What is the pathophysiology and management of Bartter syndrome?

Pathophysiology and Management of Bartter Syndrome

Bartter syndrome is fundamentally a group of inherited salt-losing tubulopathies characterized by impaired salt reabsorption in the thick ascending limb of the loop of Henle, resulting in hypokalemic metabolic alkalosis, hyperreninemic hyperaldosteronism, and increased prostaglandin production. 1

Pathophysiology

Molecular Defects

Bartter syndrome results from mutations in genes encoding proteins involved in salt transport in the thick ascending limb of Henle's loop:

• Five genetic types identified: 2, 1
  • Type 1 (BS1): Mutations in SLC12A1 gene encoding NKCC2 (Na-K-2Cl cotransporter)
  • Type 2 (BS2): Mutations in KCNJ1 gene encoding ROMK (potassium channel)
  • Type 3 (BS3): Mutations in CLCNKB gene encoding ClC-Kb (chloride channel)
  • Type 4a (BS4a): Mutations in BSND gene encoding barttin (accessory subunit)
  • Type 4b (BS4b): Combined mutations in CLCNKA and CLCNKB genes
  • Type 5 (BS5): X-linked mutations in MAGED2 gene (regulates trafficking of NKCC2 and NCC)

Physiological Consequences

The primary defect leads to: 2

1. Salt wasting: Impaired NaCl reabsorption in the thick ascending limb
2. Activation of RAAS: Renin-angiotensin-aldosterone system activation due to volume depletion
3. Hypokalemic alkalosis: Due to secondary hyperaldosteronism
4. Prostaglandin overproduction: Activation of COX-2 at the macula densa produces PGE2
5. Hypercalciuria: Reduced calcium reabsorption (except in BS3)
6. Isosthenuria: Inability to concentrate or dilute urine due to disrupted medullary osmotic gradient

Clinical Presentation

Clinical features vary by type but typically include: 2, 1

• Antenatal manifestations: Polyhydramnios, premature birth (BS1, BS2, BS4, BS5)

• Postnatal manifestations:

  • Polyuria and polydipsia
  • Dehydration episodes
  • Failure to thrive and growth retardation
  • Muscle weakness and tetany
  • Nephrocalcinosis (in BS1, BS2, BS4)
  • Sensorineural deafness (in BS4)

• Age of onset:

  • BS1, BS2, BS4: Antenatal/neonatal presentation with severe symptoms
  • BS3: Later childhood or adulthood with milder symptoms
  • BS5: Antenatal presentation with spontaneous resolution around birth

Diagnosis

Diagnosis is based on: 2, 1

1. Clinical findings: History of polyhydramnios, premature birth, failure to thrive
2. Laboratory abnormalities:
   • Hypokalemia, hypochloremia, metabolic alkalosis
   • Elevated renin and aldosterone levels
   • Hypercalciuria (in BS1, BS2, BS4)
   • Normal blood pressure despite hyperreninemia
3. Renal ultrasound: May show nephrocalcinosis
4. Genetic testing: Confirms diagnosis and identifies specific type

Management

The cornerstone of Bartter syndrome management is electrolyte supplementation and prostaglandin inhibition with NSAIDs, individualized based on syndrome severity, patient age, and renal function. 2, 1

Electrolyte Supplementation

1. Sodium chloride supplementation: 2

   • Recommended dose: 5-10 mmol/kg/day
   • Supports extracellular volume and improves electrolyte abnormalities
   • Caution: Avoid in patients with secondary nephrogenic diabetes insipidus (some BS1/BS2) as it may worsen polyuria

2. Potassium chloride supplementation: 2

   • Use potassium chloride specifically (not other potassium salts)
   • Other potassium salts (e.g., citrate) may worsen metabolic alkalosis

3. Fluid supplementation:

   • Adjusted based on symptoms, severity, age, and renal function

Pharmacological Treatment

1. NSAIDs: 2, 1

   • First-line treatment for most patients during early years
   • Reduces prostaglandin production and improves salt reabsorption
   • Indomethacin is commonly used
   • Caution: Monitor for potential renal toxicity with long-term use

2. Potassium-sparing diuretics: 2, 3

   • May help manage severe hypokalemia
   • Limited evidence for efficacy and safety

3. ACE inhibitors/ARBs: 2

   • Limited evidence supporting their use
   • May help reduce potassium wasting

Prenatal Management

For pregnancies with suspected fetal Bartter syndrome: 2

• Prenatal genetic testing is the most reliable diagnostic method
• Serial amniocentesis and maternal NSAID therapy have been reported but carry risks
• Caution: Maternal NSAID therapy can cause fetal ductus arteriosus constriction and requires close monitoring with fetal echocardiography

Monitoring

Regular monitoring of: 1

• Serum electrolytes
• Renal function
• Growth and development
• Complications (nephrocalcinosis, chronic kidney disease)

Complications and Prognosis

Potential complications include: 2, 1, 4

• Chronic kidney disease (particularly with long-term NSAID use)
• Growth retardation
• Cardiac arrhythmias from electrolyte imbalances
• Recurrent dehydration episodes
• Nephrocalcinosis progression

Despite advances in understanding the genetic basis of Bartter syndrome, information on long-term outcomes remains limited. Early diagnosis and appropriate management are crucial to prevent complications and improve quality of life.