Diagnosis: Bartter Syndrome (Most Likely Type 1 or 2)
The clinical presentation of bilateral medullary nephrocalcinosis, hypokalemia, and normal sodium/chloride strongly suggests Bartter syndrome, specifically type 1 or 2, which characteristically present with hypercalciuria and nephrocalcinosis. 1 The elevated bilirubin (both direct and indirect) may represent Gilbert syndrome coexisting with Bartter syndrome, as Gilbert syndrome causes fluctuating indirect hyperbilirubinemia unrelated to the renal tubulopathy. 1
Diagnostic Confirmation
Immediate laboratory workup should include:
- Serum electrolytes with specific attention to potassium, calcium, and magnesium levels 1, 2
- Acid-base status to document the expected hypochloremic metabolic alkalosis 1
- Plasma renin activity and aldosterone levels (both will be elevated) 1, 2
- Urinary calcium-creatinine ratio to confirm hypercalciuria 1, 2
- Fractional excretion of chloride 1
Genetic testing with a gene panel including SLC12A1 (type 1) and KCNJ1 (type 2) should be performed to confirm the diagnosis (grade B recommendation). 1 These are the two Bartter syndrome subtypes that characteristically present with hypercalciuria and medullary nephrocalcinosis. 1
The normal sodium and chloride levels are atypical but can occur in Bartter syndrome, particularly when secondary nephrogenic diabetes insipidus develops, which may reduce urinary sodium and chloride losses. 3
Treatment Protocol
Electrolyte Supplementation
Sodium chloride supplementation at pharmacologic doses (5-10 mmol/kg/day) is the cornerstone of therapy (grade C recommendation). 1, 2 This should be spread throughout the day rather than given in large boluses. 1
Potassium chloride (not potassium citrate) must be used for potassium replacement, as potassium salts worsen metabolic alkalosis. 1, 2 Target plasma potassium should be approximately 3.0 mmol/L, though complete normalization is neither expected nor recommended. 1
If magnesium supplementation is needed, use organic magnesium salts (aspartate, citrate, or lactate) rather than magnesium oxide or hydroxide due to superior bioavailability, targeting plasma magnesium >0.6 mmol/l. 1
Anti-Inflammatory Therapy
NSAIDs (indomethacin) are recommended as mainstay therapy, particularly during early childhood (grade B recommendation). 1, 2 NSAIDs work by inhibiting prostaglandin E2 production, which is markedly elevated in Bartter syndrome. 1
Gastric acid inhibitors must be co-administered with NSAIDs to prevent gastrointestinal complications (grade C recommendation). 1
Monitoring for NSAID Complications
The long-term use of NSAIDs carries risks that must be balanced against benefits, particularly regarding potential chronic kidney disease progression. 1, 2 However, NSAIDs remain essential therapy especially in early life when symptoms are most severe. 1, 2
Management of Hyperbilirubinemia
The elevated bilirubin requires differentiation between Gilbert syndrome (indirect hyperbilirubinemia) and hepatocellular injury. 1 Measure both total and direct bilirubin levels, as Gilbert syndrome causes fluctuating total bilirubin with minimal direct bilirubin elevation. 1 If Gilbert syndrome is confirmed, the bilirubin elevation is benign and requires no specific treatment beyond monitoring. 1
Therapies NOT Recommended
Do not use thiazide diuretics to reduce hypercalciuria in Bartter syndrome (grade D recommendation), as they worsen the underlying salt-wasting. 1
Routine use of potassium-sparing diuretics, ACE inhibitors, or angiotensin receptor blockers is not recommended (grade D recommendation). 1
In patients with secondary nephrogenic diabetes insipidus, salt supplementation should be withheld (grade D recommendation). 1
Critical Pitfalls to Avoid
Bartter syndrome can be confused with nephrogenic diabetes insipidus when secondary NDI develops, leading to low urinary sodium and chloride concentrations despite the underlying salt-wasting tubulopathy. 3 This can delay diagnosis significantly.
Hypokalemia in Bartter syndrome can cause life-threatening complications including paralysis, rhabdomyolysis, cardiac arrhythmias, and sudden death. 1 Aggressive potassium replacement is essential despite the difficulty achieving normal levels.
The nephrocalcinosis in Bartter syndrome types 1 and 2 typically develops after 1-2 months of life and persists despite treatment, but long-term renal function may be preserved with appropriate management. 1, 4