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Recent progress in the diagnosis and treatment of primary aldosteronism

Hypertension Research volume 46, pages 1738–1744 (2023)Cite this article

Abstract

Primary aldosteronism (PA) is caused by excessive secretion of aldosterone from the adrenal glands, with subsequent changes in the renin-angiotensin system. In Japan, chemiluminescent enzyme immunoassay is currently performed for aldosterone assay rather than the earlier method of radioimmunoassay. This change in aldosterone measurement methods has resulted in faster and more accurate measurement of blood aldosterone levels. Since 2019, esaxerenone, a mineralocorticoid receptor antagonist (MRA) with a non-steroidal skeleton, has been available in Japan for the treatment of hypertension. Esaxerenone has been reported to have various effects, such as strong antihypertensive and anti-albuminuric/proteinuric effects. Treatment of PA with MRAs has been reported to improve the patient’s quality of life and to suppress the onset of cardiovascular events independent of their effects on blood pressure. Measuring renin levels is recommended for monitoring the extent of mineralocorticoid receptor blockade during MRA treatment. Patients receiving MRAs are prone to developing hyperkalemia, and combining MRAs with sodium/glucose cotransporter 2 inhibitors is expected to prevent severe hyperkalemia and provide additional cardiorenal protection. Mineralocorticoid receptor-associated hypertension is a broad concept of hypertension that includes not only PA, but also hypertension caused by borderline aldosteronism, obesity, diabetes, and sleep apnea syndrome.

New findings on primary aldosteronism, which is part of MR-associated hypertension. Aldosterone measurements have been changed to the CLEIA method. Treatment of primary aldosteronism with MRAs has a variety of positive effects. CT-guided radiofrequency ablation and transarterial embolization are alternatives to surgery for aldosterone-producing adenomas. BP blood pressure, CLEIA chemiluminescent enzyme immunoassay, CT computed tomography, K serum potassium, MR mineralocorticoid receptor, MRA mineralocorticoid receptor antagonist, QOL quality of life, SGLT2i sodium/glucose cotransporter 2 inhibitor.

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References

  1. Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab. 2004;89:1045–50.

    Article  CAS  PubMed  Google Scholar 

  2. Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, et al. A prospective study of the prevalence of primary aldosteronism in 1125 hypertensive patients. J Am Coll Cardiol. 2006;48:2293–300.

    Article  CAS  PubMed  Google Scholar 

  3. Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101:1889–916.

    Article  CAS  PubMed  Google Scholar 

  4. Born-Frontsberg E, Reincke M, Rump LC, Hahner S, Diederich S, Lorenz R, et al. Cardiovascular and cerebrovascular comorbidities of hypokalemic and normokalemic primary aldosteronism: results of the German Conn’s Registry. J Clin Endocrinol Metab. 2009;94:1125–30.

    Article  CAS  PubMed  Google Scholar 

  5. Ohno Y, Sone M, Inagaki N, Yamasaki T, Ogawa O, Takeda Y, et al. Prevalence of cardiovascular disease and its risk factors in primary aldosteronism: a multicenter study in Japan. Hypertension. 2018;71:530–7.

    Article  CAS  PubMed  Google Scholar 

  6. Ozeki Y, Tanimura Y, Nagai S, Nomura T, Kinoshita M, Shibuta K, et al. Development of a new chemiluminescent enzyme immunoassay using a two-step sandwich method for measuring aldosterone concentrations. Diagnostics (Basel). 2021;11:433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Teruyama K, Naruse M, Tsuiki M, Kobayashi H. Novel chemiluminescent immunoassay to measure plasma aldosterone and plasma active renin concentrations for the diagnosis of primary aldosteronism. J Hum Hypertens. 2022;36:77–85.

    Article  CAS  PubMed  Google Scholar 

  8. Nishikawa T, Satoh F, Takashi Y, Yanase T, Itoh H, Kurihara I, et al. Comparison and commutability study between standardized liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) and chemiluminescent enzyme immunoassay for aldosterone measurement in blood. Endocr J. 2022;69:45–54.

    Article  CAS  PubMed  Google Scholar 

  9. Ozeki Y, Kinoshita M, Miyamoto S, Yoshida Y, Okamoto M, Gotoh K, et al. Re-assessment of the oral salt loading test using a new chemiluminescent enzyme immunoassay based on a two-step sandwich method to measure 24-hour urine aldosterone excretion. Front Endocrinol (Lausanne). 2022;13:859347.

    Article  PubMed  Google Scholar 

  10. Naruse M, Katabami T, Shibata H, Sone M, Takahashi K, Tanabe A, et al. Japan Endocrine Society clinical practice guideline for the diagnosis and management of primary aldosteronism 2021. Endocr J. 2022;69:327–59.

    Article  PubMed  Google Scholar 

  11. Morimoto R, Ono Y, Tezuka Y, Kudo M, Yamamoto S, Arai T, et al. Rapid screening of primary aldosteronism by a novel chemiluminescent immunoassay. Hypertension. 2017;70:334–41.

    Article  CAS  PubMed  Google Scholar 

  12. Amar L, Baguet JP, Bardet S, Chaffanjon P, Chamontin B, Douillard C, et al. SFE/SFHTA/AFCE primary aldosteronism consensus: Introduction and handbook. Ann Endocrinol (Paris). 2016;77:179–86.

    Article  PubMed  Google Scholar 

  13. Umemura S, Arima H, Arima S, Asayama K, Dohi Y, Hirooka Y, et al. The Japanese Society of Hypertension guidelines for the management of Hypertension (JSH 2019). Hypertens Res. 2019;42:1235–481.

    Article  PubMed  Google Scholar 

  14. Jeunemaitre X, Chatellier G, Kreft-Jais C, Charru A, DeVries C, Plouin PF, et al. Efficacy and tolerance of spironolactone in essential hypertension. Am J Cardiol. 1987;60:820–5.

    Article  CAS  PubMed  Google Scholar 

  15. Karagiannis A, Tziomalos K, Papageorgiou A, Kakafika AI, Pagourelias ED, Anagnostis P, et al. Spironolactone versus eplerenone for the treatment of idiopathic hyperaldosteronism. Expert Opin Pharmacother. 2008;9:509–15.

    Article  CAS  PubMed  Google Scholar 

  16. Karashima S, Yoneda T, Kometani M, Ohe M, Mori S, Sawamura T, et al. Comparison of eplerenone and spironolactone for the treatment of primary aldosteronism. Hypertens Res. 2016;39:133–7.

    Article  CAS  PubMed  Google Scholar 

  17. Parthasarathy HK, Ménard J, White WB, Young WF Jr, Williams GH, Williams B, 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.

    Article  CAS  PubMed  Google Scholar 

  18. Rakugi H, Yamakawa S, Sugimoto K. Management of hyperkalemia during treatment with mineralocorticoid receptor blockers: findings from esaxerenone. Hypertens Res. 2021;44:371–85.

    Article  CAS  PubMed  Google Scholar 

  19. Arai K, Homma T, Morikawa Y, Ubukata N, Tsuruoka H, Aoki K, et al. Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist. Eur J Pharm. 2015;761:226–34.

    Article  CAS  Google Scholar 

  20. Kario K, Ito S, Itoh H, Rakugi H, Okuda Y, Yamakawa S. Effect of esaxerenone on nocturnal blood pressure and natriuretic peptide in different dipping phenotypes. Hypertens Res. 2022;45:97–105.

    Article  CAS  PubMed  Google Scholar 

  21. Satoh F, Ito S, Itoh H, Rakugi H, Shibata H, Ichihara A, et al. Efficacy and safety of esaxerenone (CS-3150), a newly available nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with primary aldosteronism. Hypertens Res. 2021;44:464–72.

    Article  CAS  PubMed  Google Scholar 

  22. Ito S, Itoh H, Rakugi H, Okuda Y, Iijima S. Antihypertensive effects and safety of esaxerenone in patients with moderate kidney dysfunction. Hypertens Res. 2021;44:489–97.

    Article  CAS  PubMed  Google Scholar 

  23. Ichikawa S, Tsutsumi J, Sugimoto K, Yamakawa S. Antihypertensive effect of long-term monotherapy with esaxerenone in patients with essential hypertension: relationship between baseline urinary sodium excretion and its antihypertensive effect. Adv Ther. 2022;39:4779–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ito S, Kashihara N, Shikata K, Nangaku M, Wada T, Okuda Y, et al. Esaxerenone (CS-3150) in patients with type 2 diabetes and microalbuminuria (ESAX-DN): phase 3 randomized controlled clinical trial. Clin J Am Soc Nephrol. 2020;15:1715–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Uchida HA, Nakajima H, Hashimoto M, Nakamura A, Nunoue T, Murakami K, et al. Efficacy and safety of esaxerenone in hypertensive patients with diabetic kidney disease: a multicenter, open-label, prospective study. Adv Ther. 2022;39:5158–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Bavuu O, Fukuda D, Ganbaatar B, Matsuura T, Ise T, Kusunose K, et al. Esaxerenone, a selective mineralocorticoid receptor blocker, improves insulin sensitivity in mice consuming high-fat diet. Eur J Pharm. 2022;931:175190.

    Article  CAS  Google Scholar 

  27. Qiang P, Hao J, Yang F, Han Y, Chang Y, Xian Y, et al. Esaxerenone inhibits the macrophage-to-myofibroblast transition through mineralocorticoid receptor/TGF-β1 pathway in mice induced with aldosterone. Front Immunol. 2022;13:948658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yamamoto H, Yoshida N, Kihara S. Esaxerenone blocks vascular endothelial inflammation through SGK1. J Cardiovasc Pharm. 2022;80:583–91.

    CAS  Google Scholar 

  29. Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N. Engl J Med. 2020;383:2219–29.

    Article  CAS  PubMed  Google Scholar 

  30. Pitt B, Filippatos G, Agarwal R, Anker SD, Bakris GL, Rossing P, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N. Engl J Med. 2021;385:2252–63.

    Article  CAS  PubMed  Google Scholar 

  31. Agarwal R, Filippatos G, Pitt B, Anker SD, Rossing P, Joseph A, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022;43:474–84.

    Article  CAS  PubMed  Google Scholar 

  32. Ahmed AH, Gordon RD, Sukor N, Pimenta E, Stowasser M. Quality of life in patients with bilateral primary aldosteronism before and during treatment with spironolactone and/or amiloride, including a comparison with our previously published results in those with unilateral disease treated surgically. J Clin Endocrinol Metab. 2011;96:2904–11.

    Article  CAS  PubMed  Google Scholar 

  33. Velema M, Dekkers T, Hermus A, Timmers H, Lenders J, Groenewoud H, 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.

    Article  PubMed  Google Scholar 

  34. Yoshida Y, Yoshida R, Shibuta K, Ozeki Y, Okamoto M, Gotoh K, et al. Quality of life of primary aldosteronism patients by mineralocorticoid receptor antagonists. J Endocr Soc. 2021;5:bvab020.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A. Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study. Lancet Diabetes Endocrinol. 2018;6:51–9.

    Article  PubMed  Google Scholar 

  36. Yoshida Y, Fujiki R, Kinoshita M, Sada K, Miyamoto S, Ozeki Y, et al. Importance of dietary salt restriction for patients with primary aldosteronism during treatment with mineralocorticoid receptor antagonists: The potential importance of post-treatment plasma renin levels. Hypertens Res. 2023;46:100–7.

    Article  CAS  PubMed  Google Scholar 

  37. Nomura M, Kurihara I, Itoh H, Ichijo T, Katabami T, Tsuiki M, et al. Association of cardiovascular disease risk and changes in renin levels by mineralocorticoid receptor antagonists in patients with primary aldosteronism. Hypertens Res. 2022;45:1476–85.

    Article  CAS  PubMed  Google Scholar 

  38. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128:e240–327.

    PubMed  Google Scholar 

  39. Epstein M, Calhoun DA. Aldosterone blockers (mineralocorticoid receptor antagonism) and potassium-sparing diuretics. J Clin Hypertens (Greenwich). 2011;13:644–8.

    Article  CAS  PubMed  Google Scholar 

  40. Shikata K, Ito S, Kashihara N, Nangaku M, Wada T, Okuda Y, et al. Reduction in the magnitude of serum potassium elevation in combination therapy with esaxerenone (CS-3150) and sodium-glucose cotransporter 2 inhibitor in patients with diabetic kidney disease: subanalysis of two phase III studies. J Diabetes Investig. 2022;13:1190–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bohm M, Anker SD, Butler J, Filippatos G, Ferreira JP, Pocock SJ, et al. Empagliflozin improves cardiovascular and renal outcomes in heart failure irrespective of systolic blood pressure. J Am Coll Cardiol. 2021;78:1337–48.

    Article  PubMed  Google Scholar 

  42. Mogi M, Maruhashi T, Higashi Y, Masuda T, Nagata D, Nagai M, et al. Update on Hypertension Research in 2021. Hypertens Res. 2022;45:1276–97.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Tanaka A, Shibata H, Node K. Suspected borderline aldosteronism in hypertension: the next target? J Am Coll Cardiol. 2020;76:759–60.

    Article  PubMed  Google Scholar 

  44. Shibata H, Itoh H. Mineralocorticoid receptor-associated hypertension and its organ damage: clinical relevance for resistant hypertension. Am J Hypertens. 2012;25:514–23.

    Article  CAS  PubMed  Google Scholar 

  45. Shibata H. Exosomes and exosomal cargo in urinary extracellular vesicles: novel potential biomarkers for mineralocorticoid-receptor-associated hypertension. Hypertens Res. 2021;44:1668–70.

    Article  CAS  PubMed  Google Scholar 

  46. Burrello J, Burrello A, Pieroni J, Sconfienza E, Forestiero V, Rabbia P, et al. Development and validation of prediction models for subtype diagnosis of patients with primary aldosteronism. J Clin Endocrinol Metab. 2020;105:dgaa379.

    Article  PubMed  Google Scholar 

  47. Kaneko H, Umakoshi H, Ogata M, Wada N, Iwahashi N, Fukumoto T, et al. Machine learning based models for prediction of subtype diagnosis of primary aldosteronism using blood test. Sci Rep. 2021;11:9140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Karashima S, Kawakami M, Nambo H, Kometani M, Kurihara I, Ichijo T, et al. A hyperaldosteronism subtypes predictive model using ensemble learning. Sci Rep. 2023;13:3043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chen Cardenas SM, Santhanam P. (11)C-metomidate PET in the diagnosis of adrenal masses and primary aldosteronism: a review of the literature. Endocrine. 2020;70:479–87.

    Article  CAS  PubMed  Google Scholar 

  50. Liu SY, Chu CM, Kong AP, Wong SK, Chiu PW, Chow FC, et al. Radiofrequency ablation compared with laparoscopic adrenalectomy for aldosterone-producing adenoma. Br J Surg. 2016;103:1476–86.

    Article  CAS  PubMed  Google Scholar 

  51. Sun F, Liu X, Zhang H, Zhou X, Zhao Z, He H, et al. Catheter-based adrenal ablation: an alternative therapy for patients with aldosterone-producing adenoma. Hypertens Res. 2023;46:91–9.

    Article  PubMed  Google Scholar 

  52. Williams TA, Gomez-Sanchez CE, Rainey WE, Giordano TJ, Lam AK, Marker A, et al. International histopathology consensus for unilateral primary aldosteronism. J Clin Endocrinol Metab. 2021;106:42–54.

    Article  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Masaki Mogi, Tatsuo Shimosawa, Kazuomi Kario, and Hiroshi Itoh, members of the Japanese Society of Hypertension for providing us with the opportunity to write this paper.

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  1. Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Japan

    Yuichi Yoshida & Hirotaka Shibata

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Correspondence to Hirotaka Shibata.

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HS has honorarium from Daiichi-Sankyo Company, Mochida Pharmaceuticals, Astrazeneca, Novartis Pharma, Bayer, and Astellas. HS also received scholarship from Chugai and Bayer.

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Yoshida, Y., Shibata, H. Recent progress in the diagnosis and treatment of primary aldosteronism. Hypertens Res 46, 1738–1744 (2023). https://doi.org/10.1038/s41440-023-01288-w

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