Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mineralocorticoid receptor antagonists for cardioprotection in chronic kidney disease: a step into the future

Abstract

Chronic kidney disease (CKD) and cardiovascular disease (CVD) share major risk factors and mechanistic pathways for progression. Furthermore, either decreased glomerular filtration rate or increased albuminuria are major risk factors for cardiovascular events. Evidence from previous renal outcome trials in patients with proteinuric CKD showed that angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs) effectively slow CKD progression, establishing these agents as fundamental CKD pharmacologic treatments. However, in all these trials and subsequent meta-analyses, ACEIs and ARBs did not significantly reduce cardiovascular events or mortality, indicating a high residual risk for CVD progression in individuals with CKD. In contrast to the above, several outcome trials with old and novel mineralocorticoid receptor-antagonists (MRAs) clearly suggest that these agents, apart from nephroprotection, offer important cardioprotection in this population. This article is an overview of previous and recent evidence on the effects of MRAs on cardiovascular outcomes in patients with CKD attempting to highlight a pathway able to improve both cardiovascular and renal prognosis in this population.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Effects of finerenone on the key cardiovascular outcome (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or hospitalization for heart failure) in FIDELIO-DKD trial.
Fig. 2: Comparison of the effects of different renin-angiotensin-aldosterone system blockers on kidney and cardiovascular outcomes in patients with chronic kidney disease.

References

  1. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007;298:2038–47.

    CAS  PubMed  Google Scholar 

  2. GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395:709–33.

    Google Scholar 

  3. Jager KJ, Kovesdy C, Langham R, Rosenberg M, Jha V, Zoccali C. A single number for advocacy and communication-worldwide more than 850 million individuals have kidney diseases. Kidney Int. 2019;96:1048–50.

    PubMed  Google Scholar 

  4. Johansen KL, Chertow GM, Foley RN, Gilbertson DT, Herzog CA, Ishani A, et al. US renal data system 2020 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis. 2021;77:A7–A8.

    PubMed  PubMed Central  Google Scholar 

  5. Vanholder R, Massy Z, Argiles A, Spasovski G, Verbeke F, Lameire N, et al. Chronic kidney disease as cause of cardiovascular morbidity and mortality. Nephrol Dial Transplant. 2005;20:1048–56.

    CAS  PubMed  Google Scholar 

  6. Stenvinkel P, Carrero JJ, Axelsson J, Lindholm B, Heimbürger O, Massy Z. Emerging biomarkers for evaluating cardiovascular risk in the chronic kidney disease patient: how do new pieces fit into the uremic puzzle? Clin J Am Soc Nephrol. 2008;3:505–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Ruiz-Hurtado G, Sarafidis P, Fernández-Alfonso MS, Waeber B, Ruilope LM. Global cardiovascular protection in chronic kidney disease. Nat Rev Cardiol. 2016;13:603–8.

    CAS  PubMed  Google Scholar 

  8. Cheung AK, Rahman M, Reboussin DM, Craven TE, Greene T, Kimmel PL, et al. Effects of Intensive BP Control in CKD. J Am Soc Nephrol. 2017;28:2812–23.

    PubMed  PubMed Central  Google Scholar 

  9. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3:1–150.

    Google Scholar 

  10. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension. J Hypertens. 2018;36:1953–2041.

    CAS  PubMed  Google Scholar 

  11. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18:891–975.

    PubMed  Google Scholar 

  12. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9.

    CAS  PubMed  Google Scholar 

  13. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–60.

    CAS  PubMed  Google Scholar 

  14. Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs JP, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA. 2001;285:2719–28.

    CAS  PubMed  Google Scholar 

  15. Sarafidis PA, Stafylas PC, Kanaki AI, Lasaridis AN. Effects of renin-angiotensin system blockers on renal outcomes and all-cause mortality in patients with diabetic nephropathy: an updated meta-analysis. Am J Hypertens. 2008;21:922–9.

    CAS  PubMed  Google Scholar 

  16. Sharma P, Blackburn RC, Parke CL, McCullough K, Marks A, Black C. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease. Cochrane Database Syst Rev. 2011;CD007751.

  17. Zhao H-J, Li Y, Liu S-M, Sun X-G, Li M, Hao Y, et al. Effect of calcium channels blockers and inhibitors of the renin-angiotensin system on renal outcomes and mortality in patients suffering from chronic kidney disease: systematic review and meta-analysis. Ren Fail. 2016;38:849–56.

    CAS  PubMed  Google Scholar 

  18. Lin Y-C, Lin J-W, Wu M-S, Chen K-C, Peng C-C, Kang Y-N. Effects of calcium channel blockers comparing to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with hypertension and chronic kidney disease stage 3 to 5 and dialysis: a systematic review and meta-analysis. PLoS ONE. 2017;12:e0188975.

    PubMed  PubMed Central  Google Scholar 

  19. Sarafidis PA, Alexandrou ME, Ruilope LM. A review of chemical therapies for treating diabetic hypertension. Expert Opin Pharmacother. 2017;18:909–23.

    CAS  PubMed  Google Scholar 

  20. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367:2204–13.

    CAS  PubMed  Google Scholar 

  21. Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369:1892–903.

    CAS  PubMed  Google Scholar 

  22. Sarafidis PA, Ruilope LM. Aggressive blood pressure reduction and renin-angiotensin system blockade in chronic kidney disease: time for re-evaluation? Kidney Int. 2014;85:536–46.

    CAS  PubMed  Google Scholar 

  23. Rossignol P, Frimat L, Zannad F. The safety of mineralocorticoid antagonists in maintenance hemodialysis patients: two steps forward. Kidney Int. 2019;95:747–9.

    PubMed  Google Scholar 

  24. 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.

    CAS  PubMed  Google Scholar 

  25. Filippatos G, Anker SD, Agarwal R, Pitt B, Ruilope LM, Rossing P, et al. Finerenone and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes. Circulation. 2021;143:540–52.

    CAS  PubMed  Google Scholar 

  26. Sarafidis PA, Memmos E, Alexandrou M-E, Papagianni A. Mineralocorticoid receptor antagonists for nephroprotection: current evidence and future perspectives. Curr Pharm Des. 2018;24:5528–36.

    CAS  PubMed  Google Scholar 

  27. Agarwal R, Kolkhof P, Bakris G, Bauersachs J, Haller H, Wada T, et al. Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine. Eur Heart J. 2021;42:152–61.

    CAS  PubMed  Google Scholar 

  28. Gomez-Sanchez E, Gomez-Sanchez CE. The multifaceted mineralocorticoid receptor. Compr Physiol. 2014;4:965–94.

    PubMed  PubMed Central  Google Scholar 

  29. Seckl JR, Walker BR. Minireview: 11beta-hydroxysteroid dehydrogenase type 1- a tissue-specific amplifier of glucocorticoid action. Endocrinology. 2001;142:1371–6.

    CAS  PubMed  Google Scholar 

  30. Barrera-Chimal J, Girerd S, Jaisser F. Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis. Kidney Int. 2019;96:302–19.

    CAS  PubMed  Google Scholar 

  31. Young MJ, Kanki M, Fuller PJ, Yang J. Identifying new cellular mechanisms of mineralocorticoid receptor activation in the heart. J Hum Hypertens. 2021;35:124–30.

    PubMed  Google Scholar 

  32. Yang J, Chang C, Safi R, Morgan J, McDonnell DP, Fuller PJ, et al. Identification of ligand-selective peptide antagonists of the mineralocorticoid receptor using phage display. Mol Endocrinol. 2011;25:32–43.

    PubMed  PubMed Central  Google Scholar 

  33. Viengchareun S, Le Menuet D, Martinerie L, Munier M, Pascual-Le Tallec L, Lombès M. The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology. Nucl Recept Signal. 2007;5:e012.

    PubMed  PubMed Central  Google Scholar 

  34. Connell JMC, Davies E. The new biology of aldosterone. J Endocrinol. 2005;186:1–20.

    CAS  PubMed  Google Scholar 

  35. Hermidorff MM, de Assis LVM, Isoldi MC. Genomic and rapid effects of aldosterone: what we know and do not know thus far. Heart Fail Rev. 2017;22:65–89.

    CAS  PubMed  Google Scholar 

  36. Funder JW. The nongenomic actions of aldosterone. Endocr Rev. 2005;26:313–21.

    CAS  PubMed  Google Scholar 

  37. Gilbert KC, Brown NJ. Aldosterone and inflammation. Curr Opin Endocrinol Diabetes Obes. 2010;17:199–204.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhu X, Manning RD, Lu D, Gomez-Sanchez CE, Fu Y, Juncos LA, et al. Aldosterone stimulates superoxide production in macula densa cells. Am J Physiol Ren Physiol. 2011;301:F529–535.

    CAS  Google Scholar 

  39. Nagase M, Fujita T. Aldosterone and glomerular podocyte injury. Clin Exp Nephrol. 2008;12:233–42.

    CAS  PubMed  Google Scholar 

  40. Brown NJ. Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nat Rev Nephrol. 2013;9:459–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Lavall D, Selzer C, Schuster P, Lenski M, Adam O, Schäfers H-J, et al. The mineralocorticoid receptor promotes fibrotic remodeling in atrial fibrillation. J Biol Chem. 2014;289:6656–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Nagase M, Ayuzawa N, Kawarazaki W, Ishizawa K, Ueda K, Yoshida S, et al. Oxidative stress causes mineralocorticoid receptor activation in rat cardiomyocytes: role of small GTPase Rac1. Hypertension. 2012;59:500–6.

    CAS  PubMed  Google Scholar 

  43. Köhler E, Bertschin S, Woodtli T, Resink T, Erne P. Does aldosterone-induced cardiac fibrosis involve direct effects on cardiac fibroblasts? J Vasc Res. 1996;33:315–26.

    PubMed  Google Scholar 

  44. Chai W, Garrelds IM, de Vries R, Batenburg WW, van Kats JP, Danser AHJ. Nongenomic effects of aldosterone in the human heart: interaction with angiotensin II. Hypertension. 2005;46:701–6.

    CAS  PubMed  Google Scholar 

  45. Terada Y, Kobayashi T, Kuwana H, Tanaka H, Inoshita S, Kuwahara M, et al. Aldosterone stimulates proliferation of mesangial cells by activating mitogen-activated protein kinase 1/2, Cyclin D1, and Cyclin A. J Am Soc Nephrol. 2005;16:2296–305.

    CAS  PubMed  Google Scholar 

  46. Shibata S, Nagase M, Yoshida S, Kawachi H, Fujita T. Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1. Hypertension. 2007;49:355–64.

    CAS  PubMed  Google Scholar 

  47. Calò LA, Zaghetto F, Pagnin E, Davis PA, De Mozzi P, Sartorato P, et al. Effect of aldosterone and glycyrrhetinic acid on the protein expression of PAI-1 and p22(phox) in human mononuclear leukocytes. J Clin Endocrinol Metab. 2004;89:1973–6.

    PubMed  Google Scholar 

  48. Rocha R, Rudolph AE, Frierdich GE, Nachowiak DA, Kekec BK, Blomme EAG, et al. Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol. 2002;283:H1802–1810.

    CAS  PubMed  Google Scholar 

  49. Greene EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model in the rat. J Clin Investig. 1996;98:1063–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sun Y, Zhang J, Lu L, Chen SS, Quinn MT, Weber KT. Aldosterone-induced inflammation in the rat heart: role of oxidative stress. Am J Pathol. 2002;161:1773–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Rocha R, Stier CT, Kifor I, Ochoa-Maya MR, Rennke HG, Williams GH, et al. Aldosterone: a mediator of myocardial necrosis and renal arteriopathy. Endocrinology. 2000;141:3871–8.

    CAS  PubMed  Google Scholar 

  52. Briet M, Schiffrin EL. Vascular actions of aldosterone. J Vasc Res. 2013;50:89–99.

    CAS  PubMed  Google Scholar 

  53. Iwashima F, Yoshimoto T, Minami I, Sakurada M, Hirono Y, Hirata Y. Aldosterone induces superoxide generation via Rac1 activation in endothelial cells. Endocrinology. 2008;149:1009–14.

    CAS  PubMed  Google Scholar 

  54. Bomback AS, Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol. 2007;3:486–92.

    CAS  PubMed  Google Scholar 

  55. Sarafidis PA, Ruilope LM. Cardiorenal disease development under chronic renin-angiotensin-aldosterone system suppression. J Renin angiotensin aldosterone Syst. 2012;13:217–9.

    PubMed  Google Scholar 

  56. Shrestha A, Che R-C, Zhang A-H. Role of aldosterone in renal fibrosis. Adv Exp Med Biol. 2019;1165:325–46.

    CAS  PubMed  Google Scholar 

  57. Stavropoulos K, Imprialos K, Papademetriou V, Faselis C, Tsioufis K, Dimitriadis K, et al. Primary aldosteronism: novel insights. Curr Hypertens Rev. 2020;16:19–23.

    CAS  PubMed  Google Scholar 

  58. Epstein M, Williams GH, Weinberger M, Lewin A, Krause S, Mukherjee R, et al. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol. 2006;1:940–51.

    CAS  PubMed  Google Scholar 

  59. Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol. 2009;20:2641–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Alexandrou M-E, Papagianni A, Tsapas A, Loutradis C, Boutou A, Piperidou A, et al. Effects of mineralocorticoid receptor antagonists in proteinuric kidney disease: a systematic review and meta-analysis of randomized controlled trials. J Hypertens. 2019;37:2307–24.

    CAS  PubMed  Google Scholar 

  61. Bakris GL, Agarwal R, Chan JC, Cooper ME, Gansevoort RT, Haller H, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA. 2015;314:884–94.

    CAS  PubMed  Google Scholar 

  62. Wan N, Rahman A, Nishiyama A. Esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker (MRB) in hypertension and chronic kidney disease. J Hum Hypertens. 2021;35:148–56.

    CAS  PubMed  Google Scholar 

  63. Fuller PJ, Yang J, Young MJ. 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Coregulators as mediators of mineralocorticoid receptor signalling diversity. J Endocrinol. 2017;234:T23–T34.

    CAS  PubMed  Google Scholar 

  64. Kolkhof P, Delbeck M, Kretschmer A, Steinke W, Hartmann E, Bärfacker L, et al. Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury. J Cardiovasc Pharmacol. 2014;64:69–78.

    CAS  PubMed  Google Scholar 

  65. Grune J, Beyhoff N, Smeir E, Chudek R, Blumrich A, Ban Z, et al. Selective mineralocorticoid receptor cofactor modulation as molecular basis for finerenone’s antifibrotic activity. Hypertension. 2018;71:599–608.

    CAS  PubMed  Google Scholar 

  66. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N. Engl J Med. 1999;341:709–17.

    CAS  PubMed  Google Scholar 

  67. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–21.

    CAS  PubMed  Google Scholar 

  68. Zannad F, McMurray JJV, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11–21.

    CAS  PubMed  Google Scholar 

  69. Ferreira JP, Abreu P, McMurray JJV, van Veldhuisen DJ, Swedberg K, Pocock SJ, et al. Renal function stratified dose comparisons of eplerenone versus placebo in the EMPHASIS-HF trial. Eur J Heart Fail. 2019;21:345–51.

    CAS  PubMed  Google Scholar 

  70. Matsumoto Y, Mori Y, Kageyama S, Arihara K, Sugiyama T, Ohmura H, et al. Spironolactone reduces cardiovascular and cerebrovascular morbidity and mortality in hemodialysis patients. J Am Coll Cardiol. 2014;63:528–36.

    CAS  PubMed  Google Scholar 

  71. Lin C, Zhang Q, Zhang H, Lin A. Long-term effects of low-dose spironolactone on chronic dialysis patients: a randomized placebo-controlled study. J Clin Hypertens. 2016;18:121–8.

    CAS  Google Scholar 

  72. Sarafidis PA, Persu A, Agarwal R, Burnier M, de Leeuw P, Ferro C, et al. Hypertension in dialysis patients: a consensus document by the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension (ESH). J Hypertens. 2017;35:657–76.

    CAS  PubMed  Google Scholar 

  73. Georgianos PI, Sarafidis PA, Liakopoulos V, Balaskas EV, Zebekakis PE. Mineralocorticoid receptor antagonism for cardiovascular protection in end-stage renal disease: new data but the controversy continues. J Clin Hypertens. 2016;18:197–9.

    Google Scholar 

  74. University Hospital, Brest. ALdosterone Antagonist Chronic HEModialysis Interventional Survival Trial (ALCHEMIST), Phase III b. 2020 https://clinicaltrials.gov/ct2/show/NCT01848639. Accessed 11 Feb 2021.

  75. Population Health Research Institute. Aldosterone bloCkade for Health Improvement EValuation in End-stage Renal Disease. 2020 https://clinicaltrials.gov/ct2/show/NCT03020303. Accessed 11 Feb 2021.

  76. Bianchi S, Bigazzi R, Campese VM. Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int. 2006;70:2116–23.

    CAS  PubMed  Google Scholar 

  77. Ando K, Ohtsu H, Uchida S, Kaname S, Arakawa Y, Fujita T. Anti-albuminuric effect of the aldosterone blocker eplerenone in non-diabetic hypertensive patients with albuminuria: a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2:944–53.

    CAS  PubMed  Google Scholar 

  78. Lindhardt M, Persson F, Oxlund C, Jacobsen IA, Zurbig P, Mischak H, et al. Predicting albuminuria response to spironolactone treatment with urinary proteomics in patients with type 2 diabetes and hypertension. Nephrol Dial Transplant. 2018;33:296–303.

    CAS  PubMed  Google Scholar 

  79. Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Nowack C, et al. Design and baseline characteristics of the finerenone in reducing kidney failure and disease progression in diabetic kidney disease trial. Am J Nephrol. 2019;50:333–44.

    CAS  PubMed  Google Scholar 

  80. Research Center for Drug Evaluation and Research. FDA approves drug to reduce risk of serious kidney and heart complications in adults with chronic kidney disease associated with type 2 diabetes. FDA. 2021.https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-drug-reduce-risk-serious-kidney-and-heart-complications-adults-chronic-kidney-disease. Accessed 15 July 2021.

  81. 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. https://doi.org/10.1056/NEJMoa2110956. Online ahead of print.

  82. Packer M, Butler J, Zannad F, Filippatos G, Ferreira JP, Pocock SJ, et al. Effect of empagliflozin on worsening heart failure events in patients with heart failure and preserved ejection fraction: EMPEROR-preserved trial. Circulation. 2021;144:1284–94.

    PubMed  PubMed Central  Google Scholar 

  83. Kasiakogias A, Rosei EA, Camafort M, Ehret G, Faconti L, Ferreira JP, et al. Hypertension and heart failure with preserved ejection fraction: position paper by the European Society of Hypertension. J Hypertens. 2021;39:1522–45.

    CAS  PubMed  Google Scholar 

  84. Bonsu KO, Arunmanakul P, Chaiyakunapruk N. Pharmacological treatments for heart failure with preserved ejection fraction-a systematic review and indirect comparison. Heart Fail Rev. 2018;23:147–56.

    CAS  PubMed  Google Scholar 

  85. A Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled Study to Evaluate the Efficacy and Safety of Finerenone on Morbidity and Mortality in Participants With Heart Failure (NYHA II-IV) and Left Ventricular Ejection Fraction ≥ 40% (LVEF ≥ 40%). 2021. https://clinicaltrials.gov/ct2/show/NCT04435626. Accessed 20 Sep 2021.

  86. Takahashi M, Ubukata O, Homma T, Asoh Y, Honzumi M, Hayashi N, et al. Crystal structure of the mineralocorticoid receptor ligand-binding domain in complex with a potent and selective nonsteroidal blocker, esaxerenone (CS-3150). FEBS Lett. 2020;594:1615–23.

  87. Ito S, Itoh H, Rakugi H, Okuda Y, Yoshimura M, Yamakawa S. Double-blind randomized phase 3 study comparing esaxerenone (CS-3150) and eplerenone in patients with essential. Hypertension. 2020;75:51–58.

    CAS  PubMed  Google Scholar 

  88. Ito S, Shikata K, Nangaku M, Okuda Y, Sawanobori T. Efficacy and safety of esaxerenone (CS-3150) for the treatment of type 2 diabetes with microalbuminuria: a randomized, double-blind, placebo-controlled, phase II trial. Clin J Am Soc Nephrol. 2019;14:1161–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 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.

    CAS  PubMed  Google Scholar 

  90. Palmer BF. A physiologic-based approach to the evaluation of a patient with hyperkalemia. Am J Kidney Dis. 2010;56:387–93.

    PubMed  Google Scholar 

  91. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004;351:543–51.

    CAS  PubMed  Google Scholar 

  92. Moura-Neto JA, Ronco C. The RALES legacy and finerenone use on CKD patients. Clin J Am Soc Nephrol. 2021;16:1432–4.

    PubMed  Google Scholar 

  93. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou F-F, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383:1436–46.

    CAS  Google Scholar 

  94. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N. Engl J Med. 2019;380:2295–306.

    CAS  PubMed  Google Scholar 

  95. Sarafidis P, Ortiz A, Ferro CJ, Halimi J-M, Kreutz R, Mallamaci F, et al. Sodium_glucose co-transporter-2 inhibitors for patients with diabetic and nondiabetic chronic kidney disease: a new era has already begun. J Hypertens. 2021;39:1090–7.

    CAS  PubMed  Google Scholar 

  96. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995–2008.

    CAS  Google Scholar 

  97. McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004.

    PubMed  Google Scholar 

  98. Vaduganathan M, Claggett BL, Jhund PS, Cunningham JW, Pedro Ferreira J, Zannad F, et al. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Lancet. 2020;396:121–8.

    CAS  PubMed  Google Scholar 

  99. Sarafidis P, Ferro CJ, Morales E, Ortiz A, Malyszko J, Hojs R, et al. SGLT-2 inhibitors and GLP-1 receptor agonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease. A consensus statement by the EURECA-m and the DIABESITY working groups of the ERA-EDTA. Nephrol Dial Transplant. 2019;34:208–30.

    CAS  PubMed  Google Scholar 

  100. Sarafidis P, Papadopoulos CE, Kamperidis V, Giannakoulas G, Doumas M. Cardiovascular protection with sodium-glucose cotransporter-2 inhibitors and mineralocorticoid receptor antagonists in chronic kidney disease: a milestone achieved. Hypertension. 2021;77:1442–55.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed to this study, which was conceived by PS and MK, and drafted by all authors (MA, MT, MK, and PS).

Corresponding author

Correspondence to Pantelis A. Sarafidis.

Ethics declarations

Competing interests

PS is an advisor/speaker to Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Elpen Pharmaceuticals, Genesis Pharma, Menarini, Innovis Pharma, Sanofi, Winmedica and has received research support for an Investigator-Initiated Study from Astra Zeneca. MA, MPT, and MK have no competing interests in relation to the work described.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Alexandrou, ME., Theodorakopoulou, M.P., Kanbay, M. et al. Mineralocorticoid receptor antagonists for cardioprotection in chronic kidney disease: a step into the future. J Hum Hypertens (2022). https://doi.org/10.1038/s41371-021-00641-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41371-021-00641-1

Search

Quick links