CHANNELOPATHIES IN PAEDIATRICS: ION CHANNELS IN TRANSEPITHELIAL ELECTROLYTE TRANSPORT OF THE KIDNEY

H.W. Seyberth

Children's Hospital of the Philipps University, Marburg, Germany

Channelopathy is a new term for a variety of hereditary diseases with molecular defects in ion channels. These channels are intrinsic proteins in the lipid layer of the cell membrane which create an aqueous channel for ions. Ion channels are responsible for generating electrical impulses in excitable tissue such as brain, heart, and muscle, or they provide crucial pathways for regulating absorption or secretion of ions and water in epithelial responsible for salt and fluid homeostasis. To the first category of channelopathies belong syncobal-like diseases such as benign neonatal convulsion, long QT syndrome, malignant hyperthermia and myotonia congenita, while to the second category of diseases with disturbed transepithelial NaCl transport defect belong autosomal recessive salt wasting tubulopathies (SLTs) such as the amiloride-, Bartter- and fursemide-like-SLTs. The amiloride-like SLT, also called pseudohypoaldosteronism type 1, is caused by loss of function in the amiloride sensitive epithelial Na+ channel (ENAC) at the luminal side in the distal convoluted tubule and exhibit a severe phenotype of salt wasting, hypokalaemia, and metabolic acidosis. The Bartter-like SLT is caused by defects in the voltage gated Cl– channel CLC-Kb at the interstitiale side in the distal tubule and is characterized by severe to mild salt wasting, but pronounced hypokalaemic alkalosis with no major imbalances in renal calcium handling. The fursemide-like SLT type 2, also called hyperprostaglandin E syndrome/antenatal Bartter syndrome, is caused by loss of function in the inwardly rectifying K+ channel ROMK at the luminal side in the thick ascending limb of Hele's loop and is the most severe phenotype characterized by fetal polyuria leading to polyhydramnios and premature delivery, postnatal development of nephrocalcinosis, isosthenuria, and persistent hypercalcinuria and salt wasting without severe hypokalaemic alkalosis.

This most recent progress of interdisciplinary research in the field of ion channels has improved our pathophysiological understanding of a great number of hereditary diseases including also a variety of renal tubulophaties. Moreover, new pharmacological targets for diuretics have been identified such as the ion channels CLC-Kb and ROMK in the renal tubule.