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New mineralocorticoid receptor antagonists: update on their use in chronic kidney disease and heart failure

  • Irene Capelli
  • Lorenzo Gasperoni
  • Marco Ruggeri
  • Gabriele Donati
  • Olga Baraldi
  • Giovanni Sorrenti
  • Maria Turchese Caletti
  • Valeria Aiello
  • Giuseppe Cianciolo
  • Gaetano La MannaEmail author
Review

Abstract

Aldosterone is a mineralocorticoid hormone with a well-known effect on the renal tubule leading to water retention and potassium reabsorption. Other major effects of the hormone include the induction of proinflammatory activity that leads to progressive fibrotic damage of the target organs, heart and kidney. Blocking the aldosterone receptor therefore represents an important pharmacological strategy to avoid the clinical conditions deriving from heart failure (CHF) and chronic kidney disease (CKD). However, steroidal mineralocorticoid receptor antagonists (MRA) have a low safety profile, especially in CKD patients due to the high incidence of hyperkalemia. A new generation of nonsteroidal MRA has recently been developed to obtain a selective receptor block avoiding side-effects like hyperkalemia and thereby making the drugs suitable for administration to CKD patients. This review summarizes the results of published preclinical and clinical studies on the nonsteroidal MRA, apararenone esaxerenone and finerenone. The trials showed a better safety profile with maintained drug efficacy compared with steroidal MRA. For this reason, nonsteroidal MRA represent an interesting new therapeutic approach for the prevention of CHF and CKD progression. Some basic research findings also yielded interesting results in acute clinical settings such as myocardial infarction and acute kidney injury.

Keywords

Aldosterone Mineralocorticoid receptor (MR) MR antagonist Finerenone Chronic kidney disease (CKD) 

Notes

Funding

The authors declare no funding. Authors declare that this work has not been published before, that it is not under consideration for publication anywhere else and that that its publication has been approved by all co-authors.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical commitment

This article does not contain any studies with human participants performed by any of the authors.

References

  1. 1.
    Funder JW (2005) Mineralocorticoid receptors: distribution and activation. Heart Fail Rev 10(1):15–22.  https://doi.org/10.1007/s10741-005-2344-2 Google Scholar
  2. 2.
    Funder JW (2005) Mineralocorticoid-receptor blockade, hypertension and heart failure. Nat Clin Pract Endocrinol Metab 1(1):4–5.  https://doi.org/10.1038/ncpendmet0016 Google Scholar
  3. 3.
    Funder JW (2010) Minireview: aldosterone and mineralocorticoid receptors: past, present, and future. Endocrinology 151(11):5098–5102.  https://doi.org/10.1210/en.2010-0465 Google Scholar
  4. 4.
    Vashistha V, Lee M, Wu YL, Kaur S, Ovbiagele B (2016) Low glomerular filtration rate and risk of myocardial infarction: a systematic review and meta-analysis. Int J Cardiol 223:401–409  https://doi.org/10.1016/j.ijcard.2016.07.175 Google Scholar
  5. 5.
    Bansal N, Hsu CY, Go AS (2014) Intersection of cardiovascular disease and kidney disease: atrial fibrillation. Curr Opin Nephrol Hypertens 23(3):275–282.  https://doi.org/10.1097/01.mnh.0000444820.80249.56 Google Scholar
  6. 6.
    La Manna G, Boriani G, Capelli I, Marchetti A, Grandinetti V, Spazzoli A, Dalmastri V, Todeschini P, Rucci P, Stefoni S (2013) Incidence and predictors of postoperative atrial fibrillation in kidney transplant recipients. Transplantation 96(11):981–986.  https://doi.org/10.1097/TP.0b013e3182a2b492 Google Scholar
  7. 7.
    Guerraty MA, Chai B, Hsu JY, Ojo AO, Gao Y, Yang W, Keane MG, Budoff MJ, Mohler ER 3rd, CRIC Study Investigators (2015) Relation of aortic valve calcium to chronic kidney disease (from the Chronic Renal Insufficiency Cohort Study). Am J Cardiol 115(9):1281–1286.  https://doi.org/10.1016/j.amjcard.2015.02.011 Google Scholar
  8. 8.
    Funder JW (2010) Aldosterone and mineralocorticoid receptors in the cardiovascular system. Prog Cardiovasc Dis 52(5):393–400.  https://doi.org/10.1016/j.pcad.2009.12.003 Google Scholar
  9. 9.
    Jaisser F, Farman N (2016) Emerging roles of the mineralocorticoid receptor in pathology: toward new paradigms in clinical pharmacology. Pharmacol Rev 68(1):49–75.  https://doi.org/10.1124/pr.115.011106 Google Scholar
  10. 10.
    He BJ, Anderson ME (2013) Aldosterone and cardiovascular disease: the heart of the matter. Trends Endocrinol Metab 24(1):21–30.  https://doi.org/10.1016/j.tem.2012.09.004 Google Scholar
  11. 11.
    Namsolleck P, Unger T (2014) Aldosterone synthase inhibitors in cardiovascular and renal diseases. Nephrol Dial Transplant 29(1):i62–i68.  https://doi.org/10.1093/ndt/gft402 Google Scholar
  12. 12.
    Lösel R, Schultz A, Boldyreff B, Wehling M (2004) Rapid effects of aldosterone on vascular cells: clinical implications. Steroids 69(8–9):575–578Google Scholar
  13. 13.
    Hermidorff MM, Assis LDe, Isoldi LVM MC (2017) Genomic and rapid effects of aldosterone: what we know and do not know thus far. Heart Fail Rev 22(1):65–89.  https://doi.org/10.2174/1389450119666180326125926 Google Scholar
  14. 14.
    Chen R, Sun W, Gu H, Cheng Y (2015) Aldosterone-induced expression of ENaC-a is associatedwith activity of p65/p50 in renal epithelial cells. 30(1):73–79.  https://doi.org/10.1007/s40620-015-0231-z
  15. 15.
    Sato A. Saruta T (2004) Aldosterone-induced organ damage: plasma aldosterone level and inappropriate salt status. Hypertens Res 27(5):303–310Google Scholar
  16. 16.
    Shavit L, Lifschitz MD, Epstein M (2012) Aldosterone blockade and the mineralocorticoid receptor in the management of chronic kidney disease: current concepts and emerging treatment paradigms. Kidney Int 81(10): 955–968.  https://doi.org/10.1038/ki.2011.505 Google Scholar
  17. 17.
    Rickard AJ, Young MJ (2009) Corticosteroid receptors, macrophages and cardiovascular disease. J Mol Endocrinol 42(6):449–459Google Scholar
  18. 18.
    Shen JZ, Morgan J, Tesch GH, Rickard AJ, Chrissobolis S, Drummond GR, Fuller PJ, Young MJ (2016) Cardiac tissue injury and remodeling is dependent upon MR regulation of activation pathways in cardiac tissue macrophages. Endocrinology 157(8):3213–3223.  https://doi.org/10.1210/en.2016-1040 Google Scholar
  19. 19.
    Fraccarollo D, Berger S, Galuppo P, Kneitz S, Hein L, Schütz G, Frantz S, Ertl G, Bauersachs J (2011) Deletion of cardiomyocyte mineralocorticoid receptor ameliorates adverse remodeling after myocardial infarction. Circulation 123(4):400–408.  https://doi.org/10.1161/CIRCULATIONAHA.110.983023 Google Scholar
  20. 20.
    Tesch GH, Young MJ (2017) Mineralocorticoid receptor signaling as a therapeutic target for renal and cardiac fibrosis. Front Pharmacol 8:313.  https://doi.org/10.3389/fphar.2017.00313 Google Scholar
  21. 21.
    Nagase M, Ayuzawa N, Kawarazaki W, Ishizawa K, Ueda K, Yoshida S, Fujita T (2012) Oxidative stress causes mineralocorticoid receptor activation in rat cardiomyocytes: role of small GTPase Rac1. Hypertension 59(2):500–506.  https://doi.org/10.1161/HYPERTENSIONAHA.111.185520 Google Scholar
  22. 22.
    Ayuzawa N, Nagase M, Ueda K, Nishimoto M, Kawarazaki W, Marumo T, Aiba A, Sakurai T, Shindo T, Fujita T (2016) Rac1-mediated activation of mineralocorticoid receptor in pressure overload-induced cardiac injury. Hypertension 67(1):99–106.  https://doi.org/10.1161/HYPERTENSIONAHA.115.06054 Google Scholar
  23. 23.
    Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J (1999) The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 341(10):709–717Google Scholar
  24. 24.
    McMurray JJ et al (2012) ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 14(8):803–869.  https://doi.org/10.1093/eurjhf/hfs105 Google Scholar
  25. 25.
    Berl T, Katz FH, Henrich WL, de Torrente A, Schrier RW (1978) Role of aldosterone in the control of sodium excretion in patients with advanced chronic renal failure. Kidney Int 14(3):228–235Google Scholar
  26. 26.
    Hené RJ, Boer P, Koomans HA, Mees EJ (1982) Plasma aldosterone concentrations in chronic renal disease. Kidney Int 21(1):98–101Google Scholar
  27. 27.
    Reams GP, Bauer JH (1986) Effect of enalapril in subjects with hypertension associated with moderate to severe renal dysfunction. Arch Intern Med 146(11):2145–2148Google Scholar
  28. 28.
    Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ (2008) Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review. Am J Kidney Dis 51(2):199–211.  https://doi.org/10.1053/j.ajkd.2007.10.040 Google Scholar
  29. 29.
    Gross E, Rothstein M, Dombek S, Juknis HI (2005) Effect of spironolactone on blood pressure and the renin–angiotensin–aldosterone system in oligo-anuric hemodialysis patients. Am J Kidney Dis 46(1):94–101Google Scholar
  30. 30.
    Shavit L, Neykin D, Lifschitz M, Slotki I (2011) Effect of eplerenone on blood pressure and the renin–angiotensin–aldosterone system in oligo-anuric chronic hemodialysis patients—a pilot study. Clin Nephrol 76(5):388–395Google Scholar
  31. 31.
    Bomback AS (2016) Mineralocorticoid receptor antagonists in end-stage renal disease: efficacy and safety. Blood Purif 41(1–3):166–170.  https://doi.org/10.1159/000441262 Google Scholar
  32. 32.
    Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD (2009) Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol 20(12):2641–2650.  https://doi.org/10.1681/ASN.2009070737 Google Scholar
  33. 33.
    Mavrakanas TA, Gariani K, Martin PY (2014) Mineralocorticoid receptor blockade in addition to angiotensin converting enzyme inhibitor or angiotensin II receptor blocker treatment: an emerging paradigm in diabetic nephropathy: a systematic review. Eur J Intern Med 25(2):173–176.  https://doi.org/10.1016/j.ejim.2013.11.007 Google Scholar
  34. 34.
    Bellizzi V, Conte G, Borrelli S, Cupisti A, De Nicola L, Di Iorio RB, Cabiddu G. Mandreoli M, Paoletti E, Piccoli GB, Quintaliani G, Ravera M, Santoro D, Torraca S, Minutolo R (2016) On behalf of the “conservative treatment of CKD” study group of the Italian society of nephrology. 30(2):159–170.  https://doi.org/10.1007/s40620-016-0338-x
  35. 35.
    Stefoni S, Cianciolo G, Baraldi O, Iorio M, Angelini ML (2014) Emerging drugs for chronic kidney disease. Expert Opin Emerg Drugs 19(2):183–199.  https://doi.org/10.1517/14728214.2014.900044 Google Scholar
  36. 36.
    Ruilope LM, Tamargo J (2017) Renin-angiotensin system blockade: finerenone. Nephrol Ther 13(Suppl 1):S47–S53.  https://doi.org/10.1016/j.nephro.2017.02.003 Google Scholar
  37. 37.
    Weinberger MH, Roniker B, Krause SL, Weiss RJ (2002) Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens 15(8):709–716Google Scholar
  38. 38.
    Albert NM, Yancy CW, Liang L, Zhao X, Hernandez AF, Peterson ED, Cannon CP, Fonarow GC (2009) Use of aldosterone antagonists in heart failure. JAMA 302(15):1658–1665.  https://doi.org/10.1001/jama.2009.1493 Google Scholar
  39. 39.
    De Nicola L, Di Lullo L, Paoletti E, Cupisti A, Bianchi S (2018) Chronic hyperkalemia in non-dialysis CKD: controversial issues in nephrology practice.  https://doi.org/10.1007/s40620-018-0502-6 (Epub ahead of print)
  40. 40.
    Epstein M (2016) Hyperkalemia constitutes a constraint for implementing renin–angiotensin–aldosterone inhibition: the widening gap between mandated treatment guidelines and the real-world clinical arena. Kidney Int Suppl 6(1):20–28Google Scholar
  41. 41.
    Shirazian S, Grant CD, Mujeeb S, Sharif S, Kumari P, Bhagat M, Mattana J (2015) Underprescription of renin–angiotensin system blockers in moderate to severe chronic kidney disease. Am J Med Sci 349(6):510–515.  https://doi.org/10.1097/MAJ.0000000000000475 Google Scholar
  42. 42.
    Arai K, Homma T, Morikawa Y, Ubukata N, Tsuruoka H, Aoki K, Ishikawa H, Mizuno M, Sada T (2015) Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist. Eur J Pharmacol, 761:226–234.  https://doi.org/10.1016/j.ejphar.2015.06.015 Google Scholar
  43. 43.
    Yamada M, Takei M, Suzuki E, Takakusa H, Kotsuma M, Washio T, Murayama N, Inoue SI, Izumi T (2017) Pharmacokinetics, distribution, and disposition of esaxerenone, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist, in rats and monkeys. Xenobiotica 47(12):1090–1103.  https://doi.org/10.1080/00498254.2016.1263766 Google Scholar
  44. 44.
    Arai K, Tsuruoka H, Homma T (2015) CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, prevents hypertension and cardiorenal injury in Dahl salt-sensitive hypertensive rats. Eur J Pharmacol 769:266–273.  https://doi.org/10.1016/j.ejphar.2015.11.028 Google Scholar
  45. 45.
    Arai K, Morikawa Y, Ubukata N, Tsuruoka H, Homma T (2016) CS-3150, a novel nonsteroidal mineralocorticoid receptor antagonist, shows preventive and therapeutic effects on renal injury in deoxycorticosterone acetate/salt-induced hypertensive rats. J Pharmacol Exp Ther 358(3):548–557.  https://doi.org/10.1124/jpet.116.234765 Google Scholar
  46. 46.
    Kolkhof P, Bärfacker L (2017) 30 Years of the mineralocorticoid receptor: Mineralocorticoid receptor antagonists: 60 years of research and development. J Endocrinol 234(1):T125–T140.  https://doi.org/10.1530/JOE-16-0600 Google Scholar
  47. 47.
    Amazit L, Le Billan F, Kolkhof P, Lamribet K, Viengchareun S, Fay MR, Khan JA, Hillisch A, Lombès M, Rafestin-Oblin ME, Fagart J (2015) Finerenone impedes aldosterone-dependent nuclear import of the mineralocorticoid receptor and prevents genomic recruitment of steroid receptor coactivator-1. J Biol Chem 290(36):21876–21889.  https://doi.org/10.1074/jbc.M115.657957 Google Scholar
  48. 48.
    Kolkhof P, Delbeck M, Kretschmer A, Steinke W, Hartmann E, Bärfacker L, Eitner F, Albrecht-Küpper B, Schäfer S (2014) Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury. J Cardiovasc Pharmacol 64(1):69–78.  https://doi.org/10.1097/FJC.0000000000000091 Google Scholar
  49. 49.
    Grune J, Benz V, Brix S, Salatzki J, Blumrich A, Höft B, Klopfleisch R, Foryst-Ludwig A, Kolkhof P, Kintscher U (2016) Steroidal and nonsteroidal mineralocorticoid receptor antagonists cause differential cardiac gene expression in pressure overload-induced cardiac hypertrophy. J Cardiovasc Pharmacol 67(5):402–411.  https://doi.org/10.1097/FJC.0000000000000366 Google Scholar
  50. 50.
    Filippatos G. Anker SD, Böhm M, Gheorghiade M, Køber L, Krum H, Maggioni AP, Ponikowski P, Voors AA, Zannad F, Kim SY, Nowack C, Palombo G, Kolkhof P, Kimmeskamp-Kirschbaum N, Pieper A, Pitt B (2016) A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J 37(27): 2105–2114.  https://doi.org/10.1093/eurheartj/ehw132 Google Scholar
  51. 51.
    Bakris GL, Agarwal R, Chan JC, Cooper ME, Gansevoort RT, Haller H, Remuzzi G, Rossing P, Schmieder RE, Nowack C, Kolkhof P, Joseph A, Pieper A, Kimmeskamp-Kirschbaum N, Ruilope LM, Mineralocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy (ARTS-DN) Study Group (2015) Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA 314(9):884–894.  https://doi.org/10.1001/jama.2015.10081 Google Scholar
  52. 52.
    Lattenist L, Lechner SM, Messaoudi S, Le Mercier A, El Moghrabi S, Prince S, Bobadilla NA, Kolkhof P, Jaisser F, Barrera-Chimal J (2017) Nonsteroidal mineralocorticoid receptor antagonist finerenone protects against acute kidney injury-mediated chronic kidney disease: role of oxidative stress. Hypertension 69(5):870–878.  https://doi.org/10.1161/HYPERTENSIONAHA.116.08526 Google Scholar
  53. 53.
    Barrera-Chimal J, André-Grégoire G, Nguyen Dinh Cat A, Lechner SM, Cau J, Prince S, Kolkhof P, Loirand G, Sauzeau V, Hauet T, Jaisser F (2017) Benefit of mineralocorticoid receptor antagonism in AKI: role of vascular smooth muscle Rac1. J Am Soc Nephrol 28(4):1216–1226.  https://doi.org/10.1681/ASN.2016040477 Google Scholar
  54. 54.
    Barrera-Chimal J, Estrela GR, Lechner SM, Giraud S, El Moghrabi S, Kaaki S, Kolkhof P, Hauet T, Jaisser F (2018) The myeloid mineralocorticoid receptor controls inflammatory and fibrotic responses after renal injury via macrophage interleukin-4 receptor signaling. Kidney Int 93(6):1344–1355.  https://doi.org/10.1016/j.kint.2017.12.016 Google Scholar
  55. 55.
    Martínez-Martínez E, Buonafine M, Boukhalfa I, Ibarrola J, Fernández-Celis A, Kolkhof P, Rossignol P, Girerd N, Mulder P, López-Andrés N, Ouvrard-Pascaud A, Jaisser F (2017) Aldosterone target NGAL (neutrophil gelatinase-associated lipocalin) is involved in cardiac remodeling after myocardial infarction through NFκB pathway. Hypertension 70(6):1148–1156.  https://doi.org/10.1161/HYPERTENSIONAHA.117.09791 Google Scholar
  56. 56.
    Dutzmann J, Musmann RJ, Haertlé M, Daniel JM, Sonnenschein K, Schäfer A, Kolkhof P, Bauersachs J, Sedding DG (2017) The novel mineralocorticoid receptor antagonist finerenone attenuates neointima formation after vascular injury. PLoS One 12(9):0184888.  https://doi.org/10.1371/journal.pone.0184888 Google Scholar

Copyright information

© Italian Society of Nephrology 2019

Authors and Affiliations

  • Irene Capelli
    • 1
  • Lorenzo Gasperoni
    • 1
  • Marco Ruggeri
    • 1
  • Gabriele Donati
    • 1
  • Olga Baraldi
    • 1
  • Giovanni Sorrenti
    • 2
  • Maria Turchese Caletti
    • 3
  • Valeria Aiello
    • 1
  • Giuseppe Cianciolo
    • 1
  • Gaetano La Manna
    • 1
    Email author
  1. 1.Department of Experimental Diagnostic and Specialty Medicine (DIMES), Nephrology, Dialysis and Renal Transplant Unit, S. Orsola HospitalUniversity of BolognaBolognaItaly
  2. 2.Suzzara HospitalSuzzaraItaly
  3. 3.Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital“Alma Mater Studiorum” UniversityBolognaItaly

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