UNLABELLED: Long standing confusion exists in the terminology of hypokalaemic salt-losing tubulopathies (SLTs). SLTs are autosomal recessively transmitted and characterized by normotensive secondary hyperreninism/hyperaldosteronism with hypokalaemic metabolic alkalosis. Historically, four phenotypical variants have been described: (1) the (classic) Bartter syndrome (cBS), (2) the hypomagnesaemic hypocalciuric Gitelman syndrome (GS), (3) the hypercalciuric hyperprostaglandin-E-syndrome (HPS) or antenatal Bartter syndrome (aBS) and (4) the hyperprostaglandin-E-syndrome with sensorineural deafness (HPS + SND). The latter two syndromes are the most severe variants with antenatal manifestation with polyhydramnios and life-threatening course of salt- and water-loss. Defects in five renal membrane proteins involved in electrolyte reabsorption have been identified: In HPS-patients mutations in (1) either the furosemide-sensitive sodium-potassium-chloride cotransporter NKCC2, or (2) in the potassium channel ROMK have been identified, and (3) HPS + SND is caused by mutations in the beta-subunit of the chloride channels ClC-Kb and -Ka (named barttin), all mimicking the major pharmacological effects of furosemide with minor potassium-wasting in ROMK-patients as seen in patients treated with simultaneous furosemide and amiloride, and minor calcium-wasting in Barttin-patients resembling the combination of furosemide and thiazides. (4) cBS is caused by mutations in the chloride channel ClC-Kb with similar clinical characteristics as seen under combination of thiazides and furosemide, (5) GS is caused by mutations in the thiazide-sensitive sodium-chloride cotransporter NCCT resembling the effect of long-term thiazide administration. CONCLUSION: The combination of pharmacology and genetics suggests a new terminology for the above described SLTs: Furosemide-like-SLT for HPS caused by NKCC2-mutations, furosemide/amiloride-like-SLT for HPS caused by ROMK-mutations, furosemide/thiazide-like-SLT for HPS + SND, thiazide/furosemide-like-SLT for cBS, and thiazide-like-SLT for GS.
UNLABELLED: Long standing confusion exists in the terminology of hypokalaemic salt-losing tubulopathies (SLTs). SLTs are autosomal recessively transmitted and characterized by normotensive secondary hyperreninism/hyperaldosteronism with hypokalaemic metabolic alkalosis. Historically, four phenotypical variants have been described: (1) the (classic) Bartter syndrome (cBS), (2) the hypomagnesaemic hypocalciuric Gitelman syndrome (GS), (3) the hypercalciuric hyperprostaglandin-E-syndrome (HPS) or antenatal Bartter syndrome (aBS) and (4) the hyperprostaglandin-E-syndrome with sensorineural deafness (HPS + SND). The latter two syndromes are the most severe variants with antenatal manifestation with polyhydramnios and life-threatening course of salt- and water-loss. Defects in five renal membrane proteins involved in electrolyte reabsorption have been identified: In HPS-patients mutations in (1) either the furosemide-sensitive sodium-potassium-chloride cotransporter NKCC2, or (2) in the potassium channel ROMK have been identified, and (3) HPS + SND is caused by mutations in the beta-subunit of the chloride channels ClC-Kb and -Ka (named barttin), all mimicking the major pharmacological effects of furosemide with minor potassium-wasting in ROMK-patients as seen in patients treated with simultaneous furosemide and amiloride, and minor calcium-wasting in Barttin-patients resembling the combination of furosemide and thiazides. (4) cBS is caused by mutations in the chloride channel ClC-Kb with similar clinical characteristics as seen under combination of thiazides and furosemide, (5) GS is caused by mutations in the thiazide-sensitive sodium-chloride cotransporter NCCT resembling the effect of long-term thiazide administration. CONCLUSION: The combination of pharmacology and genetics suggests a new terminology for the above described SLTs: Furosemide-like-SLT for HPS caused by NKCC2-mutations, furosemide/amiloride-like-SLT for HPS caused by ROMK-mutations, furosemide/thiazide-like-SLT for HPS + SND, thiazide/furosemide-like-SLT for cBS, and thiazide-like-SLT for GS.
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Authors: Shawn P Walsh; Aurash Shahripour; Haifeng Tang; Nardos Teumelsan; Jessica Frie; Yuping Zhu; Birgit T Priest; Andrew M Swensen; Jessica Liu; Michael Margulis; Richard Visconti; Adam Weinglass; John P Felix; Richard M Brochu; Timothy Bailey; Brande Thomas-Fowlkes; Magdalena Alonso-Galicia; Xiaoyan Zhou; Lee-Yuh Pai; Aaron Corona; Caryn Hampton; Melba Hernandez; Ross Bentley; Jing Chen; Kashmira Shah; Joseph Metzger; Michael Forrest; Karen Owens; Vincent Tong; Sookhee Ha; Sophie Roy; Gregory J Kaczorowski; Lihu Yang; Emma Parmee; Maria L Garcia; Kathleen Sullivan; Alexander Pasternak Journal: ACS Med Chem Lett Date: 2015-05-07 Impact factor: 4.345
Authors: Haifeng Tang; Shawn P Walsh; Yan Yan; Reynalda K de Jesus; Aurash Shahripour; Nardos Teumelsan; Yuping Zhu; Sookhee Ha; Karen A Owens; Brande S Thomas-Fowlkes; John P Felix; Jessica Liu; Martin Kohler; Birgit T Priest; Timothy Bailey; Richard Brochu; Magdalena Alonso-Galicia; Gregory J Kaczorowski; Sophie Roy; Lihu Yang; Sander G Mills; Maria L Garcia; Alexander Pasternak Journal: ACS Med Chem Lett Date: 2012-03-28 Impact factor: 4.345
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Authors: Pia Welker; Alexandra Böhlick; Kerim Mutig; Michele Salanova; Thomas Kahl; Hartmut Schlüter; Dieter Blottner; Jose Ponce-Coria; Gerardo Gamba; Sebastian Bachmann Journal: Am J Physiol Renal Physiol Date: 2008-06-25