The most common causes of metabolic alkalosis are vomiting and diuretic use.

Urine chloride levels are usually low among patients with vomiting and among those using diuretics, but may be high if the patient took diuretics recently.

In patients with metabolic alkalosis and high urine chloride, assessment of effective arterial blood volume and blood pressure may distinguish those with metabolic alkalosis caused by a diuretic from those with primary excess mineralocorticoid effect.

In patients with metabolic alkalosis, high urine chloride, and low effective arterial blood volume, measuring urine chloride repeatedly may distinguish Bartter syndrome or Gitelman syndrome from occult diuretic use.

A 23-year-old woman with no notable medical history was seen in our nephrology clinic for electrolyte abnormalities detected on laboratory testing ordered by her primary care physician, who she had seen after noting mild muscle weakness during exercise. She reported no use of daily medications, including diuretics or laxatives, and had no history of vomiting or diarrhea. Her blood pressure was 95/70 mm Hg, her body mass index was 24, and her jugular venous pressure was 1 cm below the level of the sternal angle while supine.

The results of laboratory testing are shown in Table 1. The patient had metabolic alkalosis, hypokalemia, and hypomagnesemia. The findings of low blood pressure, low extracellular fluid volume on physical examination, and elevated concentration of chloride ions in a random urine sample suggested that a diuretic effect was causing her electrolyte abnormalities. A diuretic effect can be caused by diuretic use (e.g., furosemide, thiazide) or by a genetic disorder that causes decreased reabsorption of sodium chloride in the loop of Henle (i.e., Bartter syndrome, which mimics the effects of loop diuretics) or in the distal convoluted tubule (i.e., Gitelman syndrome, which mimics the effects of thiazide diuretics). To distinguish between these 2 possibilities, we asked the patient to provide 5 random urine samples over 48 hours. Chloride was elevated In each of these samples, which was consistent with a genetic defect that impaired reabsorption of sodium chloride by the kidney. The hypomagnesemia and hypocalciuria suggested a diagnosis of Gitelman syndrome. Genetic testing revealed heterozygous, biallelic, pathogenic variants in SLCl2A3, the gene that encodes the sodium chloride cotransporter in the distal convoluted tubule, confirming the diagnosis of Gitelman syndrome.

Laboratory values in a 23-year-old woman with metabolic alkalosis

We prescribed potassium chloride (40 mmol/d) and magnesium oxide (420 mg, twice daily). The patient’s plasma magnesium improved to 0.61 mmol/L, but she remained hypokalemic at 3.0 (normal 3.5–5.0) mmol/L. Accordingly, we prescribed amiloride (5 mg/d); 4 weeks later, her serum potassium had increased to 3.6 mmol/L, her bicarbonate was 27 (normal 25–30) mmol/L, and her magnesium was unchanged. However, because the patient developed postural lightheadedness, we stopped the amiloride and increased the potassium chloride to 80 mmol/d. One year later, she continues taking the same doses of potassium chloride and magnesium oxide. Her potassium and magnesium levels are in the low-to-normal range at 3.5 mmol/L and 0.65 mmol/L, respectively, and her bicarbonate is 29 mmol/L.

Metabolic alkalosis is defined as a plasma bicarbonate concentration greater than 30 mmol/L and an arterial pH above 7.45. An elevated bicarbonate level can be a compensatory response to chronic respiratory acidosis, but a diagnosis of primary metabolic alkalosis can be made if the clinical history is not consistent with that condition. Measurement of the venous blood pH can confirm the diagnosis of metabolic alkalosis, noting that arterial blood pH is typically 0.03 higher than venous blood pH.1

Metabolic alkalosis represents an increase in the quantity of bicarbonate relative to the volume of water in the extracellular fluid. This may result from a loss of extracellular fluid (i.e., contraction alkalosis), the addition of bicarbonate, or both.2,3

Bicarbonate is added to the extracellular fluid from exogenous or endogenous sources. Exogenous sources include the ingestion or infusion of bicarbonate salts or of anions (e.g., lactate, citrate) that are converted to bicarbonate, but metabolic alkalosis will develop only if the glomerular filtration rate (GFR) is markedly low (i.e., < 15 mL/min).

The 2 major endogenous sources of bicarbonate are the stomach and the kidneys. In the stomach, bicarbonate is generated when hydrochloric acid is secreted by the parietal cells into the gastric lumen. Under normal physiologic conditions, hydrochloric acid is subsequently titrated in the small intestine by an equal amount of bicarbonate secreted by the pancreas, thereby negating the previous bicarbonate gain. Metabolic alkalosis will occur if gastric fluid is lost from vomiting or suctioning of stomach contents.

In the kidney, metabolism of glutamine in the proximal tubule cells produces ammonium and α-ketoglutarate anion, which is metabolized to bicarbonate (Figure 1A). To retain this newly generated bicarbonate, the kidney must excrete ammonium in the urine. If it cannot do so, ammonium is shunted to the liver and metabolized into urea in a process that consumes bicarbonate. Increased ammonium excretion in the urine, which results in more bicarbonate being added to the body, occurs when more ammonium is produced by the proximal tubule and when the secretion of hydrogen ions by the distal kidney tubule cells increases, which leads to more ammonium being trapped in the urine. Ammonium production is stimulated by an acidic milieu in the proximal tubule cell, which may occur because of hypokalemia or because of high partial pressure of carbon dioxide in the peritubular capillaries.4 Aldosterone increases ammonium excretion by causing hypokalemia, which, again, stimulates ammonium production in the proximal tubule, and by increasing the rate of hydrogen secretion from the distal tubules.

(A) Generation of bicarbonate in the proximal tubule cell. Metabolism of glutamine in the proximal tubule cells produces ammonium (NH4+) and α-ketoglutarate, which is metabolized to bicarbonate (HCO3−). This process is stimulated by a rise in concentration of hydrogen (H+) ions in proximal tubule cells. Ammonium (NH4+) ions are secreted into the lumen by the sodium–hydrogen exchanger. The newly formed HCO3− ions exit the cells with sodium ions (Na+) on a sodium–bicarbonate cotransporter. (B) Maintenance of metabolic alkalosis by bicarbonate reabsorption in the proximal tubule cell. Bicarbonate reabsorption in the proximal tubule is mediated by the sodium–hydrogen exchanger. This cation exchanger is stimulated by increased levels of angiotensin II and increased concentration of H+ ions in cells.

Metabolic alkalosis is maintained only if the kidneys are unable to excrete the excess bicarbonate because of a decreased filtered load of bicarbonate, caused by a low GFR, an increased rate of bicarbonate reabsorption, or both. Reabsorption of bicarbonate occurs mainly in the proximal tubule and is mediated by a sodium–hydrogen exchanger, which reabsorbs sodium and secretes hydrogen into the lumen. The secreted hydrogen titrates the filtered bicarbonate to form carbon dioxide and water, which together enter cells to be converted back into bicarbonate, which is then returned to the blood. This exchanger is activated by increased angiotensin II levels and an acidic proximal tubule cell (Figure 1B). In the distal kidney tubule, pendrin — a chloride–bicarbonate exchanger — reabsorbs chloride and secretes bicarbonate into the lumen.5 Chloride depletion diminishes the delivery of chloride to the exchanger, which further maintains a state of metabolic alkalosis as less bicarbonate is secreted into the lumen.

The evaluation of patients with metabolic alkalosis begins by taking a history to rule out the 2 most common causes of this condition, namely vomiting and diuretic use (Table 2).6 Some patients may deny vomiting or using diuretics, so assessment of chloride in a random urine sample helps determine the cause of metabolic alkalosis. A low urine chloride level (i.e., < 20 mmol/L) is expected among patients who have depleted effective arterial blood volume and chloride from vomiting, diuretics, chloride-wasting diarrhea, or loss of chloride in sweat. However, urine chloride will not be low if the urine sample was collected when a diuretic was still acting. If the urine chloride is not low, assessment of the effective arterial blood volume and the blood pressure may distinguish patients with metabolic alkalosis caused by a diuretic effect from those with a primary excess mineralocorticoid effect (Figure 2). Patients with the former condition do not usually have high blood pressure and their effective arterial blood volume may be contracted. An exception would be in patients with hypertension who take diuretics as they may develop metabolic alkalosis from hypokalemia and may not have contracted effective arterial blood volume. Those experiencing a mineralocorticoid effect may be hypertensive, and have either normal or expanded blood volume. Further characterization of the cause of the mineralocorticoid effect can be aided by measuring plasma renin and aldosterone levels.

Common causes of metabolic alkalosis

Approach to the patient with metabolic alkalosis. This approach has not been evaluated or validated in clinical studies. *There are limitations of physical examination in the assessment of extracellular fluid (ECF) volume.7 †These conditions may be hereditary or acquired. Acquired Bartter syndrome may result from activation of the calcium-sensing receptor in the medullary thick ascending limb of the loop of Henle by calcium (among patients with hypercalcemia) or by other cationic ligands (e.g., amikacin, gentamicin, immunoglobulins). Acquired Gitelman syndrome has been associated with Sjögren syndrome and cisplatin use. ‡Cortisol acts as a mineralocorticoid if the enzyme 11-β hydroxydehydrogenase (which inactivates cortisol by metabolizing it to cortisone) is deficient (e.g., apparent mineralocorticoid excess syndrome), if it is inhibited (e.g., from ingestion of a compound containing glycyrrhizinic acid, such as licorice), or if its activity is overwhelmed by an excess production of cortisol (e.g., adrenocorticotropic hormone–producing tumour). Note: BP = blood pressure, EABV = effective arterial blood volume.

Measurement of chloride in repeat random urine samples may distinguish patients with genetic tubulopathies from those who use diuretics, as the former will have persistently elevated urine chloride, whereas the latter will have intermittently elevated urine chloride. An assay for diuretics in the urine may be ordered if chloride levels are persistently high in random urine samples but surreptitious use of diuretics is still suspected. Genetic testing for Gitelman syndrome and Bartter syndrome, which is available through commercial laboratories, can help confirm those diagnoses.

Treatment of patients with metabolic alkalosis involves addressing the processes causing the addition of bicarbonate and correcting the conditions preventing the kidney from excreting the excess bicarbonate (e.g., low effective arterial blood volume, hypokalemia).

Gitelman syndrome is one of the most frequent inherited disorders of the kidney, with a prevalence of 1 per 40 000 people. It is caused by mutations in the SLC12A3 gene, which encodes the sodium chloride cotransporter in the distal convoluted tubule.8 Gitelman syndrome usually presents in adolescence and adulthood with symptoms linked to electrolyte disturbances, including salt craving, thirst, cramps, and muscle weakness. Biochemically, patients have hypokalemia and metabolic alkalosis. Hypomagnesemia (< 0.7 mmol/L) is also common and hypocalciuria (calcium-to-creatinine ratio < 0.2 from spot urine sample) is characteristic.8,9 Management of Gitelman syndrome involves lifelong supplementation with oral potassium chloride and magnesium at doses sufficient to reach levels of at least 3.0 mmol/L for potassium, and 0.6 mmol/L for magnesium.8

In patients in whom supplementation is insufficient or associated with intolerable adverse effects, amiloride (an epithelial sodium-channel blocker) or eplerenone (an aldosterone receptor antagonist) may be added, although these medications can cause postural symptoms. In an open-label, cross-over randomized trial of 6 weeks’ duration, these medications increased serum potassium levels by 0.3 mmol/L when added to potassium and magnesium supplementation.10 In the same study, indomethacin also raised the serum potassium level by a similar amount. However, its association with gastrointestinal intolerance and long-term kidney dysfunction limit its use.

Metabolic alkalosis is a primary acid–base disorder characterized by elevated blood pH and plasma bicarbonate concentration. The most common causes of metabolic alkalosis are vomiting and the use of diuretics. Measurement of urine chloride and assessment of the effective arterial blood volume and blood pressure can help differentiate the different cause of alkalosis. Patients with high urine chloride levels may require special investigations, including genetic testing for Bartter and Gitelman syndromes and measurement of plasma renin and aldosterone levels. The management of metabolic alkalosis involves correcting the underlying disorder, leading to the addition of bicarbonate and correcting conditions that prevent the kidney from excreting the excess bicarbonate.

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The authors thank Joel G. Ray and Catherine Yu for their critique and helpful suggestions in the preparation of the manuscript.

Competing interests: None declared.

This article has been peer reviewed.

The authors have obtained patient consent.

Contributors: All of the authors contributed to the conception and design of the work, drafted the manuscript, revised it critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work. Joshua Shapiro and Ziv Harel contributed equally to the work.

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