title: Indomethacin, amiloride, or eplerenone for treating hypokalemia in Gitelman syndrome.
abstract: Patients with Gitelman syndrome (GS), an inherited salt-losing tubulopathy, are usually treated with potassium-sparing diuretics or nonsteroidal anti-inflammatory drugs and oral potassium and magnesium supplementations. However, evidence supporting these treatment options is limited to case series studies. We designed an open-label, randomized, crossover study with blind end point evaluation to compare the efficacy and safety of 6-week treatments with one time daily 75 mg slow-release indomethacin, 150 mg eplerenone, or 20 mg amiloride added to constant potassium and magnesium supplementation in 30 patients with GS (individual participation: 48 weeks). Baseline plasma potassium concentration was 2.8±0.4 mmol/L and increased by 0.38 mmol/L (95% confidence interval [95% CI], 0.23 to 0.53; P<0.001) with indomethacin, 0.15 mmol/L (95% CI, 0.02 to 0.29; P=0.03) with eplerenone, and 0.19 mmol/L (95% CI, 0.05 to 0.33; P<0.01) with amiloride. Fifteen patients became normokalemic: six with indomethacin, three with eplerenone, and six with amiloride. Indomethacin significantly reduced eGFR and plasma renin concentration. Eplerenone and amiloride each increased plasma aldosterone by 3-fold and renin concentration slightly but did not significantly change eGFR. BP did not significantly change. Eight patients discontinued treatment early because of gastrointestinal intolerance to indomethacin (six patients) and hypotension with eplerenone (two patients). In conclusion, each drug increases plasma potassium concentration in patients with GS. Indomethacin was the most effective but can cause gastrointestinal intolerance and decreased eGFR. Amiloride and eplerenone have similar but lower efficacies and increase sodium depletion. The benefit/risk ratio of each drug should be carefully evaluated for each patient.
authors.affiliation: Université Paris Descartes, Faculté de Médecine, Sorbonne Paris Cité, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Centre d'Investigation Clinique, Paris, France; Institut National de la Santé et de la Recherche Médicale, Centre d'Investigation Clinique 1418, Paris, France; anne.blanchard@egp.aphp.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Blanchard
authors.affiliation: Département de génétique and Institut National de la Santé et de la Recherche Médicale, UMR970, Paris-Cardiovascular Research Center, Paris, France;
authors.forename: Rosa
authors.initials: R
authors.lastname: Vargas-Poussou
authors.affiliation: Service des explorations fonctionnelles physiologiques, Hôpital de Rangueil, Toulouse, France;
authors.forename: Marion
authors.initials: M
authors.lastname: Vallet
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Unité d'Épidémiologie et de Recherche Clinique, Paris, France; Institut National de la Santé et de la Recherche Médicale, Centre d'Investigation Épidémiologique 4, Paris, France;
authors.forename: Aurore
authors.initials: A
authors.lastname: Caumont-Prim
authors.affiliation: Centre Hospitalier Universitaire Dupuytren, Service de néphrologie, Centre d'Investigation Clinique Centre d'Investigation Clinique Institut National de la Santé et de la Recherche Médicale 0801, Limoges, France;
authors.forename: Julien
authors.initials: J
authors.lastname: Allard
authors.affiliation: Centre Hospitalier Universitaire de Poitiers, Service de néphrologie, Centre d'Investigation Clinique Centre d'Investigation Clinique Institut National de la Santé et de la Recherche Médicale 1402, Université de Poitiers, Poitiers, France; and.
authors.forename: Estelle
authors.initials: E
authors.lastname: Desport
authors.affiliation: Hôpital Edouard Herriot, Lyon, Paris, Hospices civils de Lyon, Lyon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Dubourg
authors.affiliation: Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Centre d'Investigation Clinique, Paris, France;
authors.forename: Matthieu
authors.initials: M
authors.lastname: Monge
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Centre d'Investigation Clinique 1418, Paris, France;
authors.forename: Damien
authors.initials: D
authors.lastname: Bergerot
authors.affiliation: Université Paris Descartes, Faculté de Médecine, Sorbonne Paris Cité, Paris, France; Service d'explorations fonctionnelles, Hôpital Européen Georges Pompidou, Paris, France;
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Baron
authors.affiliation: Centre Hospitalier Universitaire Dupuytren, Service de néphrologie, Centre d'Investigation Clinique Centre d'Investigation Clinique Institut National de la Santé et de la Recherche Médicale 0801, Limoges, France;
authors.forename: Marie
authors.initials: M
authors.lastname: Essig
authors.affiliation: Centre Hospitalier Universitaire de Poitiers, Service de néphrologie, Centre d'Investigation Clinique Centre d'Investigation Clinique Institut National de la Santé et de la Recherche Médicale 1402, Université de Poitiers, Poitiers, France; and.
authors.forename: Frank
authors.initials: F
authors.lastname: Bridoux
authors.affiliation: Service des explorations fonctionnelles physiologiques, Hôpital de Rangueil, Toulouse, France;
authors.forename: Ivan
authors.initials: I
authors.lastname: Tack
authors.affiliation: Université Paris Descartes, Faculté de Médecine, Sorbonne Paris Cité, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Centre d'Investigation Clinique, Paris, France; Institut National de la Santé et de la Recherche Médicale, Centre d'Investigation Clinique 1418, Paris, France;
authors.forename: Michel
authors.initials: M
authors.lastname: Azizi
mesh_terms: D000293:Adolescent; D000328:Adult; D000584:Amiloride / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D000077545:Eplerenone; D005260:Female; D053579:Gitelman Syndrome / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007008:Hypokalemia / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D007213:Indomethacin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011188:Potassium / Q000097:blood; D012083:Renin / Q000097:blood; D013148:Spironolactone / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D013148:Spironolactone; D000077545:Eplerenone; D000584:Amiloride; D012083:Renin; D011188:Potassium; D007213:Indomethacin
keywords: Gitelman syndrome; distal tubule; diuretics