What is Bartter syndrome?

Bartter Syndrome

Bartter syndrome is an inherited salt-losing tubulopathy characterized by polyuria, hypokalemia, hypochloremic metabolic alkalosis, and normotensive hyperreninemic hyperaldosteronism caused by impaired salt reabsorption in the thick ascending limb of the loop of Henle. 1

Pathophysiology

• The primary molecular defect in all types of Bartter syndrome leads to impaired salt reabsorption in the thick ascending limb of the loop of Henle, resulting in renal tubular salt wasting with activation of the renin-angiotensin system and consequent hypokalemic and hypochloremic metabolic alkalosis 1
• The tubuloglomerular feedback is altered at the macula densa level, activating cyclooxygenases (primarily COX-2) to produce high amounts of prostaglandins (primarily prostaglandin E2), which stimulate renin secretion and aldosterone production 1
• Impaired salt reabsorption in the thick ascending limb leads to reduced calcium reabsorption with hypercalciuria/nephrocalcinosis and blunting of the osmotic gradient in the renal medulla, causing isosthenuria (impaired ability to dilute or concentrate urine) 1

Genetic Classification

• Five different forms (BS1-5) have been identified based on molecular genetics 1:
  • Type 1 (BS1): Mutations in SLC12A1 gene encoding NKCC2 (Na-K-2Cl cotransporter) 1, 2
  • Type 2 (BS2): Mutations in KCNJ1 gene encoding ROMK (potassium channel) 1, 2
  • Type 3 (BS3): Mutations in CLCNKB gene encoding ClC-Kb (chloride channel) 1, 2
  • Type 4 (BS4): Mutations in BSND gene encoding Barttin (accessory subunit) or combined defects in ClC-Ka and ClC-Kb 1
  • Type 5 (BS5): Mutations in MAGED2 gene affecting transporter trafficking 1, 2
• The mode of inheritance is autosomal recessive in BS1-4 and X-linked recessive in BS5 1

Clinical Presentation

• Clinical characteristics include polyuria, dehydration, failure to thrive, growth retardation, and a medical history of polyhydramnios with premature birth 1
• Hypercalciuria and nephrocalcinosis are typical for some forms, particularly BS1, BS2, and BS4 1, 3
• Several patients with BS3 have features that are virtually indistinguishable from Gitelman syndrome, another salt-losing tubulopathy 1
• Sensorineural deafness is present in BS4 (Barttin mutations) 1
• The severity of symptoms varies by type, with antenatal/neonatal presentation common in BS1, BS2, BS4, and BS5, while BS3 often presents later in childhood 1, 4

Diagnostic Approach

• Diagnosis is primarily based on clinical, biochemical, and sonographic findings 1
• Laboratory findings include:
  • Hypokalemia and hypochloremic metabolic alkalosis 1
  • Elevated renin and aldosterone levels 1
  • Elevated urinary chloride excretion despite hypochloremia (fractional chloride excretion >0.5%) 5
  • Hypercalciuria (in BS1, BS2, and BS4) 1
• Early polyhydramnios of fetal origin should raise clinical suspicion of BS 1
• Genetic testing is the most reliable method for definitive diagnosis 1, 4

Treatment

• Most patients with BS require supplementation with:
  • Sodium chloride (5-10 mmol/kg/day) 2
  • Potassium chloride (often requiring large amounts, 5.0 mEq/kg/day in children and 2.1 mEq/kg/day in adults) 3
  • Fluids adjusted individually based on symptoms, tolerability, severity of the tubulopathy, age, and glomerular filtration rate 1
• Nonsteroidal anti-inflammatory drugs (NSAIDs) are a mainstay of treatment for most patients, at least during the first years of life (except in transient BS5), to reduce prostaglandin production 1, 2
• Potassium-sparing diuretics (e.g., spironolactone) may be used to help maintain potassium levels 3, 4
• The use of other therapies, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, has been reported, but evidence supporting their efficacy, tolerability, and safety is limited 1

Long-term Outcomes and Complications

• Despite treatment, growth impairment remains significant, with 41% of patients having short stature (height less than 3rd percentile) after 8 years of follow-up 3
• Impaired kidney function can develop in some patients (11% developed CKD G3-G5 in one study) 3
• Nephrocalcinosis is a common finding but may improve with age in some patients 3
• Information on long-term outcomes is still limited, particularly regarding the risk of chronic renal failure and its potential relationship to prolonged use of NSAIDs, chronic hypokalemia, and sonographic findings 1
• The incidence of secondary hypertension and cardiac arrhythmias is not well documented 1

Clinical Pearls and Pitfalls

• BS3 can be confused with Gitelman syndrome due to similar clinical and biochemical features 1
• Patients require lifelong treatment with potassium supplementation and often potassium-sparing agents, though symptoms tend to improve with age 3
• Growth hormone deficiency has been reported in some cases and should be considered in patients with severe growth retardation 6
• Genetic counseling is essential for families affected by this condition 7