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.



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 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.

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

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

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Interventions

Surgery

Primary Prevention

Secondary Prevention

References


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