Bartter Syndrome


Article Author:
Syed Rizwan Bokhari
Hassam Zulfiqar


Article Editor:
Abeera Mansur


Editors In Chief:
Linda Lindsay


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
8/28/2019 12:30:11 PM

Introduction

Bartter syndrome is an autosomal recessive disorder of salt reabsorption resulting in extracellular fluid volume depletion with low/normal blood pressure.[1] It is characterized by several electrolyte abnormalities including low potassium and chloride and, in few cases, hypomagnesemia. Other abnormalities include high renin, secondary hyperaldosteronism, and elevated levels of prostaglandin E2. Acid-base manifestation is typically metabolic alkalosis.

Patients often present in infancy with failure to thrive. Various phenotypes are classified according to the site of impaired salt transport.

Important clinical variants are: Neonatal (antenatal) Bartter syndrome, classical Bartter syndrome, and Gitelman syndrome.

Etiology

Impairment in the sodium-potassium-chloride cotransporter (NKCC2) or the potassium channel (ROMK) affect the transport of sodium, potassium, and chloride in the thick ascending limb of the loop of Henle (TALH). This results in increased distal delivery of these ions, where only some sodium is reabsorbed, and potassium is secreted.

Types of Bartter syndrome:

  • Type I results from mutations in the sodium chloride/potassium chloride cotransporter gene (NKCC2)
  • Type II results from mutations in the ROMK gene 
  • Type III results from mutations in the chloride channel gene (CLC-Kb)
  • Type IV results from the loss-of-function mutations in gene encoding barttin [2][3]
  • Type V results from mutations in extracellular calcium ion-sensing receptor and in the genes that encode the chloride channel subunits, ClC-Ka and ClC-Kb[4]

Bartter syndrome can be secondary to aminoglycoside use. Hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalcemia commonly are seen with an aminoglycoside-induced Bartter-like syndrome.[5]

An antenatal variant of Bartter syndrome presents with severe hypokalemia, metabolic alkalosis, and profound systemic manifestations. Bartter syndrome III and V usually present later in life and have mild symptoms.

Epidemiology

Bartter syndrome is seen in 1 in 1,000,000 individuals and is much less common than Gitelman syndrome.

Pathophysiology

Bartter syndrome is a renal tubular salt-wasting disorder in which the kidneys cannot reabsorb sodium and chloride in the thick ascending limb of the loop of Henle. This leads to increased distal delivery of salt and excessive salt and water loss from the body. The resultant volume depletion causes activation of the renin-angiotensin-aldosterone system (RAAS) and subsequent secondary hyperaldosteronism. Long-term stimulation causes hyperplasia of the juxtaglomerular apparatus and hence increased renin levels.[6]

Excessive distal delivery of sodium results in enhanced distal convoluted tubule sodium reabsorption and exchange with the negatively charged potassium or hydrogen ion and leads to increased loss of potassium in urine and increased hydrogen H secretion. Decreased chloride reabsorption leads to a decreased exchange of bicarbonate for chloride, thus increased bicarbonate retention and hypokalemia results in metabolic alkalosis.[7]

Urinary concentrating and diluting abilities are compromised in Bartter syndrome. Impaired urinary concentrating ability is secondary to defective sodium absorption in the loop of Henle.[8] Under normal circumstances, salt absorption in the loop of Henle in the presence of normal ADH is the main driving force for maintaining concentration gradient in medulla needed for concentrated urine formation. Other implicated factors include polyuria, hypokalemia, and elevated prostaglandin E2 levels. The defective sodium chloride transport in the loop of Henle associated with Bartter syndrome leads to the impaired electrochemical gradient, which is necessary for calcium and magnesium reabsorption, leading to increased urinary loss of calcium and magnesium.

Nephrocalcinosis commonly is seen in patients with Bartter syndrome. Likely explanation is secondary to excess calcium wasting in urine. Chloride transporters malfunction in the thick ascending limb of loop of Henle (TAL), resulting in malabsorption of calcium in TAL. Under normal conditions, calcium and magnesium are absorbed paracellularly under the influence of positive charge in lumen due to reabsorption of negatively charged chloride ions.

History and Physical

A thorough history, including family history and detailed physical examination, are helpful. Bartter syndrome usually is seen in children and adolescents who also have stunted growth and complaints of polyuria, polydipsia, cramps, vomiting, dehydration, constipation, growth delays, and failure to thrive. A family history of nephrocalcinosis and detailed personal history ruling out the possibility of surreptitious vomiting and diuretic abuse should be practiced before making the diagnosis. Patients usually are emaciated with prominent forehead, large eyes, strabismus, protruding ears, sensorineural deafness, and drooping mouth. Normal or low blood pressures usually are recorded. Long-standing cases may present with elevated blood pressures.

Offspring with antenatal Bartter syndrome present with polyhydramnios secondary to intrauterine polyuria and usually are delivered prematurely. [9] Fever, sensorineural deafness, profound polyuria, vomiting, and diarrhea leading to dehydration are common observations after birth.

Evaluation

Diagnosis is made by pertinent findings in the history and physical exam, potentiated with specific laboratory abnormalities. Bartter syndrome is associated with electrolyte and acid-base abnormalities, including hypokalemia and metabolic alkalosis in almost all cases. Other abnormalities include increased serum renin and aldosterone levels with decreased magnesium and phosphate levels in few patients. Urine electrolytes show elevated sodium, potassium, and PGE2 excretion. Elevated 24-hour urine calcium excretion helps exclude Gitelman syndrome, which is associated with low calcium excretion. Spot urine chloride concentration helps differentiate from surreptitious vomiting, where it is less than 25 meq/L. Usually, urine chloride is elevated (greater than 35 meq/L) in Bartter syndrome.

Polyhydramnios and intrauterine growth retardation are seen on ultrasound with the neonatal Barrter syndrome. Amniotic fluid chloride levels may be elevated.

Abdominal radiographs, intravenous pyelograms (IVPs), renal ultrasonograms, or spiral CT scans can be done to document nephrocalcinosis. Genetic testing can be considered to rule out specific mutations.

Treatment / Management

A saline infusion may be needed in the neonatal period. The target is to normalize potassium levels in serum which can be achieved with oral potassium supplementation such as kcal 25 to 100 mmol/day. ACE inhibitors and angiotensin receptor blockers (ARB) help decrease elevated angiotensin II and aldosterone levels, limit proteinuria, and increase serum potassium in some cases. Other options include Amiloride 5 to 40 mg/day, spironolactone, NSAID (indomethacin 1-3 mg/kg/24 hour) to antagonize increased urine PGE2 level. Magnesium supplementation should be considered, as hypomagnesemia may aggravate potassium wasting.

Tubular abnormalities usually are resolved after kidney transplantation with no recurrence.

Differential Diagnosis

  • Diuretic abuse

  • Cyclical vomiting

  • Hyperprostaglandin E syndrome

  • Familial hypomagnesemia with hypercalciuria/nephrocalcinosis

  • Pyloric stenosis

  • Gitelman syndrome

  • Cystic fibrosis

  • Gullner syndrome - Familial hypokalemic alkalosis with proximal tubulopathy

  • Mineralocorticoid excess

  • Activating mutations of the CaSR calcium-sensing receptor

  • Hypomagnesemia

  • Congenital chloride diarrhea

  • Hypochloremic alkalosis

  • Hypokalemia

Pearls and Other Issues

Bartter syndrome is difficult to treat and has no complete cure available to date. Untreated cases are associated with significant morbidity and mortality with a major contribution from chronic kidney disease. Overall prognosis depends on the extent of receptor malfunction, and despite these facts, most patients can lead normal lives with strict compliance with their treatment plan. Early recognition and treatment in childhood can prevent growth retardation.

The Bartter-like syndrome associated with aminoglycosides can be seen for 2 to 6 weeks after termination of antibiotics. Close monitoring and prompt replacement of potassium, calcium, and magnesium are recommended.[10]

Fortunately, there is no reported recurrence post-renal transplantation.

Enhancing Healthcare Team Outcomes

Bartter syndrome is difficult to recognize. Untreated cases are associated with significant morbidity and mortality, as such the healthcare team including nurses, nephrology nurses, nurse practitioners, physician assistants, and physicians must work together to identify and manage the treatment. The pharmacist should evaluate medication choice,  drug-drug interactions, and compliance. The nurse should assist with the coordination of care in the interdisciplinary team and patient education.

The team should be aware Bartter-like syndrome is associated with aminoglycoside and can be seen for 2 to 6 weeks after termination of antibiotics. This requires the team to monitor the patient closing and provide prompt replacement of potassium, calcium, and magnesium as needed.


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Bartter Syndrome - Questions

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A 16-year-old male has weakness, problems walking, excessive thirst, and increased urination. The child has not had any gastrointestinal issues and is on no medications. The vital signs and physical exam is normal. Laboratory tests reveal a sodium 140 meq/L, potassium 2.4 meq/L, bicarbonate 31 meq/L, and chloride 102 meq/L. A 24-hour urine collection shows sodium 210 mmol, potassium 52 mmol, chloride 32 mmol, and calcium 20 mmol. There is bilateral symmetrical enlargement of the kidneys but no hydronephrosis on ultrasound. Plasma renin is elevated. Which of the following is the most likely pathophysiology?



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A 15-month-old male has shown poor growth and has intermittent constipation. He has had three admissions for dehydration in the past 6 months. On examination, he was an emaciated baby with anthropometric measurements at <5th percentile. Serum electrolytes were deranged showing hyponatremia and hypokalemia. Serum renin and aldosterone were raised (renin-9.33 ng/dl and aldosterone-36 ng/dl). Serum magnesium, calcium and ultrasound KUB were normal. Which of the following is the most likely diagnosis?



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A 7-year-old boy presented with complaints of weakness, lethargy, and polyuria. There was no history of vomiting or any drug intake. On examination, pulse 88/min, temp 98.5 F, BP 110/70 mmHg. Labs showed sodium 139 mEq/L, potassium 2.4 mEq/L, bicarbonate 32 mEqL, Chloride 101 mEq/L. 24-hour urine sodium 189 mEq/d, potassium 48 mEq/d, and chloride 99 mEq/L. Plasma renin level was elevated, renal ultrasound showed normal sized kidneys with no gross abnormality. What is the most likely diagnosis?



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A 16-year-old boy with Bartter syndrome comes to the clinic for refills of his medications, but he did not bring the prescription with him. His blood pressure is 96/60 mmHg. Recent laboratory tests reveal serum sodium of 140 meq/L, potassium 2.4 meq/L, bicarbonate 31 meq/L, and chloride 102 meq/L. A 24-hour urine collection shows sodium 210 mmol, potassium 52 mmol, chloride 32 mmol, and calcium 20 mmol. Which of the following is most likely to be the prescribed medication?



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A preterm male baby is born at 33 weeks of a consanguineous marriage to a multigravida mother by an emergency cesarean section for severe polyhydramnios. There is a history of previous two miscarriages due to unknown reasons. By 7th postnatal day, the baby has lost 12% of his birth weight. There is no history of diarrhea or vomiting. Examination findings are suggestive of symmetrical growth retardation. Chest x-ray and renal ultrasound are normal. ABGs shows metabolic alkalosis, and serum electrolytes reveal hypochloremia, hyponatremia, hypokalemia, and normocalcaemia. Urinary sodium, chloride, and potassium are high, and 24-hour urinary calcium comes out to be normal. What is the most likely diagnosis?



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Bartter Syndrome - References

References

Primary molecular disorders and secondary biological adaptations in bartter syndrome., Deschênes G,Fila M,, International journal of nephrology, 2011     [PubMed]
Disease-causing dysfunctions of barttin in Bartter syndrome type IV., Janssen AG,Scholl U,Domeyer C,Nothmann D,Leinenweber A,Fahlke C,, Journal of the American Society of Nephrology : JASN, 2009 Jan     [PubMed]
A compound heterozygous mutation in the BSND gene detected in Bartter syndrome type IV., Kitanaka S,Sato U,Maruyama K,Igarashi T,, Pediatric nephrology (Berlin, Germany), 2006 Feb     [PubMed]
Mechanisms of Disease: the kidney-specific chloride channels ClCKA and ClCKB, the Barttin subunit, and their clinical relevance., Krämer BK,Bergler T,Stoelcker B,Waldegger S,, Nature clinical practice. Nephrology, 2008 Jan     [PubMed]
Prenatal diagnosis of Bartter syndrome with biochemical examination of amniotic fluid: case report., Dane B,Yayla M,Dane C,Cetin A,, Fetal diagnosis and therapy, 2007     [PubMed]
Adult presentation of Bartter syndrome type IV with erythrocytosis., Heilberg IP,Tótoli C,Calado JT,, Einstein (Sao Paulo, Brazil), 2015 Dec     [PubMed]
Bartter and Gitelman syndromes: Spectrum of clinical manifestations caused by different mutations., Al Shibli A,Narchi H,, World journal of methodology, 2015 Jun 26     [PubMed]
Aminoglycoside antibiotics induce pH-sensitive activation of the calcium-sensing receptor., McLarnon S,Holden D,Ward D,Jones M,Elliott A,Riccardi D,, Biochemical and biophysical research communications, 2002 Sep 13     [PubMed]
Acquired bartter-like syndrome associated with gentamicin administration., Chou CL,Chen YH,Chau T,Lin SH,, The American journal of the medical sciences, 2005 Mar     [PubMed]
Soylu Ustkoyuncu P,Nalcacioglu H,Bastug F,Yel S,Altuner Torun Y, Association of Mucopolysaccharidosis Type 4A and Bartter Syndrome. Iranian journal of kidney diseases. 2019 Jan;     [PubMed]

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