Bartter syndrome overview

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Main article:Bartter syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Tayyaba Ali, M.D.[2]

Overview

Bartter syndrome was first discovered by Bartter et al.and introduced in a seminal paper in the December issue of the American Journal of Medicine in 1962. Authors in the paper reported two pediatric patients with growth and developmental delay associated with hypokalemic alkalosis and normal blood pressure despite high aldosterone production. The syndrome named after Bartter. This disease was observed in children as well as in adults, females as well as males.Authors described in the paper that this disease is characterized by hypokalemia, metabolic alkalosis, hyperreninemia, secondary hyperaldosteronism, and normal blood pressure.Bartter Syndrome can be classified into five different types based on genotype. Bartter syndrome can result from homozygous or mixed heterozygous mutations in any of the genes. Thus, affecting the function of genes responsible for synthesis or membrane insertion of the transporters in the ascending limb of the loop of Henle. Bartter syndrome types 1, 2, and 4 present at a younger age. They present with symptoms, often quite severe in the neonatal period. Bartter syndrome type 3 also called classic Bartter syndrome present later in life and maybe sporadically asymptomatic or mildly symptomatic. The thick ascending limb of the loop of Henle is not permeable to water and reabsorbs a large proportion of the filtered sodium chloride as shown in the figure, which leads to interstitial hypertonicity that powers the countercurrent exchange and urinary concentration mechanisms. In case of impairment of this function, a major loss of water and sodium occurs, as seen with loop diuretics.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. Impairment of sodium and chloride reabsorption is the primary defect in the Bartter syndrome that initiates the cascade. This leads to increased delivery of salt to the distal tubules 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 elevates renin levels. Excessive distal delivery of sodium follows by sodium (Na) reabsorption in the distal convoluted tubule. Na reabsorption exchange with the secretion of positively charged potassium or hydrogen ion and leads to increased loss of potassium (K+) in urine and increased hydrogen (H+) secretion. Decreased chloride (Cl-) reabsorption decreases the exchange with bicarbonate (HCO3-). Thus, increased bicarbonate retention and hypokalemia result in metabolic alkalosis. Calcium and magnesium reabsorb in the ascending limb of the loop of Henle as a result of a positive electrochemical gradient in the lumen created by the back leak of K+ ion in the lumen, drives passive paracellular sodium, calcium, and magnesium reabsorption as shown in the figure. The defective sodium chloride transport in the ascending limb of the loop of Henle associated with Bartter syndrome leads to the impaired electrochemical gradient leading to increased urinary loss of calcium and magnesium. This leads to the development of nephrocalcinosis in Bartter syndrome. Bartter syndrome can be caused by mutations in at least five genes. Mutations in the SLC12A1 gene cause type I. Type II results from mutations in the KCNJ1 gene. Mutations in the CLCNKB gene are responsible for type III. Type IV can result from mutations in the BSND gene or from a combination of mutations in the CLCNKA and CLCNKB genes as shown in the table. Aminoglycoside can induce Bartter syndrome presenting with severe hypokalemia, metabolic alkalosis, and profound systemic manifestations. Bartter syndrome diagnosis should be differentiated from other diseases manifesting with hypokalemia and hypochloremic metabolic alkalosis such as Gitelman syndrome, EAST syndrome also is known as SeSAME syndrome, Diuretic abuse, cyclical vomiting, Hyperprostaglandin E syndrome(HPS), Familial hypomagnesemia, cystic fibrosis, Gullner syndrome, Mineralocorticoid excess, Activating mutation of the calcium-sensing receptor (CaSR) gene, Hypomagnesemia is often associated with hypokalemia, hypocalcemia, and metabolic alkalosis, Congenital chloride diarrhea, Hypochloremic alkalosis and Hypokalemia. Prolonged hypokalemia can lead to impaired ability of kidneys to concentrate urine, increased bicarbonate reabsorption. The prevalence of Barter Syndrome is approximately 1 in 1,000,000 individuals. The annual incidence of the syndrome has been estimated at 1.2 per million people. According to a review of twenty-eight patients with Bartter syndrome during the years 1964-1986 who were followed for an average of 10 years, their mean age at the time of diagnosis was 32.9 years. These patients were observed to have short stature than normal subjects. Bartter syndrome usually occurs in childhood. Bartter syndrome type I and type II are salt-wasting renal tubular disorders that are clinically characterized by polyhydramnios leading to premature delivery, marked polyuria, and a tendency towards nephrocalcinosis. Common complications of Bartter syndrome include Gallstones, Rhabdomyolysis, Prolonged QT interval, Life-threatening arrhythmia, Syncope, Sudden death, weakening of the bones and Renal failure. The limited prognostic information available suggests that early diagnosis and appropriate treatment of infants and young children with classic Bartter Syndrome (type 3) may improve growth and perhaps neuro-intellectual development. On the other hand, sustained hypokalemia and hyperreninemia can cause progressive tubulointerstitial nephritis, resulting in end-stage renal disease (Kidney failure). With the early treatment of the electrolyte imbalances, the prognosis for patients with Classic Bartter Syndrome is good. Patients with Bartter syndrome type I and II tend to present a satisfactory prognosis after a median follow-up of more than 10 years. Bartter syndrome is an autosomal recessive disorder that often presents in childhood and may be associated with stunted growth, mental retardation, hypokalemia, metabolic alkalosis, polyuria and polydipsia, normal to increased urinary calcium excretion, normal or mildly decreased serum magnesium concentration, hypophosphatemia and hypercalciuria. Laboratory findings such as Hypokalemia, Metabolic alkalosis, Elevated plasma renin and aldosterone, Elevated urine potassium and chloride, Low serum and urine magnesium levels. Abdominal radiographs and intravenous pyelograms (IVPs) can be done to document nephrocalcinosis. Polyhydramnios and intrauterine growth retardation are seen on ultrasound with the neonatal Barrter syndrome. There are no echocardiographic findings associated with Bartter syndrome. Genetic analysis is required to make an accurate diagnosis. Amniotic fluid chloride concentration ranged from 114 to 123 mEq/L has been reported in four newborns Bartter syndrome patients. In Bartter syndrome, a biopsy of the kidney typically shows redundant growth of kidney cells called the juxtaglomerular apparatus. However, this is not found in all patients, especially in young children. Prostaglandin synthetase inhibitors suppress the production of prostaglandin. Potassium chloride supplements are given for hypokalemia. Spironolactone, Amiloride, Triamterene, Angiotensin-converting enzyme (ACE) inhibitors, Nonsteroidal drug anti-inflammatory drugs (NSAID) are given to patients for the treatment of Bartter syndrome. Growth hormone (GH) is given for growth retardation. Calcium or magnesium supplements are given for muscle spasm and tetany. Bilateral nephrectomy and kidney transplantation have been performed successfully, in two patients with severe neonatal Bartter syndrome.

Historical Perspective

Bartter syndrome was first discovered by Bartter et al.and introduced in a seminal paper in the December issue of the American Journal of Medicine in 1962. Authors in the paper reported two pediatric patients with growth and developmental delay associated with hypokalemic alkalosis and normal blood pressure despite high aldosterone production. The syndrome named after Bartter. This disease was observed in children as well as in adults, females as well as males.Authors described in the paper that this disease is characterized by hypokalemia, metabolic alkalosis, hyperreninemia, secondary hyperaldosteronism, and normal blood pressure.

Classification

Bartter Syndrome can be classified into five different types based on genotype. Bartter syndrome can result from homozygous or mixed heterozygous mutations in any of the genes. Thus, affecting the function of genes responsible for synthesis or membrane insertion of the transporters in the ascending limb of the loop of Henle.

• Bartter syndrome type 1: Mutation in NKCC2 gene results in impairment of sodium-potassium-chloride. cotransporter (Na-K-2Cl) in the apical membrane.
• Bartter syndrome type 2: Mutation in ROMK gene results in defective functioning of the luminal potassium channel.
• Bartter syndrome type 3: Mutation in the ClC-Kb gene results in the impairment of the basolateral chloride channel.
• Bartter syndrome type 4: Defects that reduce the activity of both ClC-Ka and ClC-Kb cause Bartter syndrome associated with sensorineural deafness (types IV and IVb).
• Bartter syndrome type 5: It results from a gain-of-function mutation in the Ca-sensing receptor (CaSR). A gain-of-function mutation in CaSR in the basolateral membrane of the thick ascending limb enhances the function of this receptor. This results in hypocalcemia and impairs sodium chloride transport.

Bartter syndrome types 1, 2, and 4 present at a younger age. They present with symptoms, often quite severe in the neonatal period. Bartter syndrome type 3 also called classic Bartter syndrome present later in life and maybe sporadically asymptomatic or mildly symptomatic.

Pathophysiology

The thick ascending limb of the loop of Henle is not permeable to water and reabsorbs a large proportion of the filtered sodium chloride as shown in the figure, which leads to interstitial hypertonicity that powers the countercurrent exchange and urinary concentration mechanisms. In case of impairment of this function, a major loss of water and sodium occurs, as seen with loop diuretics.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. Impairment of sodium and chloride reabsorption is the primary defect in the Bartter syndrome that initiates the cascade. This leads to increased delivery of salt to the distal tubules 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 elevates renin levels. Excessive distal delivery of sodium follows by sodium (Na) reabsorption in the distal convoluted tubule. Na reabsorption exchange with the secretion of positively charged potassium or hydrogen ion and leads to increased loss of potassium (K+) in urine and increased hydrogen (H+) secretion. Decreased chloride (Cl-) reabsorption decreases the exchange with bicarbonate (HCO3-). Thus, increased bicarbonate retention and hypokalemia result in metabolic alkalosis. Calcium and magnesium reabsorb in the ascending limb of the loop of Henle as a result of a positive electrochemical gradient in the lumen created by the back leak of K+ ion in the lumen, drives passive paracellular sodium, calcium, and magnesium reabsorption as shown in the figure. The defective sodium chloride transport in the ascending limb of the loop of Henle associated with Bartter syndrome leads to the impaired electrochemical gradient leading to increased urinary loss of calcium and magnesium. This leads to the development of nephrocalcinosis in Bartter syndrome.

Causes

Bartter syndrome can be caused by mutations in at least five genes. Mutations in the SLC12A1 gene cause type I. Type II results from mutations in the KCNJ1 gene. Mutations in the CLCNKB gene are responsible for type III. Type IV can result from mutations in the BSND gene or from a combination of mutations in the CLCNKA and CLCNKB genes as shown in the table. Aminoglycoside can induce Bartter syndrome presenting with severe hypokalemia, metabolic alkalosis, and profound systemic manifestations.

Differentiating Bartter syndrome from Other Diseases

Bartter syndrome diagnosis should be differentiated from other diseases manifesting with hypokalemia and hypochloremic metabolic alkalosis such as Gitelman syndrome, EAST syndrome also is known as SeSAME syndrome, Diuretic abuse, cyclical vomiting, Hyperprostaglandin E syndrome(HPS), Familial hypomagnesemia, cystic fibrosis, Gullner syndrome, Mineralocorticoid excess, Activating mutation of the calcium-sensing receptor (CaSR) gene, Hypomagnesemia is often associated with hypokalemia, hypocalcemia, and metabolic alkalosis, Congenital chloride diarrhea, Hypochloremic alkalosis and Hypokalemia. Prolonged hypokalemia can lead to impaired ability of kidneys to concentrate urine, increased bicarbonate reabsorption.

Epidemiology and Demographics

The prevalence of Barter Syndrome is approximately 1 in 1,000,000 individuals. The annual incidence of the syndrome has been estimated at 1.2 per million people. According to a review of twenty-eight patients with Bartter syndrome during the years 1964-1986 who were followed for an average of 10 years, their mean age at the time of diagnosis was 32.9 years. These patients were observed to have short stature than normal subjects.

Risk Factors

Anyone with a family history of Bartter syndrome is at risk.

Screening

Genetic screening for Bartter syndrome mutated genes can be performed among individuals with unexplained hypertension and hypokalemia.

Natural History, Complications, and Prognosis

Bartter syndrome usually occurs in childhood. Bartter syndrome type I and type II are salt-wasting renal tubular disorders that are clinically characterized by polyhydramnios leading to premature delivery, marked polyuria, and a tendency towards nephrocalcinosis. Common complications of Bartter syndrome include Gallstones, Rhabdomyolysis, Prolonged QT interval, Life-threatening arrhythmia, Syncope, Sudden death, weakening of the bones and Renal failure. The limited prognostic information available suggests that early diagnosis and appropriate treatment of infants and young children with classic Bartter Syndrome (type 3) may improve growth and perhaps neuro-intellectual development. On the other hand, sustained hypokalemia and hyperreninemia can cause progressive tubulointerstitial nephritis, resulting in end-stage renal disease (Kidney failure). With the early treatment of the electrolyte imbalances, the prognosis for patients with Classic Bartter Syndrome is good. Patients with Bartter syndrome type I and II tend to present a satisfactory prognosis after a median follow-up of more than 10 years.

Diagnosis

History and Symptoms

Bartter syndrome is an autosomal recessive disorder that often presents in childhood and may be associated with stunted growth, mental retardation, hypokalemia, metabolic alkalosis, polyuria and polydipsia, normal to increased urinary calcium excretion, normal or mildly decreased serum magnesium concentration, hypophosphatemia and hypercalciuria.

Physical Examination

Physical examination findings include Prominent forehead, a large head, triangular facies with the drooping mouth, and large eyes and pinnae, low blood pressure, dehydrated, stunted growth, and muscle weakness.

Laboratory Findings

Laboratory findings such as Hypokalemia, Metabolic alkalosis, Elevated plasma renin and aldosterone, Elevated urine potassium and chloride, Low serum and urine magnesium levels.

Electrocardiogram

Hypokalemia in Bartter syndrome can lead to prolonged QT interval, life-threatening arrhythmia, syncope, and sudden death.

X-ray

Abdominal radiographs and intravenous pyelograms (IVPs) can be done to document nephrocalcinosis.

Echocardiography and Ultrasound

Polyhydramnios and intrauterine growth retardation are seen on ultrasound with the neonatal Barrter syndrome. There are no echocardiographic findings associated with Bartter syndrome.

CT scan

Spiral CT scan can be performed to look for nephrocalcinosis in Bartter syndrome.

MRI

There are no MRI findings associated with Bartter syndrome.

Other Diagnostic Studies

Genetic analysis is required to make an accurate diagnosis. Amniotic fluid chloride concentration ranged from 114 to 123 mEq/L has been reported in four newborns Bartter syndrome patients. In Bartter syndrome, a biopsy of the kidney typically shows redundant growth of kidney cells called the juxtaglomerular apparatus. However, this is not found in all patients, especially in young children

Treatment

Medical Therapy

Prostaglandin synthetase inhibitors suppress the production of prostaglandin. Potassium chloride supplements are given for hypokalemia. Spironolactone, Amiloride, Triamterene, Angiotensin-converting enzyme (ACE) inhibitors, Nonsteroidal drug anti-inflammatory drugs (NSAID) are given to patients for the treatment of Bartter syndrome. Growth hormone (GH) is given for growth retardation. Calcium or magnesium supplements are given for muscle spasm and tetany.

Surgery

Bilateral nephrectomy and kidney transplantation have been performed successfully, in two patients with severe neonatal Bartter syndrome.

Future or Investigational therapies

Experimental treatments that are being examined depend on the revelation that a few mutations causing Bartter syndrome create carriers with normal function. In any case, the mutations bring about the sequestration of these carriers inside intracellular compartments with the goal that they neglect to effectively embed into the suitable cell membrane. When these proteins can be effectively embedded into the cell membrane, they can become functional and correct the defect. The delivery and insertion of these fully or partially functional proteins into the cell membrane and partially rescue sodium chloride reabsorption can be improved by the utilization of the molecular chaperones, such as 4-phenylbutyrate.

Primary Prevention

There is no primary prevention associated with Bartter syndrome.

Secondary Prevention

Careful monitoring is required since NSAIDs can have significant adverse effects including renal and gastrointestinal toxicity.

References

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