Macrolides for KCNJ5–mutated aldosterone-producing adenoma (MAPA): design of a study for personalized diagnosis of primary aldosteronism
Purpose: Aldosterone-producing adenoma (APA) is the main curable cause of endocrine hypertension cause of primary aldosteronism (PA) and it is in up to 66% of all cases investigated with adrenal vein sampling (AVS). Mutations in the KCNJ5 potassium channel involve up to 70% of APA and cause the most...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2018-07-01
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| Series: | Blood Pressure |
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| Online Access: | http://dx.doi.org/10.1080/08037051.2018.1436961 |
| _version_ | 1797685091457040384 |
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| author | Giuseppe Maiolino Giulio Ceolotto Michele Battistel Giulio Barbiero Maurizio Cesari Laurence Amar Brasilina Caroccia Roberto Padrini Michel Azizi Gian Paolo Rossi |
| author_facet | Giuseppe Maiolino Giulio Ceolotto Michele Battistel Giulio Barbiero Maurizio Cesari Laurence Amar Brasilina Caroccia Roberto Padrini Michel Azizi Gian Paolo Rossi |
| author_sort | Giuseppe Maiolino |
| collection | DOAJ |
| description | Purpose: Aldosterone-producing adenoma (APA) is the main curable cause of endocrine hypertension cause of primary aldosteronism (PA) and it is in up to 66% of all cases investigated with adrenal vein sampling (AVS). Mutations in the KCNJ5 potassium channel involve up to 70% of APA and cause the most florid PA phenotypes. The recent finding that macrolide antibiotics specifically inhibit in vitro the altered function of mutated KCNJ5 channels has opened new horizons for the diagnosis and treatment of APA with KCNJ5 mutations in that it can allow identification and target treatment of PA patients harbouring a mutated APA. Thus, we aimed at investigating if clarithromycin and roxithromycin, two macrolides that potently blunt mutated Kir3.4 channel function in vitro, affect plasma aldosterone concentration in adrenal vein blood during AVS and in peripheral blood, respectively, in PA patients with a mutated APA. Methods and design: We designed two proof of concept studies. In study A: consecutive patients with an unambiguous biochemical evidence of PA will be exposed to a single dose of 250 mg clarithromycin during AVS, to assess its effect on the relative aldosterone secretion index in adrenal vein blood from the gland with and without APA. In study B: consecutive hypertensive patients submitted to the work-up for hypertension will receive a single oral dose of 150 mg roxithromycin. The experimental endpoints will be the change induced by roxithromycin of plasma aldosterone concentration and other steroids, direct active renin concentration, serum K+, systolic and diastolic blood pressure. Discussion: We expect to prove that: (i) clarithromycin allows identification of mutated APA before adrenalectomy and sequencing of tumour DNA; (ii) the acute changes of plasma aldosterone concentration, direct active renin concentration, and blood pressure in peripheral venous blood after roxithromycin can be a proxy for the presence of an APA with somatic mutations. |
| first_indexed | 2024-03-12T00:39:18Z |
| format | Article |
| id | doaj.art-922588af06e741f090d50c4a3ead5dbf |
| institution | Directory Open Access Journal |
| issn | 0803-7051 1651-1999 |
| language | English |
| last_indexed | 2024-03-12T00:39:18Z |
| publishDate | 2018-07-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Blood Pressure |
| spelling | doaj.art-922588af06e741f090d50c4a3ead5dbf2023-09-15T08:45:22ZengTaylor & Francis GroupBlood Pressure0803-70511651-19992018-07-0127420020510.1080/08037051.2018.14369611436961Macrolides for KCNJ5–mutated aldosterone-producing adenoma (MAPA): design of a study for personalized diagnosis of primary aldosteronismGiuseppe Maiolino0Giulio Ceolotto1Michele Battistel2Giulio Barbiero3Maurizio Cesari4Laurence Amar5Brasilina Caroccia6Roberto Padrini7Michel Azizi8Gian Paolo Rossi9University of PadovaUniversity of PadovaUniversity of PadovaUniversity of PadovaUniversity of PadovaUniversity of PadovaUniversity of PadovaGeorges Pompidou European Hospital and Paris Descartes UniversityUniversity of PadovaUniversity of PadovaPurpose: Aldosterone-producing adenoma (APA) is the main curable cause of endocrine hypertension cause of primary aldosteronism (PA) and it is in up to 66% of all cases investigated with adrenal vein sampling (AVS). Mutations in the KCNJ5 potassium channel involve up to 70% of APA and cause the most florid PA phenotypes. The recent finding that macrolide antibiotics specifically inhibit in vitro the altered function of mutated KCNJ5 channels has opened new horizons for the diagnosis and treatment of APA with KCNJ5 mutations in that it can allow identification and target treatment of PA patients harbouring a mutated APA. Thus, we aimed at investigating if clarithromycin and roxithromycin, two macrolides that potently blunt mutated Kir3.4 channel function in vitro, affect plasma aldosterone concentration in adrenal vein blood during AVS and in peripheral blood, respectively, in PA patients with a mutated APA. Methods and design: We designed two proof of concept studies. In study A: consecutive patients with an unambiguous biochemical evidence of PA will be exposed to a single dose of 250 mg clarithromycin during AVS, to assess its effect on the relative aldosterone secretion index in adrenal vein blood from the gland with and without APA. In study B: consecutive hypertensive patients submitted to the work-up for hypertension will receive a single oral dose of 150 mg roxithromycin. The experimental endpoints will be the change induced by roxithromycin of plasma aldosterone concentration and other steroids, direct active renin concentration, serum K+, systolic and diastolic blood pressure. Discussion: We expect to prove that: (i) clarithromycin allows identification of mutated APA before adrenalectomy and sequencing of tumour DNA; (ii) the acute changes of plasma aldosterone concentration, direct active renin concentration, and blood pressure in peripheral venous blood after roxithromycin can be a proxy for the presence of an APA with somatic mutations.http://dx.doi.org/10.1080/08037051.2018.1436961macrolidesprimary aldosteronismkcnj5 potassium channelaldosterone-producing adenoma |
| spellingShingle | Giuseppe Maiolino Giulio Ceolotto Michele Battistel Giulio Barbiero Maurizio Cesari Laurence Amar Brasilina Caroccia Roberto Padrini Michel Azizi Gian Paolo Rossi Macrolides for KCNJ5–mutated aldosterone-producing adenoma (MAPA): design of a study for personalized diagnosis of primary aldosteronism Blood Pressure macrolides primary aldosteronism kcnj5 potassium channel aldosterone-producing adenoma |
| title | Macrolides for KCNJ5–mutated aldosterone-producing adenoma (MAPA): design of a study for personalized diagnosis of primary aldosteronism |
| title_full | Macrolides for KCNJ5–mutated aldosterone-producing adenoma (MAPA): design of a study for personalized diagnosis of primary aldosteronism |
| title_fullStr | Macrolides for KCNJ5–mutated aldosterone-producing adenoma (MAPA): design of a study for personalized diagnosis of primary aldosteronism |
| title_full_unstemmed | Macrolides for KCNJ5–mutated aldosterone-producing adenoma (MAPA): design of a study for personalized diagnosis of primary aldosteronism |
| title_short | Macrolides for KCNJ5–mutated aldosterone-producing adenoma (MAPA): design of a study for personalized diagnosis of primary aldosteronism |
| title_sort | macrolides for kcnj5 mutated aldosterone producing adenoma mapa design of a study for personalized diagnosis of primary aldosteronism |
| topic | macrolides primary aldosteronism kcnj5 potassium channel aldosterone-producing adenoma |
| url | http://dx.doi.org/10.1080/08037051.2018.1436961 |
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