Bartter syndrome and Gitelman syndrome are autosomal recessive kidney 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 (for Bartter syndrome) and electrolyte replacement.
Bartter and Gitelman syndromes are rare disorders, and there are few data to determine their prevalence. The annual incidence of Bartter syndrome was 1.2/million in a Swedish database study (1). The prevalence of Gitelman syndrome is estimated to be approximately 1 in 40,000 in the United States (2) and approximately 3% in Japan and China (3).
General references
1. Rudin A. Bartter's syndrome. A review of 28 patients followed for 10 years. Acta Med Scand. 1988;224(2):165-171.
2. Ji W, Foo JN, O'Roak BJ, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008;40(5):592-599. doi:10.1038/ng.118
3. Hsu YJ, Yang SS, Chu NF, Sytwu HK, Cheng CJ, Lin SHNephrol Dial Transplant. 2009;24(4):1170-1175. doi:10.1093/ndt/gfn619
Pathophysiology of Bartter Syndrome and Gitelman Syndrome
Bartter syndrome and Gitelman syndrome result from
Defective 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. Sodium wasting contributes to a chronic mild plasma volume contraction reflected by a normal to low blood pressure despite high renin and angiotensin levels.
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.
The features at clinical presentation vary (see table Some Differences Between Bartter Syndrome and Gitelman Syndrome).
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 of Bartter Syndrome and Gitelman Syndrome
Both syndromes are usually autosomal recessive, although sporadic cases and other types of familial patterns can occur. Of note, there is an X-linked mutation in the MAGED2 gene, which can cause severe antenatal Bartter syndrome that is transient and resolves by 1 to 2 years of life.
There are several genotypes of both syndromes (see table Subtypes of Bartter Syndrome); different genotypes can have different manifestations (1).
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 |
IVa | 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 | Due to CaSR gain of function, which may reduce ROMK and NKCC2 activity |
* 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 of Bartter Syndrome and Gitelman Syndrome
Patients with Bartter syndrome tend to present prenatally or during infancy or early childhood. Patients with Gitelman syndrome tend to present during late childhood to adulthood.
Of note, some patients, especially those with Gitelman syndrome, are asymptomatic and diagnosed incidentally after blood tests are done.
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.
Inability to retain potassium, calcium, or magnesium can lead to muscle weakness, cramping, spasms, tetany, or fatigue. This is especially apparent in Gitelman syndrome. Polydipsia, polyuria, salt cravings, and vomiting may be present in both syndromes.
Most patients with Bartter syndrome or Gitelman syndrome have low or low-normal blood pressure and may have signs of volume depletion.
In general, neither Bartter syndrome nor Gitelman syndrome typically leads to chronic kidney disease.
Diagnosis of Bartter Syndrome and Gitelman Syndrome
Serum and urine electrolyte levels
Exclusion of similar disorders
Genetic testing
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 Distinguishing Primary and Secondary 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 2 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.
Children of carriers have a 25% chance of being affected by a recessive form, so asymptomatic siblings should be screened for electrolyte derangements, primarily hypokalemia and metabolic alkalosis, as well as hypomagnesemia. Parents of an affected child can consider consulting a genetic counselor regarding prenatal and preimplantation genetic screening for subsequent pregnancies.
Treatment of Bartter Syndrome and Gitelman Syndrome
For Bartter syndrome, nonsteroidal anti-inflammatory drugs (NSAIDs)
Sodium, potassium, and magnesium supplements
magnesium salts, such as aspartate, citrate, or lactate, have better bioavailability. A high solute load, such as that resulting from sodium supplementation, should be avoided in patients who have a urinary concentrating defect, secondary nephrogenic diabetes insipidus, or both because it exacerbates polyuria and polydipsia resulting from obligate water loss and could precipitate significant hypernatremia. In general, electrolyte supplementation should try to maintain adequate serum levels with minimal fluctuation, thus, dosing should be spread out as long as it does not significantly increase the risk of nonadherence.
Although potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers have been used in some patients, current consensus is that these therapies are largely unproved (1).
Thiazide diuretics for management of hypercalciuria are generally not recommended. They may complicate sodium supplementation, which can worsen the risk of nephrolithiasis and nephrocalcinosis.
Nutritional optimization is important, especially for infants and young children.
Exogenous growth hormone may be considered to treat short stature.
Treatment reference
1. Konrad M, Nijenhuis T, Ariceta G, et al: Diagnosis and management of Bartter syndrome: Executive summary of the consensus and recommendations from the European Rare Kidney Disease Reference Network Working Group for Tubular Disorders. Kidney Int 99(2):324–335, 2021. doi: 10.1016/j.kint.2020.10.035
Key Points
Both Bartter and Gitelman 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 electrolyte replacement; for Bartter syndrome, NSAIDs also are given.
