原发性醛固酮增多症的药物治疗

doi:10.24920/004137

摘要/Abstract

摘要：

原发性醛固酮增多症（primary aldosteronism，PA）是继发性高血压最常见的形式，主要表现为高血压和低钾血症。原发性醛固酮增多症的早期识别是非常重要的，因为原发性醛固酮增多症患者发生心血管并发症的可能性更高，如房颤、卒中和心肌梗死。在过去的十年中，原发性醛固酮增多症的遗传学研究取得了惊人的进展，为其治疗提供了新的指导。单侧病变首选手术治疗，双侧病变可用盐皮质激素受体拮抗剂（mineralocorticoid receptor antagonist，MRA）治疗。新一代非甾体MRA正在研究中。新的药物治疗策略包括钙通道阻滞剂、大环内酯类抗生素、醛固酮合成酶抑制剂，为原发性醛固酮增多症的治疗提供了新的视角。

关键词: 原发性醛固酮增多症, 盐皮质激素受体拮抗剂, 钙离子通道阻断剂, 大环内酯类抗生素, 醛固酮合酶抑制剂

Abstract:

Primary aldosteronism (PA) is the most common form of secondary hypertension, with its main manifestations including hypertension and hypokalemia. Early identification of PA is extremely important as PA patients can easily develop cardiovascular complications such as atrial fibrillation, stroke, and myocardial infarction. The past decade has witnessed the rapid advances in the genetics of PA, which has shed new light on PA treatment. While surgery is the first choice for unilateral diseases, bilateral lesions can be treated with mineralocorticoid receptor antagonists (MRAs). The next-generation non-steroidal MRAs are under investigations. New medications including calcium channel blockers, macrophage antibiotics, and aldosterone synthase inhibitors have provided a new perspective for the medical treatment of PA.

Key words: primary aldosteronism, mineralocorticoid receptor antagonists, calcium channel blockers, macrolide antibiotics, aldosterone synthase inhibitors

Ying-Jie Li, Zhi-Gang Ji, Jin Wen. Advances in Medical Treatment of Primary Aldosteronism[J].Chinese Medical Sciences Journal, 2023, 38(1): 49-56.

图/表 1

参考文献 56

[1]	Brown JM, Siddiqui M, Calhoun DA, et al. The unrecognized prevalence of primary aldosteronism: a cross-sectional study. Ann Internal Med 2020; 173(1):10-20. doi: 10.7326/M20-0065. doi: 10.7326/M20-0065
[2]	Choy KW, Fuller PJ, Russell G, et al. Primary aldosteronism. BMJ (Clinical research ed) 2022; 377: e065250. doi:10.1136/bmj-2021-065250. doi: 10.1136/bmj-2021-065250
[3]	Zennaro MC, Boulkroun S, Fernandes-Rosa FL. Pathogenesis and treatment of primary aldosteronism. Nat Rev Endocrinol 2020; 16: 578-89. doi:10.1038/s41574-020-0382-4. doi: 10.1038/s41574-020-0382-4
[4]	Reincke M, Bancos I, Mulatero P, et al. Diagnosis and treatment of primary aldosteronism. Lancet Diabetes & endocrinology 2021; 9: 876-92. doi:10.1016/s2213-8587(21)00210-2. doi: 10.1016/s2213-8587(21)00210-2
[5]	Rossi GP. Primary aldosteronism: Jacc state-of-the-art review. J Am Coll Cardiol 2019; 74: 2799-811. doi:10.1016/j.jacc.2019.09.057. doi: S0735-1097(19)37927-6 pmid: 31779795
[6]	Fernandes-Rosa FL, Boulkroun S, Zennaro MC. Genetic and genomic mechanisms of primary aldosteronism. Trends Mol Med 2020; 26: 819-32. doi:10.1016/j.molmed.2020.05.005. doi: S1471-4914(20)30134-9 pmid: 32563556
[7]	Santana LS, Guimaraes AG, Almeida MQ. Pathogenesis of primary aldosteronism: impact on clinical outcome. Front Endocrinol (Lausanne) 2022; 13: 927669. doi:10.3389/fendo.2022.927669. doi: 10.3389/fendo.2022.927669
[8]	Kitamoto T, Suematsu S, Yamazaki Y, et al. Clinical and steroidogenic characteristics of aldosterone-producing adenomas with atpase or cacna1d gene mutations. J Clin Endocrinol Metab 2016; 101: 494-503. doi:10.1210/jc.2015-3284. doi: 10.1210/jc.2015-3284 pmid: 26606680
[9]	Lifton RP, Dluhy RG, Powers M, et al. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992; 355: 262-65. doi:10.1038/355262a0. doi: 10.1038/355262a0
[10]	Scholl UI, Stölting G, Schewe J, et al. Clcn2 chloride channel mutations in familial hyperaldosteronism type ii. Nat Genet 2018; 5: 349-54. doi:10.1038/s41588-018-0048-5. doi: 10.1038/s41588-018-0048-5
[11]	Choi M, Scholl UI, Yue P, et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science (New York, NY) 2011; 331: 768-72. doi:10.1126/science.1198785. doi: 10.1126/science.1198785
[12]	Fernandes-Rosa FL, Daniil G, Orozco IJ, et al. A gain-of-function mutation in the clcn2 chloride channel gene causes primary aldosteronism. Nat Genet 2018; 50: 355-61. doi:10.1038/s41588-018-0053-8. doi: 10.1038/s41588-018-0053-8 pmid: 29403012
[13]	Nanba K, Omata K, Else T, et al. Targeted molecular characterization of aldosterone-producing adenomas in white americans. J Clin Endocrinol Metab 2018; 103: 3869-76. doi:10.1210/jc.2018-01004. doi: 10.1210/jc.2018-01004 pmid: 30085035
[14]	De Sousa K, Boulkroun S, Baron S, et al. Genetic, cellular, and molecular heterogeneity in adrenals with aldosterone-producing adenoma. Hypertension 2020; 75: 1034-44. doi:10.1161/hypertensionaha.119.14177. doi: 10.1161/HYPERTENSIONAHA.119.14177 pmid: 32114847
[15]	Scholl UI, Goh G, Stölting G, et al. Somatic and germline cacna1d calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet 2013; 45: 1050-54. doi:10.1038/ng.2695. doi: 10.1038/ng.2695 pmid: 23913001
[16]	Young WF Jr. Diagnosis and treatment of primary aldosteronism: Practical clinical perspectives. J Intern Med 2019; 285: 126-48. doi:10.1111/joim.12831. doi: 10.1111/joim.12831 pmid: 30255616
[17]	Tauber P, Aichinger B, Christ C, et al. Cellular pathophysiology of an adrenal adenoma-associated mutant of the plasma membrane ca(2+)-atpase atp2b3. Endocrinology 2016; 157: 2489-99. doi:10.1210/en.2015-2029. doi: 10.1210/en.2015-2029 pmid: 27035656
[18]	Dutta RK, Arnesen T, Heie A, et al. A somatic mutation in clcn2 identified in a sporadic aldosterone-producing adenoma. Eur J Endocrinol 2019; 181: K37-41. doi:10.1530/eje-19-0377. doi: 10.1530/eje-19-0377
[19]	Williams TA, Lenders JWM, Mulatero P, et al. Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. Lancet Diabetes Endocrinol 2017; 5: 689-99. doi:10.1016/s2213-8587(17)30135-3. doi: 10.1016/s2213-8587(17)30135-3
[20]	Lechner B, Lechner K, Heinrich D, et al. Therapy of endocrine disease: Medical treatment of primary aldosteronism. European J Endocrinol 2019; 181: R147-53. doi:10.1530/eje-19-0215. doi: 10.1530/eje-19-0215
[21]	Ahmed S, Hundemer GL. Benefits of surgical over medical treatment for unilateral primary aldosteronism. Front Endocrinol (Lausanne) 2022; 13: 861581. doi:10.3389/fendo.2022.861581. doi: 10.3389/fendo.2022.861581
[22]	El-Asmar N, Rajpal A, Arafah BM. Primary hyperaldosteronism: Approach to diagnosis and management. Med Clin N Am 2021; 105: 1065-80. doi:10.1016/j.mcna.2021.06.007. doi: 10.1016/j.mcna.2021.06.007
[23]	Pan CT, Liao CW, Tsai CH, et al. Influence of different treatment strategies on new-onset atrial fibrillation among patients with primary aldosteronism: a nationwide longitudinal cohort-based study. J Am Heart Assoc 2020; 9: e013699. doi:10.1161/jaha.119.013699. doi: 10.1161/jaha.119.013699
[24]	Velema M, Dekkers T, Hermus A, et al. Quality of life in primary aldosteronism: A comparative effectiveness study of adrenalectomy and medical treatment. J Clin Endocrinol Metab 2018; 103: 16-24. doi:10.1210/jc.2017-01442. doi: 10.1210/jc.2017-01442 pmid: 29099925
[25]	Parthasarathy HK, Ménard J, White WB, et al. A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism. J Hypertens 2011; 29: 980-90. doi:10.1097/HJH.0b013e3283455ca5. doi: 10.1097/HJH.0b013e3283455ca5 pmid: 21451421
[26]	Karashima S, Yoneda T, Kometani M, et al. Comparison of eplerenone and spironolactone for the treatment of primary aldosteronism. Hypertens Res 2016; 39: 133-7. doi:10.1038/hr.2015.129. doi: 10.1038/hr.2015.129 pmid: 26606875
[27]	Reincke M, Fischer E, Gerum S, et al. Observational study mortality in treated primary aldosteronism: The german conn's registry. Hypertension 2012; 60: 618-24. doi:10.1161/hypertensionaha.112.197111. doi: 10.1161/HYPERTENSIONAHA.112.197111 pmid: 22824982
[28]	Catena C, Colussi G, Lapenna R, et al. Long-term cardiac effects of adrenalectomy or mineralocorticoid antagonists in patients with primary aldosteronism. Hypertension 2007; 50: 911-8. doi:10.1161/hypertensionaha.107.095448. doi: 10.1161/HYPERTENSIONAHA.107.095448 pmid: 17893375
[29]	Indra T, Holaj R, Štrauch B, et al. Long-term effects of adrenalectomy or spironolactone on blood pressure control and regression of left ventricle hypertrophy in patients with primary aldosteronism. J Renin Angiotensin Aldosterone Syst 2015; 16: 1109-17. doi:10.1177/1470320314549220. doi: 10.1177/1470320314549220
[30]	Hundemer GL, Curhan GC, Yozamp N, et al. Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: A retrospective cohort study. Lancet Diabetes Endocrinol 2018; 6: 51-9. doi:10.1016/s2213-8587(17)30367-4. doi: 10.1016/s2213-8587(17)30367-4
[31]	Hundemer GL, Curhan GC, Yozamp N, et al. Incidence of atrial fibrillation and mineralocorticoid receptor activity in patients with medically and surgically treated primary aldosteronism. JAMA Cardiol 2018; 3: 768-74. doi:10.1001/jamacardio.2018.2003. doi: 10.1001/jamacardio.2018.2003 pmid: 30027227
[32]	Kolkhof P, Bärfacker L. 30 years of the mineralocorticoid receptor: Mineralocorticoid receptor antagonists: 60 years of research and development. J Endocrinol 2017; 234: T125-40. doi:10.1530/joe-16-0600. doi: 10.1530/joe-16-0600
[33]	Pandey AK, Bhatt DL, Cosentino F, et al. Non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease. Eur Heart J 2022; 43(31):2931-45. doi: 10.1093/eurheartj/ehac299. doi: 10.1093/eurheartj/ehac299 pmid: 35713973
[34]	Bramlage P, Swift SL, Thoenes M, et al. Non-steroidal mineralocorticoid receptor antagonism for the treatment of cardiovascular and renal disease. Eur J Heart Fail 2017; 19: 811. doi:10.1002/ejhf.888. doi: 10.1002/ejhf.888 pmid: 28586538
[35]	Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 2020; 383: 2219-29. doi:10.1056/NEJMoa2025845. doi: 10.1056/NEJMoa2025845
[36]	Motomura N, Yamazaki Y, Gao X, et al. Visualization of calcium channel blockers in human adrenal tissues and their possible effects on steroidogenesis in the patients with primary aldosteronism (pa). J Steroid Biochem 2022; 218: 106062. doi:10.1016/j.jsbmb.2022.106062. doi: 10.1016/j.jsbmb.2022.106062
[37]	Yang T, He M, Zhang H, et al. L- and t-type calcium channels control aldosterone production from human adrenals. J Endocrinol 2020; 244: 237-47. doi:10.1530/joe-19-0259. doi: 10.1530/JOE-19-0259 pmid: 31652415
[38]	Tauber P, Penton D, Stindl J, et al. Pharmacology and pathophysiology of mutated kcnj5 found in adrenal aldosterone-producing adenomas. Endocrinology 2014; 155: 1353-62. doi:10.1210/en.2013-1944. doi: 10.1210/en.2013-1944 pmid: 24506072
[39]	Wang F, Ma X, Tong A, et al. The effects of different calcium channel blockers on aldosterone-producing adenoma cells. Front Endocrinol (Lausanne) 2020; 11: 260. doi:10.3389/fendo.2020.00260. doi: 10.3389/fendo.2020.00260
[40]	De Mingo Alemany MC, Mifsud Grau L, Moreno Macián F, et al. A de novo cacna1d missense mutation in a patient with congenital hyperinsulinism, primary hyperaldosteronism and hypotonia. Channels (Austin, Tex) 2020; 14: 175-80. doi:10.1080/19336950.2020.1761171. doi: 10.1080/19336950.2020.1761171
[41]	Scholl UI, Abriola L, Zhang C, et al. Macrolides selectively inhibit mutant kcnj5 potassium channels that cause aldosterone-producing adenoma. J Clin Invest 2017; 127: 2739-50. doi:10.1172/JCI91733. doi: 10.1172/JCI91733 pmid: 28604387
[42]	Caroccia B, Prisco S, Seccia TM, et al. Macrolides blunt aldosterone biosynthesis: A proof-of-concept study in kcnj5 mutated adenoma cells ex vivo. Hypertension 2017; 70: 1238-42. doi:10.1161/HYPERTENSIONAHA.117.10226. doi: 10.1161/HYPERTENSIONAHA.117.10226
[43]	Maiolino G, Ceolotto G, Battistel M, et al. Macrolides for kcnj5-mutated aldosterone-producing adenoma (mapa): design of a study for personalized diagnosis of primary aldosteronism. Blood Press 2018; 27: 200-5. doi:10.1080/08037051.2018.1436961. doi: 10.1080/08037051.2018.1436961
[44]	Calhoun DA, White WB, Krum H, et al. Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial. Circulation 2011; 124: 1945-55. doi:10.1161/circulationaha.111.029892. doi: 10.1161/CIRCULATIONAHA.111.029892 pmid: 21986283
[45]	Zhang SL, Gao JW, Guo Y, et al. Associations between metabolic profiles and target-organ damage in chinese individuals with primary aldosteronism. Front Endocrinol (Lausanne) 2020; 11: 547356. doi:10.3389/fendo.2020.547356. doi: 10.3389/fendo.2020.547356
[46]	Wu J, Ding X, Tan X. A patent review of aldosterone synthase inhibitors (2014-present). Expert opinion on therapeutic patents 2022; 32: 13-28. doi:10.1080/13543776.2021.1965991. doi: 10.1080/13543776.2021.1965991
[47]	Weldon SM, Brown NF. Inhibitors of aldosterone synthase. Vitam Horm 2019; 109: 211-39. doi:10.1016/bs.vh.2018.10.002. doi: S0083-6729(18)30074-8 pmid: 30678857
[48]	Amar L, Azizi M, Menard J, et al. Sequential comparison of aldosterone synthase inhibition and mineralocorticoid blockade in patients with primary aldosteronism. J Hypertens 2013; 31: 624-29; discussion 629. doi:10.1097/HJH.0b013e32835d6d49. doi: 10.1097/HJH.0b013e32835d6d49 pmid: 23314743
[49]	Lenzini L, Zanotti G, Bonchio M, et al. Aldosterone synthase inhibitors for cardiovascular diseases: a comprehensive review of preclinical, clinical and in silico data. Pharmacological research 2021; 163: 105332. doi:10.1016/j.phrs.2020.105332. doi: 10.1016/j.phrs.2020.105332
[50]	Bogman K, Schwab D, Delporte ML, et al. Preclinical and early clinical profile of a highly selective and potent oral inhibitor of aldosterone synthase (cyp11b2). Hypertension 2017; 69: 189-1. doi:10.1161/HYPERTENSIONAHA.116.07716. doi: 10.1161/HYPERTENSIONAHA.116.07716 pmid: 27872236
[51]	Fu SJ, Hu MC, Peng YJ, et al. Cul4-ddb1-crbn e 3 ubiquitin ligase regulates proteostasis of clc-2 chloride channels: implication for aldosteronism and leukodystrophy. Cells 2020; 9. doi:10.3390/cells9061332. doi: 10.3390/cells9061332
[52]	Rossi GP, Lenzini L. Vitamin d supplementation: A novel therapy for aldosteronism? Nat Rev Endocrinol 2020; 16: 303-4. doi:10.1038/s41574-020-0359-3. doi: 10.1038/s41574-020-0359-3 pmid: 32286517
[53]	Ismail NA, Kamaruddin NA, Azhar Shah S, et al. The effect of vitamin d treatment on clinical and biochemical outcomes of primary aldosteronism. Clin Endocrinol (Oxf) 2020; 92: 509-17. doi:10.1111/cen.14177. doi: 10.1111/cen.14177
[54]	Kumar KG, Trevaskis JL, Lam DD, et al. Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell metabolism 2008; 8: 468-81. doi:10.1016/j.cmet.2008.10.011. doi: 10.1016/j.cmet.2008.10.011 pmid: 19041763
[55]	Stelcer E, Milecka P, Komarowska H, et al. Adropin stimulates proliferation and inhibits adrenocortical steroidogenesis in the human adrenal carcinoma (hac15) cell line. Front Endocrinol (Lausanne) 2020; 11: 561370. doi:10.3389/fendo.2020.561370. doi: 10.3389/fendo.2020.561370
[56]	Watanabe D, Morimoto S, Morishima N, et al. Adrenal (pro)renin receptor expression and serum soluble (pro)renin receptor concentration in primary aldosteronism. Int J Endocrinol 2020; 2020: 9640103. doi:10.1155/2020/9640103. doi: 10.1155/2020/9640103

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