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 Nephrotoxin Puromycin Aminonucleoside Induces Injury in Kidney Organoids Differentiated from Induced Pluripotent Stem Cells

“…MMP acts together with ACE2 for the production of ANG (1-7) to counteract against overproduced ANGII, which finally prevents hypertension and organ damage [ 58 , 59 ]. Even though NR3C2 is involved in the regulation of fluid, electrolytes and blood pressure homoeostasis [ 60 ], an over-activation can cause organ injury induced by inflammatory and fibrotic processes [ 61 , 62 ].…”

Management of hypertension in advanced kidney disease

“…The observation that the use of currently available steroidal MRAs in daily clinical practice is associated with intolerable side effects, such as with an increased risk of hyperkalaemia, has led to the discovery and development of nonsteroidal MRAs with the aim to maintain the potent and selective inhibition of the mineralocorticoid receptor with a more favourable safety profile [21 ▪▪ ,22]. Agents that belong to the novel class of nonsteroidal MRAs and have progressed into an advanced stage of clinical development are the following: finerenone, esaxerenone and KBP-5074.…”

“…Agents that belong to the novel class of nonsteroidal MRAs and have progressed into an advanced stage of clinical development are the following: finerenone, esaxerenone and KBP-5074. Differences in clinical efficacy among nonsteroidal MRAs, such as BP-lowering action, appear to exist, but the superiority of one agent over the other remains unclear in the absence of trials to provide direct head-to-head comparisons [21 ▪▪ ,22].…”

Efficacy and Safety of Finerenone in Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

“…More recently, third-generation MRA using non-steroidal molecules have been developed that more selectively enhance benefits and minimize risks owing to altered receptor affinity and tissue tropism (Bramlage et al, 2016). Finerenone (BAY 94-8662) is a novel potent, non-steroidal, selective MRA developed for the treatment of CKD (Georgianos and Agarwal, 2021). Compared with the currently available steroid-based MRAs, finerenone has greater selectivity for the MR over other steroid hormone receptors than spironolactone and improved affinity for MR in relation to eplerenone while maintaining very low affinity for androgen, glucocorticoid, and progesterone receptors, with more potent antiinflammatory and antifibrotic efficacy in preclinical models (Bramlage et al, 2016;Grune et al, 2018).…”