Basics
Description
- Bartter syndrome is a hereditary renal salt-wasting tubulopathy characterized by hypokalemic, hypochloremic metabolic alkalosis and normal or low blood pressure.
- The genetic defect is localized to the thick ascending limb of the loop of Henle.
- Timing and severity of presentation are variable depending on the type of genetic defect.
- Two phenotypes:
- Antenatal (types I, II, and IV)
- Associated with polyhydramnios and premature delivery
- Presents in the first 4-6 weeks of life, often with polyuria and signs/symptoms of severe dehydration
- Associated with hypercalciuria and nephrocalcinosis
- Type IV is associated with sensorineural deafness.
- Classic (type III)
- Symptoms begin at age 2 years and diagnosis is usually made later in childhood or during adolescence.
Epidemiology
- Bartter syndrome is a very rare disorder.
- Prevalence: 1 per million
- Prevalence is higher in areas where consanguinity is common.
Etiology
- Mode of transmission: autosomal recessive except for type V which is autosomal dominant
- Five genetic subtypes and their various genetic defects:
- Type I: sodium-potassium-chloride cotransporter (NKCC)
- Type II: potassium channel (ROMK)
- Type III: chloride channel (ClC-Kb)
- Type IV: barttin protein
- Type V: Calcium-sensing receptor associated with autosomal dominant hypocalcemia
Pathophysiology
- Mutations in NKCC, ROMK, barttin, or ClC-Kb result in the Bartter syndrome phenotype of salt wasting and hypokalemia by disrupting the molecular pathways for electrolyte transport in the thick ascending limb as described below.
- In the thick ascending limb of the loop of Henle, approximately 25% of filtered sodium chloride is reabsorbed via the sodium-potassium-2-chloride cotransporter (NKCC2), which is the target of loop diuretics such as furosemide.
- Potassium exits the cell via potassium channels (ROMK) on the apical (lumen) side of the tubule and is recycled via the NKCC2, thus permitting continued sodium chloride reabsorption.
- Chloride exits the cell and enters the bloodstream via a basolateral chloride channel (ClC-Kb) that is anchored by an accessory protein, barttin.
- A calcium-sensing receptor on the blood (basolateral) side, when activated by calcium, inhibits ROMK activity, which interferes with NKCC activity. A gain-of-function mutation in the calcium-sensing receptor results in a Bartter-like syndrome (type V).
- Calcium and magnesium are normally reabsorbed paracellularly in the thick ascending limb, driven by the lumen-positive potential that is created by sodium chloride transport across NKCC.
- Hypercalciuria, and sometimes hypermagnesuria, occurs due to decreased paracellular transport of calcium and magnesium in the setting of salt wasting.
- Renin and aldosterone levels are typically increased (triggered by volume depletion) and contribute to metabolic alkalosis and hypokalemia.
- A functional thick ascending limb is necessary for the function of the countercurrent multiplier that is responsible for renal concentrating ability; impaired function of the thick ascending limb results in impaired urinary concentration.
- Prostaglandin E levels are typically very elevated in Bartter syndrome.
Diagnosis
History
- Dehydration
- Emesis
- Diarrhea
- Recurrent fevers
- Failure to thrive
- Polydipsia
- Polyuria
- Growth retardation
- Anorexia
- Symptoms of hypokalemia
- Muscle weakness
- Constipation
- Cognitive and developmental delay
- Salt craving
- Seizures
- Kidney stones (antenatal Bartter)
- History of hearing loss (antenatal Bartter)
Physical Exam
- Constitutional: failure to thrive
- Head: large forehead
- Eyes: large eyes
- Ears: protuberant
- Face: triangular facies
- Neurologic: developmental and cognitive delay
- Skin: decreased turgor, prolonged capillary refill
Diagnostic Tests & Interpretation
Lab
- Serum electrolytes
- To identify the presence of hypochloremic metabolic alkalosis and hypokalemia
- Phosphorus level (can be low)
- Serum creatinine: to evaluate GFR
- Urine electrolytes
- Urine chloride is typically > 10 mEq/day.
- Urine sodium and potassium are elevated.
- Urinalysis
- Low specific gravity due to urinary concentrating defect
- Random urine for calcium/creatinine ratio
- To detect hypercalciuria
- Normal values are age-dependent.
- Renin level (typically elevated)
- 24-hour urine aldosterone excretion (typically elevated)
Imaging
Renal ultrasound: to determine presence of nephrocalcinosis and kidney stones
Diagnostic Procedures/Other
Differential Diagnosis
- Chronic or cyclical vomiting
- Chloride-losing diarrhea
- Pyloric stenosis
- Cystic fibrosis
- Diuretic abuse
- Gitelman syndrome
- Mineralocorticoid excess
Treatment
Medication
- Sodium chloride supplementation
- Potassium chloride supplementation
- Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin
- Potassium-sparing diuretic such as spironolactone to help counter hypokalemia
- Angiotensin-converting enzyme inhibitors
- Growth hormone
Additional Therapies
General Measures
- High-salt and high-potassium diet
- Adequate fluid intake to match urinary losses in the setting of salt wasting and polyuria
Ongoing Care
Follow-up Recommendations
- Frequent monitoring of serum electrolytes
- Close follow-up of linear growth
- Monitor for signs of kidney stone.
Prognosis
Can progress to chronic kidney disease or end-stage renal disease due to hypokalemia-induced interstitial disease and concurrent chronic NSAID use
Additional Reading
- Chadha V, Alon US. Hereditary renal tubular disorders. Semin Nephrol. 2009;29(4):399-411. [View Abstract]
- Fremont OT, Chan JC. Understanding Bartter syndrome and Gitelman syndrome. World J Pediatr. 2012;8(1):25-30. [View Abstract]
- Seyberth HW. An improved terminology and classification of Bartter-like syndromes. Nat Clin Pract Nephrol. 2008;4(10):560-567. [View Abstract]
Codes
ICD09
ICD10
- E26.81 Bartter's syndrome
SNOMED
- 71275003 Pseudoprimary aldosteronism (disorder)
- 700107006 Bartter syndrome antenatal type 1 (disorder)
- 700109009 Bartter syndrome antenatal type 2 (disorder)
- 700112007 Bartter syndrome type 4 (disorder)
- 236465009 Bartter's syndrome with hypercalciuria and nephrocalcinosis (disorder)
- 700111000 Bartter syndrome type 3 (disorder)
FAQ
- Q: Can Bartter syndrome be treated with renal transplantation?
- A: Yes. A few cases of renal transplantation in Bartter syndrome have been described for correction of severe electrolyte disorders, growth disturbances, or treatment of chronic kidney disease.
- Q: How can vomiting be distinguished from Bartter syndrome?
- A: In vomiting, urine chloride is typically <10 mEq/L, whereas in Bartter syndrome, the urine chloride is typically much higher (typically >40 mEq/L).
- Q: How does Bartter syndrome differ from Gitelman syndrome?
- A: Gitelman syndrome is a defect of the thiazide-sensitive sodium chloride cotransporter in the distal convoluted tubule. Patients with Gitelman syndrome also present with hypokalemic metabolic alkalosis but typically have hypocalciuria in contrast to normal or increased urinary calcium in patients with Bartter syndrome. Patients with Gitelman also typically have persistent hypomagnesemia and high urinary fractional excretion of magnesium. In addition, patients with Gitelman syndrome typically have a blunted thiazide response (manifested by an increase in the fractional excretion of chloride after thiazide administration), whereas patients with Bartter syndrome will respond to thiazide diuretics
- Q: How can Bartter syndrome be distinguished from diuretic abuse?
- A: Both Bartter syndrome and diuretic abuse will present with similar electrolyte abnormalities and an elevated urinary chloride. The best test for diuretic abuse is a urinary diuretic screen.
- Q: What is the role of genetic testing in Bartter syndrome?
- A: Genetic testing is available but is currently expensive and may not include all known or as yet unrecognized mutations, which limits its use.