How does Bartter's disease cause hypokalemia?

Pathophysiology of Hypokalemia in Bartter Syndrome

Bartter syndrome causes hypokalemia primarily through impaired salt reabsorption in the thick ascending limb of the loop of Henle, leading to renal tubular salt wasting that activates the renin-angiotensin-aldosterone system, resulting in hypokalemic metabolic alkalosis. 1, 2

Primary Molecular Defect and Pathophysiological Cascade

• Bartter syndrome encompasses five different inherited salt-losing tubulopathies (BS1-5) caused by mutations in genes encoding transporters and channels in the thick ascending limb of the loop of Henle 1, 2

• The molecular defects affect proteins essential for salt reabsorption:

  • NKCC2 (sodium-potassium-chloride cotransporter) in BS1
  • ROMK (renal outer medullary potassium channel) in BS2
  • ClC-Kb (chloride channel) in BS3
  • Barttin (accessory subunit for chloride channels) in BS4a
  • ClC-Ka and ClC-Kb in BS4b
  • MAGE-D2 in BS5 1, 2

• These mutations result in impaired sodium, potassium, and chloride reabsorption in the thick ascending limb, causing increased distal delivery of these electrolytes 2

Renin-Angiotensin-Aldosterone Activation

• The salt wasting leads to volume contraction, which activates the renin-angiotensin-aldosterone system 1, 2
• The tubuloglomerular feedback is altered at the macula densa level, which senses low tubular chloride concentrations 1
• This activates cyclooxygenases (primarily COX-2) to produce high amounts of prostaglandins (primarily prostaglandin E2) 1, 2
• Prostaglandins stimulate further renin secretion and aldosterone production, creating a vicious cycle 1, 2

Mechanism of Potassium Loss

• Increased aldosterone levels enhance sodium reabsorption in the distal tubule and collecting duct 2
• This increased sodium reabsorption creates a more negative electrical potential in the tubular lumen 2
• The negative electrical gradient promotes potassium secretion into the tubular lumen, resulting in renal potassium wasting and hypokalemia 2, 3
• The increased distal sodium delivery further exacerbates potassium secretion in the distal nephron 2

Associated Electrolyte Abnormalities

• Hypochloremic metabolic alkalosis develops due to:
  • Increased bicarbonate reabsorption secondary to volume contraction
  • Increased hydrogen ion secretion in the distal tubule (stimulated by aldosterone)
  • Loss of chloride in excess of sodium 2, 4
• Hypercalciuria and nephrocalcinosis occur in some forms (particularly BS1 and BS2) due to reduced calcium reabsorption in the thick ascending limb 1, 2
• Impaired salt reabsorption also leads to blunting of the osmotic gradient in the renal medulla, causing isosthenuria (inability to concentrate or dilute urine) 1, 2

Clinical Manifestations of Hypokalemia

• Patients require lifelong potassium supplementation, often at high doses (5.0 mEq/kg/day in children, 2.1 mEq/kg/day in adults) 5
• Symptoms include failure to thrive, growth retardation, muscle weakness, tetany, and fatigue 2, 3
• Chronic hypokalemia may contribute to long-term complications such as nephrocalcinosis and chronic kidney disease 5, 3

Treatment Implications

• NSAIDs are a mainstay of treatment as they reduce prostaglandin production, thereby decreasing renin and aldosterone levels 2, 3
• Potassium-sparing diuretics may help manage severe hypokalemia by blocking the effect of aldosterone 3, 6
• Sodium chloride supplementation (5-10 mmol/kg/day) is often required to address salt wasting 2

Diagnostic Pearls

• Fractional excretion of chloride is typically elevated (>0.5%) despite hypochloremia, which helps distinguish Bartter syndrome from other causes of hypokalemia 4
• Elevated renin and aldosterone levels with normal blood pressure are characteristic findings 2, 7