AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Bartter syndrome, originally described by Bartter and colleagues in 1962, represents a set of closely related autosomal recessive renal tubular disorders characterized by hypokalemia, hypochloremia, metabolic alkalosis, and hyperreninemia with normal blood pressure. The underlying renal abnormality results in excessive urinary losses of sodium, chloride, and potassium. Bartter syndrome has traditionally been classified into 3 main clinical variants: neonatal Bartter syndrome, classic Bartter syndrome, and Gitelman syndrome. Advances in molecular diagnostics have revealed that Bartter syndrome results from mutations in numerous genes that affect the function of ion channels and transporters that normally mediate transepithelial salt reabsorption in the distal nephron segments. 

A modern, and more clinically relevant, classification of Bartter syndrome takes into account the 3 main anatomic and pathophysiologic disturbances that lead to the salt-losing tubulopathy. 

• The first type involves distal convoluted tubule dysfunction that leads to hypokalemia; this is currently known as classic Bartter syndrome or Gitelman syndrome, which can be caused by defects in the NCCT and CLCNKB genes, respectively.
• The second type involves polyuric loop dysfunction that is more severe; this is referred to as antenatal Bartter syndrome or neonatal Bartter syndrome, which is characterized by defects in the NKCC2 and ROMK genes. 
• The third type involves the most severe combined loop and distal convoluted tubule dysfunction and is now referred to as antenatal Bartter syndrome with sensorineural deafness; this is caused by defects in the chloride channel genes CLCNKB and CLCNKA or their beta subunit BSND. 

Pathophysiology

Whereas 60% of the filtered sodium chloride is reabsorbed in the proximal tubule, an additional 30% must be reabsorbed by the thick ascending limb of the Henle loop in order to maintain fluid and electrolyte homeostasis. The reabsorption of sodium in the ascending Henle loop primarily occurs by an electroneutral bumetanide-sensitive sodium-chloride potassium-chloride cotransporter (encoded by the gene NKCC2), with a function driven by the low intracellular concentration of sodium. The low sodium concentration in the cell is maintained by the basolateral membrane sodium-potassium pump, which extrudes sodium. Chloride exits the cell through a basolateral channel or a potassium chloride cotransporter; potassium is secreted in the luminal fluid through the apical ATP-regulated potassium channel (encoded by the ROMK gene) See Media file 1.

Defects in either the sodium-chloride potassium-chloride cotransporter or potassium channel affect the transport of sodium, potassium, and chloride in the thick ascending limb of the loop of Henle. The result is the delivery of large volumes of urine with a high content of these ions to the distal segments of the renal tubule, where only some sodium is reabsorbed and potassium is secreted.

In the subset of patients with neonatal Bartter syndrome, at least 2 genotypes have been identified. Type I results from mutations in the sodium-chloride potassium-chloride cotransporter gene (NKCC2 gene). See Media file 2. Type II results from mutations in the ROMK gene. See Media file 3.

In the classic form of Bartter syndrome, the defect in sodium reabsorption appears to result from mutations in the chloride-channel (CLCNKB) gene; this constitutes type III. The consequent inability of chloride to exit the cell inhibits the sodium-chloride potassium-chloride cotransporter (see Media file 4). Increased delivery of sodium chloride to the distal sites of the nephron leads to salt wasting, polyuria, volume contraction, and stimulation of the renin-angiotensin-aldosterone axis, with resultant hypokalemic metabolic alkalosis. The hypokalemia, volume contraction, and elevated angiotensin levels increase intrarenal prostaglandin E2 synthesis, which contributes to a vicious cycle by further stimulating the renin-aldosterone axis and inhibiting sodium chloride reabsorption in the thick ascending loop of Henle.

Studies have identified a novel type IV Bartter syndrome.^{7, 8, 19} This is a type of neonatal Bartter syndrome associated with sensorineural deafness and has been shown to be caused by mutations in the BSND gene.^{2, 5, 8} This gene encodes barttin, an essential beta-subunit that is required for the trafficking of the chloride channel CLC-K (both ClC-Ka and ClC-Kb) to the plasma membrane in both the thick ascending limb and the marginal cells in the scala media of the inner ear that secrete potassium ion-rich endolymph.⁷ Thus, loss-of-function mutations in barttin cause Bartter syndrome with sensorineural deafness. Therefore, in contrast to other Bartter types, the underlying genetic defect in type IV is not directly in an ion-transporting protein but is instead due to indirect interference with the barttin-dependent insertion in the plasma membrane of chloride channel subunits ClC-Ka and ClC-Kb.

Other observations have identified type V Bartter syndrome. This is a type of neonatal Bartter syndrome associated with sensorineural deafness but with no mutations in the BSND gene. Type V Bartter syndrome has been shown to be a digenic disorder due to loss-of-function mutations in the genes that encode the chloride channel subunits ClC-Ka and ClC-Kb.⁹ The specific genetic defect includes both a large deletion in the gene that encodes ClC-Kb (ie, CLCNKB) and a point mutation in the gene that encodes ClC-Ka (CLCNKA).

A summary of currently identified genotype-phenotype correlations is in the table below. For completion, the gene defect in Gitelman syndrome (the thiazide-sensitive sodium-chloride cotransporter, encoded by the gene NCCT) is also appended.

Bartter Syndrome Genotype-Phenotype Correlations

Frequency

United States

Bartter syndrome is rare; the precise incidence is unknown.

International

The disease is seen throughout the world.

Mortality/Morbidity

Significant morbidity and mortality occur if Bartter syndrome is untreated. With treatment, the outlook is markedly improved; however, long-term prognosis remains guarded because of the slow progression to chronic renal failure.

Race

No racial predilection is recognized.

Sex

The incidence is similar in both sexes.

Age

The neonatal form of the disease can be suspected before birth or can be diagnosed immediately after birth. In the classic form, symptoms begin in neonates or infants aged 2 years or younger.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

The history of patients with Bartter syndrome may include the following:

• Neonatal Bartter syndrome
• • Maternal polyhydramnios, secondary to fetal polyuria, is evident by 24-30 weeks' gestation. Delivery often occurs before term. The newborn has massive polyuria (rate as high as 12-50 mL/kg/h).
  • The subsequent course is characterized by life-threatening episodes of fluid loss, clinical volume depletion, and failure to thrive.
  • A subset of patients with neonatal Bartter syndrome (types IV and V) develop sensorineural deafness.
• Classic Bartter syndrome
• • Patients have a history of maternal polyhydramnios and premature delivery.
  • Symptoms include polyuria, polydipsia, vomiting, constipation, salt craving, tendency for volume depletion, failure to thrive, and linear growth retardation.
  • Other symptoms, which appear during late childhood, include fatigue, muscle weakness, cramps, and recurrent carpopedal spasms.
  • Developmental delay and minimal brain dysfunction with nonspecific electroencephalographic changes are also present.

Physical

Findings with Bartter syndrome include the following:

• Neonatal Bartter syndrome
• • Patients are thin and have reduced muscle mass and a triangularly shaped face, which is characterized by a prominent forehead, large eyes, protruding ears, and drooping mouth.
  • Strabismus is frequently present.
  • Blood pressure is within the reference range.
  • A subset of patients with Bartter syndrome (types IV and V) develop sensorineural deafness, which is detectable with audiometry.
• Classic Bartter syndrome: The patient's facial appearance may be similar to that encountered in the neonatal type. However, this finding is infrequent.

Causes

Causes of Bartter syndrome include the following:

• Neonatal Bartter syndrome
• • An autosomal recessive mode of inheritance is observed in some patients, although many cases are sporadic.
  • In type I Bartter syndrome, loss-of-function mutations in the sodium-chloride potassium-chloride cotransporter gene NKCC2 (locus SLC12A1 on chromosome bands 15q15-21) have been detected.
  • In type II Bartter syndrome, mutations occur in the ROMK gene (locus KCNJ1 on chromosome bands 11q24-25).
  • Newly described genetic defects include type IV (in the BSND gene) and type V (digenic, in both CLCNKB and CLCNKA genes).
• Classic Bartter syndrome
• • Some patients have an autosomal recessive mode of inheritance, although many cases are sporadic.
  • A subset of patients display mutations in the chloride-channel gene CLCNKB (locus CLCNKB on chromosome band 1p36). These represent type III Bartter syndrome.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Cyclical vomiting
Congenital chloride diarrhea
Diuretic abuse
Gitelman syndrome
Gullner syndrome - Familial hypokalemic alkalosis with proximal tubulopathy
Mineralocorticoid excess
Pyloric stenosis

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• Blood and urine chemistries
• • Evaluation of hypokalemia, hypochloremia, and metabolic alkalosis is essential for diagnosis. Hypokalemia is usually severe (1.5-2.5 mEq/L).
  • Hypomagnesemia may be present and necessitates exclusion of Gitelman syndrome, in which hypomagnesemia is a cardinal finding. The differentiation is made by measuring the urinary excretion of magnesium (which is high in Gitelman syndrome and within the reference range in Bartter syndrome) and calcium (which is high in Bartter syndrome and within the referencer range in Gitelman syndrome).
  • Hyperuricemia is present in 50% of patients with Bartter syndrome, whereas in Gullner syndrome (familial hypokalemic alkalosis with proximal tubulopathy), hypouricemia, secondary to impaired proximal tubular function, is present.
  • Renin and aldosterone levels are elevated, but BP remains normal.
• CBC count: Polycythemia may be present from hemoconcentration.
• Renal function
• • The glomerular filtration rate is preserved during the early stages of the disease; however, it may decrease as a result of chronic hypokalemia.
  • Increases in the fractional urinary excretion of sodium, potassium, and chloride are typical.
  • Patients with Bartter syndrome have high urinary excretion of calcium and normal urinary excretion of magnesium.
  • Patients with Gitelman syndrome have low urinary excretion of calcium and high urinary excretion of magnesium.
  • The urinary excretion of prostaglandin E2 is elevated in both neonatal and classic forms of the disease.
• Amniotic fluid: If the diagnosis is being made prenatally, assess the amniotic fluid. The chloride content may be elevated in either Gitelman or Bartter syndrome.

Imaging Studies

• Renal ultrasonography may reveal nephrocalcinosis in neonatal Bartter syndrome.
• Hydronephrosis and hydroureter secondary to chronic polyuria may also be evident.

Other Tests

• An ECG may reveal changes characteristic of hypokalemia such as flattened T waves and prominent U waves.

Procedures

• Although renal biopsy is not usually required, histologic findings may be useful in confirming the diagnosis.

Histologic Findings

• In both neonatal and classic Bartter syndrome, the cardinal finding is hyperplasia of the juxtaglomerular apparatus. Less frequently, hyperplasia of the medullary interstitial cells is present.
• Glomerular hyalinization, apical vacuolization of the proximal tubular cells, tubular atrophy, and interstitial fibrosis may be present as a consequence of chronic hypokalemia.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

Care for patients with Bartter syndrome involves the following:

• Neonatal Bartter syndrome
• • Correct dehydration and electrolyte abnormalities immediately after birth.
  • The cornerstones of medical therapy are the administration of indomethacin and potassium supplementation.
• Classic Bartter syndrome
• • Supplementation with potassium chloride is always necessary but often insufficient.
  • The addition of a potassium-sparing diuretic may be effective initially, but the effect is transient.
  • Correction of hypokalemia is best achieved with prostaglandin synthetase inhibitors, such as indomethacin, acetylsalicylic acid, ibuprofen, or ketoprofen. Indomethacin is prescribed most frequently and is usually well tolerated.

Surgical Care

One approach involves preemptive nephrectomy and renal transplantation in children with severe Bartter syndrome.³ The rationale for this approach lies in the fact that Bartter syndrome is an incurable genetic disease, and the poorly controlled forms may result in frequent life-threatening episodes of dehydration and electrolyte imbalances. Preemptive bilateral nephrectomies and successful kidney transplantation prior to the onset of end-stage renal disease (ESRD) has resulted in correction of metabolic abnormalities and excellent graft function.

Consultations

Consult a pediatric nephrologist to assist with the initial diagnosis and for periodic outpatient evaluation of growth, development, renal function, serum electrolytes, and response to therapy.

Diet

Patients should consume foods and drinks that contain high levels of potassium (eg, tomatoes, bananas, orange juice).

Activity

No restriction on general activity is required, but precautions against dehydration should be taken. Patients should avoid strenuous exercise avoided because of the danger of dehydration and functional cardiac abnormalities secondary to potassium imbalance.

MEDICATION

Section 7 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
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• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Drug Category: Potassium supplements

Correction of hypokalemia is the most important goal of medical therapy.

Drug Category: Prostaglandin synthetase inhibitors

These medications blunt the prostaglandin overproduction, which is responsible for the pressor resistance to angiotensin II and norepinephrine, hyperreninemia and increased sympathoadrenal activity. By inhibiting PGE2 synthesis, they also contribute to the correction of the hemoconcentration defect.

Drug Category: Potassium-sparing diuretics

These medications enhance the effect of potassium supplementation by decreasing urinary potassium losses.

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Further Outpatient Care

• Growth, development, renal function, and serum electrolytes should be evaluated periodically, ideally in a pediatric nephrology clinic. Cases of coexisting growth hormone deficiency that respond to growth hormone therapy with catch-up growth have been reported.

Complications

• Cardiac arrhythmia and sudden death may result from electrolyte imbalances.
• Failure to thrive, growth retardation, and developmental delay are common in untreated patients.
• Chronic hypokalemia results in slow progression to chronic renal insufficiency.
• A significant decrease in bone mineral density has been documented in patients with both neonatal and classic forms.

Prognosis

• The effects of prostaglandin synthetase inhibition include an increase in the plasma potassium concentration (however, this rarely exceeds 3.5 mEq/L), a decrease in the magnitude of polyuria, and improved general well being.
• With treatment, plasma renin and aldosterone levels normalize.
• Therapy improves the patient's clinical condition and allows catch-up growth.
• Bone age is usually appropriate for chronological age, and pubertal and intellectual development are normal with treatment.
• The effectiveness of long-term use of prostaglandin synthetase inhibitors is well established. Some patients may experience a recurrence of hypokalemia, which can be managed by adjusting the indomethacin dose or with potassium supplementation.
• The disease does not recur in the patient with a transplanted kidney.

Patient Education

• Diet: Patients should be educated about which foods have high potassium content.
• Exercise: Patients should avoid strenuous exercise because of the danger of dehydration and functional cardiac abnormalities secondary to potassium imbalance.
• Medication: The importance of compliance with medications should be stressed. Patients should be aware of potential adverse effects of medical therapy, especially GI irritation and bleeding.
• For excellent patient education resources, visit eMedicine's Growth Hormone Deficiency Center. Also, see eMedicine's patient education articles Growth Hormone Deficiency, Growth Failure in Children, Growth Hormone Deficiency in Children, and Growth Hormone Deficiency FAQs.

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to consider Bartter syndrome in patients with hypokalemia, frequent episodes of dehydration, or growth retardation
• Failure to institute therapy with potassium supplements and prostaglandin synthetase inhibitors in young patients

Special Concerns

• Special attention should be paid to correcting electrolyte abnormalities when patients undergo surgical procedures.

ACKNOWLEDGMENTS

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Abubakr Imam, MD, to the development and writing of the initial version of this article.

MULTIMEDIA

Section 11 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  Normal transport mechanisms in the thick ascending limb of the loop of Henle. Reabsorption of sodium chloride is achieved with the sodium-chloride potassium-chloride cotransporter, which is driven by the low intracellular concentrations of sodium, chloride, and potassium. Low concentrations are maintained by the basolateral sodium pump (sodium-potassium adenosine triphosphatase), basolateral chloride channel (ClC-kb), and apical potassium channel (ROMK).
	View Full Size Image
Media type:  Graph

Media file 2:  Type I neonatal Bartter syndrome. Mutations in the sodium-chloride potassium-chloride cotransporter gene result in defective reabsorption of sodium, chloride, and potassium.
	View Full Size Image
Media type:  Graph

Media file 3:  Type II neonatal Bartter syndrome. Mutations in the ROMK gene result in an inability to recycle potassium from the cell back into the tubular lumen, with resultant inhibition of the sodium-chloride potassium-chloride cotransporter.
	View Full Size Image
Media type:  Graph

Media file 4:  Classic Bartter syndrome. Mutations in the ClC-kb chloride channel lead to an inability of chloride to exit the cell, with resultant inhibition of the sodium-chloride potassium-chloride cotransporter.
	View Full Size Image
Media type:  Graph

REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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Article Last Updated: Oct 1, 2008