How is Bartter syndrome managed?

Management of Bartter Syndrome

The cornerstone of Bartter syndrome management is pharmacologic sodium chloride supplementation at 5-10 mmol/kg/day combined with potassium chloride replacement, with NSAIDs (particularly indomethacin) added for symptomatic patients to address the underlying prostaglandin-mediated pathophysiology and prevent life-threatening complications including cardiac arrhythmias, rhabdomyolysis, and sudden death. 1, 2

Electrolyte Supplementation Strategy

Salt supplementation forms the physiologic foundation of therapy:

• Administer 5-10 mmol/kg/day of sodium chloride to support extracellular volume and correct electrolyte abnormalities 3, 1
• Beyond infancy, some supplementation may be provided by the patient's natural salt craving and high spontaneous salt intake 3

Critical exception for salt supplementation:

• Do NOT give salt supplementation in patients with BS1 and BS2 subtypes who have secondary nephrogenic diabetes insipidus presenting with hypernatremic dehydration and urine osmolality lower than plasma 3, 1
• Salt worsens polyuria and increases the risk of life-threatening hypernatremic dehydration in these patients 1, 2

Potassium replacement protocol:

• Use ONLY potassium chloride for supplementation—never potassium citrate or other potassium salts 3, 1, 2
• Potassium citrate and other non-chloride salts worsen metabolic alkalosis by aggravating the alkalosis 3
• Target plasma potassium of 3.0 mmol/L, not complete normalization 1, 2
• Complete normalization is often unachievable and unnecessary; some patients may require even lower realistic targets 1
• Severe hypokalemia can cause paralysis, rhabdomyolysis, cardiac arrhythmias, and sudden death 1, 2

Magnesium supplementation:

• Use oral magnesium supplements when needed, preferably organic magnesium salts due to better bioavailability 3

NSAID Therapy

NSAIDs address the underlying pathophysiology by suppressing prostaglandin formation:

• Indomethacin has demonstrated clinical benefit with improved growth and electrolyte profiles 1, 2
• Dosing regimens:
  • Indomethacin: 1-4 mg/kg/day divided in 3-4 doses 1, 2
  • Ibuprofen: 15-30 mg/kg/day in 3 doses 1, 2
  • Celecoxib: 2-10 mg/kg/day in 2 doses 1, 2

Critical safety measures for NSAID use:

• Achieve euvolemia BEFORE initiating NSAIDs to minimize nephrotoxicity risk 1, 2
• Always use gastric acid inhibitors (proton pump inhibitors or H2 blockers) with nonselective COX inhibitors to prevent gastrointestinal complications 1, 2
• NSAIDs may prevent fever and mask the severity of infectious diseases during intercurrent illness 3
• Monitor renin and aldosterone levels to assess adequacy of NSAID treatment 3

Medications to AVOID

The following medications can cause life-threatening complications and should NOT be routinely used:

• Do NOT routinely use potassium-sparing diuretics, ACE inhibitors, or angiotensin receptor blockers 3, 1, 2
• While these drugs can ameliorate electrolyte abnormalities, Bartter syndrome is primarily a salt-wasting disorder where enhanced sodium reabsorption in the collecting duct is a key compensatory mechanism 3
• These drugs worsen salt wasting and risk critical, potentially fatal hypovolemia 3
• Some sudden deaths in Bartter syndrome may have been caused by hypovolemia rather than hypokalemia 3
• Consider these drugs only in individual cases with severe symptoms despite maximization of routine treatment with NSAIDs and salt supplements 3

Thiazide diuretics:

• Do NOT use thiazide diuretics to manage hypercalciuria in Bartter syndrome 3, 1, 2
• There are no data on their efficacy in Bartter syndrome 3
• Compensatory salt reabsorption in the distal convoluted tubule is critical for volume homeostasis 3
• Thiazides can lead to life-threatening hypovolemia 3

Growth Hormone Considerations

Growth failure with growth hormone deficiency has been reported in Bartter syndrome:

• Most reports concern patients with BS3 who have the most severe metabolic abnormalities 3
• Elevated systemic prostaglandins may contribute to growth failure 3
• Before commencing recombinant human GH, optimization of metabolic control should be attempted 3
• In one report, GH deficiency failed to respond to recombinant human GH supplementation until treatment with a COX inhibitor was commenced 3

Monitoring and Follow-Up Protocol

Visit frequency:

• Infants and young children: every 3-6 months depending on severity 1, 2
• Older stable children: every 6-12 months 1, 2

Clinical monitoring at each visit:

• Assess dehydration status, polyuria, muscular weakness, growth, and psychomotor development 1, 2
• In children, emphasize growth and pubertal development 3
• Monitor for adverse effects of NSAIDs 3

Laboratory monitoring:

• Acid-base status, electrolytes (including bicarbonate, chloride, magnesium), renal function, PTH, and urinary calcium excretion 1, 2
• Renin and aldosterone levels may be helpful in assessing adequacy of NSAID treatment 3

Imaging surveillance:

• Renal ultrasound every 12-24 months to monitor nephrocalcinosis, kidney stones, and obstructive uropathy 1, 2

Multidisciplinary involvement:

• According to age and/or genotype, involve dieticians, social workers, psychologists, endocrinologists, and otolaryngologists 3

Long-Term Outcomes and Complications

Chronic kidney disease is common in Bartter syndrome:

• Patients with BS1 and BS4 may have more severe chronic kidney disease progression than those with BS2 and BS3 3
• Risk factors include the molecular defect itself, premature birth/low birth weight, nephrocalcinosis, chronic dehydration, progressive proteinuria from hyperfiltration, and NSAID treatment 3
• Nephrocalcinosis and hypercalciuria are present in the majority of patients (except BS3), though symptomatic urolithiasis prevalence is relatively low 3
• Nephrotic-range proteinuria has been reported, often with diffuse glomerular and tubulointerstitial lesions, enlarged glomeruli, and focal segmental glomerulosclerosis 3

Common Pitfalls to Avoid

• Attempting complete normalization of potassium levels—this is often unachievable and unnecessary 1, 2
• Using potassium citrate instead of potassium chloride, which worsens alkalosis 1, 2
• Giving salt supplementation to patients with secondary nephrogenic diabetes insipidus 1, 2
• Starting NSAIDs before achieving euvolemia 1, 2
• Failing to provide gastric protection with NSAIDs 1, 2
• Using thiazides for hypercalciuria management 1, 2
• Routinely using potassium-sparing diuretics, ACE inhibitors, or ARBs which risk life-threatening hypovolemia 1, 2

Patient Education

• Disease-specific education is highly important and can be provided through age-appropriate personal education, information leaflets, web-based information, and patient/family group support events 2
• Patients must know "sick day rules" for intercurrent illness 2
• Optimize nutritional support to facilitate optimal growth, particularly in pediatric patients 1