Bartter syndrome is an autosomal recessive disorder of salt reabsorption resulting in extracellular fluid volume depletion with low/normal blood pressure. 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.
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:
Bartter syndrome can be secondary to aminoglycoside use. Hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalcemia commonly are seen with an aminoglycoside-induced Bartter-like syndrome.
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.
Bartter syndrome is seen in 1 in 1,000,000 individuals and is much less common than Gitelman syndrome.
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.
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.
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. 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.
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.  Fever, sensorineural deafness, profound polyuria, vomiting, and diarrhea leading to dehydration are common observations after birth.
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.
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.
Hyperprostaglandin E syndrome
Familial hypomagnesemia with hypercalciuria/nephrocalcinosis
Gullner syndrome - Familial hypokalemic alkalosis with proximal tubulopathy
Activating mutations of the CaSR calcium-sensing receptor
Congenital chloride diarrhea
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.
Fortunately, there is no reported recurrence post-renal transplantation.
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.
|||Adult presentation of Bartter syndrome type IV with erythrocytosis., Heilberg IP,Tótoli C,Calado JT,, Einstein (Sao Paulo, Brazil), 2015 Dec [PubMed PMID: 26537508]|
|||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 PMID: 18776122]|
|||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 PMID: 16328537]|
|||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 PMID: 18094726]|
|||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 PMID: 12220510]|
|||Primary molecular disorders and secondary biological adaptations in bartter syndrome., Deschênes G,Fila M,, International journal of nephrology, 2011 [PubMed PMID: 21941653]|
|||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 PMID: 30851722]|
|||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 PMID: 26140272]|
|||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 PMID: 17228161]|
|||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 PMID: 15767821]|