Various types of Bartter syndrome
In Bartter syndrome, renal salt wasting occurs in the thick ascending limb of Henle (TAL). It is a heterogeneous, autosomal-recessive renal-tubular disorder characterized by hypokalemia, hypochloremia, metabolic alkalosis, and hyperreninemia with low-normal blood pressure. The primary defect is an impaired transepithelial transport of sodium chloride across the TAL, resulting in excessive urinary losses of sodium, chloride, and potassium. The combination of secondary hyperaldosteronism and increased distal sodium delivery enhances potassium (and hydrogen) secretion at the secretory sites in the distal nephron, leading to hypokalemia. In addition to volume depletion, increased renal release of vasodilating prostaglandins PGE2 contributes to the features of Bartter syndrome.
Failure to thrive is a typical occurrence in children with neonatal Bartter syndrome, caused by loss-of-function mutations in the Na-K-2Cl cotransporter (NKCC2, Bartter type 1) and the kidney outer medullary potassium channel (ROMK, Bartter type 2), both of which are expressed at the apical membrane of TAL epithelia.
In comparison, the classic Bartter syndrome (type 3) is caused by loss-of-function mutations in the basolateral chloride channel Kb (CLCNKB), often diagnosed at school age or later in adulthood. Increased urinary calcium excretion is significantly milder in classic Bartter; however, kidney stones can develop. Kidney function is typically normal; however, progression to end-stage kidney disease has been reported. Since CLCNKB is also expressed in the DCT, type 3 Bartter syndrome is classified by some authors as a mixed disorder of the TAL and DCT or as a disorder of the thiazideāfurosemide pharmacotype; therefore hypomagnesemia can be present in classic Bartter syndrome.
Type 4 Bartter syndrome is caused by mutations in Barttin (BSND), an accessory Ī²-subunit of the CLCNKB, and associated with sensorineural deafness. Hearing loss in Bartter type 4 is explained by loss-of-function of Barttin, which is also expressed in the inner, serving also as a subunit to the chloride channel CLCNKA. The recently described Bartter type 4b is caused by simultaneous homozygous mutations in both CLCNKB and CLCNKA and is also associated with deafness. Both type 4 and 4b can manifest in early childhood and can be associated with kidney failure.
Autosomal-dominant gain-of-function mutations in the calcium-sensing receptor gene (CASR) can also cause renal salt wasting in a subset of affected individuals. Although parathyroid hormone levels are severely suppressed in this syndrome, this condition is classified by some as a variant or phenocopy of Bartter (type 5) due to the expression of CASR on the basolateral membrane of TAL epithelia. Hypomagnesemia can be seen.
