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Bartter Syndrome and Gitelman Syndrome

(Bartter's Syndrome; Gitelman's Syndrome)

By

Christopher J. LaRosa

, MD, Perelman School of Medicine at The University of Pennsylvania

Last full review/revision Jan 2020| Content last modified Jan 2020
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Bartter syndrome and Gitelman syndrome are autosomal recessive renal disorders characterized by fluid, electrolyte, urinary, and hormonal abnormalities, including renal potassium, sodium, chloride, and hydrogen wasting; hypokalemia; hyperreninemia and hyperaldosteronism without hypertension; and metabolic alkalosis. Findings include electrolyte, growth, and sometimes neuromuscular abnormalities. Diagnosis is assisted by urine electrolyte measurements and hormone assays but is typically a diagnosis of exclusion. Treatment consists of nonsteroidal anti-inflammatory drugs, potassium-sparing diuretics, low-dose angiotensin-converting enzyme inhibitors, and electrolyte replacement.

Pathophysiology

Bartter syndrome and the more common Gitelman syndrome result from

  • Deranged sodium chloride reabsorption

In Bartter syndrome, the defect is in the ascending thick limb of the loop of Henle. In Gitelman syndrome, the defect is in the distal tubule.

In both syndromes, the impairment of sodium chloride reabsorption causes mild volume depletion, which leads to increases in renin and aldosterone release, resulting in potassium and hydrogen losses. In Bartter syndrome, there is increased prostaglandin secretion as well as a urinary concentrating defect due to impaired generation of the medullary concentration gradient. In Gitelman syndrome, hypomagnesemia and a low urinary calcium excretion are common. In both disorders, sodium wasting contributes to a chronic mild plasma volume contraction reflected by a normal to low blood pressure despite high renin and angiotensin levels.

The features at clinical presentation vary (see Table: Some Differences Between Bartter Syndrome and Gitelman Syndrome).

Table
icon

Some Differences Between Bartter Syndrome and Gitelman Syndrome

Feature

Bartter Syndrome

Gitelman Syndrome

Location of kidney defect

Ascending loop of Henle (mimics effects of loop diuretics)

Distal tubule (mimics effects of thiazides)

Urinary calcium excretion

Normal or increased, commonly with nephrocalcinosis

Decreased

Serum magnesium level

Normal or decreased

Decreased, sometimes greatly

Renal prostaglandin E2 production

Increased

Normal

Usual age at presentation

Before birth to early childhood, often with intellectual disability and growth disturbance

Late childhood to adulthood

Neuromuscular symptoms (eg, muscle spasms, weakness)

Uncommon or mild

Common

Etiology

Both syndromes are usually autosomal recessive, although sporadic cases and other types of familial patterns can occur. There are several genotypes of both syndromes (see table Subtypes of Bartter Syndrome); different genotypes can have different manifestations (1).

Table
icon

Subtypes of Bartter Syndrome*

Subtype

Gene (Protein)†

Age of Onset

Clinical Features

I

SLC12A1 (NKCC2)†

Antenatal/neonatal

Polyhydramnios, prematurity, hypokalemia/alkalosis, polyuria, hypercalciuria, nephrocalcinosis

II

KCNJ1 (ROMK1)†

Antenatal/neonatal

Similar to type I

III

CLCNKB (ClC-Kb)†

Later onset (childhood)

Similar to type I, may be less severe

Some children present with Gitelman phenotype as ClC-Kb found in the distal convoluted tubule and in the connecting tubule

IV

BSND (Barttin)†

Antenatal/neonatal

Similar to type I, nephrocalcinosis less common

Associated with sensorineural hearing loss

IVb

CLCNKA (ClC-Ka)† and CLCNKB (ClC-Kb)†

Antenatal/neonatal

Similar to type IV

Associated with sensorineural hearing loss

V

CASR (CaSR)†

Later onset

Bartter phenotype with low/normal intact parathyroid hormone, hypocalcemia, hypercalciuria, and nephrocalcinosis

Due to CaSR gain of function, which may reduce ROMK and NKCC2 activity

* Bartter classification: Gene abnormalities alter sodium chloride and potassium transport in the thick ascending limb of the loop of Henle.

† Protein abbreviations: Barttin = beta subunit of ClC-Ka and ClC-Kb; CaSR = calcium-sensing receptor; ClC-Kb = basolateral chloride channel kidney B; ClC-Ka = basolateral chloride channel kidney A; NKCC2 = Na-K-2Cl channel; ROMK = luminal potassium channel.

Etiology reference

  • 1. Fulchiero R, Seo-Mayer P: Bartter syndrome and Gitelman syndrome. Pediatr Clin North Am 66(1):121–134, 2019. doi: 10.1016/j.pcl.2018.08.010.

Symptoms and Signs

Bartter syndrome tends to manifest prenatally or during infancy or early childhood. Gitelman syndrome tends to manifest during late childhood to adulthood. Bartter syndrome can manifest prenatally with intrauterine growth restriction and polyhydramnios. Different forms of Bartter syndrome can have specific manifestations, including hearing loss, hypocalcemia, and nephrocalcinosis, depending on the underlying genetic defect. Children with Bartter syndrome, more so than those with Gitelman syndrome, may be born prematurely and may have poor growth and development postnatally, and some children have intellectual disability.

Most patients have low or low-normal blood pressure and may have signs of volume depletion. Inability to retain potassium, calcium, or magnesium can lead to muscle weakness, cramping, spasms, tetany, or fatigue, particularly in Gitelman syndrome. Polydipsia, polyuria, and vomiting may be present.

In general, neither Bartter syndrome nor Gitelman syndrome typically leads to chronic renal insufficiency.

Diagnosis

  • Serum and urine electrolyte levels

  • Exclusion of similar disorders

Bartter syndrome and Gitelman syndrome should be suspected in children with characteristic symptoms or incidentally noted laboratory abnormalities, such as metabolic alkalosis and hypokalemia. Measurement of urine electrolytes shows high levels of sodium, potassium, and chloride that are inappropriate for the euvolemic or hypovolemic state of the patient. Diagnosis is by exclusion of other disorders:

  • Primary and secondary aldosteronism can often be distinguished by the presence of hypertension and normal or low plasma levels of renin (see Table: Differential Diagnosis of Aldosteronism).

  • Surreptitious vomiting or laxative abuse can often be distinguished by low levels of urinary chloride (usually < 20 mmol/L).

  • Surreptitious diuretic abuse can often be distinguished by low levels of urinary chloride and by a urine assay for diuretics.

A 24-hour measurement of urinary calcium or the urine calcium/creatinine ratio may help distinguish the two syndromes; the levels are typically normal to increased in Bartter syndrome and low in Gitelman syndrome.

Definitive diagnosis, including identification of disease subtypes, is through genetic testing, which is now becoming more widely available.

Treatment

  • For Bartter syndrome, nonsteroidal anti-inflammatory drugs (NSAIDs)

  • Spironolactone or amiloride

  • Low-dose angiotensin-converting enzyme (ACE) inhibitors

  • Potassium and magnesium supplements

Because renal prostaglandin E2 secretion contributes to the pathogenesis in Bartter syndrome, NSAIDs (eg, oral indomethacin 1 to 5 mg/kg once a day) should be given (1); patients are also given oral potassium-sparing diuretics (eg, spironolactone 150 mg 2 times a day or amiloride 10 to 20 mg 2 times a day). Potassium-sparing diuretics alone are used in Gitelman syndrome. Low-dose ACE inhibitors can help limit the aldosterone-mediated electrolyte derangements. However, no therapy can completely eliminate potassium wasting, and oral potassium supplementation (potassium chloride 20 to 40 mEq one or 2 times a day) is often necessary. Magnesium supplements may also be needed.

Exogenous growth hormone can be considered to treat short stature.

Treatment reference

Key Points

  • Both syndromes have impaired sodium chloride reabsorption, which causes mild volume depletion, leading to increases in renin and aldosterone release, resulting in urinary potassium and hydrogen losses.

  • Manifestations vary depending on genotype, but growth and development may be affected and electrolyte abnormalities may cause muscle weakness, cramping, spasms, tetany, or fatigue.

  • Diagnosis involves serum and urinary electrolyte measurement; genetic testing is becoming more available for confirmation and identification of the Bartter subtypes.

  • Treatment involves potassium and sometimes magnesium replacement.

  • Potassium-sparing diuretics and low-dose ACE inhibitors may be used; for Bartter syndrome, NSAIDs also are given.

Drugs Mentioned In This Article

Drug Name Select Trade
K-TAB, KLOR-CON
ALDACTONE
INDOCIN
MIDAMOR
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