Advertisement
American Journal of Kidney Diseases

Aldosterone, Mineralocorticoid Receptor Activation, and CKD: A Review of Evolving Treatment Paradigms

Published:September 01, 2022DOI:https://doi.org/10.1053/j.ajkd.2022.04.016
      Mineralocorticoid receptor (MR) activation is involved in propagating kidney injury, inflammation, and fibrosis and in the progression of chronic kidney disease (CKD). Multiple clinical studies have defined the efficacy of MR antagonism in attenuating progressive kidney disease, and the US Food and Drug Administration recently approved the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone for this indication. In this review, we consider the basic science and clinical applicability of MR antagonism. Because hyperkalemia constitutes a constraint to implementing evidence-based MR blockade, we review MRA-associated hyperkalemia in the context of finerenone and discuss evolving mitigation strategies to enhance the safety and efficacy of this treatment. Although the FIDELIO-DKD and FIGARO-DKD clinical trials focused solely on patients with type 2 diabetes mellitus, we propose that MR activation and the resulting inflammation and fibrosis act as a substantive pathogenetic mediator not only in people with diabetic CKD but also in those with CKD without diabetes. We close by briefly discussing both recently initiated and future clinical trials that focus on extending the attributes of MR antagonism to a wider array of nondiabetic kidney disorders, such as patients with nonalbuminuric CKD.

      Index Words

      The past 8 decades have provided a wonderful backdrop for appreciating the extraordinary trajectory in elucidating the pathogenetic role of aldosterone and mineralocorticoid receptor (MR) activation as determinants of chronic kidney disease (CKD) progression independent of the renin-angiotensin system (RAS). Strong evidence has now accumulated to show that MR activation leads to many “off-target” effects on the heart, the vasculature, and the kidney.
      • Epstein M.
      Aldosterone and mineralocorticoid receptor signaling as determinants of cardiovascular and renal injury: from Hans Selye to the present.
      • Jaisser F.
      • Tan X.
      • Chi S.
      • et al.
      The non-steroidal mineralocorticoid receptor antagonist KBP-5074 limits albuminuria and has improved therapeutic index compared with eplerenone in a rat model with mineralocorticoid-induced renal injury.
      • Kintscher U.
      • Bakris G.L.
      • Kolkhof P.
      Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease.
      In this review, we summarize our growing understanding of role of MR activation in propagating kidney injury, inflammation, and fibrosis and the consequent progression of CKD. We review the recent clinical studies that investigated and defined the efficacy of MR antagonism in attenuating progressive kidney disease
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      ,
      • Pitt B.
      • Filippatos G.
      • Agarwal R.
      • et al.
      FIGARO-DKD Investigators
      Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
      and that culminated in an MR antagonist (MRA) becoming an approved treatment for retarding CKD progression.
      US Food and Drug Administration
      FDA approves drug to reduce risk of serious kidney and heart complications in adults with chronic kidney disease associated with type 2 diabetes. July 7, 2021.
      We also critically consider both the efficacy and safety of a newly approved novel nonsteroidal mineralocorticoid MRA, finerenone, and evolving mitigation strategies for MRA-associated hyperkalemia to enhance the safety and efficacy of new and emerging treatment paradigms.

      MR Activation in Kidney Pathophysiology

      Evolving Understanding of the Role of Aldosterone in Kidney Physiology

      The steroid aldosterone is the primary mineralocorticoid hormone; its synthesis is prompted by hyperkalemia or sodium and volume depletion as the end result of RAS activation.
      • Ayuzawa N.
      • Nishimoto M.
      • Ueda K.
      • et al.
      Two mineralocorticoid receptor-mediated mechanisms of pendrin activation in distal nephrons.
      • Buonafine M.
      • Bonnard B.
      • Jaisser F.
      Mineralocorticoid receptor and cardiovascular disease.
      • Fuller P.J.
      • Yang J.
      • Young M.J.
      30 Years of the mineralocorticoid receptor: coregulators as mediators of mineralocorticoid receptor signalling diversity.
      • Funder J.W.
      Minireview: aldosterone and mineralocorticoid receptors: past, present, and future.
      Among other tissues, the kidney, colon, heart, central nervous system, brown adipose tissue, and sweat glands all express MR and thus are responsive to aldosterone signaling.
      • Epstein M.
      Aldosterone and mineralocorticoid receptor signaling as determinants of cardiovascular and renal injury: from Hans Selye to the present.
      ,
      • Fuller P.J.
      • Yang J.
      • Young M.J.
      30 Years of the mineralocorticoid receptor: coregulators as mediators of mineralocorticoid receptor signalling diversity.
      ,
      • Sakima A.
      • Arima H.
      • Matayoshi T.
      • Ishida A.
      • Ohya Y.
      Effect of mineralocorticoid receptor blockade on arterial stiffness and endothelial function: a meta-analysis of randomized trials.
      Aldosterone is an important contributor to both blood pressure control and—by provoking renal sodium reabsorption and potassium excretion—maintenance of extracellular volume homeostasis.
      • Epstein M.
      Aldosterone and mineralocorticoid receptor signaling as determinants of cardiovascular and renal injury: from Hans Selye to the present.
      ,
      • Agarwal R.
      • Kolkhof P.
      • Bakris G.
      • et al.
      Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine.
      • Epstein M.
      Renal effects of head-out water immersion in humans: a 15-year update.
      • Gomez-Sanchez E.
      • Gomez-Sanchez C.E.
      The multifaceted mineralocorticoid receptor.
      Our understanding of the role of aldosterone is markedly evolving. It is now accepted that
      • Angiotensin is not the main trigger for aldosterone secretion.
        • Epstein M.
        Aldosterone and mineralocorticoid receptor signaling as determinants of cardiovascular and renal injury: from Hans Selye to the present.
      • MR is stimulated by several ligands (aldosterone, cortisol) and undergoes nonligand activation (via the regulatory protein Rac family small guanosine triphosphatase 1 [Rac1], elevated glucose, and high salt levels).
        • Epstein M.
        Aldosterone and mineralocorticoid receptor signaling as determinants of cardiovascular and renal injury: from Hans Selye to the present.
        ,
        • Fuller P.J.
        • Yang J.
        • Young M.J.
        30 Years of the mineralocorticoid receptor: coregulators as mediators of mineralocorticoid receptor signalling diversity.
        ,
        • Gomez-Sanchez E.
        • Gomez-Sanchez C.E.
        The multifaceted mineralocorticoid receptor.
        ,
        • Barrera-Chimal J.
        • Girerd S.
        • Jaisser F.
        Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis.
      • Leptin affects aldosterone synthesis, acting directly on adrenal glomerulosa cells to upregulate the expression of aldosterone synthase (encoded by CYP11B2) and increase the production of aldosterone via calcium-dependent mechanisms.
        • Huby A.C.
        • Antonova G.
        • Groenendyk J.
        • et al.
        Adipocyte-derived hormone leptin is a direct regulator of aldosterone secretion, which promotes endothelial dysfunction and cardiac fibrosis.
      Over the past decade emerging data have implicated aldosterone and MR activation in many aspects of renal and cardiovascular injury, including progression of CKD and cardiovascular disease as well as heart failure with reduced ejection fraction (HFrEF), arterial stiffness, and the metabolic syndrome.
      • Epstein M.
      Aldosterone and mineralocorticoid receptor signaling as determinants of cardiovascular and renal injury: from Hans Selye to the present.
      ,
      • Fuller P.J.
      • Yang J.
      • Young M.J.
      30 Years of the mineralocorticoid receptor: coregulators as mediators of mineralocorticoid receptor signalling diversity.
      ,
      • Sakima A.
      • Arima H.
      • Matayoshi T.
      • Ishida A.
      • Ohya Y.
      Effect of mineralocorticoid receptor blockade on arterial stiffness and endothelial function: a meta-analysis of randomized trials.
      ,
      • Barrera-Chimal J.
      • Girerd S.
      • Jaisser F.
      Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis.
      ,
      • Huby A.C.
      • Antonova G.
      • Groenendyk J.
      • et al.
      Adipocyte-derived hormone leptin is a direct regulator of aldosterone secretion, which promotes endothelial dysfunction and cardiac fibrosis.

      The Role of Nonepithelial MR Activation in CKD Progression

      The best-known function of aldosterone is its contribution to the control of electrolyte and fluid balance by interaction with MR expressed in aldosterone-sensitive kidney epithelial cells in the distal nephron. What is not as widely appreciated is that nonepithelial tissues also express MR, including the heart, adipocytes, podocytes, inflammatory cells, endothelial cells and vascular smooth muscle cells (VSMCs) (summarized in Fig 1 and Box 1). Several lines of evidence suggest that the MR in nonepithelial cells offers an attractive target for protecting against inflammation and fibrosis in both the kidneys and the cardiovascular system.
      • Epstein M.
      Aldosterone and mineralocorticoid receptor signaling as determinants of cardiovascular and renal injury: from Hans Selye to the present.
      ,
      • Buonafine M.
      • Bonnard B.
      • Jaisser F.
      Mineralocorticoid receptor and cardiovascular disease.
      ,
      • Agarwal R.
      • Kolkhof P.
      • Bakris G.
      • et al.
      Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine.
      ,
      • Tesch G.H.
      • Young M.J.
      Mineralocorticoid receptor signaling as a therapeutic target for renal and cardiac fibrosis.
      The development of cell-specific MR knockout mouse model facilitates our ability to understand exactly how MR in podocytes, vascular cells (endothelial cells and VSMCs), inflammatory cells, and fibroblasts relates to MR overactivation–associated kidney injury. These cascades of injury have recently been reviewed in Kintscher et al,
      • Kintscher U.
      • Bakris G.L.
      • Kolkhof P.
      Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease.
      and are summarized in Box 1 and Figure 1.
      Figure thumbnail gr1
      Figure 1Complementary interplay of cascades of injury, inflammation, and fibrosis that are initiated and sustained by MR activation. The MR is activated by several ligands (eg, aldosterone and cortisol) and by nonligand activation. MR expression occurs in numerous tissues, including nonepithelial tissues. Multipronged and complementary systemic and local molecular and signaling mechanisms act on the various cell types to promote cardiovascular and kidney injury. Abbreviations: MR, mineralocorticoid receptor; Rac1, Rac family small guanosine triphosphatase 1.
      MR Activation in Nonepithelial Cells
      Podocytes
      • MR activation increases autophagy of podocytes in vivo and restores autophagy in podocytes under mechanical stress.
      • Addition of aldosterone to podocytes in vitro induces the downregulation of nephrin, podocin, podoplanin, and podocalyxin.
      Fibroblasts
      • MR activation in renal fibroblasts may contribute to kidney remodeling during CKD.
      • Aldosterone stimulates fibronectin synthesis in isolated renal fibroblasts.
      • Conversely, incubation of fibroblasts with MRAs reduces extracellular matrix component production induced by either platelet-derived growth factor or connective tissue growth factor.
      Endothelial cells
      • Aldosterone increases ICAM-1, VCAM-1, E-selectin, and MCP-1 expression.
      • Aldosterone promotes oxidative injury through increasing the expression of the NADPH oxidase subunits Nox2, p47phox, p22phox and by stimulating Rac1 activation.
      • Aldosterone impairs endothelial function through a reduction in eNOS phosphorylation.
      Representative examples compiled from Jaisser et al,
      • Jaisser F.
      • Tan X.
      • Chi S.
      • et al.
      The non-steroidal mineralocorticoid receptor antagonist KBP-5074 limits albuminuria and has improved therapeutic index compared with eplerenone in a rat model with mineralocorticoid-induced renal injury.
      Kintscher et al,
      • Kintscher U.
      • Bakris G.L.
      • Kolkhof P.
      Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease.
      Buonafine et al,
      • Buonafine M.
      • Bonnard B.
      • Jaisser F.
      Mineralocorticoid receptor and cardiovascular disease.
      Fuller et al,
      • Fuller P.J.
      • Yang J.
      • Young M.J.
      30 Years of the mineralocorticoid receptor: coregulators as mediators of mineralocorticoid receptor signalling diversity.
      and Barrera-Chimal et al.
      • Barrera-Chimal J.
      • Girerd S.
      • Jaisser F.
      Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis.
      Abbreviations: CKD, chronic kidney disease; eNOS, endothelial nitric oxide synthase; ICAM-1, intercellular adhesion molecule 1; MCP-1, monocyte chemoattractant protein 1; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist; NADPH, reduced nicotinamide adenine dinucleotide phosphate; Nox2, NADPH oxidase 2; Rac1, Rac family small guanosine triphosphatase 1; VCAM-1, vascular cell adhesion molecule 1.

      The Interrelationship of Fibroblast Growth Factor 23 and Aldosterone

      As we detailed in a recent review,
      • Epstein M.
      • Freundlich M.
      The intersection of mineralocorticoid receptor activation and the FGF23-Klotho cascade: a duopoly that promotes renal and cardiovascular injury.
      fibroblast growth factor 23 (FGF-23) and membrane αKlotho (hereafter called Klotho) intersect with the renin-angiotensin-aldosterone system (RAAS). Of interest, FGF-23 is involved in local RAAS activation, including aldosterone, in the heart.
      • Epstein M.
      • Freundlich M.
      The intersection of mineralocorticoid receptor activation and the FGF23-Klotho cascade: a duopoly that promotes renal and cardiovascular injury.
      ,
      • Leifheit-Nestler M.
      • Kirchhoff F.
      • Nespor J.
      • et al.
      Fibroblast growth factor 23 is induced by an activated renin-angiotensin-aldosterone system in cardiac myocytes and promotes the pro-fibrotic crosstalk between cardiac myocytes and fibroblasts.
      Aldosterone and angiotensin II increase FGF-23 expression in bone and boost levels of FGF-23 in the circulation.
      • Epstein M.
      • Freundlich M.
      The intersection of mineralocorticoid receptor activation and the FGF23-Klotho cascade: a duopoly that promotes renal and cardiovascular injury.
      ,
      • Leifheit-Nestler M.
      • Kirchhoff F.
      • Nespor J.
      • et al.
      Fibroblast growth factor 23 is induced by an activated renin-angiotensin-aldosterone system in cardiac myocytes and promotes the pro-fibrotic crosstalk between cardiac myocytes and fibroblasts.
      Taken together, these findings imply that aldosterone may play an important role in increased FGF-23 secretion in patients with CKD.
      Levels of circulating FGF-23 and aldosterone have been observed to move in tandem in patients with CKD across glomerular rate filtration (GFR) categories 1-5 (CKD G1-G5).
      • Radloff J.
      • Pagitz M.
      • Andrukhova O.
      • Oberbauer R.
      • Burgener I.A.
      • Erben R.G.
      Aldosterone is positively associated with circulating FGF23 levels in chronic kidney disease across four species, and may drive FGF23 secretion directly.
      ,
      • Xu H.
      • Hashem A.
      • Witasp A.
      • et al.
      Fibroblast growth factor 23 is associated with fractional excretion of sodium in patients with chronic kidney disease.
      Also, after the administration of the MRA canrenone, an active metabolite of spironolactone, uremic mice with elevated aldosterone levels were shown to have a significant decrease in previously elevated concentrations of circulating FGF-23; this provides evidence that aldosterone may directly influence FGF-23 secretion by the bone.
      • Radloff J.
      • Pagitz M.
      • Andrukhova O.
      • Oberbauer R.
      • Burgener I.A.
      • Erben R.G.
      Aldosterone is positively associated with circulating FGF23 levels in chronic kidney disease across four species, and may drive FGF23 secretion directly.
      Concomitantly, once Klotho in the kidney is released from its membrane-bound form into the circulation, it demonstrates an array of cardiorenal protective properties.
      • Epstein M.
      • Freundlich M.
      The intersection of mineralocorticoid receptor activation and the FGF23-Klotho cascade: a duopoly that promotes renal and cardiovascular injury.
      ,
      • Neyra J.A.
      • Hu M.C.
      Potential application of klotho in human chronic kidney disease.
      ,
      • Lu R.
      • Zhang Y.
      • Zhu X.
      • et al.
      Effects of mineralocorticoid receptor antagonists on left ventricular mass in chronic kidney disease patients: a systematic review and meta-analysis.
      In experimental CKD, Klotho lessens tissue injury and fibrosis and improves hypertension by downregulating RAAS activity.
      • Epstein M.
      • Freundlich M.
      The intersection of mineralocorticoid receptor activation and the FGF23-Klotho cascade: a duopoly that promotes renal and cardiovascular injury.
      As we have recently proposed,
      • Epstein M.
      • Freundlich M.
      The intersection of mineralocorticoid receptor activation and the FGF23-Klotho cascade: a duopoly that promotes renal and cardiovascular injury.
      the many examples of the links between these seemingly disparate relationships detailed previously may provide new therapeutic avenues to block the vicious cycle of aldosterone/MR overactivation and FGF-23 secretion with concomitant Klotho insufficiency, which often exists in patients with CKD. Whether therapeutic MR antagonism in the setting of preserved soluble Klotho concentrations is able to retard the progression of kidney and cardiac injury in CKD is a hypothesis to be tested.

      MR Antagonism as a Therapeutic Strategy

      Steroidal MRAs

      In a pioneering study 80 years ago, Hans Selye and colleagues showed that, with administration of deoxycorticosterone acetate to a rodent model with partial kidney ablation, a high salt intake (3% saline) was needed to bring about vascular inflammatory changes in the heart and the kidney.
      • Selye H.
      • Hall C.E.
      • Rowley E.M.
      Malignant hypertension produced by treatment with desoxycorticosterone acetate and sodium chloride.
      Subsequent studies extended Selye’s early observations and delineated a role for aldosterone, independent of the RAS, as a determinant of CKD progression.
      • Selye H.
      • Hall C.E.
      • Rowley E.M.
      Malignant hypertension produced by treatment with desoxycorticosterone acetate and sodium chloride.
      • Epstein M.
      Aldosterone blockade: an emerging strategy for abrogating progressive renal disease.
      • Greene E.L.
      • Kren S.
      • Hostetter T.H.
      Role of aldosterone in the remnant kidney model in the rat.
      • Hostetter T.H.
      • Ibrahim H.N.
      Aldosterone in chronic kidney and cardiac disease.
      • Ponda M.P.
      • Hostetter T.H.
      Aldosterone antagonism in chronic kidney disease.
      • Rocha R.
      • Chander P.N.
      • Zuckerman A.
      • Stier Jr., C.T.
      Role of aldosterone in renal vascular injury in stroke-prone hypertensive rats.
      • Schjoedt K.J.
      • Rossing K.
      • Juhl T.R.
      • et al.
      Beneficial impact of spironolactone in diabetic nephropathy.
      Selectively blocking aldosterone (ie, separate from renin angiotensin blockade) lowers proteinuria and nephrosclerosis in the spontaneously hypertensive stroke-prone rat model and reduces proteinuria and glomerulosclerosis in a subtotal nephrectomy rat model (ie, remnant kidney).
      • Epstein M.
      Aldosterone blockade: an emerging strategy for abrogating progressive renal disease.
      ,
      • Greene E.L.
      • Kren S.
      • Hostetter T.H.
      Role of aldosterone in the remnant kidney model in the rat.
      ,
      • Rocha R.
      • Chander P.N.
      • Zuckerman A.
      • Stier Jr., C.T.
      Role of aldosterone in renal vascular injury in stroke-prone hypertensive rats.
      ,
      • Epstein M.
      • Williams G.H.
      • Weinberger M.
      • et al.
      Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes.
      When aldosterone is selectively reinfused, these signs of damage recur despite ongoing renin-angiotensin blockade.
      • Epstein M.
      Aldosterone blockade: an emerging strategy for abrogating progressive renal disease.
      In a subsequent study in a clinical cohort, selective aldosterone blockade with eplerenone, a second-generation MRA, was found to successfully retard CKD progression.
      • Epstein M.
      • Williams G.H.
      • Weinberger M.
      • et al.
      Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes.
      In 2006 came the first assessment of the albuminuria-lowering effects of eplerenone in patients with type 2 diabetes mellitus (T2DM).
      • Epstein M.
      • Williams G.H.
      • Weinberger M.
      • et al.
      Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes.
      This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in 268 patients compared the effect of coadministration of 2 different doses of the selective aldosterone blocker eplerenone or placebo together with an angiotensin-converting enzyme inhibitor (ACEI), enalapril, on albumin excretion in patients with T2DM and albuminuria. Adding eplerenone, in doses of 50 or 100 mg, to enalapril resulted in a substantive and statistically significant reduction in albuminuria in patients with T2DM.
      • Epstein M.
      • Williams G.H.
      • Weinberger M.
      • et al.
      Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes.

      Novel Nonsteroidal MRAs

      In response to concerns about the benefit-safety profile of steroidal MRAs, several new selective nonsteroidal MRAs were developed with the dual goal of improving efficacy and reducing unwanted side effects, primarily hyperkalemia.
      • Kintscher U.
      • Bakris G.L.
      • Kolkhof P.
      Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease.
      ,
      • Kolkhof P.
      • Hartmann E.
      • Freyberger A.
      • et al.
      Effects of finerenone combined with empagliflozin in a model of hypertension-induced end-organ damage.
      Figure 2 provides a direct comparison between the steroidal MRAs (spironolactone and eplerenone) and the recently approved and most widely investigated nonsteroidal MRA finerenone. The figure contrasts the differing binding modes of the 3 agents and summarizes key pharmacodynamic and pharmacokinetic differences.
      Figure thumbnail gr2
      Figure 2Schematic of spironolactone, eplerenone, and finerenone binding with proposed/hypothesized conformational change of helix 12 and summary of respective key pharmacodynamic and pharmacokinetic characteristics. Abbreviations: BP, blood pressure; CNS, central nervous system; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist. Reproduced from Kintscher
      • Kintscher U.
      • Bakris G.L.
      • Kolkhof P.
      Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease.
      under the terms of the Creative Commons Attribution License (CC BY 4.0).
      Presently, multiple novel compounds are at different stages of development and/or approved for clinical use, including esaxerenone, AZD9977, apararenone, KBP-5074, and finerenone. We will briefly focus on esaxerenone, KBP-5074 and finerenone, which are the 3 drugs at the most advanced stage of clinical development. For a more detailed review, the reader is referred to Kintscher et al.
      • Kintscher U.
      • Bakris G.L.
      • Kolkhof P.
      Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease.

      Esaxerenone

      Esaxerenone (also known as CS-3150; Daiichi Sankyo) is a nonsteroidal MRA recently approved in Japan to treat arterial hypertension. It is highly selective, with a greater than 3-fold higher preference for MR in comparison with glucocorticoid, progesterone, or androgen receptors.
      • Arai K.
      • Homma T.
      • Morikawa Y.
      • et al.
      Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist.
      Esaxerenone’s high affinity and selectivity for MR is bolstered by both preclinical and clinical data. Moreover, the latter indicate that esaxerenone effectively lowers blood pressure in hypertensive patients
      • Sueta D.
      • Yamamoto E.
      • Tsujita K.
      Mineralocorticoid receptor blockers: novel selective nonsteroidal mineralocorticoid receptor antagonists.
      and is safe and effective in hypertensive patients with HFrEF.
      • Iwahana T.
      • Saito Y.
      • Okada S.
      • Kato H.
      • Ono R.
      • Kobayashi Y.
      Safety and efficacy of esaxerenone in Japanese hypertensive patients with heart failure with reduced ejection fraction: a retrospective study.

      KBP-5074

      KBP-5074 (KBP BioSciences) is a nonsteroidal MRA with a MR binding affinity higher than for spironolactone and eplerenone (its half-maximal inhibitory concentration [IC50] is 2.7 nM). In addition, it shows selectivity in binding to MR as opposed to other steroid hormone receptors.
      • Chow C.P.
      • Liu J.R.
      • Tan X.J.
      • Yang F.
      • Huang Z.H.
      Preclinical development of KBP-5074, a novel non-steroidal mineralocorticoid receptor antagonist for the treatment of cardiorenal diseases.
      The first phase 2 study with KBP-5074, BLOCK-CKD, was recently published.
      • Bakris G.
      • Pergola P.E.
      • Delgado B.
      • et al.
      Effect of KBP-5074 on blood pressure in advanced chronic kidney disease: results of the BLOCK-CKD Study.
      This multicenter, randomized, double-blind, placebo-controlled study investigated the safety and efficacy of KBP-5074 (0.25 or 0.5 mg/d) in 162 patients with resistant or poorly controlled hypertension and advanced CKD (G3b-G4; ie, an estimated GFR between 15 and 44 mL/min/1.73 m2). Compared with placebo, the 2 doses lowered systolic blood pressure by 8 and 10 mm Hg, respectively. A phase 3 study is planned.

      Finerenone

      The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD)
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      and Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD)
      • Pitt B.
      • Filippatos G.
      • Agarwal R.
      • et al.
      FIGARO-DKD Investigators
      Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
      studies have advanced our understanding of the clinical utility of MRA blockade on clinical outcomes. In the first, patients with CKD and T2DM who received finerenone were observed to have a lower risk of a primary outcome event (defined as kidney failure, or a sustained decrease of ≥40% in the estimated GFR from baseline, or death from kidney causes) than the comparator placebo arm (17.8% vs 21.1%; hazard ratio, 0.82 [95% CI, 0.73-0.93]; P = 0.001). Patients in the intervention group also showed a lower risk of key secondary outcome events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure (HHF).
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      The reno- and cardioprotective effects of finerenone were confirmed in the FIGARO-DKD study.
      • Pitt B.
      • Filippatos G.
      • Agarwal R.
      • et al.
      FIGARO-DKD Investigators
      Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
      After the publication of FIDELIO and FIGARO trials, a prespecified pooled analysis (FIDELITY) of these 2 complementary trials was performed, comprising 13,026 patients with a median follow-up period of 3.0 years.
      • Agarwal R.
      • Filippatos G.
      • Pitt B.
      • et al.
      Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis.
      The main time-to-event efficacy outcomes were a composite cardiovascular outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or HHF) and a composite kidney outcome (kidney failure, a sustained ≥57% decrease in estimated GFR from baseline over ≥4 weeks, or death from kidney causes). The combined analysis showed consistency across all kidney end points, which is reassuring and corroborates the individual FIDELIO and FIGARO results.
      We wish to emphasize 2 important points derived from the FIDELITY analysis. First, it provides the best evidence to date that finerenone prevents HHF in a high-risk population. Second, the reduction in HHF was the primary contributor to finerenone’s cardiovascular benefit, with a relative risk reduction of 22% compared with placebo (P = 0.003) in a study population in which patients with chronic symptomatic HFrEF at the run-in visit were excluded. This is an important and highly relevant finding for nephrologists because heart failure is a key contributor to morbidity and health care costs among patients with CKD and T2DM.
      • Zareini B.
      • Blanche P.
      • D'Souza M.
      • et al.
      Type 2 diabetes mellitus and impact of heart failure on prognosis compared to other cardiovascular diseases: a nationwide study.
      ,
      • Ziaeian B.
      • Fonarow G.C.
      Epidemiology and aetiology of heart failure.
      An important limitation of FIDELITY is that it did not include patients with nonalbuminuric CKD, highlighting the importance of conducting similar finerenone studies in a nonalbuminuric CKD cohort.
      The results of FIDELIO-DKD and FIGARO-DKD (and the pooled analysis in FIDELITY) imply that finerenone is an effective treatment for kidney and cardiovascular protection in patients with CKD and T2DM. It is noteworthy the benefits of finerenone were seen early—as soon as 1 month after drug initiation for the cardiovascular outcome and just after 12 months for the kidney outcome—and persisted for the 3-year duration of the trials. Based on these 2 studies, finerenone was recently approved by the US Food and Drug Administration (FDA).
      US Food and Drug Administration
      FDA approves drug to reduce risk of serious kidney and heart complications in adults with chronic kidney disease associated with type 2 diabetes. July 7, 2021.
      Furthermore, the recently published, much-anticipated annual American Diabetes Association Standards of Medical Care in Diabetes guidelines recommend using finerenone to reduce CKD progression and cardiovascular events (recommendation 11.3c).
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes 2022.

      Barriers to Implementing Guideline-Recommended MR Blockade

      Hyperkalemia

      Despite strong recommendations for treatment with RAS inhibitors and MRA by numerous guidelines, implementation in real-world practice remains suboptimal, with hyperkalemia constituting one, if not the major, cause. The groundbreaking RALES trial reported that spironolactone reduced all-cause mortality by 30% in patients with reduced ejection fraction who were on RAS inhibitors and had levels of potassium ≤5.0 mEq/L and creatinine ≤2.5 mg/dL at baseline.
      • Pitt B.
      • Zannad F.
      • Remme W.J.
      • et al.
      The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.
      Subsequently, a population-based study assessing the postpublication impact of the RALES trial found higher spironolactone prescriptions in patients with heart failure on RAS inhibitors and, concerningly, higher hyperkalemia-induced hospitalization and death.
      • Juurlink D.N.
      • Mamdani M.M.
      • Lee D.S.
      • et al.
      Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study.
      Regretfully, no information on the indications for spironolactone use were available in this study; further, potassium monitoring and appropriateness of prescription in terms of whether patients met the ejection fraction and baseline potassium and creatinine criteria were unknown. Nevertheless, this publication has resulted in a lingering cloud of concern regarding the dangers of MRA-induced hyperkalemia and may have been the major driver limiting their use.
      • Epstein M.
      • Pecoits-Filho R.
      • Clase C.M.
      • Sood M.M.
      • Kovesdy C.P.
      Hyperkalemia with mineralocorticoid receptor antagonist use in people with CKD: understanding and mitigating the risks.
      ,
      • Moura-Neto J.A.
      • Ronco C.
      The rales legacy and finerenone use on CKD patients.
      Contemporary data from a Swedish general population cohort indicated that a plasma potassium level of >5.0 mEq/L occurred in ∼19% of individuals newly started on an MRA; of these, only a fraction restarted the MRA during subsequent follow-up.
      • Trevisan M.
      • de Deco P.
      • Xu H.
      • et al.
      Incidence, predictors and clinical management of hyperkalaemia in new users of mineralocorticoid receptor antagonists.
      Although patients who stopped MRA treatment after a hyperkalemia episode experienced fewer subsequent hyperkalemia events compared with those who continued the MRA despite hyperkalemia, importantly they also had a higher risk of cardiovascular events. Notwithstanding the possibility that MRA therapy could be beneficial despite inducing hyperkalemia, the (real or perceived) short-term risks of hyperkalemia may prompt health care providers to discontinue and subsequently not restart the MRA. It is unfortunate and indeed ironic that the precise populations that could benefit most from MRA therapy are those who are at increased risk for hyperkalemia.
      • Epstein M.
      • Pecoits-Filho R.
      • Clase C.M.
      • Sood M.M.
      • Kovesdy C.P.
      Hyperkalemia with mineralocorticoid receptor antagonist use in people with CKD: understanding and mitigating the risks.
      ,
      • Trevisan M.
      • de Deco P.
      • Xu H.
      • et al.
      Incidence, predictors and clinical management of hyperkalaemia in new users of mineralocorticoid receptor antagonists.
      The development of a novel class of nonsteroidal MRAs (including finerenone, aparenone, and esaxerenone, as discussed previously) generates excitement due to the promise of provoking less hyperkalemia than steroidal MRAs (spironolactone and eplerenone), owing to differences in their chemical structure and an altered mechanism of action.
      • Epstein M.
      Aldosterone and mineralocorticoid receptor signaling as determinants of cardiovascular and renal injury: from Hans Selye to the present.
      ,
      • Kintscher U.
      • Bakris G.L.
      • Kolkhof P.
      Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease.
      To date, only 1 head-to-head comparison of finerenone with spironolactone exists: a randomized controlled trial of patients with HFrEF and mild CKD wherein serum potassium rose by end of study (3-4 weeks) in all groups.
      • Pitt B.
      • Kober L.
      • Ponikowski P.
      • et al.
      Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.
      The increase was 0.21 mmol/L in patients receiving finerenone at 10 mg daily, 0.30 mmol/L in patients receiving finerenone at 5 mg twice daily, and 0.45 mmol/L in patients receiving spironolactone (mean dose of 37 mg). Interpretation is challenging because all 3 agents were administered at different (nonequivalent) doses. It is important to recognize, therefore, that even the newer nonsteroidal MRAs are expected to raise potassium levels compared with placebo.
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      ,
      • Pitt B.
      • Filippatos G.
      • Agarwal R.
      • et al.
      FIGARO-DKD Investigators
      Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
      ,
      • Agarwal R.
      • Joseph A.
      • Anker S.D.
      • et al.
      Hyperkalemia risk with finerenone: results from the FIDELIO-DKD Trial.
      Furthermore, it should be emphasized that the observed potassium levels were incurred in the context of treatment on top of maximally tolerated RAS inhibitor therapy
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      ,
      • Pitt B.
      • Filippatos G.
      • Agarwal R.
      • et al.
      FIGARO-DKD Investigators
      Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
      and there were relatively small absolute between-group differences in FIDELIO and FIGARO (of 0.23 and 0.16 mmol/L, respectively).
      Notwithstanding the reality of the risks posed by hyperkalemia, it is our belief that we should approach this question with respect but not fear. This requires a nuanced approach that allows the application of an effective therapy while mitigating its potential risks. First, it is important to accurately understand the magnitude of the risk of hyperkalemia. In FIDELITY, the total incidence of hyperkalemia-related adverse events was 14.0% for finerenone compared with 6.9% for placebo; meanwhile, the number of hospitalizations due to hyperkalemia was 0.9% versus 0.2%, and the number of permanent discontinuations due to hyperkalemia was 1.7% versus 0.6%.
      • Agarwal R.
      • Filippatos G.
      • Pitt B.
      • et al.
      Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis.
      Four months after treatment start, the mean increase in serum potassium was 0.21 mEq/L with finerenone and 0.02 mEq/L with placebo. Most importantly, in patients receiving finerenone there were no deaths attributable to hyperkalemia.
      The low incidence of permanent discontinuation of finerenone and the absence of deaths attributable to hyperkalemia were in large part due to a proactive approach aimed at minimizing the occurrence of hyperkalemia (Box 2).
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      ,
      • Pitt B.
      • Filippatos G.
      • Agarwal R.
      • et al.
      FIGARO-DKD Investigators
      Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
      ,
      • Agarwal R.
      • Joseph A.
      • Anker S.D.
      • et al.
      Hyperkalemia risk with finerenone: results from the FIDELIO-DKD Trial.
      The FDA specifies a similar monitoring and mitigation strategy in its finerenone label: limiting the prescribing of the drug to patients with prespecified characteristics, including GFR ≥25 mL/min/1.73 m2, and systematically applying careful monitoring and mitigation strategies.
      US Food and Drug Administration
      FDA approves drug to reduce risk of serious kidney and heart complications in adults with chronic kidney disease associated with type 2 diabetes. July 7, 2021.
      This should enable the safe and continued use of finerenone (and potentially other new MRAs) in patients with CKD who meet the trial’s inclusion criteria.
      Strategies Used to Mitigate Hyperkalemia in Patients Treated With Finerenone
      • Requirement for pretreatment serum potassium of ≤4.8 mEq/La
      • Serum potassium monitoring: 1 month after start and every 4 months afterward; also after each dose change
      • Dose adjustment strategy
        • First measurement after start:
          • Serum potassium ≤ 4.8 mEq/L: if on 10 mg daily, increase dose to 20 mg daily; if on 20 mg daily, continue same dose
          • Serum potassium 4.9–5.5 mEq/L: continue on same dose
          • Serum potassium > 5.5 mEq/L: withhold drug and recheck potassium within 72 hours
        • Subsequent measurements:
          • Serum potassium ≤ 5.0 mEq/L: restart study drug at 10 mg daily dose
          • Serum potassium > 5.0 mEq/L: continue to withhold drug and monitor serum potassium; only restart finerenone (at the 10 mg daily dose) once serum potassium ≤ 5.0 mEq/L
      • Permanent discontinuation: if hyperkalemia was recurrent soon after a previous event despite discontinuation of drug without alternative explanation for the hyperkalemia
      • Diet: no restrictions on potassium intake
      • Potassium binders: permitted, discontinuation encouraged once serum potassium returned to normal
      Based on use of finerenone in the FIDELIO-DKD and FIGARO-DKD clinical trial protocol.
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      ,
      • Pitt B.
      • Filippatos G.
      • Agarwal R.
      • et al.
      FIGARO-DKD Investigators
      Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
      aIn the FDA package insert, this is ≤5.0 mEq/L.
      Importantly both newer potassium binders and sodium/glucose cotransporter 2 (SGLT2) inhibitors provide additional mitigation possibilities to reduce the risk of hyperkalemia.
      • Clase C.M.
      • Carrero J.J.
      • Ellison D.H.
      • et al.
      Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference.
      ,
      • Neuen B.L.
      • Oshima M.
      • Perkovic V.
      • et al.
      Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial.
      A recent post hoc analysis of the CREDENCE trial demonstrated that canagliflozin reduced the risk of investigator-reported hyperkalemia or initiation of potassium binders compared with placebo
      • Neuen B.L.
      • Oshima M.
      • Perkovic V.
      • et al.
      Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial.
      (see the section on future treatment paradigms).

      Cost

      Because cost is often cited as a barrier to use, it is appropriate to compare the relative costs of recently available drugs that can be prescribed for diabetic kidney disease (DKD) patients. The wholesale cost for finerenone oral tablet, 10 mg, is around US$604 for a supply of 30 tablets. For comparison, dapagliflozin costs US$529 per month. Monthly costs for popular glucagon-like peptide 1 receptor agonists (GLP-1RAs) include US$826 for exenatide, US$913 (dulaglutide), and US$1,385 (liraglutide).
      GoodRx.
      However, it is important to note that this comparison is imperfect owing to the rebates and confidential discounts offered on some drugs to patients who are commercially insured.

      Future Treatment Paradigms With Nonsteroidal MRAs

      Nondiabetic Kidney Disease

      To date, the finerenone clinical development program has concentrated on showing the efficacy of finerenone in kidney and cardiovascular protection in patients with CKD and T2DM. Although FIDELIO-DKD and FIGARO-DKD, as well as many of the recent clinical SGLT2 inhibitor clinical trials, have primarily involved albuminuric patients with T2DM, we suggest that MR activation and the associated inflammation and fibrosis may be relevant not just in patients with diabetes and CKD but also in the pathogenesis of nondiabetic kidney disease. Accordingly, it is reasonable to argue that MR antagonism may be an effective therapeutic in nondiabetic CKD. Therefore, we propose that FIDELIO-DKD and FIGARO-DKD should constitute a platform for implementing a constellation of future clinical trials beyond the narrow focus of people with type 2 diabetes. In this final section of this review, we briefly discuss recently initiated and future clinical trials that are planned to extend and leverage the attributes of MR antagonism to a wide array of kidney disorders.
      A recently initiated major clinical trial will examine finerenone in nondiabetic kidney disease. FIND-CKD (Clinicaltrials.gov identifier NCT05047263) is currently enrolling patients to examine the effects of finerenone plus guideline-directed therapy on CKD progression, with expected completion in November 2025. Box 3 summarizes the primary and secondary end points as well as the exclusion and inclusion criteria of this trial.
      Study Design of FIND-CKD
      Inclusion criteria
      • Aged ≥ 18 years with diagnosis of CKD based on UACR of 200-3,500 mg/g (90% ≥ 500 mg/g) and eGFR 25-90 mL/min/1.73 m2
      • Stable and maximally tolerated dose, according to the label, of an ACEI or ARB for at least 4 weeks before screening, documented in the medical history
      • Serum potassium ≤ 4.8 mmol/L at screening
      Exclusion criteria
      • T2DM and T1DM
      • Autosomal dominant or autosomal recessive PKD, lupus nephritis, or ANCA-associated vasculitis
      • Any other primary or secondary kidney disease requiring immunosuppressive therapy within 6 months before screening
      • SBP ≥ 160 mm Hg, DBP ≥ 100 mm Hg
      • HFrEF requiring MRA
      Primary end point
      • Mean rate of slope as measured by the total slope of eGFR from baseline to month 32
      Secondary end points
      • Time to the composite of kidney failure, sustained eGFR decline of ≥57%, HHF, or cardiovascular death
      • Time to the composite of kidney failure or sustained eGFR decline of ≥57%
      • Time to the composite of HHF or cardiovascular death
      • Number of participants with TEAEs, TESAEs, and AESI
      • Background therapy
      SGLT2 inhibitor therapy
      • If there is an indication for SGLT2 inhibitor treatment, it should be started before inclusion into the study, and the participant should be on a stable dose for at least 1 month before screening. In the exceptional case where the participant is started on an SGLT2 inhibitor after randomization, then the participant must be on a stable dose of study intervention for at least 1 month before SGLT2 inhibitor initiation.
      Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; AESI, adverse event of special interest; ANCA, antineutrophil cytoplasmic antibody; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HFrEF, heart failure with reduced ejection fraction; HHF, hospitalization for heart failure; MRA, mineralocorticoid receptor antagonist; PKD, polycystic kidney disease; SBP, systolic blood pressure; SGLT2, sodium/glucose cotransporter 2; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TEAEs, treatment emergent adverse events; TESAEs, treatment emergent serious adverse events; UACR, urinary albumin-creatinine ratio.
      FIONA is 6-month multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of an age- and body-weight-adjusted oral finerenone regimen in addition to an ACEI or angiotensin receptor blocker for the treatment of children with CKD and proteinuria. It includes participants aged 6 months to younger than 18 years of age with glomerular and nonglomerular CKD (EudraCT number 2021-002071-19). The first patient was enrolled in March 2022.

      Combination Therapy

      The potential value of a combination therapy with the nonsteroidal MR antagonist finerenone and SGLT2 inhibitors remains unestablished. Kolkhof et al
      • Kolkhof P.
      • Hartmann E.
      • Freyberger A.
      • et al.
      Effects of finerenone combined with empagliflozin in a model of hypertension-induced end-organ damage.
      recently investigated cardiorenal protection afforded by both monotherapy and combination therapy of these 2 drug classes in a preclinical model of hypertension-induced end-organ damage. In this animal model of nondiabetic cardiorenal disease, Kolkhof et al
      • Kolkhof P.
      • Hartmann E.
      • Freyberger A.
      • et al.
      Effects of finerenone combined with empagliflozin in a model of hypertension-induced end-organ damage.
      demonstrated that a combination of finerenone with the SGLT2 inhibitor empagliflozin, administered at low dosages, led to improvements in an array of relevant outcomes such as proteinuria, blood pressure, plasma creatinine, plasma uric acid, and mortality. Coadministration of low dosages of finerenone and empagliflozin led to a stronger survival benefit than equivalent or higher doses given individually. CONFIDENCE is a planned phase 2 clinical trial that will leverage the preclinical studies and examine the effects of finerenone and empagliflozin alone and in combination versus placebo on reduction of albuminuria in patients with CKD and T2DM (Clinicaltrials.gov identifier NCT05254002). Although we are unaware of any preclinical or clinical data to suggest how MRAs, SGLT2 inhibitors, and GLP-1RAs should be used sequentially, such investigations should be initiated.

      Conclusion

      With the recent publication of FIDELIO-DKD and FIGARO-DKD, and with several other novel nonsteroidal MRAs under robust development, treatment paradigms encompassing nonsteroidal MRAs will gain in importance in the clinical practice of nephrology. We have reviewed the key differences between steroidal and nonsteroidal MRAs in terms of clinical efficacy and serious adverse events. An important and overriding challenge is the hyperkalemia evoked by treatment with MRAs. We encourage systematic application of careful monitoring and an array of mitigation strategies that should enable sustained therapy with finerenone (and potentially other new MRAs) in most patients with CKD while obviating the need to permanently discontinue MRAs due to hyperkalemia.
      We propose that activation of MR, along with the associated inflammation and fibrosis, is relevant to the pathogenesis of CKD whether or not there is co-occurring diabetes. We conclude on a propitious note by briefly discussing recently initiated or planned clinical trials (CKD-FIND, FIONA, CONFIDENCE) that are investigating either the efficacy of finerenone in retarding and abrogating progression in patients with nondiabetic CKD, or finerenone in combination with SGLT2 inhibitors. We are not aware of any new evidence on the efficacy of MRAs for patients without albuminuria or any planned studies in this area.

      Article Information

      Authors’ Full Names and Academic Degrees

      Murray Epstein, MD, Csaba P. Kovesdy, MD, Catherine M. Clase, MB, BChir, BA, MSc, Manish M. Sood, MD, MSc, and Roberto Pecoits-Filho, MD, PhD.

      Support

      None of the authors received either personal or institutional funding for preparation of this article. Figure 1 was developed by CAST Pharma with the support of an unrestricted grant from Bayer Pharma AG, which markets finerenone.

      Financial Disclosure

      Dr Clase reports having consultancy agreements with Amgen, Astellas, Baxter, Boehringer-Ingelheim, Janssen, Leo Pharma, the Ministry of Health Ontario, and Pfizer, and receiving arm’s-length honoraria for speaking from AstraZeneca and Sanofi; she works on secondary analysis of trials funded by Boehringer-Ingelheim; has served as coinvestigator on studies funded by Astellas and Baxter; has received honoraria from Astellas, Janssen, Sanofi, and the University of Alberta; has served as the KDIGO (Kidney Disease: Improving Global Outcomes) potassium controversies conference cochair (sponsored by AstraZeneca , Bayer HealthCare, Boehringer-Ingelheim, Fresenius Medical Care, Relypsa, and Vifor Fresenius Medical Care); and spoke at an event organized by Sanofi in May 2019 and an event sponsored at arm’s length by AstraZeneca in November 2021. Dr Epstein reports having consultancy agreements with Alnylam Pharmaceuticals, Bayer HealthCare, and Vifor Pharma; receiving honoraria from Alnylam Pharmaceuticals , Bayer HealthCare, and Vifor Pharma; and serving as a scientific advisor or member of Bayer HealthCare and Vifor Pharma. Dr Kovesdy reports consultancy agreements with and receiving honoraria from Abbott, Akebia, AstraZeneca, Bayer, Boehringer-Ingelheim, Cara, CSL Behring, GlaxoSmithKline, Rockwell, and Vifor; and receiving royalties from Springer and UpToDate. Dr Pecoits-Filho reports consultancy agreements with George Clinical; receiving research funding from Fresenius Medical Care; receiving honoraria from Akebia, AstraZeneca , Bayer, Fresenius Medical Care, and Rethrophin; and serving on the speakers bureau for AstraZeneca, Bayer, and Boehringer. Dr Sood reports receiving honoraria from AstraZeneca and serving on a scientific steering committee for an AstraZeneca-sponsored trial as well as serving as an editor of Canadian Journal of Kidney Disease and Health.

      Other Disclosures

      Dr Pecoits-Filho reports serving as a scientific advisor or member of the Standardised Outcomes in Nephrology (SONG) Initiative Executive Committee, International Society of Nephrology, KDIGO, and the editorial boards of AJKD, Blood Purification, Hemodialysis International, Nephrology, and Peritoneal Dialysis International. Dr Sood reports serving as a scientific advisor or member of the editorial boards of AJKD, Canadian Journal of Cardiology, and Clinical Journal of the American Society of Nephrology, and serving as a member of the American Society of Nephrology Highlights ESRD Team.

      Acknowledgments

      We acknowledge the contribution of Alexander Röder of CAST Pharma for designing Figure 1 and the assistance of Sally Baron in the preparation of the manuscript.

      Peer Review

      Received January 26, 2022, in response to an invitation from the journal. Evaluated by 2 external peer reviewers, with direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form April 19, 2022.

      References

        • Epstein M.
        Aldosterone and mineralocorticoid receptor signaling as determinants of cardiovascular and renal injury: from Hans Selye to the present.
        Am J Nephrol. 2021; 52: 209-216
        • Jaisser F.
        • Tan X.
        • Chi S.
        • et al.
        The non-steroidal mineralocorticoid receptor antagonist KBP-5074 limits albuminuria and has improved therapeutic index compared with eplerenone in a rat model with mineralocorticoid-induced renal injury.
        Front Pharmacol. 2021; 12604928
        • Kintscher U.
        • Bakris G.L.
        • Kolkhof P.
        Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease.
        Br J Pharmacol. 2022; 179: 3220-3234
        • Bakris G.L.
        • Agarwal R.
        • Anker S.D.
        • et al.
        Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
        N Engl J Med. 2020; 383: 2219-2229
        • Pitt B.
        • Filippatos G.
        • Agarwal R.
        • et al.
        • FIGARO-DKD Investigators
        Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
        N Engl J Med. 2021; 385: 2252-2263
        • US Food and Drug Administration
        FDA approves drug to reduce risk of serious kidney and heart complications in adults with chronic kidney disease associated with type 2 diabetes. July 7, 2021.
        • Ayuzawa N.
        • Nishimoto M.
        • Ueda K.
        • et al.
        Two mineralocorticoid receptor-mediated mechanisms of pendrin activation in distal nephrons.
        J Am Soc Nephrol. 2020; 31: 748-764
        • Buonafine M.
        • Bonnard B.
        • Jaisser F.
        Mineralocorticoid receptor and cardiovascular disease.
        Am J Hypertens. 2018; 31: 1165-1174
        • Fuller P.J.
        • Yang J.
        • Young M.J.
        30 Years of the mineralocorticoid receptor: coregulators as mediators of mineralocorticoid receptor signalling diversity.
        J Endocrinol. 2017; 234: T23-T34
        • Funder J.W.
        Minireview: aldosterone and mineralocorticoid receptors: past, present, and future.
        Endocrinology. 2010; 151: 5098-5102
        • Sakima A.
        • Arima H.
        • Matayoshi T.
        • Ishida A.
        • Ohya Y.
        Effect of mineralocorticoid receptor blockade on arterial stiffness and endothelial function: a meta-analysis of randomized trials.
        Hypertension. 2021; 77: 929-937
        • Agarwal R.
        • Kolkhof P.
        • Bakris G.
        • et al.
        Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine.
        Eur Heart J. 2021; 42: 152-161
        • Epstein M.
        Renal effects of head-out water immersion in humans: a 15-year update.
        Physiol Rev. 1992; 72: 563-621
        • Gomez-Sanchez E.
        • Gomez-Sanchez C.E.
        The multifaceted mineralocorticoid receptor.
        Compr Physiol. 2014; 4: 965-994
        • Barrera-Chimal J.
        • Girerd S.
        • Jaisser F.
        Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis.
        Kidney Int. 2019; 96: 302-319
        • Huby A.C.
        • Antonova G.
        • Groenendyk J.
        • et al.
        Adipocyte-derived hormone leptin is a direct regulator of aldosterone secretion, which promotes endothelial dysfunction and cardiac fibrosis.
        Circulation. 2015; 132: 2134-2145
        • Tesch G.H.
        • Young M.J.
        Mineralocorticoid receptor signaling as a therapeutic target for renal and cardiac fibrosis.
        Front Pharmacol. 2017; 8: 313
        • Epstein M.
        • Freundlich M.
        The intersection of mineralocorticoid receptor activation and the FGF23-Klotho cascade: a duopoly that promotes renal and cardiovascular injury.
        Nephrol Dial Transplant. 2022; 37: 211-221
        • Leifheit-Nestler M.
        • Kirchhoff F.
        • Nespor J.
        • et al.
        Fibroblast growth factor 23 is induced by an activated renin-angiotensin-aldosterone system in cardiac myocytes and promotes the pro-fibrotic crosstalk between cardiac myocytes and fibroblasts.
        Nephrol Dial Transplant. 2018; 33: 1722-1734
        • Radloff J.
        • Pagitz M.
        • Andrukhova O.
        • Oberbauer R.
        • Burgener I.A.
        • Erben R.G.
        Aldosterone is positively associated with circulating FGF23 levels in chronic kidney disease across four species, and may drive FGF23 secretion directly.
        Front Physiol. 2021; 12649921
        • Xu H.
        • Hashem A.
        • Witasp A.
        • et al.
        Fibroblast growth factor 23 is associated with fractional excretion of sodium in patients with chronic kidney disease.
        Nephrol Dial Transplant. 2019; 34: 2051-2057
        • Neyra J.A.
        • Hu M.C.
        Potential application of klotho in human chronic kidney disease.
        Bone. 2017; 100: 41-49
        • Lu R.
        • Zhang Y.
        • Zhu X.
        • et al.
        Effects of mineralocorticoid receptor antagonists on left ventricular mass in chronic kidney disease patients: a systematic review and meta-analysis.
        Int Urol Nephrol. 2016; 48: 1499-1509
        • Selye H.
        • Hall C.E.
        • Rowley E.M.
        Malignant hypertension produced by treatment with desoxycorticosterone acetate and sodium chloride.
        Can Med Assoc J. 1943; 49: 88-92
        • Epstein M.
        Aldosterone blockade: an emerging strategy for abrogating progressive renal disease.
        Am J Med. 2006; 119: 912-919
        • Greene E.L.
        • Kren S.
        • Hostetter T.H.
        Role of aldosterone in the remnant kidney model in the rat.
        J Clin Invest. 1996; 98: 1063-1068
        • Hostetter T.H.
        • Ibrahim H.N.
        Aldosterone in chronic kidney and cardiac disease.
        J Am Soc Nephrol. 2003; 14: 2395-2401
        • Ponda M.P.
        • Hostetter T.H.
        Aldosterone antagonism in chronic kidney disease.
        Clin J Am Soc Nephrol. 2006; 1: 668-677
        • Rocha R.
        • Chander P.N.
        • Zuckerman A.
        • Stier Jr., C.T.
        Role of aldosterone in renal vascular injury in stroke-prone hypertensive rats.
        Hypertension. 1999; 33: 232-237
        • Schjoedt K.J.
        • Rossing K.
        • Juhl T.R.
        • et al.
        Beneficial impact of spironolactone in diabetic nephropathy.
        Kidney Int. 2005; 68: 2829-2836
        • Epstein M.
        • Williams G.H.
        • Weinberger M.
        • et al.
        Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes.
        Clin J Am Soc Nephrol. 2006; 1: 940-951
        • Kolkhof P.
        • Hartmann E.
        • Freyberger A.
        • et al.
        Effects of finerenone combined with empagliflozin in a model of hypertension-induced end-organ damage.
        Am J Nephrol. 2021; 52: 642-652
        • Arai K.
        • Homma T.
        • Morikawa Y.
        • et al.
        Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist.
        Eur J Pharmacol. 2015; 761: 226-234
        • Sueta D.
        • Yamamoto E.
        • Tsujita K.
        Mineralocorticoid receptor blockers: novel selective nonsteroidal mineralocorticoid receptor antagonists.
        Curr Hypertens Rep. 2020; 22: 21
        • Iwahana T.
        • Saito Y.
        • Okada S.
        • Kato H.
        • Ono R.
        • Kobayashi Y.
        Safety and efficacy of esaxerenone in Japanese hypertensive patients with heart failure with reduced ejection fraction: a retrospective study.
        PLoS One. 2021; 16e0259485
        • Chow C.P.
        • Liu J.R.
        • Tan X.J.
        • Yang F.
        • Huang Z.H.
        Preclinical development of KBP-5074, a novel non-steroidal mineralocorticoid receptor antagonist for the treatment of cardiorenal diseases.
        J Drug Res Dev. 2018; 4: 143
        • Bakris G.
        • Pergola P.E.
        • Delgado B.
        • et al.
        Effect of KBP-5074 on blood pressure in advanced chronic kidney disease: results of the BLOCK-CKD Study.
        Hypertension. 2021; 78: 74-81
        • Agarwal R.
        • Filippatos G.
        • Pitt B.
        • 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: 474-484
        • Zareini B.
        • Blanche P.
        • D'Souza M.
        • et al.
        Type 2 diabetes mellitus and impact of heart failure on prognosis compared to other cardiovascular diseases: a nationwide study.
        Circ Cardiovasc Qual Outcomes. 2020; 13e006260
        • Ziaeian B.
        • Fonarow G.C.
        Epidemiology and aetiology of heart failure.
        Nat Rev Cardiol. 2016; 13: 368-378
        • American Diabetes Association Professional Practice Committee
        11. Chronic kidney disease and risk management: standards of medical care in diabetes 2022.
        Diabetes Care. 2021; 45: S175-S184
        • Pitt B.
        • Zannad F.
        • Remme W.J.
        • 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: 709-717
        • Juurlink D.N.
        • Mamdani M.M.
        • Lee D.S.
        • et al.
        Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study.
        N Engl J Med. 2004; 351: 543-551
        • Epstein M.
        • Pecoits-Filho R.
        • Clase C.M.
        • Sood M.M.
        • Kovesdy C.P.
        Hyperkalemia with mineralocorticoid receptor antagonist use in people with CKD: understanding and mitigating the risks.
        Clin J Am Soc Nephrol. 2022; 17: 455-457
        • Moura-Neto J.A.
        • Ronco C.
        The rales legacy and finerenone use on CKD patients.
        Clin J Am Soc Nephrol. 2021; 16: 1432-1434
        • Trevisan M.
        • de Deco P.
        • Xu H.
        • et al.
        Incidence, predictors and clinical management of hyperkalaemia in new users of mineralocorticoid receptor antagonists.
        Eur J Heart Fail. 2018; 20: 1217-1226
        • Pitt B.
        • Kober L.
        • Ponikowski P.
        • et al.
        Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.
        Eur Heart J. 2013; 34: 2453-2463
        • Agarwal R.
        • Joseph A.
        • Anker S.D.
        • et al.
        Hyperkalemia risk with finerenone: results from the FIDELIO-DKD Trial.
        J Am Soc Nephrol. 2022; 33: 225-237
        • Clase C.M.
        • Carrero J.J.
        • Ellison D.H.
        • et al.
        Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference.
        Kidney Int. 2020; 97: 42-61
        • Neuen B.L.
        • Oshima M.
        • Perkovic V.
        • et al.
        Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial.
        Eur Heart J. 2021; 42: 4891-4901
      1. GoodRx.
        https://www.goodrx.com
        Date accessed: March 14, 2022