Bartter Syndrome

Bartter syndrome is a rare autosomal recessive disorder that affects the kidneys and presents either antenatally with severe or life-threatening manifestations or in childhood or adulthood with a milder course, depending on the genetic defect. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb of the loop of Henle, where 30% of filtered salt is normally reabsorbed. Bartter syndrome is characterized by salt wasting and hypokalemia and presents with electrolyte abnormalities and their consequences, such as vomiting and dehydration. Diagnosis is made by lab testing that shows the typical hypokalemic metabolic alkalosis and hypercalciuria. Additional lab abnormalities include increased serum renin and aldosterone, but patients clinically have normal blood pressure. Management is focused on normalizing serum electrolyte levels. ACE inhibitors and angiotensin receptor blockers are used to improve hypokalemia and limit proteinuria.

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Overview

Definition

Bartter syndrome (BS) is a rare genetic (autosomal recessive) disorder that results from a defect in sodium chloride reabsorption in the thick ascending limb of the loop of Henle, leading to hypokalemia and metabolic alkalosis. The disorder mimics long-term ingestion of a loop diuretic.

Epidemiology

  • Prevalence: 1 in 1 million people in the United States
  • BS is less common than Gitelman syndrome (a similar disorder of the renal tubule, which is seen in 1–10 in 40,000 people).
  • The prevalence of heterozygotes with one of the genetic mutations that cause BS is > 1% in the United States and as high as 3% in Asia.

Pathophysiology and Classification

Normal physiology in the Loop of Henle

In the cells lining the loop of Henle:

  • The sodium/potassium–adenosine triphosphatase (Na+/K+-ATPase) pump on the basolateral membrane brings 3 Na+ out of the cell (into the blood) and 2 K+ into the cell, resulting in:
    • ↓ Intracellular Na+ concentration
    • ↑ Intracellular K+ concentration
  • The Na+/K+-2Cl cotransporter (also known as NKCC2) on the apical membrane reabsorbs 1 Na+, 1 K+, and 2 Cl from the tubular lumen.
    • Electroneutral (2 positive and 2 negative charges moving in the same direction)
    • Driven by the low Na+ concentration within the cell
  • Na+ that is brought in through the NKCC2 is pumped out through the Na+/K+-ATPase
  • Cl that is brought in through the NKCC2 leaves primarily through the NKCC2 on the basolateral membrane (called chloride channel B (ClC-Kb))
    • ClC-Ka (chloride channel Ka) is another chloride channel thought to have redundant functionality
    • A small protein subunit called barttin is required for both ClC-Kb and ClC-Ka to function properly
    • Note: These same chloride channels are found in the ear, and mutations in these channels can lead to deafness.
  • K+ that is brought into the cell through NKCC2 is recycled back into the lumen through the renal outer medullary potassium (ROMK) channels → allows for continued NaCl reabsorption
  • Calcium and magnesium reabsorption:
    • The movement of positively charged K+ into the lumen and negatively charged Cl out of the lumen (and into the blood) causes the lumen to become more positively charged than the peritubular space.
    • This positive charge drives the paracellular reabsorption of Na+, Ca2+, and Mg2+.
Ion transport in the thick ascending limb of the loop of Henle

Ion transport in the thick ascending limb of the loop of Henle
ATPase: adenosine triphosphatase
ClC-Ka: chloride channel Ka
ClC-Kb: chloride channel Kb
NKCC2: Na+/K+-Cl cotransporter 2
ROMK: renal outer medullary potassium

Image by Lecturio.

Pathophysiology in Bartter syndrome

Because of one of several autosomal recessive genetic defects, there is a variable renal tubular disorder characterized by salt-wasting and hypokalemia in all subtypes. 

  • Bartter syndrome is characterized by impairment of NKCC2, which is found in the thick ascending limb of the loop of Henle (TAL). 
  • Impairment of this transporter will ↓ reabsorption in the TAL of:
    • Sodium
    • Potassium
    • Chloride 
  • ↓ Reabsorption of ions →  leads to ↑ distal delivery of these ions 
    • These ions remain in the tubular lumen as the urine travels distally 
    • ↑ Distal delivery of Na+ → ↑ the electronegative gradient across the luminal membrane → ↑ excretion of K+ → hypokalemia
    • ↑ Distal delivery of K+ → ↑ exchange of K+ for H+ in the collected duct → ↑ H+ excretion → metabolic alkalosis
  • ↑ Na+ in the urine → ↑ free water in the urine, resulting in:
    • Impaired ability to concentrate the urine
    • Volume depletion → causes activation of the RAAS and leads to secondary hyperaldosteronism
      • Long-term stimulation of the RAAS causes hyperplasia of the juxtaglomerular apparatus and increased renin levels.
  • ↑ Renal release of prostaglandin E2
    • ↑ Renal blood flow and GFR 
    • ↑ Renin secretion
    • ↑ Na+ and free water excretion  
  • Also urinary loss of calcium and magnesium.
    • ↓ NaCl reabsorption → ↓ Ca2+ and Mg+ reabsorption
    • Calcium wasting in the urine can lead to nephrocalcinosis.
  • Activating mutations in the calcium-sensing receptor (CaSR) on the basolateral membrane can also impair NaCl transport → generates a mild form of BS
    • ↑ CaSR function → ↓ K+ efflux through ROMK → ↓ activity of NKCC2
    • This mutation is autosomal dominant.
    • Also leads to a downward “resetting” of the normal serum calcium range → results in ↓ parathyroid hormone (PTH) and hypocalcemia

Classification by mutations

There is significant genetic heterogeneity in BS; it may result from homozygous or mixed heterozygous mutations in any of the genes that reduce the activity of electrolyte transporters in the TAL. Thus, the severity and clinical presentation of BS vary with each type.

Table: Summary of 5 Bartter syndrome subtypes depending on the gene involved and the transporter being affected
NameTypeDefective proteinSeverity of presentation
Neonatal Bartter syndrome (hyperprostaglandin E syndrome)INKCC2Severe
Neonatal Bartter syndromeIIROMK channelSevere
Classic Bartter syndromeIIIClC-KbMild
Classic Bartter syndrome with sensorineural deafness (hyperprostaglandin E syndrome)IVaBarttin (the β-subunit of ClC-Ka and ClC-Kb)Severe
IVbSimultaneous mutations in ClC-Ka and ClC-KbSevere
Bartter syndrome with hypocalcemia (also called autosomal dominant hypoparathyroidism)VCaSRMild
Different Channelopathies in Bartter’s syndrome

Different channelopathies in Bartter’s syndrome
ATPase: adenosine triphosphatase
ClC-Ka: chloride channel Ka
ClC-Kb: chloride channel Kb
NKCC2: Na+/K+-Cl cotransporter 2
ROMK: renal outer medullary potassium

Image by Lecturio.

Clinical Presentation

The clinical manifestations of BS are mostly due to electrolyte imbalances and their consequences. Symptoms are much less pronounced in heterozygotes. The tubular defects in ion transport produce a clinical disorder that appears similar to that seen with long-term ingestion of a loop diuretic (e.g., furosemide).

Presentations in neonates

Typically seen in types I, II, IVa, and IVb. Common findings include:

  • Polyhydramnios antenatally
  • Preterm birth
  • Sensorineural deafness (types IVa and IVb)
  • Electrolyte abnormalities:
    • Hypokalemia
    • Metabolic alkalosis
    • Hypercalciuria
  • Polyuria
  • Vomiting
  • Diarrhea
  • Emaciation/failure to thrive 
  • Growth and developmental delay
  • Abnormal facial features
    • Prominent forehead
    • Large eyes
    • Strabismus
    • Protruding ears
    • Drooping mouth
Child with Bartter syndrome before treatment

Child with Bartter syndrome showing severe dehydration before treatment

Image: “Bartter’s child before treatment showing severe dehydration” by Sampathkumar K et al. License: CC BY 2.0

Presentations in children, adolescents, and adults

Common findings include:

  • Electrolyte abnormalities:
    • Hypokalemia
    • Metabolic alkalosis
    • Hypercalciuria
    • Hypophosphatemia in occasional patients with secondary hyperparathyroidism
    • Normal or mildly decreased serum magnesium level
  • Vomiting
  • Polyuria and polydipsia due to decreased urinary concentrating ability
  • Abdominal cramping
  • Dehydration/hypovolemia
  • Hypotension
  • Constipation
  • Muscle weakness
  • Renal dysfunction (late manifestation): 
    • Proteinuria
    • ↓ GFR

Diagnosis

The diagnosis of BS is made by lab findings after clinical suspicion arises from the history and physical examination.

History and exam

  • Evaluate for surreptitious vomiting; findings may include:
    • Scarring on the hand from insertion into the mouth
    • Dental erosion
    • Parotitis
  • Rule out unprescribed diuretic use.
  • Ask about family history of nephrocalcinosis.
  • Look for characteristic facial features.
  • Hypotension (Primary hyperaldosteronism will typically present with hypertension.)

Laboratory

  • Serum electrolytes:
    • Unexplained hypokalemia (a key diagnostic feature of BS)
    • Metabolic alkalosis
    • Hypomagnesemia
    • Hypophosphatemia
  • Urine electrolytes:
    • ↑ Urinary chloride (differentiates BS from surreptitious vomiting, which will have a ↓ urine Cl)
    • ↑ Urinary calcium (differentiates BS from Gitelman syndrome, which will have a ↓ urine Ca2+)
    • ↑ Urinary sodium
    • ↑ Urinary potassium
  • Additional lab abnormalities:
    • ↑ Serum renin
    • ↑ Serum aldosterone
    • ↑ Prostaglandin E2
    • ↑ PTH
  • Genetic testing can be considered to look for specific mutations.
  • Prenatal testing:  
    • Amniotic fluid chloride levels may be elevated.
    • Alpha-fetoprotein level is low in antenatal BS.

Management and Complications

The tubular defects in BS cannot be corrected (except by kidney transplantation). The goal of management is to decrease the effects of elevated prostaglandins, renin, and angiotensin in types I, II, and IV.  In the milder adult form, or classic BS, the primary goal is to normalize serum potassium levels.

Prenatal Bartter syndrome with severe polyhydramnios

  • NSAIDs to antagonize the effects of the ↑ prostaglandins 
    • Avoid NSAIDs after 32 weeks of gestation (may cause premature closure of the ductus arteriosus).
    • If NSAIDs are used, repeated ultrasound assessment for the development of tricuspid regurgitation
  • Consider intermittent amniocentesis in the 3rd trimester to treat severe polyhydramnios by draining excessive amniotic fluid.

Neonatal Bartter syndrome types I, II, and IV

  • IV saline infusion may be needed to treat dehydration.
  • Oral potassium supplementation will likely needed.

Childhood or adult Bartter syndrome type III

  • Oral supplementation of electrolytes:
    • To correct fluid and electrolyte imbalances
    • Most likely to require:
      • Potassium
      • Sodium
      • Magnesium
  • NSAIDs:
    • Antagonize the effects of increased prostaglandins
    • Examples: indomethacin, celecoxib
  • Potassium-sparing diuretics:
    • Blocks distal tubule sodium–potassium exchange → can ↑ serum K+ and reverse metabolic alkalosis
    • Examples: amiloride, spironolactone 
  • ACE inhibitors and angiotensin receptor blockers: 
    • Decrease elevated angiotensin II and aldosterone levels
    • Limit proteinuria
    • Increase serum potassium 
  • Kidney transplantation:
    • For rare patients with end-stage renal disease and/or nephrocalcinosis
    • Tubular abnormalities resolve after kidney transplantation, without recurrence.

Complications

  • Cardiac arrhythmias and sudden cardiac death due to electrolyte imbalances
  • Failure to thrive
  • Developmental delay
  • Osteopenia or osteoporosis due to calcium loss in bone

Differential Diagnosis

  • Gitelman syndrome: autosomal recessive disorder caused by one of several mutations in the genes encoding sodium chloride and magnesium transporters in the thiazide-sensitive segments of the distal nephron. Gitelman syndrome is characterized by renal potassium loss, hypokalemia, metabolic alkalosis, hypocalciuria, hypomagnesemia, and hyperreninemic hyperaldosteronism with normal blood pressure. A key feature differentiating Gitelman syndrome from Bartter syndrome is the urine calcium level, which will typically be high-normal in BS and low in GS. 
  • Diuretic abuse with loop diuretics: target the TAL and increase the excretion of sodium, potassium, chloride, calcium, magnesium, and water. Hypokalemia is a common side effect and can be significant. Loop diuretics are used mainly to treat edematous conditions, such as heart failure and cirrhosis, and they may also be used in the management of hypertension.
  • Cyclic vomiting syndrome: condition characterized by recurrent, prolonged episodes of severe nausea and vomiting.  Metabolic alkalosis and hypokalemia may result from GI losses. The cause is unknown and can begin at any age. Episodes of vomiting may last hours or days with symptom-free intervals in between for weeks. Diagnosis is made clinically after ruling out other conditions. Management is aimed at controlling symptoms and avoiding triggers, as well as medications to prevent or relieve nausea.
  • Bulimia nervosa: eating disorder characterized by recurrent episodes of binge eating with inappropriate compensatory behavior, often including self-induced vomiting and/or diuretic, laxative, or thyroid hormone abuse. Bulimia nervosa frequently involves comorbid psychopathology. Treatment consists of psychotherapy and often psychopharmacologic agents.
  • Pyloric stenosis: obstruction of outflow from the stomach due to hypertrophy and hyperplasia of the pyloric sphincter muscle. Pyloric stenosis is the most common cause of GI obstruction in infants. Affected newborns typically present after the 3rd to 5th week of life with progressive nonbilious vomiting and a firm olive-like mass in the epigastrium. Diagnosis is by ultrasonography, and management consists of fluid resuscitation, correction of electrolyte imbalances, and surgery.
  • Hyperaldosteronism: defined as increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Hyperaldosteronism may be primary or may be secondary to other causes. Classically, primary hyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis.  Diagnosis is made by lab testing and imaging of the adrenal glands.  Management involves the use of aldosterone receptor antagonist medications and surgical excision of any aldosterone-secreting tumors.

References:

  1. Emmett, M., Ellison, D. H. (2019).  Bartter and Gitelman syndromes. UpToDate. https://www.uptodate.com/contents/bartter-and-gitelman-syndromes
  2. Bartter syndrome. Retrieved May 5, 2021, from https://rarediseases.info.nih.gov/diseases/5893/bartter-syndrome#:~:text=Bartter%20syndrome%20is%20a%20group%20of%20very%20similar,volume%20of%20fluid%20surrounding%20the%20fetus%20%28amniotic%20fluid%29
  3. Online Mendelian Inheritance in Man. (n.d.). Bartter syndrome, Retrieved May 5, 2021, from https://www.omim.org/entry/607364
  4. Al Shibli, A., Narchi, H. (2015). Bartter and Gitelman syndromes: spectrum of clinical manifestations caused by different mutations. World Journal of Methodology 5(2):55–61.
  5. Bokhari, S.R.A., et al. (2021). Bartter syndrome. StatPearls. Retrieved May 5, 2021, from: https://www.ncbi.nlm.nih.gov/books/NBK442019/

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