title: The pharmacological characteristics of molecular-based inherited salt-losing tubulopathies.
abstract: BACKGROUND
  Our understanding of inherited salt-losing tubulopathies has improved with recent advances in molecular genetics. However, the terminology of Bartter syndrome and Gitelman syndrome does not always accurately reflect their pathophysiological basis or clinical presentation, and some patients are difficult to diagnose from their clinical presentations.
  
  
  OBJECTIVE
  In the present study, we conducted molecular analysis and diuretic tests for patients with inherited salt-losing tubulopathies to clarify the pharmacological characteristics of these disorders.
  
  
  METHODS
  We detected mutations and subsequently conducted diuretic tests using furosemide and thiazide for 16 patients with salt-losing tubulopathies (two with SLC12A1; two with KCNJ1; nine with CLCNKB; and three with SLC12A3).
  
  
  RESULTS
  Patients with SLC12A1 mutations showed no response to furosemide, whereas those with SLC12A3 mutations showed no response to thiazide. However, patients with CLCNKB mutations showed no response to thiazide and a normal response to furosemide, and those with KCNJ1 mutations showed a good response to both diuretics. This study revealed the following characteristics of these disorders: 1) subjects with CLCNKB mutations showed one or more biochemical features of Gitelman syndrome (including hypomagnesemia, hypocalciuria, and fractional chloride excretion insensitivity to thiazide administration); and 2) subjects with KCNJ1 mutations appeared to show normal fractional chloride excretion sensitivity to furosemide and thiazide administration.
  
  
  CONCLUSIONS
  These results indicate that these disorders are difficult to distinguish in some patients, even when using diuretic challenge. This clinical report provides important findings that can improve our understanding of inherited salt-losing tubulopathies and renal tubular physiology.
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Kusunokicho 7-5-1, Chuo, Kobe, Hyogo, Japan. nozu@med.kobe-u.ac.jp
authors.forename: Kandai
authors.initials: K
authors.lastname: Nozu
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Iijima
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kanda
authors.forename: Koichi
authors.initials: K
authors.lastname: Nakanishi
authors.forename: Norishige
authors.initials: N
authors.lastname: Yoshikawa
authors.forename: Kenichi
authors.initials: K
authors.lastname: Satomura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kaito
authors.forename: Yuya
authors.initials: Y
authors.lastname: Hashimura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ninchoji
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Komatsu
authors.forename: Koichi
authors.initials: K
authors.lastname: Kamei
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Miyashita
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kugo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohashi
authors.forename: Hajime
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Hiroyo
authors.initials: H
authors.lastname: Mabe
authors.forename: Asa
authors.initials: A
authors.lastname: Otsubo
authors.forename: Takashi
authors.initials: T
authors.lastname: Igarashi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Matsuo
mesh_terms: D000293:Adolescent; D000328:Adult; D001477:Bartter Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D004252:DNA Mutational Analysis; D004232:Diuretics / Q000627:therapeutic use; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D005665:Furosemide / Q000627:therapeutic use; D053579:Gitelman Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D009154:Mutation; D011955:Receptors, Drug / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000235:genetics; D049971:Thiazides / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D004232:Diuretics; D011955:Receptors, Drug; C578714:SLC12A1 protein, human; C578874:SLC12A3 protein, human; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D049971:Thiazides; D005665:Furosemide