Maiolino Giuseppe, Ceolotto Giulio, Battistel Michele, Barbiero Giulio, Cesari Maurizio, Amar Laurence, Caroccia Brasilina, Padrini Roberto, Azizi Michel, Rossi Gian Paolo
a Department of Medicine-DIMED, Clinica dell'Ipertensione Arteriosa , University of Padova , Padova , Italy.
b Department of Medicine-DIMED, Institute of Radiology , University of Padova , Padova , Italy.
Blood Press. 2018 Aug;27(4):200-205. doi: 10.1080/08037051.2018.1436961. Epub 2018 Feb 6.
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.
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.
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.
醛固酮瘤（APA）是原发性醛固酮增多症（PA）可治愈的主要内分泌高血压病因，在接受肾上腺静脉采血（AVS）检查的所有病例中，其占比高达66%。钾通道KCNJ5的突变在高达70%的APA中存在，并导致最典型的PA表型。最近发现大环内酯类抗生素在体外可特异性抑制突变KCNJ5通道的功能改变，这为诊断和治疗伴有KCNJ5突变的APA开辟了新途径，因为它可以识别并靶向治疗携带突变APA的PA患者。因此，我们旨在研究克拉霉素和罗红霉素这两种在体外能有效抑制突变Kir3.4通道功能改变的大环内酯类药物，是否分别影响伴有突变APA的PA患者在AVS期间肾上腺静脉血以及外周血中的血浆醛固酮浓度。
我们设计了两项概念验证研究。在研究A中：有明确PA生化证据的连续患者在AVS期间将接受单剂量250mg克拉霉素，以评估其对来自有和无APA腺体的肾上腺静脉血中醛固酮相对分泌指数的影响。在研究B中：接受高血压检查的连续高血压患者将口服单剂量150mg罗红霉素。实验终点将是罗红霉素引起的血浆醛固酮浓度及其他类固醇、直接活性肾素浓度、血清钾、收缩压和舒张压的变化。
我们期望证明：（i）克拉霉素能在肾上腺切除术和肿瘤DNA测序之前识别突变的APA；（ii）罗红霉素后外周静脉血中血浆醛固酮浓度、直接活性肾素浓度和血压的急性变化可作为存在体细胞突变的APA的替代指标。
