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A. Characteristics

  1. Familial hypokalemic, hypochloremic (salt losing) metabolic alkaloses
  2. Set of closely related disorders
    1. Classic Bartter Syndrome
    2. Gitelman Syndrome (Bartter variant)
    3. Antenatal Bartter Syndrome
  3. Due to ion channel abnormalities of renal tubular cells
    1. All variants have hypokalemic alkalosis
    2. All variants have high urinary chloride (Cl) excretion, Cl(urine) >20mM
  4. Loss of function mutations in multiple genes can lead to these syndromes
    1. Sodium-potassium-chloride cotransporter (gene SLC12A1, protein NKCC2)
    2. Renal outer medullary potassium channel (gene KCNJ1, protein ROMK)
    3. Basolateral chloride channel (gene CLCNKB, protein CIC-Kb)
    4. Thiazide-sensitive sodium-chloride cotransporter (gene SLC12A3, protein NCCT)
    5. Mutations in two chloride channels can also cause antenatal variant with deafness [3]
  5. Patients have salt-losing tubular disease
  6. Hypertension is NOT present, despite high renin and angiotensin II levels
  7. Treatment generally based on correcting symptoms and electrolyte anomalies
  8. Indomethacin to inhibit prostaglandin secretion is variably effective

B. Classic Bartter Syndrome

  1. Presents in infancy or early childhood
  2. Prematurity or polyhydramnios is uncommon
  3. Delayed growth prominant; mild cognitive developmental deficits
  4. Polyuria and polydipsia
  5. Rare tetany
  6. Hypomagnesemia in ~20%
  7. Normal to high urine calcium
  8. Nephrocalcinosis variable
  9. High urine prostaglandins
  10. Renin-Angiotensin-Aldosterone (RAA) Axis
    1. Renin markedly elevated
    2. Angiotensin II markedly elevated
    3. Aldosterone markedly elevated
  11. Pathogenesis
    [Figure] "Loop of Henle TAL Cell"
    1. This is one syndrome with multiple separate related genetic causes
    2. Primary defect in renal thick ascending limb (Henle) chloride transport
    3. Unclear which of the ion channels involved in chloride transport regulation are mutated
    4. Mutations in CIC-Kb probably cause most cases
    5. Mutations in NCCT, ROMK, and NKCC2 should be evaluated in normal CIC-Kb
    6. Chloride transport regulation is complex (see figure)
  12. Minimal response to indomethacin

C. Gitelman Syndrome [4]

  1. Presents in childhood or adolescence
    1. Prematurity or polyhydramnios is not found
    2. Normal growth and cognitive development
  2. Polyuria and polydipsia may be present
  3. Prominant Neuromuscular Irritability
    1. Positive Chvostek and Trousseau signs (with normal serum calcium levels)
    2. Tremor
    3. Fasciculations
    4. Tetany is common
    5. Presyncope, vertigo, ataxia have been reported
  4. Cardiac Arrhythmias [4]
    1. Electrolyte imbalances may lead to cardiac arrhythmias, syncopal events
    2. Up to 50% of patients may have QTc prolongation
  5. Hypomagnesemia in ~100%
    1. Chondrocalcinosis occurs
    2. Low magnesium blunts release and function of parathyroid hormone (PTH)
    3. This can lead to hypocalcemia (despite chondrocalcinosis)
  6. Calcium
    1. Blood ionized calcium levels are reduced in some patients with Gitelman Syndrome
    2. Low urine calcium
    3. Nephrocalcinosis does not occur
  7. Normal urine prostaglandins 8 RAA Axis
    1. Renin elevated
    2. Angiotensin II elevated
    3. Aldosterone normal to high
  8. Genetics
    [Figure] "Loop of Henle TAL Cell"
    1. About 75% due to mutations in gene SLC12A3 leading to dysufnction of NCCT
    2. About 10% due to mutations ingene CLCNKB leading to dysfunction of CIC-Kb
  9. Treatment
    1. No response to indomethacin
    2. Correct electrolyte anomalies

D. Antenatal Bartter Syndrome
[Figure] "Loop of Henle TAL Cell"

  1. Presents in utero or infancy
  2. Prematurity (31 weeks median) and polyhydramnios is common
  3. Post-Partum Fever and Dehydration
    1. Profound dehydration
    2. Vomiting and diarrhea
    3. Marked electrolyte abnormalities if untreated
    4. Life-threatening condition
  4. Delayed growth and cognitive development
  5. Hypercalciuria prominant with nephrocalcinosis
  6. Prostaglandins
    1. Very high urine prostaglandins (formerly hyperprostaglandin E syndrome)
    2. Urine PGE2 excretion >100ng/hr/1.73m2
  7. RAA Axis
    1. Renin markedly elevated
    2. Angiotensin II markedly elevated
    3. Aldosterone markedly elevated
  8. Tetany does not occur
  9. Hypomagnesemia in uncommon; mild when it occurs
  10. Genetics
    1. Over 50% due to KCNJ1 mutations, ROMK dysfunction
    2. About 20% due to SLC12A1 mutations, NKCC2 dysfunction
  11. Treatment
    1. Excellent (life-saving) response to indomethacin
    2. Correct dehydration and electrolyte anomalies
    3. Consider ACE inhibition

References

  1. Peters M, Jeck N, Reinalter S, et al. 2002. Am J Med. 2002. 112(3):183 abstract
  2. Scheinman SJ, Guay-Woodford L, Thakker RV, Warnock DG. 1999. NEJM. 340(15):1177 abstract
  3. Schlingmann KP, Konrad M, Jeck N, et al. 2004. NEJM. 350(13):1314 abstract
  4. Pachulski RT, Lopez F, Sharaf R. 2005. NEJM. 353(8):850 abstract