**4.2 Pseudo Bartter's syndrome**

94 Basic Nephrology and Acute Kidney Injury

prostaglandin-stimulated renin release (such as indomethacin and specific cyclo-

Antenatal Bartter's syndrome (Type 2) is clinically indistinguishable from Type 1. It is caused by loss-of-function mutations in the *KCNJ1* gene (alias *ROMK1*) encoding the ATPsensitive potassium channel ROMK1, also located apically in the TAL (Simon, et al., 1996b). ROMK1 allows potassium recycling from the TAL cells back to the luminal filtrate, and is electrogenic driving paracellular reabsorption of sodium, calcium and magnesium. ROMK1 is a regulator of the NKCC2 co-transporter and functional coupling of ROMK1 with NKCC2 is essential for effective NaCl reabsorption. Therefore, functional defects in the ROMK1 protein severely disrupt electrogenic chloride reabsorption in TAL, resulting in a similar antenatal phenotype, although the hypokalemia may be less severe (Kurtz, 1998). The

treatment of Bartter's syndrome Type 2 is the same as for Bartter's syndrome Type 1.

Classic Bartter's syndrome (Type 3) is caused by mutations in *CLCNKB* encoding the CLC chloride channel member CLC-KB. This channel protein is located on the basolateral membrane of TAL cells, where it co-localizes with Barttin. The presentation of Type 3 / Classic Bartter's syndrome tends to be with weakness and hypovolemia during early childhood, with a milder defect of urinary concentrating ability and normal urinary calcium levels. Hence, nephrocalcinosis or nephrolithiasis is rarely a feature. Severe and chronic hypokalemia may lead to medullary cyst formation (Ariceta &Rodriguez-Soriano, 2006). Hyperuricemia may occur due to volume contraction. Renal function is usually preserved initially but may decrease as a result of chronic hypokalemia and tubulointerstitial damage. The primary defect alters chloride reabsorption, with defective basolateral exit of chloride via CLC-KB in the TAL. Clinical features in Type 3 Bartter's syndrome include short stature and salt wasting. However, *CLCNKB* mutations may present with variable phenotype, ranging from neonatal salt losing crises to asymptomatic patients detected in adulthood by routine electrolyte testing (Konrad, et al., 2000). A milder phenotype may be confused with Gitelman's syndrome. Indeed, some patients with *CLCKNB* mutations have profound hypomagnesaemia and hypocalciuria, closely mimicking Gitelman's syndrome (Jeck, et al.,

Bartter's syndrome Type 4A is a form of infantile Bartter's syndrome caused by a mutation in the gene *BSND* encoding Barttin (Estevez, et al., 2001). Barttin is two-transmembrane protein and an essential subunit of the CLC chloride channels CLC-KB and CLC-KA. Barttin modulates both membrane insertion and function of both CLC-KA and CLC-KB (Scholl, et al., 2006,Waldegger, et al., 2002). In the kidney Barttin is expressed in the thin limb and the TAL of Henle. This type of Bartter's syndrome is associated with congenital sensorineural deafness (termed BSND) which may explained by the localisation of Barttin protein as a subunit for CLC-KA in inner ear cells. Again, the phenotype can be severe neonatal salt

Type 4B Bartter's syndrome is associated with simultaneous mutations in both chloride channel genes, *CLCNKA* and *CLCNKB* resulting in sensorineural deafness and renal salt wasting. This form of Bartter's syndrome is rare but should be considered when BSND mutations are not detected. Children from consanguineous parents with homozygous mutations in both genes (Schlingmann, et al., 2004) and non consanguineous parents with

Bartter's syndrome Type 5 is better known as autosomal dominant hypocalcaemia with Bartter'syndrome. Mutations in the *CASR* gene encoding the Calcium-sensing receptor can occasionally be associated with a Bartter's like phenotype (Vargas-Poussou, et al.,

digenic compound heterozygous mutations have been described (Nozu, et al., 2008).

wasting or a more mild adult presentation (Miyamura, et al., 2003).

oxygensae (COX-2) inhibitors).

2000,Konrad, et al., 2000).

Pseudo antenatal Bartter's syndrome has been reported in a preterm child with cyanotic heart disease treated with high dose prostaglandins (Langhendries, et al., 1989). The biochemical phenotype of Bartter's may also be mimicked by loop diuretic abuse. Hypokalemic metabolic alkalosis may also be seen in patients with cystic fibrosis, bulimia and laxative abuse. In such cases, urinary chloride levels are low, given the salt wasting is not secondary to a tubular defect.
