Hereditary Hypokalemic Salt-losing Tubular Disorders

The inherited hypokalemic tubular disorders are frequently summarized under the heading "Bartter syndrome" since they shareseveral clinical and biochemical findings such as renal salt wasting, hypokalemic metabolic alkalosis, normal blood pressure despite hypereninemic hyperaldosteronism and hyperplasia of the juxtaglomerular apparatus. However, careful characterization of the clinical phenotype and the correlation with the underlying molecular basis justifies the differentiation into at least four distinct disease entities: (i) the hyperprostaglandin E syndrome or antenatal variant of Bartter syndrome (HPS/aBS), which is caused by mutations in either the Na-K-2Cl cotransporter or the potassium channel of the medullary thick ascending limb of Henle's loop; (ii) the HPS/aBS with sensorineural deafness which results from inactivating mutations in the Barttin beta-subunit of the renal chloride channels; (iii) the classic Bartter syndrome caused by mutations in the chloride channel of the distal nephron; and (iv) Gitelman's variant of Bartter syndrome which is caused by mutations of the Na-Cl cotransporter of the distal convoluted tubule. This review will summarize the clinical characteristics of these diseases and the progress recently made in the identification of the underlying molecular defects that will hopefully add to the current knowledge of the pathogenesis of these diseases.