What is Bartter syndrome?

Bartter Syndrome: An Inherited Salt-Losing Tubulopathy

Bartter syndrome is a group of inherited salt-losing tubulopathies 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

Bartter syndrome results from genetic mutations affecting salt transport in the thick ascending limb of the loop of Henle. The primary defect leads to:

• Impaired salt reabsorption in the thick ascending limb
• Renal tubular salt wasting
• Activation of the renin-angiotensin-aldosterone system
• Hypokalemic and hypochloremic metabolic alkalosis
• Increased prostaglandin E2 production via COX-2 activation

Five different types of Bartter syndrome have been identified based on the affected genes:

Type	Gene	Protein	Inheritance
BS1	SLC12A1	NKCC2	Autosomal recessive
BS2	KCNJ1	ROMK/Kir1.1	Autosomal recessive
BS3	CLCNKB	ClC-Kb	Autosomal recessive
BS4a	BSND	Barttin	Autosomal recessive
BS4b	CLCNKA+CLCNKB	ClC-Ka+ClC-Kb	Autosomal recessive
BS5	MAGED2	MAGE-D2	X-linked recessive

The molecular defects result in two additional important consequences:

1. Reduced calcium reabsorption leading to hypercalciuria and nephrocalcinosis
2. Blunted osmotic gradient in the renal medulla causing isosthenuria (inability to concentrate or dilute urine) 1

Clinical Presentation

Clinical features vary by type but commonly include:

• Polyuria and polydipsia
• Dehydration
• Failure to thrive and growth retardation
• History of polyhydramnios with premature birth
• Vomiting
• Muscle weakness
• Tetany
• Hypercalciuria and nephrocalcinosis (in some forms) 1, 2

The age of onset varies by type:

• BS1, BS2, BS4: Typically present antenatally with polyhydramnios (between 20-30 weeks gestation) and postnatally with severe dehydration
• BS3: Usually manifests later in childhood or adulthood with milder symptoms
• BS5: Always presents antenatally but symptoms spontaneously resolve around the expected date of delivery 1, 2

Diagnosis

Diagnosis is based on:

1. Clinical findings: Polyuria, growth retardation, history of polyhydramnios/premature birth
2. Laboratory abnormalities:
   • Hypokalemia (<3.5 mEq/L)
   • Hypochloremia (<98 mmol/L)
   • Metabolic alkalosis (elevated bicarbonate >26 mEq/L, pH >7.45)
   • Elevated renin and aldosterone levels
   • Hypercalciuria (in BS1, BS2, BS4)
3. Renal ultrasound: May show medullary nephrocalcinosis
4. Genetic testing: Confirms diagnosis and identifies specific type 1, 3

Treatment

Treatment aims to correct electrolyte abnormalities and improve quality of life:

1. Electrolyte supplementation:

   • Sodium chloride supplementation
   • Potassium chloride supplementation (target potassium level: 4.0-5.0 mEq/L)
   • Fluid supplementation adjusted based on symptoms, severity, age, and renal function 1, 3

2. Medications:

   • NSAIDs (particularly indomethacin) are a mainstay of treatment, especially during the first years of life (except in transient BS5)
   • Potassium-sparing diuretics (e.g., spironolactone) may be helpful in some cases, but use with caution as they can worsen volume depletion 1, 2, 4

3. Monitoring:

   • Regular monitoring of serum electrolytes (potassium, sodium, chloride, bicarbonate)
   • Magnesium levels should be checked and corrected if deficient
   • Renal function monitoring
   • Growth and development assessment 3

Prognosis and Complications

Potential complications include:

• Chronic kidney disease (particularly with nephrocalcinosis)
• Growth retardation
• Electrolyte imbalances leading to cardiac arrhythmias
• Dehydration episodes
• Muscle weakness and tetany 1, 4

Special Considerations

• Neonatal presentation: Can mimic sepsis with respiratory distress, requiring intensive care management 5
• Adult presentation: Rare but can occur, sometimes presenting with metabolic seizures 6
• Genetic counseling: Important for families due to inheritance patterns
• Differential diagnosis: Must be distinguished from Gitelman syndrome, which affects the distal convoluted tubule and typically presents with hypomagnesemia and hypocalciuria 1, 4

Bartter syndrome requires lifelong management with careful monitoring of electrolytes and appropriate supplementation to prevent complications and improve quality of life.