Bartter Syndrome

Etiology

Impairment in the sodium-potassium-chloride cotransporter (NKCC2) or the potassium channel (ROMK) affects the transport of sodium, potassium, and chloride in the thick ascending limb of the loop of Henle (TALH). This results in increased distal delivery of these ions, with only some sodium reabsorbed and potassium secreted.

Types of Bartter syndrome include:

• Type I (antenatal Barter syndrome): Results from mutations in the sodium-chloride-potassium cotransporter gene (NKCC2)
• Type II (antenatal/neonatal Barter syndrome): Results from mutations in the ROMK gene 
• Type III (classic Barter syndrome): Results from mutations in the chloride voltage-gated channel Kb gene (CLCNKB), which encodes the kidney-specific basolateral chloride channel (ClC-Kb) involved in sodium chloride reabsorption in the renal tubule.[2]
• Type IV (Barter syndrome with sensorineural deafness): Results from the loss-of-function mutations in the gene encoding barttin (BSND).[3][4]
• Type V (Gitelman syndrome): Results from mutations in the extracellular calcium ion-sensing receptor (CaSR) and in the genes that encode the chloride channel subunits, ClC-Ka and ClC-Kb [5]

Bartter syndrome can be secondary to aminoglycoside use. Hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalcemia commonly are seen with an aminoglycoside-induced Bartter-like syndrome.[6] An antenatal variant of Bartter syndrome presents with severe hypokalemia, metabolic alkalosis, and profound systemic manifestations. Bartter syndrome III and V usually present later in life and have mild symptoms.

Epidemiology

Bartter syndrome is seen in 1 in 1,000,000 individuals and is much less common than Gitelman syndrome.

Pathophysiology

Bartter syndrome is a renal tubular salt-wasting disorder in which the kidneys cannot reabsorb sodium and chloride in the thick ascending limb of the loop of Henle. This leads to increased distal delivery of salt and excessive salt and water loss from the body. The resultant volume depletion activates the renin-angiotensin-aldosterone system (RAAS) and leads to secondary hyperaldosteronism. Long-term stimulation leads to hyperplasia of the juxtaglomerular apparatus and, consequently, increased renin levels.[7] Angiotensin II is a potent vasoconstrictor that increases systemic and renal artery vasoconstriction, preventing hypotension.

Excessive distal delivery of sodium promotes increased sodium reabsorption within the distal convoluted tubule through exchange with positively charged potassium or hydrogen ions, resulting in enhanced urinary potassium loss and increased hydrogen ion secretion. Hyperaldosteronism further amplifies these processes and contributes to elevated bicarbonate levels through reduced hydrogen ion availability.

Urinary concentrating and diluting capacity becomes impaired in Bartter syndrome as a consequence of defective sodium absorption in the loop of Henle.[8] Under normal physiologic conditions, sodium chloride reabsorption in the loop of Henle, in the presence of normal antidiuretic hormone activity, maintains the medullary concentration gradient required for urine concentration. Additional contributing factors include polyuria, hypokalemia, and elevated prostaglandin E2 levels, which also interfere with normal growth in children. Defective sodium chloride transport in the loop of Henle disrupts the electrochemical gradient necessary for paracellular calcium and magnesium reabsorption, leading to increased urinary losses of both electrolytes.

Nephrocalcinosis frequently occurs in patients with Bartter syndrome and most likely results from excessive urinary calcium wasting, manifested as hypercalciuria. Malfunction of chloride transporters within the thick ascending limb of the loop of Henle impairs calcium reabsorption in this segment. Under physiologic conditions, calcium and magnesium undergo paracellular absorption driven by the positive luminal charge generated through chloride reabsorption. In contrast, Gitelman syndrome involves dysfunction of the sodium chloride cotransporter, resulting in hypocalciuria and hypomagnesemia.

Histopathology

In neonatal and classic Bartter syndrome, the cardinal finding is hyperplasia of the juxtaglomerular apparatus. Less frequently, hyperplasia of the medullary interstitial cells is present. Glomerular hyalinization, apical vacuolization of the proximal tubular cells, tubular atrophy, and interstitial fibrosis may be present as a consequence of chronic hypokalemia.

History and Physical

A comprehensive clinical evaluation requires a thorough history, including a family history of maternal polyhydramnios, combined with a detailed physical examination. Bartter syndrome most often affects children and adolescents and commonly presents with stunted growth, polyuria, polydipsia, muscle cramps, vomiting, dehydration, constipation, growth delay, and failure to thrive. Diagnostic assessment should include careful documentation of a family history of nephrocalcinosis and a detailed personal history to exclude surreptitious vomiting and diuretic abuse before confirming the diagnosis.

Affected patients frequently appear emaciated and display characteristic facial features, including a triangular facial shape with a prominent forehead, large eyes, protruding ears, and a drooping mouth. Additional clinical findings may include strabismus, sensorineural deafness, and recurrent carpopedal spasms. Blood pressure measurements commonly reveal normal or low values, although long-standing disease may be associated with elevated blood pressure.

Offspring with antenatal Bartter syndrome demonstrate polyhydramnios due to intrauterine polyuria and often undergo premature delivery.[9] Postnatal manifestations frequently include fever, sensorineural deafness, profound polyuria, vomiting, and diarrhoea that progress to dehydration.

Evaluation

Diagnostic Evaluation Findings

Diagnosis of Bartter syndrome relies on characteristic findings from the clinical history and physical examination, supported by specific laboratory abnormalities. The disorder consistently associates with electrolyte and acid–base disturbances, including hypokalemia and metabolic alkalosis in nearly all cases.[10] Additional biochemical abnormalities include elevated serum renin and aldosterone levels, as well as reduced magnesium and phosphate levels in a subset of patients. Hypophosphatemia results from renal phosphate wasting and secondary hyperparathyroidism.

Urine electrolyte analysis typically demonstrates increased excretion of sodium, potassium, and prostaglandin E2. Elevated 24-hour urinary calcium excretion assists in excluding Gitelman syndrome, which features low urinary calcium levels. Measurement of spot urine chloride concentration aids differentiation from surreptitious vomiting, a condition associated with values below 25 meq/L, whereas Bartter syndrome typically shows urine chloride concentrations exceeding 35 meq/L.

Prenatal and Neonatal Evaluation 

Prenatal and neonatal evaluation may reveal polyhydramnios and intrauterine growth restriction on ultrasound. Amniotic fluid chloride concentrations may also appear elevated. Imaging modalities, including abdominal radiographs, intravenous pyelograms, renal ultrasonography, or spiral computed tomography (CT) scans, help document nephrocalcinosis. Electrocardiographic evaluation may demonstrate findings consistent with hypokalemia, including flattened T waves and prominent U waves. Genetic testing may support confirmation of specific pathogenic mutations.

Treatment / Management

Prenatal Management

Prenatal management focuses on careful consideration of amniotic fluid reduction and requires thorough assessment of potential fetal risks, including premature closure of the ductus arteriosus and development of necrotising enterocolitis.[11] Any intervention should proceed only after balancing anticipated benefits against these serious complications.

Postnatal Management

Postnatal management may require saline infusion during the neonatal period to address volume depletion. Therapeutic goals include normalization of serum potassium levels, achieved through oral potassium supplementation such as potassium chloride at doses ranging from 25 to 100 mmol/day. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers reduce elevated angiotensin II and aldosterone activity, limit proteinuria, and increase serum potassium levels in selected patients. Additional therapeutic options include amiloride at doses of 5 to 40 mg/day, spironolactone, nonsteroidal anti-inflammatory drugs such as indomethacin at 1 to 3 mg/kg/24 hours to counteract elevated urinary prostaglandin E2 levels, and gastric acid inhibitors. Magnesium supplementation warrants consideration, as hypomagnesemia can worsen potassium wasting and increase the risk of ventricular arrhythmias.[12] Renal tubular abnormalities typically resolve after kidney transplantation without recurrence.

Long-term Management

Long-term management requires close follow-up for patients with moderate to severe disease, scheduled every 3 to 6 months in infants and children and every 6 to 12 months in stable or older children. Clinical assessment should emphasize evaluation of dehydration, polyuria, muscular weakness, and psychomotor development. Recommended laboratory monitoring includes a renal function panel, serum electrolytes, acid–base status, parathyroid hormone levels, and urinary calcium measurements. Renal ultrasonography should occur every 12 to 24 months to monitor for nephrocalcinosis.[13](B3)

Differential Diagnosis

Differential diagnoses that should also be considered when evaluating patients with clinical features of Bartter syndrome include:

• Diuretic abuse
• Cyclical vomiting
• Hyperprostaglandin E syndrome
• Familial hypomagnesemia with hypercalciuria/nephrocalcinosis
• Pyloric stenosis
• Gitelman syndrome
• Cystic fibrosis
• Gullner syndrome (familial hypokalemic alkalosis with proximal tubulopathy)
• Mineralocorticoid excess
• Activating mutations of the CaSR calcium-sensing receptor
• Hypomagnesemia
• Congenital chloride diarrhoea
• Hypochloremic alkalosis
• Hypokalemia

Pertinent Studies and Ongoing Trials

The W610X nonsense mutation in CLCNKB is a promising candidate for translational read-through induction trials as a potential therapeutic approach.[11]

Prognosis

Bartter syndrome represents an autosomal recessive disorder without a definitive cure. Prognosis remains favorable in many cases, as disease severity depends on the specific receptor or transporter involved. Prostaglandin synthetase inhibitors improve plasma potassium levels, reduce polyuria, and help normalize plasma renin and aldosterone concentrations, supporting normal growth. Some patients experience recurrent hypokalemia, which can be managed effectively with potassium supplementation or treatment with indomethacin.

A retrospective study conducted in Korea involving 54 patients with Bartter syndrome demonstrated that a significant proportion develop growth impairment, and 11% progress to chronic kidney disease stages G3 to G5.[14] Additional research supports the observation that Bartter syndrome often leads to worse clinical outcomes, with prenatal-onset symptoms contributing to delayed growth and progression to end-stage renal disease.[15]

Complications

Complications of Bartter syndrome include:

• Cardiac arrhythmias
• Nephrocalcinosis
• Chronic renal failure
• Short stature
• Muscle weakness
• Severe dehydration
• Osteopenia
• Hearing loss