Mineralocorticoid Receptor Antagonism in Chronic Kidney Disease

Abstract

The overactivation of the mineralocorticoid receptor (MR) in animal models of chronic kidney disease (CKD) increases sodium retention and hypertension and provokes inflammation and fibrosis in the kidneys, blood vessels, and the heart; these processes play an important role in the progression of cardiorenal disease. Accordingly, blockade of the MR is an attractive therapeutic intervention to retard the progression of CKD and improve cardiovascular morbidity and mortality. Finerenone is a novel, nonsteroidal MR antagonist (MRA) with a unique mode of action that is distinct from currently available steroidal MRAs. In animal models of CKD, finerenone has a more favorable benefit/risk ratio as compared with the steroidal MRAs such as spironolactone and eplerenone. In patients with type 2 diabetes and heart and/or kidney disease, phase II trials have revealed that compared with spironolactone, eplerenone, or placebo, finerenone displays benefits that exceed the risks of MR antagonism. In patients with CKD and type 2 diabetes, a large phase III trial has shown that, compared with placebo, finerenone improved kidney failure and cardiovascular outcomes. In the first part of this article, we explore the safety and efficacy of spironolactone and eplerenone in early- and late-stage CKD. In the second part, we describe the mechanism of action of finerenone and discuss the promising role of this nonsteroidal MRA as a novel therapeutic opportunity to improve clinical outcomes in patients with CKD. The overactivation of the mineralocorticoid receptor (MR) in animal models of chronic kidney disease (CKD) increases sodium retention and hypertension and provokes inflammation and fibrosis in the kidneys, blood vessels, and the heart; these processes play an important role in the progression of cardiorenal disease. Accordingly, blockade of the MR is an attractive therapeutic intervention to retard the progression of CKD and improve cardiovascular morbidity and mortality. Finerenone is a novel, nonsteroidal MR antagonist (MRA) with a unique mode of action that is distinct from currently available steroidal MRAs. In animal models of CKD, finerenone has a more favorable benefit/risk ratio as compared with the steroidal MRAs such as spironolactone and eplerenone. In patients with type 2 diabetes and heart and/or kidney disease, phase II trials have revealed that compared with spironolactone, eplerenone, or placebo, finerenone displays benefits that exceed the risks of MR antagonism. In patients with CKD and type 2 diabetes, a large phase III trial has shown that, compared with placebo, finerenone improved kidney failure and cardiovascular outcomes. In the first part of this article, we explore the safety and efficacy of spironolactone and eplerenone in early- and late-stage CKD. In the second part, we describe the mechanism of action of finerenone and discuss the promising role of this nonsteroidal MRA as a novel therapeutic opportunity to improve clinical outcomes in patients with CKD. The MR belongs to the subfamily of nuclear hormone receptors and is expressed in several tissues/cell types, such as in the kidney, heart, vasculature, immune cells, and fibroblasts.1Agarwal R. Kolkhof P. Bakris G. et al.Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine.Eur Heart J. 2021; 42: 152-161Crossref PubMed Scopus (41) Google Scholar Physiologically, the MR plays a key role in regulating fluid, electrolytes, and blood pressure (BP). However, MR is overactivated in CKD and heart failure (HF). In addition to increased salt and water retention, MR overactivation increases the expression of target genes implicated in inflammatory and fibrotic pathways; this culminates in organ injury.1Agarwal R. Kolkhof P. Bakris G. et al.Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine.Eur Heart J. 2021; 42: 152-161Crossref PubMed Scopus (41) Google Scholar Therefore, MR blockade is an attractive pharmacological target for preserving organ function. Preserving organ function is of key importance, particularly in patients with type 2 diabetes mellitus (T2DM). Kidney injury and early-stage CKD in these patients associates with a far greater likelihood of cardiovascular morbidity than progression to end-stage kidney disease (ESRD). Therefore, MR blockade may abrogate the progression of CKD and reduce cardiovascular morbidity and mortality.2Agarwal R. Anker S.D. Bakris G. et al.Investigating new treatment opportunities for patients with chronic kidney disease in type 2 diabetes: the role of finerenone [Online ahead of print].Nephrol Dial Transplant. 2020; Google Scholar trials have shown that, patients have with the currently available steroidal MRAs and reduce the of and cardiovascular et of spironolactone morbidity and in patients with heart PubMed Scopus Google et a in patients with PubMed Scopus Google Scholar steroidal MRAs have the in clinical for the treatment of P. Anker S.D. et for the and treatment of and chronic heart the for the and treatment of and chronic heart failure of the of with the of the Heart of the Heart PubMed Scopus Google Scholar have shown that these in clinical G. et with of mineralocorticoid receptor antagonists in heart failure with an of patients from the Heart Heart PubMed Scopus Google Scholar the of spironolactone and eplerenone more in patients with kidney to the of kidney injury and R. blockade in CKD with PubMed Scopus Google Scholar spironolactone is as of Bakris et and a from the Heart PubMed Scopus Google G. et for the of the for the of hypertension of the of and the of PubMed Scopus Google Scholar this is to patients with and G. et for the of the for the of hypertension of the of and the of PubMed Scopus Google Scholar the that the of hypertension increases with the in et of hypertension with PubMed Scopus Google G. et and of treatment hypertension in chronic kidney from the PubMed Scopus Google Scholar the of increases as R. Anker S.D. et of finerenone chronic kidney disease outcomes in type 2 2020; PubMed Scopus Google P. et in patients with chronic kidney and clinical Dial Transplant. PubMed Scopus Google Scholar as a and the of spironolactone as in R. hypertension in chronic kidney disease treatment and 2020; PubMed Scopus Google Scholar The to blockade of the clinical outcomes. have shown that, compared with patients patients with or to for cardiorenal and J. of the treatment clinical and the of Google Scholar the of steroidal MRAs in patients with these in the progression of kidney injury patients with CKD that clinical trial in this is R. blockade in CKD with PubMed Scopus Google Scholar The to the progression of cardiorenal disease with a more favorable the and of nonsteroidal MRAs. Finerenone is a novel MRA with nonsteroidal and a unique mode that and for the R. Kolkhof P. Bakris G. et al.Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine.Eur Heart J. 2021; 42: 152-161Crossref PubMed Scopus (41) Google R. Anker S.D. Bakris G. et al.Investigating new treatment opportunities for patients with chronic kidney disease in type 2 diabetes: the role of finerenone [Online ahead of print].Nephrol Dial Transplant. 2020; Google Scholar that finerenone and the heart and the J. et mineralocorticoid receptor inflammatory and fibrotic injury receptor PubMed Scopus Google R. et and in a chronic kidney disease a in PubMed Scopus Google J. et mineralocorticoid receptor as for PubMed Scopus Google Scholar II clinical trials have shown a in with finerenone and with placebo, as as increases in with finerenone compared with R. et of finerenone in patients with a clinical PubMed Scopus Google G. Anker S.D. et of finerenone eplerenone in patients with chronic heart failure and diabetes mellitus and/or chronic kidney Heart J. 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