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
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.