Factors That Maintain Metabolic Alkalosis
The primary factors that maintain metabolic alkalosis are volume contraction, hypochloremia, hypokalemia, decreased glomerular filtration rate, and aldosterone excess—all of which impair the kidney's ability to excrete excess bicarbonate. 1, 2, 3, 4, 5
Key Maintenance Factors
Volume Contraction
- Volume depletion is the most critical maintenance factor, as it stimulates proximal tubular sodium and bicarbonate reabsorption, preventing the kidney from excreting excess bicarbonate even when systemic alkalosis is present 1, 3, 5
- Enhanced sodium reabsorption in the distal tubule increases hydrogen ion secretion to maintain electrical neutrality, perpetuating the alkalosis 1
- This mechanism is particularly prominent in diuretic-induced alkalosis and vomiting-related alkalosis 1, 6
Hypochloremia (Chloride Depletion)
- Chloride depletion is essential for maintaining metabolic alkalosis by limiting the kidney's capacity to excrete bicarbonate 1, 2, 3, 4
- The kidney requires chloride to exchange for bicarbonate excretion; without adequate chloride, bicarbonate reabsorption continues despite elevated serum levels 1, 5
- This explains why saline-responsive metabolic alkalosis (urinary chloride <20 mEq/L) resolves with chloride-containing fluid administration 2
Hypokalemia
- Potassium deficiency promotes both proximal and distal tubular bicarbonate reabsorption 1, 3, 4, 5
- Hypokalemia increases hydrogen ion secretion in the collecting duct, generating new bicarbonate and maintaining the alkalotic state 1, 7
- Intracellular potassium depletion causes hydrogen ions to shift into cells, further exacerbating systemic alkalosis 3, 4
Decreased Glomerular Filtration Rate
- Reduced GFR decreases the filtered load of bicarbonate, limiting the kidney's ability to excrete excess bicarbonate even when tubular reabsorption is normal 3, 4, 5
- This factor is particularly relevant in patients with chronic kidney disease or acute kidney injury 5
Aldosterone Excess
- Elevated aldosterone levels increase distal tubular hydrogen ion secretion via enhanced sodium reabsorption through the epithelial sodium channel (ENaC) 1, 7, 3, 4
- This mechanism is activated in volume-depleted states and is the primary pathophysiology in primary hyperaldosteronism, Cushing syndrome, and genetic tubulopathies like Bartter and Gitelman syndromes 2, 7, 5
Clinical Context and Interactions
Synergistic Effects
- These maintenance factors typically coexist and amplify each other's effects 3, 4, 5
- For example, diuretic therapy causes simultaneous volume contraction, hypochloremia, hypokalemia, and secondary hyperaldosteronism, creating a self-perpetuating cycle 8, 1, 6
Paradoxical Aciduria
- In the presence of volume depletion and hypokalemia, the kidney paradoxically excretes acidic urine (pH <6.0) despite systemic alkalosis, because the drive to reabsorb sodium and maintain volume takes precedence over acid-base correction 1
- This phenomenon is diagnostic of chloride-responsive metabolic alkalosis and indicates that volume and chloride repletion are needed 1
Common Clinical Scenarios
Diuretic-Induced Alkalosis
- Loop and thiazide diuretics cause all major maintenance factors: volume contraction from natriuresis, chloride loss, potassium wasting, and secondary hyperaldosteronism 8, 1, 2, 6
- High-dose furosemide (>160 mg/day) is particularly associated with severe electrolyte disturbances and metabolic alkalosis 8
Post-Hypercapnic Alkalosis
- Following rapid correction of chronic respiratory acidosis, retained bicarbonate (previously compensatory) persists due to volume contraction and chloride depletion, maintaining metabolic alkalosis 7
Heart Failure
- Congestive heart failure patients develop metabolic alkalosis through neurohormonal activation (renin-angiotensin system, sympathetic nervous system) combined with diuretic therapy, creating multiple maintenance factors simultaneously 6