What is Bartter syndrome?

What is Bartter Syndrome

Bartter syndrome is a group of inherited salt-losing kidney disorders caused by genetic defects that impair salt reabsorption in the thick ascending limb of the loop of Henle, resulting in life-threatening polyuria, dehydration, hypokalemia, hypochloremic metabolic alkalosis, and normotensive hyperreninemic hyperaldosteronism. 1

Genetic Classification

Bartter syndrome encompasses five distinct genetic subtypes (BS1-5) based on the specific mutated gene: 1

• BS Type 1: SLC12A1 gene mutation affecting the NKCC2 transporter (autosomal recessive) 1
• BS Type 2: KCNJ1 gene mutation affecting the ROMK potassium channel (autosomal recessive) 1
• BS Type 3: CLCNKB gene mutation affecting the ClC-Kb chloride channel (autosomal recessive) - most common type 1, 2
• BS Type 4a/4b: BSND or combined CLCNKA/CLCNKB mutations affecting Barttin and chloride channels (autosomal recessive) 1
• BS Type 5: MAGED2 gene mutation affecting transporter regulation (X-linked recessive) 1

Type 3 is the most frequently reported variant, accounting for approximately 59% of genetically confirmed cases. 3

Pathophysiology

The fundamental defect involves impaired sodium chloride reabsorption in the thick ascending limb of Henle's loop, which triggers a cascade of compensatory mechanisms: 1

• Primary defect: Defective salt reabsorption leads to renal tubular salt wasting 1
• Compensatory activation: The renin-angiotensin-aldosterone system becomes hyperactivated, causing hyperreninemic hyperaldosteronism despite normal blood pressure 1
• Prostaglandin overproduction: Altered tubuloglomerular feedback at the macula densa activates COX-2, producing excessive prostaglandin E2 that further stimulates renin secretion 1
• Calcium wasting: Reduced calcium reabsorption results in hypercalciuria and nephrocalcinosis (except in most BS3 patients) 1
• Urinary concentration defect: Blunted medullary osmotic gradient causes isosthenuria (inability to concentrate or dilute urine appropriately) 1

Clinical Presentation

Antenatal/Neonatal Presentation

The severe forms (BS1, BS2, BS4) typically present with: 1, 3

• Polyhydramnios during pregnancy due to fetal polyuria 1
• Premature birth 1
• Severe dehydration requiring intensive care 4
• Failure to thrive and growth retardation 1

Childhood/Adult Presentation

Classic Bartter syndrome (especially BS3) may present later with: 1, 3, 4

• Polyuria and polydipsia 3
• Vomiting and dehydration 3
• Growth retardation and short stature 1
• Muscle weakness, myalgia, and chronic fatigue 4
• Tetany from electrolyte disturbances 4

Type-Specific Features

• BS4: Associated with sensorineural deafness due to Barttin mutations affecting inner ear function 5
• BS3: Milder phenotype that can be virtually indistinguishable from Gitelman syndrome, with less severe hypercalciuria and partial urine concentration ability 1, 5

Diagnostic Approach

Diagnosis relies primarily on clinical presentation combined with characteristic biochemical abnormalities and genetic confirmation. 5

Laboratory Findings

• Hypokalemia (often severe and refractory) 1, 3
• Hypochloremic metabolic alkalosis 1, 3
• Elevated plasma renin and aldosterone despite normal blood pressure 5
• Hypercalciuria (except in most BS3 cases) 1
• Hyponatremia and hypochloremia may be present 3

Imaging

• Renal ultrasound: Nephrocalcinosis is common, particularly in BS1, BS2, and BS4, and may improve with age in some patients 2

Genetic Testing

Genetic testing is the most reliable method for definitive diagnosis and should be pursued to confirm the specific subtype. 5 Genetic confirmation was achieved in 72% of cases in recent series, with CLCNKB mutations (Type 3) being most common. 2

Treatment Strategy

Electrolyte Supplementation (Cornerstone of Therapy)

• Sodium chloride: 5-10 mmol/kg/day for all Bartter syndrome patients 1, 5, 6
• Potassium chloride: High doses required - mean of 5.0 mEq/kg/day in children and 2.1 mEq/kg/day in adults, administered in 94% of patients 2
• Fluid supplementation: Adjusted based on severity, age, and renal function 1, 5

Anti-Prostaglandin Therapy

Nonsteroidal anti-inflammatory drugs (NSAIDs), particularly indomethacin, are a mainstay of treatment for most patients during the first years of life (except transient BS5) to reduce prostaglandin E2 production and decrease renal salt and water losses. 1, 5, 4

Potassium-Sparing Diuretics

Spironolactone or amiloride are used in 68% of patients to help manage hypokalemia, though they may worsen hypovolemia in Gitelman-like presentations. 2, 4

Limited Evidence Therapies

ACE inhibitors and angiotensin receptor blockers have been reported but lack robust evidence for efficacy, tolerability, and safety. 1, 5

Long-Term Outcomes and Complications

Growth Impairment

Despite treatment, 41% of patients have short stature (height <3rd percentile) at long-term follow-up (median 8 years). 2

Chronic Kidney Disease

Approximately 11% of patients develop CKD stage 3-5, with concerns about potential contributions from prolonged NSAID use, chronic hypokalemia, and nephrocalcinosis. 1, 2 However, definitive data on the relationship between these factors and CKD progression remains lacking. 1

Other Complications

• Nephrocalcinosis: Common finding that may improve with age in some patients 2
• Chondrocalcinosis: Major complication in Gitelman-like presentations 4
• Cardiac arrhythmias and secondary hypertension: Incidence not well documented 1

Critical Clinical Pitfalls

Diagnostic Confusion

BS3 can be easily confused with Gitelman syndrome due to overlapping clinical and biochemical features, including milder hypercalciuria and preserved partial urine concentration ability. 1, 5 Genetic testing is essential to distinguish these conditions.

Neonatal Recognition

Early polyhydramnios of fetal origin should immediately raise suspicion for Bartter syndrome, particularly the severe antenatal forms requiring urgent neonatal intensive care for life-threatening dehydration. 5, 4

Treatment Monitoring

Patients require lifelong supplementation with large amounts of potassium (often 5+ mEq/kg/day in children), and symptoms tend to improve with age, but growth impairment and CKD risk persist despite aggressive management. 2

Genetic Counseling

Given the autosomal recessive inheritance pattern (BS1-4), consanguineous marriages significantly increase risk, as documented in 21 of 118 reported cases. 3 Families require genetic counseling for future pregnancies. 7