Bartter Syndrome - Etiology

Pathophysiological Basis

• Apical (lumen-facing): NKCC2 cotransporter brings Na+/K+/2Cl- into the cell; ROMK recycles K+ back into the lumen to sustain NKCC2 activity and generate a lumen-positive voltage that drives paracellular reabsorption of Na+, Ca2+, and Mg2+
• Basolateral: CLC-Kb (+ its subunit Barttin) extrudes Cl- out; CaSR on the basolateral surface tonically inhibits ROMK

Genetic Types

Key Details by Type

Types I & II - Antenatal Bartter

• The most severe forms, presenting in utero or immediately after birth
• Polyhydramnios (fetal polyuria), premature delivery, postnatal polyuria, vomiting, failure to thrive
• Prominent hypercalciuria and nephrocalcinosis
• Impaired chloride sensing at the macula densa disrupts tubuloglomerular feedback (TGF), leading to primary activation of COX-2 with excess prostaglandin E2 production - this is why COX inhibitors (indomethacin) are therapeutic
• Type II has a unique neonatal transient hyperkalemia because ROMK is also expressed in the collecting duct and is needed for K+ secretion there

Type III - Classical Bartter

• Presents in childhood or adolescence with failure to thrive, polyuria, polydipsia
• Hypokalemia, hypochloremic metabolic alkalosis, hyperreninemia, hyperaldosteronism
• Hypercalciuria in ~80%; ~20% have hypomagnesemia
• Milder because CLC-Ka (encoded by CLCNKA) can partially compensate for lost CLC-Kb function - but when both CLCNKA and CLCNKB are mutated (Type IVb), the phenotype is severe/antenatal
• Up to one-third of type 3 patients can actually present antenatally or in the neonatal period despite the "classical" designation

Type IV - Bartter with Sensorineural Deafness

• Barttin is co-expressed with CLC-Ka and CLC-Kb in the stria vascularis of the cochlea, where it is required for K+ recycling in endolymph generation
• Loss of Barttin function abolishes both chloride channels in the TAL and the inner ear simultaneously, producing the combination of severe Bartter syndrome and bilateral sensorineural deafness

Type V - CaSR Activating Mutation

• Unlike all other types, this is a gain-of-function mutation (dominant), not a loss-of-function
• Activated CaSR tonically inhibits ROMK, thus reducing TAL NaCl reabsorption
• Presents with metabolic alkalosis, hypokalemia, hypercalciuria, hypocalcemia, and low PTH - the "Bartter syndrome phenotype" in the context of autosomal dominant hypocalcemia

Downstream Consequences (Common to All Types)

1. Failure of TAL NaCl reabsorption → urinary salt wasting → extracellular volume contraction
2. Volume contraction → activation of renin-angiotensin-aldosterone system (secondary hyperreninemic hyperaldosteronism)
3. Increased NaCl delivery to the collecting duct → aldosterone-driven K+ and H+ secretion → hypokalemia and metabolic alkalosis
4. Impaired TGF at macula densa → COX-2 upregulation → excess prostaglandin E2 → further afferent arteriolar dilation, augmented renin release, and juxtaglomerular hypertrophy
5. Vascular unresponsiveness to angiotensin II (despite markedly elevated renin/aldosterone)

Inheritance & Genetics Summary

• Types I-IV: Autosomal recessive - patients are typically homozygotes or compound heterozygotes
• Type V: Autosomal dominant (activating CaSR mutation)
• A minority of patients with clear clinical Bartter syndrome have no identifiable mutation in any of the five known genes - unexplained mutations in other genes or dominant-negative effects are hypothesized

• Brenner and Rector's The Kidney, 2-Volume Set, Chapters 72 & 73
• National Kidney Foundation Primer on Kidney Diseases, 8th Edition, Chapter 14