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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 review/revision Dec 2022
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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 (for Bartter syndrome) 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.

Table

Etiology

Both syndromes are usually autosomal recessive Autosomal Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more , 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.

Table

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.

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 Hypocalcemia Hypocalcemia is a total serum calcium concentration < 8.8 mg/dL (< 2.20 mmol/L) in the presence of normal plasma protein concentrations or a serum ionized calcium concentration < 4... read more , 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 renal insufficiency.

Diagnosis

  • 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 Metabolic Alkalosis Metabolic alkalosis is primary increase in bicarbonate (HCO3) with or without compensatory increase in carbon dioxide partial pressure (Pco2); pH may be high or nearly normal. Common... read more and hypokalemia Hypokalemia Hypokalemia is serum potassium concentration < 3.5 mEq/L (< 3.5 mmol/L) caused by a deficit in total body potassium stores or abnormal movement of potassium into cells. The most common... read more . 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 ).

  • 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.

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

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

  • Sodium, potassium, and magnesium supplements

Electrolyte supplementation is the mainstay of management. Regimens usually include sodium chloride, usually 5 to 10 mEq/kg/day. Additionally, potassium chloride supplementation should be given, initially about 1 to 3 mEq/kg/day. Patients with magnesium wasting should be given magnesium salts , but this therapy may be limited by the development of diarrhea. Some 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 Nephrogenic Diabetes Insipidus Nephrogenic diabetes insipidus (NDI) is an inability to concentrate urine due to impaired renal tubule response to vasopressin (ADH), which leads to excretion of large amounts of dilute urine... read more , 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.

Thiazide diuretics for management of hypercalciuria are generally not recommended, but this 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 can be considered to treat short stature.

Treatment references

  • 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

  • 2. Konrad M, Nijenhuis T, Ariceta G, et al: Diagnosis and management of Bartter syndrome: Consensus and recommendations from the ERKNetWorking Group for Tubular Disorders. 2020. Accessed November 21, 2022.

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.

Drugs Mentioned In This Article

Drug Name Select Trade
Indocin, Indocin SR, TIVORBEX
Advil, Advil Children's, Advil Children's Fever, Advil Infants', Advil Junior Strength, Advil Migraine, Caldolor, Children's Ibuprofen, ElixSure IB, Genpril , Ibren , IBU, Midol, Midol Cramps and Body Aches, Motrin, Motrin Children's, Motrin IB, Motrin Infants', Motrin Junior Strength, Motrin Migraine Pain, PediaCare Children's Pain Reliever/Fever Reducer IB, PediaCare Infants' Pain Reliever/Fever Reducer IB, Samson-8
Celebrex, ELYXYB
4-Way Saline, Adsorbonac, Altamist, Ayr Allergy & Sinus, Ayr Baby Saline, Ayr Saline Nasal, BD Posiflush Normal Saline, BD Posiflush Sterile Field Normal Saline, BD Posiflush SureScrub Normal Saline, Blairex Broncho Saline, Breathe Free Saline, Deep Sea , Entsol, HyperSal, Hyper-Sal, Hypertears, Little Remedies for Noses, Little Remedies Stuffy Nose, Muro 128, NebuSal , Ocean, Ocean Complete, Ocean For Kids, Pediamist, PULMOSAL, Rhinaris, Rhinaris Lubricating, Saljet , Saljet Rinse, SaltAire, Sea Soft, Trichotine, Wound Wash, ZARBEE'S Soothing Saline Nasal Mist
Cena K , ED-K+10, Epiklor, K Plus, K Plus Care, K-10 , K-8, Kaon-CL, Kay Ciel , K-Dur, K-Lor, Klor-Con, Klor-Con M10, Klor-Con M15, Klor-Con M20, Klotrix, K-Lyte CL, K-Sol , K-Tab, Micro-K, Micro-K Extencaps, PROAMP, Rum-K, Slow-K, Tri-K
Mag-64, Mag-G , MagGel 600, Magonate, MagOx 400 , Mag-SR , Mag-Tab SR , Magtrate, Phillips Cramp-Free, Uro-Mag
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