process and also stimulates V-type ATPase hydrogen pumps. It also stimulates basolateral sodium-bicarbonate cotransport from the cytoplasm into the ECF (figure 1).

●Distal tubule – Aldosterone and angiotensin II directly increase the activity of V-H-ATPase pumps in the apical membrane of type A intercalated cells [13]. This pump secretes hydrogen ions into the tubular lumen, generating intracellular bicarbonate that then exits the cell electro-neutrally in exchange for chloride through the AE1 transporter on the basolateral membrane (figure 1).

Aldosterone-stimulated sodium reabsorption via the epithelial sodium channel (ENaC) on the luminal membrane of the adjacent principal cells, combined with relative resistance to reabsorption of anions from the tubular lumen, generates an electronegative potential in the lumen. This electronegative potential charge enhances both hydrogen ion and potassium secretion and reduces their passive back-diffusion into the tubular cells [14].

Type B intercalated cells, which secrete bicarbonate into the lumen in exchange for the reabsorbed chloride, also exist. Their activity usually increases in response to metabolic alkalosis [15-17]. The role of type B intercalated cells is discussed below. (See 'Renal response to metabolic alkalosis and the type B intercalated cell' below.)

In addition to overt volume depletion and reduced effective arterial blood volume, variation of the dietary sodium chloride intake of normal subjects also has an important impact on the kidney's bicarbonate reabsorptive capacity. Normal subjects ingesting a relatively high-sodium chloride diet will very readily excrete an exogenous sodium bicarbonate load with minimal change in systemic pH or bicarbonate level. However, if normal subjects ingest a low-sodium chloride diet, then the kidney's bicarbonate reabsorptive capacity increases, and a sodium bicarbonate load will raise the serum pH and bicarbonate level [18].

CHLORIDE DEPLETION — There continues to be debate over the relative importance of reduced extracellular fluid (ECF) volume (or reduced effective arterial blood volume) versus hypochloremia and chloride depletion in preventing the kidney from excreting excess bicarbonate in patients with metabolic alkalosis [19]. It is usually impossible to differentiate the effects of volume depletion from the effects of chloride depletion since these two potential mechanisms for maintenance of metabolic alkalosis are tightly linked in virtually all clinical situations. As an example, the loss of gastric fluid, which is rich in hydrogen and chloride ions, generates metabolic alkalosis, ECF volume contraction, chloride depletion, and hypochloremia. Likewise, thiazide and loop diuretics increase urinary losses of sodium chloride and ammonium chloride, thereby generating metabolic alkalosis, ECF volume contraction, chloride depletion, and hypochloremia. When these forms of metabolic alkalosis are treated with sodium chloride infusion to increase the ECF, the treatment simultaneously expands ECF volume, repletes chloride, and raises the plasma chloride concentration.

Although differentiating chloride depletion from volume depletion may not be clinically important, a number of animal experiments have attempted to generate chloride loss without volume depletion (ie, isolated chloride depletion). In these animal models, distal tubule bicarbonate secretion is blunted or blocked by the chloride deficit resulting in metabolic alkalosis [7-9,15-17]. However, it is possible that ECF volume contraction was not truly avoided in these experiments [20].

HYPOKALEMIA — Hypokalemia and potassium depletion are common in patients with metabolic alkalosis. (See "Causes of hypokalemia in adults", section on 'Increased urinary losses' and "Causes of metabolic alkalosis".)

Alkalosis due to vomiting or gastric suction increases renal potassium secretion through several mechanisms:

●Secondary hyperaldosteronism (resulting from volume depletion).

●Intermittent delivery of sodium bicarbonate to the distal tubule whenever the filtered bicarbonate load exceeds the reabsorptive capacity of the proximal tubule.

●Reduced distal tubule chloride delivery, which may enhance electrically coupled potassium and hydrogen ion secretion by intercalated cells [21]. To the extent that sodium salts are delivered to this distal site accompanied by relatively poorly reabsorbed anions, its reabsorption will generate the secretion of potassium and hydrogen ions. This promotes potassium depletion and metabolic alkalosis.

The pathophysiologic combination of increased aldosterone activity and distal sodium delivery also produces hypokalemia in patients who take diuretics (except potassium-sparing diuretics), in patients who have Bartter and Gitelman syndromes, and in patients with primary aldosteronism or analogous forms of volume-expanded metabolic alkalosis. (See "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations" and 'Metabolic alkalosis associated with extracellular volume expansion (primary aldosteronism and similar disorders)' below.)

Hypokalemia and total body potassium depletion also contributes to the generation of metabolic alkalosis by shifting hydrogen ions from the extracellular fluid (ECF) to the intracellular fluid in exchange for potassium [22]. In addition, hypokalemia contributes to the maintenance of the alkalosis by increasing renal bicarbonate reabsorption (figure 2):

●Hypokalemia causes potassium to move from cells into the ECF in exchange for extracellular sodium and hydrogen ions moving into cells. This simultaneously generates extracellular bicarbonate and acidifies the intracellular fluid (figure 3). The resulting fall in intracellular pH [23] stimulates hydrogen secretion, bicarbonate reabsorption, and ammonium synthesis and excretion [24]. (See "Potassium balance in acid-base disorders".)

●A component of distal hydrogen secretion is mediated by H-K-ATPase exchange pumps in the luminal membrane of type A intercalated cells. These pumps actively reabsorb potassium and secrete hydrogen (figure 1) [25,26]; they are stimulated by hypokalemia and potassium depletion to reabsorb and conserve potassium and simultaneously increase hydrogen secretion. The net result is that hypokalemia and aldosterone, which stimulate the H-K-ATPase and H-ATPase pumps, respectively, each potentiate distal hydrogen secretion, which contributes to the development and the maintenance of metabolic alkalosis [27].

Severe hypokalemia (plasma potassium concentration usually below 2 mEq/L) may enhance bicarbonate reabsorption by an additional mechanism related to blunted renal tubule chloride reabsorption despite volume contraction [28-30]. As a result, sodium reabsorption is associated with a greater-than-usual degree of luminal negativity since this gradient is usually dissipated in part by chloride reabsorption. The enhanced electrical gradient can promote hydrogen secretion [28].

METABOLIC ALKALOSIS ASSOCIATED WITH EXTRACELLULAR VOLUME EXPANSION (PRIMARY ALDOSTERONISM AND SIMILAR DISORDERS) — Most of the metabolic alkaloses discussed above occur in conjunction with hypovolemia. This group of metabolic alkaloses can generally be reversed with the infusion of isotonic saline and potassium chloride.

By contrast, when metabolic alkalosis develops as a result of primary aldosteronism or a disorder that mimics primary aldosteronism, the extracellular fluid (ECF) volume is expanded, blood pressure is normal or increased (rather than reduced), and renal blood flow is also normal or increased. Volume expansion will decrease sodium bicarbonate reabsorption in the proximal tubule. However, coexistent hypokalemia and potassium depletion increase sodium bicarbonate reabsorption in the proximal tubule (via the mechanisms described above). The generous delivery of sodium salts to the distal tubule in combination with high levels of aldosterone (or a state that mimics high levels of aldosterone) is largely responsible for the generation of the metabolic alkalosis and also contributes to its maintenance. (See "Pathophysiology and clinical features of primary aldosteronism" and "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)".)

The combination of hyperaldosteronism and high distal tubule sodium delivery markedly increases distal tubule sodium reabsorption, hydrogen ion secretion, and potassium secretion. The resulting potassium depletion and hypokalemia activate the sequence described above: movement of hydrogen ions into cells (generating extracellular bicarbonate), increased renal hydrogen ion secretion, ammoniagenesis and ammonium excretion, and activation of proton secretion in distal tubule type A intercalated cells via H-K-ATPase and H-ATPase.

RENAL RESPONSE TO METABOLIC ALKALOSIS AND THE TYPE B INTERCALATED CELL — The forms of metabolic alkalosis associated with extracellular fluid (ECF) volume contraction (or reduced effective arterial blood volume), such as vomiting or nasogastric suction, result in marked stimulation of both renal sodium bicarbonate and sodium chloride reabsorption. Sodium bicarbonate reabsorption is accelerated in the proximal tubule, and sodium reabsorption in the distal tubule is coupled with hydrogen and potassium secretion. The resulting potassium depletion and hypokalemia further increase bicarbonate reabsorption and hydrogen secretion. ECF volume contraction also markedly increases renal tubule chloride reabsorption.

Under these conditions, the urine becomes acidic and contains very low concentrations of chloride, sodium, and potassium. Thus, the urine pH is said to be "paradoxically" acid (paradoxical because the patient has metabolic alkalosis and one might expect an alkaline urine to be excreted). However, there are intermittent periods of incomplete tubular reabsorption of bicarbonate. They develop when the serum bicarbonate increases even further after an acute episode of vomiting or gastric aspiration. During these periods, the filtered bicarbonate cannot all be reabsorbed, and some is excreted into the urine together with sodium and potassium. Thus, the urine pH, sodium, and potassium concentrations often cycle up and down in patients with volume-contracted forms of metabolic alkalosis. However, distal tubule delivery and urinary excretion of chloride remains persistently low throughout. This is why the urine chloride concentration is used as a surrogate marker for ECF volume status when metabolic alkalosis exists, instead of the urine sodium concentration. In addition, persistently low distal nephron chloride delivery markedly blunts the function of type B intercalated cells (which require chloride absorption in exchange for HCO3 secretion), thereby impairing their ability to correct metabolic alkalosis.

By contrast, the urine chloride and sodium concentrations are typically relatively high in patients with metabolic alkalosis due to primary hyperaldosteronism and other metabolic alkaloses generated by similar pathophysiologic mechanisms; these are "ECF volume expanded" or "salt-resistant" metabolic alkaloses. In these disorders, sodium and chloride are continually delivered to the distal nephron, which is where the sodium is absorbed more efficiently than chloride and both hydrogen ions and potassium are secreted. Although there is generous delivery of chloride to the tubule segments containing type B intercalated cells, the hypervolemia generated by these disorders reduces the stimulus to reabsorb the chloride (and to secrete bicarbonate). The development of hypokalemia and potassium depletion also plays a major role in the maintenance of these forms of metabolic alkalosis. (See 'Hypokalemia' above.)

Type B intercalated cells, located in the distal nephron (ie, most abundant in the connecting tubule and collecting duct), secrete bicarbonate into the lumen in exchange for the reabsorption of chloride [15-17,31]. Bicarbonate secretion by these cells is accomplished by an anion exchange protein, called pendrin, on the apical membrane. Pendrin is a distinct anion exchanger, different from anion exchanger 1 (AE-1). In order for pendrin to secrete bicarbonate, chloride must be reabsorbed (figure 4). Thus, adequate distal tubule chloride delivery is essential for bicarbonate secretion by these cells. Increased density and activity of type B intercalated cells are probably important components of the normal renal response to a high serum bicarbonate concentration. However, hypovolemia and reduced effective arterial blood volume generally decrease chloride delivery to the distal tubule regions where the type B intercalated cells exist, and this diminishes pendrin-mediated chloride reabsorption and bicarbonate secretion.

SUMMARY

●Metabolic alkalosis is a relatively common clinical disorder that is most often due to diuretic therapy or the loss of gastric secretions due to vomiting (which may be surreptitious) or gastric suction. (See 'Introduction' above.)

●The generation and subsequent maintenance of metabolic alkalosis require two separate factors (see 'Pathogenesis' above):

•Elevation of the plasma bicarbonate concentration can be generated by excessive hydrogen ion loss into the urine or from the gastrointestinal tract, hydrogen ion movement into the cells, the administration of bicarbonate salts (or other alkalinizing salts such as sodium acetate or lactate), or volume contraction around a relatively constant amount of extracellular bicarbonate (called a contraction alkalosis).

•A decrease in renal bicarbonate excretion may be due to reduced kidney function, increased renal bicarbonate reabsorption, and/or reduced bicarbonate secretion.

●Several factors are responsible for increased net renal bicarbonate reabsorption in metabolic alkalosis. In the absence of advanced kidney failure, one or more of these factors must be present to sustain the high plasma bicarbonate concentration:

•A reduction in extracellular fluid (ECF) volume or reduced effective arterial blood volume, including reduced tissue (and kidney) perfusion in edematous states such as congestive heart failure and cirrhosis. (See 'Volume depletion' above.)

•Chloride depletion and hypochloremia. (See 'Chloride depletion' above.)

•Hypokalemia. (See 'Hypokalemia' above.)

•Increased distal nephron delivery and reabsorption of sodium ions in exchange for hydrogen and potassium ions. (See 'Metabolic alkalosis associated with extracellular volume expansion (primary aldosteronism and similar disorders)' above.)