Hereditary hypokalemic salt-losing tubulopathies

Publisher Summary The combination of autosomal recessively transmitted hypokalemic alkalosis and normotensive hyperalsosteronism is termed as Bartter syndrome. Three main phenotypical variants of this syndrome are described in this chapter: the classical Batter syndrome; the hypomagnesemic hypocalciuric, Gitelman syndrome; and the antenatal, hypercalciuric hyperprostaglandin E syndrome. The chapter describes the clinical features, genetics, pathogenesis, diagnosis, and therapy of the three variants. The hypocalciuric hypomagnesemic Gitelman syndrome is described functionally as a thiazide-like salt-losing tubulopathy (TSLT) because renal salt is relatively mild in this disorder. Affected individuals present fatigue, muscle weakness, tetany, carpopedal spasms, obstipation, chondrocalcinosis, and small stature. Hyperprostaglandin E syndrome is described as a furosemide-like salt-losing tubulopathy (FSLT). The onset of this disorder is typically prenatal. Fetal polyuria leads to the development of a polyhydraminos around the fifth month of pregnancy, which naturally results in premature birth. Classic Bartter syndrome with intermediate clinical features is classified as Bartter-like salt-losing tubulopathy (BSLT). This disorder is characterized by hypokalemic alkalosis. Four causative genes have been identified each indicating different mechanisms for disease pathogenesis. In two of the genes, SLC12A1 and KCNJ1 , encoding the NA-K-2Cl cotranspoter type 2 and the inwardly rectifying potassium channel ROMK, loss of function mutations are found that exert urine concentration disturbances corresponding to the diuretic effects of furosemide. Mutations in the third gene, SLC12A3 , encoding the NaCl cotranspoter of the distal convoluted tubule, resemble thiazide effects, while the phenotype due to defective chloride channel C1C-Kb can mimic both diuretic substances.