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Antagonistes du récepteur minéralocorticoïde chez les patients avec insuffisance rénale chronique

COSIMATO, Cosimo

Abstract

Les antagonistes du récepteur des mineralocorticoïdes (MRA), dont la spironolactone a été la première molécule, appartiennent à une classe de médicaments de plus en plus utilisée dans le traitement des pathologies cardio-rénales et néphropathie diabétique. Leur efficacité dans plusieurs indications ne laisse plus de doute. Toutefois, le risque d'effets secondaires, notamment d'hyperkaliémie et d'aggravation de la fonction rénale, ont conduit à leur sous-prescription, en particulier chez les patients avec insuffisance rénale chronique (IRC).

Les données scientifiques chez ces patients sont complexes et limitées et, surtout provenant souvent seulement d'analyse sous-groupe d'essais cliniques, initialement non-dédiées à cette catégorie de patients. Le but de notre revue c'est d'évaluer en détail le corpus d'évidence clinique sur les MRAs, depuis la spironolactone jusqu'à la 4ème génération, en se focalisant sur les risques et bénéfices de leur utilisation dans le contexte d'IRC, tout stades inclus.

COSIMATO, Cosimo. Antagonistes du récepteur minéralocorticoïde chez les patients avec insuffisance rénale chronique . Thèse de doctorat : Univ. Genève, 2021, no. Méd.

11062

PMID : 33027644

DOI : 10.13097/archive-ouverte/unige:152254 URN : urn:nbn:ch:unige-1522547

Available at:

http://archive-ouverte.unige.ch/unige:152254

Disclaimer: layout of this document may differ from the published version.

1 / 1

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Section de médecine Clinique Département de Médecine Service de

Médecine Interne Générale

Thèse préparée sous la direction du Professeur Thomas AGORITSAS et co-direction du Dr Thomas MAVRAKANAS

" Antagonistes du récepteur minéralocorticoïde chez les patients avec insuffisance rénale chronique "

Thèse

présentée à la Faculté de Médecine de l'Université de Genève

pour obtenir le grade de Docteur en médecine par

Cosimo Cosimato

de Pagani, Italie Thèse n° 11062

Genève

2021

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Référence de publication: Cosimato C, Agoritsas T, Mavrakanas TA. Mineralocorticoid receptor

antagonists in patients with chronic kidney disease. (2021). Pharmacol Ther Mar;219:107701.

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I REMERCIEMENTS

J’exprime ma profonde gratitude au Professeur Thomas Agoritsas et le Dr Thomas Mavrakanas, respectivement directeur et co-directeur de cette thèse, pour m'avoir donné l'opportunité de travailler sur ce sujet, pour leur ouverture d’esprit, leur encouragement et leurs qualités scientifiques et humaines incomparables.

Un remerciement du profonde du cœur à mon épouse, Federica, pour son inestimable soutien

quotidien, et à mes enfants, Mario et Renato, qu’avec un simple sourire ou un embrase m’ont

donné l’énergie nécessaire pour avancer dans ce parcours, même dans les moments plus

difficiles. Aux trois est dédié ce travail !

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II RESUME

Les antagonistes du récepteur des mineralocorticoïdes (MRA) appartiennent à une classe de médicaments qui est de plus en plus utilisée dans le traitement de l’insuffisance cardiaque et de l’hypertension artérielle. Le spironolactone est la première molécule de cette classe mise sur le marché à la fin des années 50, suivi par l’éplérénone et le finérénone. Il a fait épreuve d’une incontestable efficacité mais présente également certains inconvénients, notamment le risque d’insuffisance rénale aiguë, d’hyperkaliémie et d’effets hormonaux comme la gynécomastie.

C’est essentiellement à cause de ces effets indésirables que leur utilisation chez les patients avec insuffisance rénale chronique (IRC) - et par conséquence la quantité des données scientifiques dans cette catégorie de patients - est très limitée.

Nombreuses études se sont concentrées sur leur utilisation dans le contexte d’insuffisance cardiaque chez les patients avec une fonction rénale préservée ou partiellement réduite, tandis que les données en cas d’IRC avancée viennent surtout des analyses de sous-groupe des études qui n’étaient pas dédiées à cette catégorie de patients.

Cependant, la mise en évidence d’une forte implication de l’activation du récepteur des mineralocorticoïdes à la base de certains processus physiopathologiques comme l’inflammation, la fibrose et la formation de radicaux libres de stress, a réorienté l’attention sur leur rôle potentiel dans le ralentissement de l’évolution naturelle des pathologies chroniques cardio-rénales.

Afin d’obtenir le maximum de bénéfice de cette classe médicamenteuse tout en réduisant au minimum les effets secondaires potentielles, plusieurs molécules ont été développées en arrivant actuellement à la 4

ème

génération. De tels investissements ont permis d’étudier davantage ces médicaments chez les patients avec IRC même aux stades terminaux.

Les résultats actuels suggèrent que l’utilisation des MRAs chez les patients avec IRC pourrait modifier l’évolution naturelle des pathologies cardio-rénales et réduire le risque de mortalité cardio-vasculaire.

Le but de notre revue c’est d’évaluer en détail le corpus d’évidence clinique sur les MRAs, en se

focalisant sur les risques et bénéfices de leur utilisation dans le contexte d’IRC, tout stades inclus.

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III TABLE DES MATIERES

Remerciements ... I Résumé ... II Table des matières ... III

1. Introduction ... 1

2. Cas cliniques ... 3

2.1 Scenario 1 ... 3

2.2 Scenario 2 ... 4

2.2 Scenario 3 ... 5

3. Les nouveaux antagonistes du récepteur minéralocorticoïde ... 5

4. Revue publiée ... 7

5. Discussion des cas cliniques ... 17

5.1 Scenario 1 ... 17

5.2 Scenario 2 ... 17

5.2.1 L’étude FIDELIO-DKD ... 17

5.3 Scenario 3 ... 21

6. Conclusion et perspectives ... 21

7. Références supplémentaires ... 22

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1 1. INTRODUCTION

L’insuffisance rénale chronique (IRC) est un problème de santé de relevance mondiale avec qui nous nous trouvons à faire face dans notre pratique quotidienne et que se caractérise par une progressive et irréversible altération des fonctions rénales autant glomérulaire que tubulaires et endocriniennes.

Il a été bien établi qu’il s’agit d’un facteur de risque de mortalité indépendant qui augmente exponentiellement avec la progression de la maladie, tandis que la présence concomitante d’autres pathologies chroniques comme l’obésité, le diabète, l’hypertension artérielle et l’insuffisance cardiaque augmentent l’incidence d’IRC et la progression rapide vers la phase terminale de la maladie.

Une prise en charge simultanée des comorbidités est donc très importante afin de ralentir la progression de l’IRC, éviter l’évolution vers la dialyse et protéger le patient des complications cardiovasculaires.

Des études précliniques et cliniques ont mis en évidence que la voie de signalisation minéralocorticoïde joue un rôle important dans le processus physiopathologique de l’inflammation et la formation de fibrose des nombreux organes, et notamment le rein, le cœur et le pancréas. Cette voie est aussi impliquée dans le développement de l’insuffisance cardiaque chronique (ICC) et l’IRC. A partir de ces données-là, nombreuses études ont confirmé les bénéfices des antagonistes du récepteur minéralocorticoïde (MRAs) dans l’ICC.

Les recommandations européennes et américaines actuelles recommandent fortement l’utilisation des MRA chez les patients avec insuffisance cardiaque avec fraction d’éjection réduite (HFrEF) pour réduire la mortalité et morbidité (classe de recommandation [COR] I, niveau d’évidence [LOE] A). Selon une récente mise à jour des recommandations de l’American College of Cardiology/American Heart Association/Heart Failure Society of America du 2017, les MRA pourraient aussi réduire le taux de ré-hospitalisation (COR IIb, LOE B) chez les patients avec insuffisance cardiaque avec fraction d’éjection préservée (HFpEF).

Malheureusement, malgré ces évidences et recommandations, leur utilisation dans la population générale reste sub-optimale vu l’inquiétude concernant les éventuels effets secondaires, notamment la péjoration de la fonction rénale et l’hyperkaliémie.

Il faut toutefois souligner que la majorité de ces études n’ont pas inclus des patients avec IRC ou

ont bien inclus que des patients avec une IRC de stade initial. Ce manque de donnés dédiées à

cette question explique pourquoi les recommandations actuelles proposent d’éviter les MRA en

cas d’IRC, surtout en cas de filtration glomérulaire (eGFR) < 30 ml/min/1.73m

2

. Le schéma en

figure 1 décrit trois scenarios cliniques prototypaux illustrant les inconvénients et les enjeux dans

la pratique clinique quotidienne qui ont motivé le travail de synthèse et d’évaluation détaillée de

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2 l’évidence que nous avons publié dans Pharmacology & Therapeutics (IF 11.13) [1] sur l’utilisation des MRAs dans le contexte d’une IRC.

Figure 1 – Situations cliniques prototypale quand à l’utilisation des MRA dans l’IRC

Scenario 1:

Insuffisance cardiaque chronique

Scenario 2:

Néphropathie diabétique

Patients avec insuffisance rénale chronique et…

E ff et s se co nd ai re s

Hyperkaliémie

B én éf ic es po te nt ie ls

Scenario 3:

Insuffisance rénale terminale

et dialyse

Décision de les utiliser

C as c li ni qu es

Péjoration fonction rénale

Réduction du risque de mortalité et taux d’hospitalisation

Ralentissement de la progression

de la maladie

Réduction de la mortalité liée au

risque cardio-vasculaire

Patients pouvant en

bénéficier

Pourquoi l’utilisation

est limitée

Effets secondaires gérables

…MRA

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3 2. CAS CLINIQUES

2.1 Scenario 1

IRC et insuffisance cardiaque chronique

Patient de 77 ans au cours de sa 3

ème

hospitalisation de l’année pour décompensation cardiaque.

Il est connu pour obésité, une HFrEF (fraction d’éjection 40%), un status post infarctus du myocarde il y a 2 ans, et une IRC avec eGFR 45 ml/min/1.73m

2

. Le patient est traité par Torasemide augmenté progressivement jusqu’à 40mg 1x/j, Metoprolol 200mg 1x/j et Lisinopril 10mg 1x/j adapté régulièrement par son médecin traitant qui le voit une fois tous les 2 mois. La tension artérielle est dans les cibles. Le bilan biologique met en évidence une péjoration de la fonction rénale avec eGFR à 35 ml/min/1.73m

2

et une kaliémie à 4.8 mmol/l. La phase aiguë est gérée par un traitement diurétique intraveineux, nitroglycérine transcutané et ventilation en pression positive continue (CPAP) qui permettent de réduire les symptômes. Selon les recommandations, un traitement de spironolactone est indiqué mais les médecins en charge ont choisi de ne pas l’introduire vu les résultats du bilan biologique.

Réflexion: Cette situation clinique, fréquemment rencontrée au quotidien, illustre le fait que

l’inquiétude concernant une péjoration de la fonction rénale et de la kaliémie inhibe l’utilisation

d’un MRA (spironolactone ou éplérénone), bien qu’elle puisse améliorer la gestion de la phase

chronique de la maladie cardiaque et réduire le risque de mortalité et ré-hospitalisation pour causes

cardio-vasculaires. Est-ce que les évidences actuelles justifient cette attitude réticente ?

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4 2.2 Scenario 2

IRC et néphropathie diabétique

Patient de 64 ans, connu pour diabète de type 2 insulino-requérant, hypertension artérielle, hypercholestérolémie et IRC.

Traitement habituelle : Metformine 1000mg 2x/j; Canagliflozine 100mg 1x/j; Lisinopril 10 mg 1x/j; Metoprolol 150 mg 1x/j; Atorvastatine 20mg 1x/j; Insuline glargine 20 UI sc 1x/j le soir.

Un contrôle clinique et biologique chez le médecin traitant met en évidence : - tension artérielle 128/75 mmHg ; fréquence cardiaque 75 bpm ;

- glycémie capillaire 8.9 mmol/l et hémoglobine glyquée à 7.1% ;

- péjoration de la fonction rénale avec un eGFR passant de 54 à 42ml/min/1.73m

2

- bilan urinaire : péjoration de la protéinurie, actuellement à 2300 mg/g (350 mg/g une

année auparavant).

Le bilan met en évidence une progression de la néphropathie diabétique malgré un contrôle optimal de la glycémie et une tension artérielle contrôlée. A l’état actuel, mis à part le contrôle des facteurs de risque et l’utilisation d’un inhibiteur de l'enzyme de conversion (IEC) et un inhibiteur SGLT2, médicaments notamment connus pour leur effet sur la protéinurie, d’autres propositions thérapeutiques médicamenteuses ne sont pas disponibles.

Réflexion: Cette situation met en évidence les limites du traitement médicamenteux chez le patient

avec néphropathie diabétique en progression malgré un contrôle optimal de la glycémie et des

facteurs de risque cardio-vasculaires. Est-ce que les MRA peuvent jouer un rôle dans la

progression vers l’insuffisance rénale terminale ?

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5 2.3 Scenario 3

Insuffisance rénale terminale et dialyse

Patiente de 74 ans, connue principalement pour insuffisance rénale terminale en hémodialyse 3 fois par semaine, hypertension artérielle et insuffisance cardiaque avec fraction d’éjection conservée (HFpEF).

Traitement habituel: perindopril 5 mg 1x/j, bisoprolol 5 mg 1x/j, spironolactone 50mg 1x/j et Néphrotrans® 6 capsules/jour les jours libres de la dialyse.

Elle consulte le médecin traitant suite un épisode d’hypotension à 90/60 mmHg, sans répercussion hémodynamique, arrivé le lendemain d’une séance de dialyse avec retour spontané à une tension artérielle habituelle autour de 150/70 mmHg dans une heure.

Constantes : TA 154/85 mmHg ; FC 62 bpm ; SatO2 99% en AA ; T 36.6°C

Laboratoire : Sans particularités sauf une kaliémie à 5.2 mmol/l (4.8 mmol/l il y a 1 mois).

Le médecin traitant, en accord avec le néphrologue, décide d’arrêter le spironolactone

Réflexion: Cette situation met en évidence la facilité de l’arrêt d’un traitement par MRA face un évènement clinique (hypotension transitoire) et une kaliémie à la hausse. Etait-ce une décision judicieuse ? Y a-t-il d’autres stratégies à considérer avant de stopper définitivement un traitement par MRA dans ce type de situations ?

3. LES NOUVEAUX ANTAGONISTES DU RECEPTEURS MINERALCORTICOIDE

A la recherche de l’MRA idéal, partant de la spironolactone – 1

er

MRA disponible depuis la fin

des années cinquantes – nombreuses molécules ont été développées en arrivant actuellement à la

4

ème

génération des MRAs. Une des majeures nouveautés est le passage d’une structure

stéroïdienne caractéristique de la 1

ère

(spironolactone et ses dérivés dont le plus important est le

canrenone) et 2

ème

génération (éplérénone) à une structure non-stéroïdienne de la 3

ème

et 4

ème

génération. Les nouveaux MRAs de ces dernières générations qui sont actuellement à un stade

avancé de leur développement sont le finérénone et l’esaxérénone avec des données cliniques

importantes déjà présentes en littérature tandis que d’autres molécules (dont le plus avancée est

l’apararénone) sont en phase préclinique à l’heure actuelle. Le changement de structure a permis

d’augmenter la sélectivité pour le récepteur des mineralocorticoïdes (RMs), en réduisant leur

action sur d’autres récepteurs stéroïdiens et par conséquent, une partie de leurs effets indésirables

tout en augmentant leur affinité pour les RMs présents dans le reste du corps humain, notamment

cardiaque.

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6 Le finérénone est actuellement étudiée autant comme alternative à la spironolactone et l’éplérénone dans les pathologies cardiovasculaires (comme ICC et hypertension artérielle) que dans le contexte de la néphropathie diabétique avec des résultats très encourageants.

D’autres études en cours permettront de préciser les indications et les limitations à envisager quant à son emploi dans la pratique clinique.

Dans l’article de revue qui suit, après une brève introduction concernant la cascade d’évènements physiopathologiques liant l’activation des RMs à l’évolution vers l’ICC et IRC et le profil pharmacologique des MRAs, nous discutons les évidences cliniques actuelles sur leur utilisation chez les patients avec IRC (de tous les stades, y compris le stade terminal) et leur rôle potentiel dans un futur proche :

Citation :

« Cosimato C, Agoritsas T, Mavrakanas TA. Mineralocorticoid receptor antagonists in patients with chronic kidney disease. Pharmacol Ther. 2021 Mar;219:107701.

doi: 10.1016/j.pharmthera.2020.107701. ».

A la suite de cet article, nous rediscutons des trois situations cliniques prototypales et des pesées

des risques et bénéfices au vu des connaissances actuelles.

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Mineralocorticoid receptor antagonists in patients with chronic kidney disease

Cosimo Cosimato

a

, Thomas Agoritsas

a,b

, Thomas A. Mavrakanas

a,c,

aDivision of General Internal Medicine, Department of Medicine, University Hospitals of Geneva & Faculty of Medicine, Geneva, Switzerland

bDepartment of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada

cDivision of Nephrology, Department of Medicine, McGill University, Montreal, Quebec, Canada

a b s t r a c t a r t i c l e i n f o

Available online 4 October 2020

Keyswords:

Mineralocorticoid receptor antagonist Chronic kidney disease

Congestive heart failure Diabetic nephropathy end-Stage renal disease Chronic kidney disease progression

Mineralocorticoid receptor antagonists (MRA) can reduce cardiovascular morbidity and mortality in patients with heart failure and ischemic heart disease. In addition, these agents have been used in patients with diabetic nephropathy to control proteinuria and slow down chronic kidney disease (CKD) progression. Current guidelines recommend against the use of MRAs in patients with advanced CKD. However, there is growing interest on their use in this population that has unmet needs (high cardiovascular morbidity and mortality) and unique challenges (risk of acute kidney injury or hyperkalemia). This narrative review discusses the emerging role of MRAs for the management of cardiovascular disease and/or the prevention of CKD progression, highlighting results from ran- domized controlled trials and presenting real-world data from available registries. Results from recent trials in patients on maintenance dialysis are also discussed.

© 2020 Published by Elsevier Inc.

Contents

1. Introduction . . . 1

2. MRAs in patients with CHF and CKD . . . 2

3. MRAs for the prevention of worsening nephropathy in patients with CKD . . . 5

4. Use of potassium binders in association with MRAs in patients with CKD . . . 7

5. MRAs in patients with kidney failure on maintenance dialysis . . . 7

6. Conclusions and further research . . . 8

Declaration of Competing Interest . . . 9

Acknowledgment . . . 9

References. . . 9

1. Introduction

Aldosterone is the principal mineralocorticoid hormone produced in the adrenal cortex. Its secretion is stimulated by the activation of the renin-angiotensin system. Aldosterone actively participates in the regulation of the extracellular fluid volume, blood pressure, and potassium balance. Thefirst mineralocorticoid receptor antagonist (MRA), spironolactone, has been available for several decades, but it is only after the publication of the RALES (Randomized Aldactone Evaluation Study) trial (Pitt et al., 1999) that clinicians started to widely use these agents in patients with cardiovascular (CV) disease. Despite strong recommendations in several guidelines, i.e. in both the European Society of Cardiology and the American College of Pharmacology & Therapeutics 219 (2021) 107701

Abbreviations:ACEI, Angiotensin-converting-enzyme inhibitors; ARB, Angiotensin II receptor blocker; CHF, Congestive Heart Failure; CKD, Chronic Kidney Disease; CV, Cardiovascular; ESRD, End-Stage Renal Disease; HD, Hemodialysis; HFpEF, Heart Failure with Preserved Ejection Fraction; HFrEF, Heart Failure with Reduced Ejection Fraction;

LVEF, Left Ventricular Ejection Fraction; LVM, Left Ventricular Mass; MR, Mineralocorticoid Receptor; MRA, Mineralocorticoid Receptor Antagonist; UACR, Urinary albumin to creatinine ratio; WRF, Worsening Renal Function.

Corresponding author at: Department of Medicine, Geneva University Hospitals &

Faculty of Medicine, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland.

E-mail address:thomas.mavrakanas@mcgill.ca(T.A. Mavrakanas).

https://doi.org/10.1016/j.pharmthera.2020.107701 0163-7258/© 2020 Published by Elsevier Inc.

Contents lists available atScienceDirect

Pharmacology & Therapeutics

j o u r n a l h o m e p a g e :w w w . e l s e v i e r . c o m / l o c a t e / p h a r m t h e r a

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Cardiology/American Heart Association/Heart Failure Society of America congestive heart failure (CHF) guidelines, MRAs still remain underused both in the United States and in Europe (Albert et al., 2009;

Ferreira et al., 2017;Thorvaldsen, Benson, Dahlstrom, Edner, & Lund, 2016), especially among patients with chronic kidney disease (CKD) because of the higher risk of adverse events in this population. This re- view article summarizes and discusses current evidence for use of MRAs in CKD.

1.1. Pathophysiology

A“classical”and“nonclassical”tissue expression of the mineralocor- ticoid receptor (MR) has been described (Jaisser & Farman, 2016). Clas- sical MR expression occurs in the epithelium of the collecting duct, also known as the aldosterone-sensitive distal nephron, and in the distal colon, sweat and salivary gland ducts. MR activation stimulates renal so- dium reabsorption and potassium excretion (Nishiyama & Kobori, 2018;Rafiq, Hitomi, Nakano, & Nishiyama, 2011;Stockand, 2002). MR activation in nonclassical tissues, such as the podocytes,fibroblasts, cardiomyocytes, endothelial, vascular smooth muscle cells, adipocytes, and macrophages, is independent of the 11β-hydroxysteroid dehydro- genase type 2 (11b-HSD2) and involves glucocorticoid (Baker, Funder,

& Kattoula, 2013;Rafiq et al., 2011;Vitellius, Trabado, Bouligand, Delemer, & Lombès, 2018) and Rac1 signaling pathways (Shibata et al., 2008;Shibata, Ishizawa, & Uchida, 2017). We outline these mech- anisms inFig. 1MR activation at this level is associated with detrimental effects, such as glomerular and tubular sclerosis, cardiac remodeling,fi- brosis and arrhythmias. A detailed description of the pathophysiological basis of MR activation in heart and kidney disease is beyond the scope of this review.

1.2. Mineralocorticoid receptor antagonists

Spironolactonefirst became available in 1959 and is commercially available worldwide. Its active metabolite, canrenone, is also commer- cially available in several countries. Concerns about the side effects of spironolactone, due to its lack of selectivity for the MR, led to the devel- opment of newer, more selective MRAs. Thefirst of them, eplerenone, has a relatively lowin vitroaffinity for the MR with a higher fraction of the bioavailable compound, and has not been associated with sexual adverse effects because of its low affinity for the progesterone and an- drogen receptors (Kolkhof & Bärfacker, 2017). In the last two decades, third and fourth generation MRAs that share a non-steroidal structure have also been developed, withfinerenone and esaxerenone being cur- rently evaluated in clinical trials, while no clinical data are yet available for apararenone.Table 1shows the main pharmacological characteris- tics of different MRAs.

2. MRAs in patients with CHF and CKD

MRAs are an important part of medical therapy in patients with CHF.

These agents are not widely used in patients with CHF and CKD because of the higher risk of adverse events in this population.Table 2summa- rizes randomized and registry data with MRAs on cardiovascular out- comes among patients with CKD. As further discussed below, the majority of the evidence for our population of interest comes from sub- group analyses–often also post-hoc–which may limit the confidence one has in the estimates of effects (Sun, Ioannidis, Agoritsas, Alba, &

Guyatt, 2014).

2.1. Randomized control trials (RCTs) - MRA and heart failure with reduced ejection fraction (HFrEF)

Thefirst trial that assessed the efficacy and safety of spironolactone in patients with HFrEF was the RALES trial. Spironolactone was used at the dose of 25 mg with an adjustment to 12.5 mg/day if serum

potassium (K+) > 5.5 mmol/l or to 50 mg at 1 month if K+ stayed below 5 mmol/l. All patients were on standard therapy for CHF at that time [Angiotensin-converting-enzyme inhibitors (ACEI), diuretic and digoxin], whereas the majority of them were not on beta-blockers (only 10% in the placebo and 11% in the spironolactone group). The trial was stopped after a mean follow-up of 24 months due to a signifi- cant 30% decrease in all-cause mortality and 35% reduction in CHF hos- pitalizations for patients randomized in the spironolactone group (Pitt et al., 1999). In the subgroup of patients with estimated glomerularfil- tration rate (eGFR) <60 ml/min/1.73m2, spironolactone was superior to placebo for all-cause mortality and the composite outcome of all-cause mortality or CHF hospitalization with an absolute risk reduction of 10%

in all-cause mortality (Vardeny et al., 2012). Worsening renal function (WRF), defined as a reduction of >30% in eGFR from baseline, was more frequently observed in patients treated with spironolactone com- pared with placebo (17% vs. 7%). The risk of hyperkalemia was higher in CKD and most common in patients with WRF [odds ratio 3.6, 95% Con- fidence Interval (CI) 1.5–8.6]. WRF and hyperkalemia were associated with a higher probability of treatment discontinuation.

EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) was a randomized, double-blind trial, enrolling 2737 patients with New York Heart Association (NYHA) II CHF and a left ventricular ejection fraction (LVEF)≤35%, eGFR >30 ml/min/1.73 m2and K+< 5.0 mmol/l to receive eplerenone (25–50 mg/day) or placebo, in addition to recommended therapy (Zannad et al., 2011). The trial was stopped after a mean follow-up of 21 months due to a 37% reduction in the primary outcome of CV death or hospitalization for CHF for the eplerenone group compared with pla- cebo [Hazard Ratio (HR) 0.63; 95% CI 0.54–0.74;p< 0.001]. In a post hoc analysis in patients with an eGFR of 30–60 ml/min/1.73m2, eplerenone was equally effective to reduce the primary composite end point as compared with placebo (HR 0.62, 95% CI 0.49–0.79, p < 0.001) (Eschalier et al., 2013). In a second post hoc analysis in patients with CKD from the same trial, the efficacy of eplerenone was similar across the different eGFR strata (Ferreira et al., 2019). Although, the incidence of hyperkalemia was higher in eplerenone treated patients with CKD compared with placebo, there was a lower incidence of serious hyperkalemia, defined as K+> 6 mmol/l, with eplerenone (1.9%) com- pared with placebo (3.3%,p= 0.01). In addition, in patients with CKD, drop in eGFR from baseline during the follow-up was similar in both groups (2.0 ml/min/1.73m2with eplerenone versus 4.2 with placebo).

However, more patients with CKD discontinued eplerenone due to hyperkalemia compared with patients without CKD (Eschalier et al., 2013).

ARTS (MinerAlocorticoid Receptor Antagonist Tolerability Study) was a phase 2b multicentre, randomized, double-blind clinical trial eval- uating the safety and tolerability offinerenone in high-risk patients with NYHA II-III HFrEF and LVEF≤40%, CKD and/or type 2 diabetes mellitus already on standard treatment (Pitt et al., 2012). Part B of this trial was conducted in patients with moderate CKD (eGFR 30–60 mL/

min/1.73 m2), randomized 393 patients, and had an open-label active comparator (spironolactone 25-50 mg/day) in addition to the placebo group. Mean increases in serum K+levels and drop in eGFR from base- line were higher with spironolactone compared with all four doses of finerenone. Only the cumulative dose of 10 mg offinerenone daily was associated with higher incidence of hyperkalemia compared with placebo (Pitt et al., 2013). However, spironolactone seemed more effec- tive in reducing systemic blood pressure thanfinerenone, with no clear explanation.

ARTS-HF (MinerAlocorticoid Receptor antagonist Tolerability Study - Heart Failure) trial was a multicentre, randomized, double-blind, phase 2b dose-finding study comparingfinerenone (one of thefive doses of 2.5, 5, 7.5, 10, or 15 mg, up-titrated to 5, 10, 15, 20, or 20 mg/

day respectively, on day 30) and eplerenone (25 mg every other day, in- creased to 25 mg once daily on day 30, and to 50 mg once daily on day 60) for 90 days (Pitt et al., 2015). The study was designed to assess the

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safety and potential efficacy offinerenone in patients with worsening HFrEF (LVEF≤40%) complicated by CKD and/or type 2 diabetes (eGFR

>30 mL/min/1.73m2in patients with diabetes and 30–60 mL/min/

1.73m2in patients without diabetes). The incidence of the exploratory composite endpoint (death from any cause, CV hospitalization or emer- gency presentation for worsening CHF) at day 90 was lower in all finerenone groups (with the exception of the 2.5–5 mg group), com- pared with eplerenone (Filippatos et al., 2016). Hyperkalemia“at any time post baseline”defined as K+> 5.5 mmol/l was similar in both treatment groups, occurring in 4.7% of cases in the eplerenone arm and 4.2% of cases in thefinerenone arms, while serious hyperkalemia (K+> 6 mmol/l) was rare (detected in 1 and 4 cases in the eplerenone andfinerenone arms, respectively). WRF≥25%,≥30% and≥40% was de- tected in 12.5%, 7.2% and 1.8% of patients treated withfinerenone,

compared with 13.3%, 9.1% and 2.1% of patients in the eplerenone arm, respectively.

2.2. RCTs - MRA and heart failure with preserved ejection fraction (HFpEF)

The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial was thefirst study to randomize patients with HFpEF to spironolactone or placebo (Pitt et al., 2014). Al- though there was no statistically significant difference in the primary outcome of time to CV death, aborted cardiac arrest or hospitalization for CHF, a fourfold difference in the primary outcome incidence rate was identified between Russia-Georgia and the Americas, whereas spironolactone was superior to placebo for the primary outcome in Fig. 1.Possible mechanism of mineralocorticoid receptor (MR) activation and it specific role in the pathogenesis in cardiovascular disease (CVD) chronic kidney disease (CKD) , its detrimental effects on target organs and potential beneficial effects of MRAs on acute or chronic kidney graft protection. MR is activated by an aldosterone independent mechanism as Rac1 with a ligand-dependent and -independent MR activation mechanism. Glucocorticoid (GCT); Renin–angiotensin system (RAS); Adrenocorticotropic hormone (ACTH); Acute Kidney Injury (AKI); CardioVascular (CV); T-Cell Lymphocytes (TCL); Acute Heart Failure (AHF); Acute Coronary Syndrome (ACS); Macrophage markers (M1 and M2);

Phosphorylation (Phospho); calcineurin inhibitor-induced nephrotoxicity (CIN); Natriuretic peptide precursor type A (ANP); endothelial sodium channel (ENaC); Na+/H+ exchanger (NHE); vascular smooth muscle cells (VSMC). [This picture is created starting by following studies:Belden et al., 2017;Nishiyama, 2019;Barrera-Chimal et al., 2019;Capelli et al., 2020;Girerd and Jaisser, 2018]

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the subgroup of patients recruited in the Americas (HR 0.82; 95% CI 0.69–0.98) (Pfeffer et al., 2015;Pitt et al., 2014).

A recent post hoc analysis stratified patients recruited in the Americas into three subgroups based on renal function at baseline:

eGFR <45, 45 to 59, and≥60 mL/min/1.73m2(Beldhuis et al., 2019).

The effect of spironolactone on the primary outcome was consistent across the three CKD subgroups (with no statistical subgroup effect,p- value for interaction = 0.13). Spironolactone was associated with a Table 1

Pharmacological features of MRA of each generation.

Steroidal structure Non-Steroidal structure

1st Generation 2nd Generation 3rd4th Generation

Spironolactone SC-9420

Canrenone C-9376 Eplerenone CGP-30083 Finerenone BAY

94–8862

Esaxerenone CS-3150

Half-life (h) 1.4 16.5 3–6 2.2–2.8 18.6 (±2.4) to 34(±9)

SHR

IC50-MR (nM) 36 ≥1000 713 18 9.4

IC50-GR (nM) 764 ≥1000 3060 >10,000 >10,000

IC50-AR (nM) 133 NR >100,000 >10,000 >10,000

IC50-PR (nM) 1200 NR >100,000 >10,000 >10,000

Affinity target

MR High Moderate Moderate (40-fold <SPL) High (similar to SPL) Very High (4-fold >SPL and

76-fold>EPL)

Other SHR Moderate Moderate (lesser

affinity to AR than SPL)

>100-fold less affinity for GR, AR and PR >500-fold less affinity for GR, AR and PR

At least 1000 folds higher selectivity for MR over other SHR.

Tissue distribution (Kindney/Heart)

Kidney > Heart (at least 6-fold)

Kidney > Heart (~ 3-fold) Kidney = Heart

Action Partial agonist Inverse agonist

Main adverse effects

Hyperkalemia, loss of libido, gynecomastia, sexual dysfunction, menstrual irregularities

Hyponatremia, vaginal bleeding, hyperlipidemia hyperkalemia, drugs interaction mediates by CYP3A enzymes

Hyperkalemia (at lower percentage) No other major side effects but not yet widely commercially available

AR = androgen receptor, EPL = Eplerenone; GR = glucocorticoid receptor, IC50= half maximal inhibitory concentration, MR = mineralocorticoid receptor, NR = not reported, PR = progesterone receptor, SHR = Steroid hormone receptor, SPR = Spironolactone.

References:Amazit et al., 2015;Arai et al., 2015;Armanini, Sabbadin, Donà, Clari, & Bordin, 2014;Ito et al., 2020;Kolkhof & Bärfacker, 2017;Kolkhof & Borden, 2012;Sueta, Yamamoto, &

Tsujita, 2020;Yamada, Mendell, Takakusa, Shimizu, & Ando, 2019;Yang & Young, 2016.

New drugs ongoing development have not been reported due to the absence of available data.

Table 2

Clinical outcomes with MRAs in patients with CHF and CKD.

Study Treatment groups eGFR Patients with CKD

All-cause mortality

CHF admissions

Cardiovascular mortality- CHF admissions

WRF Hyperkalemia

HFrEF

RALES SPL 12.5, 25, 50 qd vs. placebo

30–60 792 (48%)

HR 0.68 (95%

CI 0.56–0.84)

NR 0.67

(0.56–0.81)

NR 25.6% vs. 8.5% (p< 0.001)

EMPHASIS-HF EPL 25–50 qd vs.

placebo

30–60 912 (33%)

NR HR 0.55

(95% CI 0.41–0.72)

HR 0.62 (95%

CI 0.49–0.79) 2.0 ± 17.0 vs. 4.2 ± 14.9 16.6% vs. 9.3% (p= 0.002) ARTS (Part B) FNR 2.5–5-10qd

SPL 25–50 qd vs.

placebo

30–60 392 (100%)

NR NR NR 1.5% (FNR), 7.9% (SPL), 0%

(placebo)p= 1.00 vs. placebo p = 0.02 vs. SPL

5.3% (FNR), 12.7% (SPL), 1.5%

(placebo)p= 0.32 vs. placebo p= 0.05 vs. SPL

ARTS-HF FNR 2.5–20 qd EPL 25–50 qd

≥30 752 (71%)

HR 0.13 (95%

CI 0.02–1.07) HR 0.58 (95% CI 0.33–1.02)

HR 0.56 (95%

CI 0.35–0.90)

p= 0.53 3.6% vs. 4.7%

HFpEF

TOPCAT SPL 15 to 45 vs.

placebo

45–59 533 (30%)

NR NR HR 0.99 (95%

CI 0.73–1.36)

HR 3.80 (95% CI 2.24–6.45) 30–45 411

(23%)

NR NR HR 0.89 (95%

CI 0.66–1.21)

HR 2.12 (95% CI 1.41 to 3.19) Acute EF

ATHENA-HF SPL 100 vs. usual care (SPL 25 or placebo)

≤50 118 (33%)

HR 12.11 (95% CI 1.37–107.22)

NR HR 0.98 (95%

CI 0.43–2.21)

−4.1 vs.−4.7 mL/min/1.73m2at 96 h (p= 0.77)

≤2% at day 30 for both groups

Results are presented for the subgroup of patients with CKD. The absolute number of patients with CKD and the percentage of the total number of study participants (in parentheses) are depicted. Doses are shown in mg. Estimated glomerularfiltration values are shown in as mL/min/1.73m2. For worsening renal function, results are presented as mean ± standard deviation.

CHF, congestive heart fauilure; CI, Confidence Interval; CKD, Chronic kidney disease; eGFR: estimated glomerularfiltration rate; EPL, Eplerenone; FNR, Finerenone; HR, hazard ratio; MRAs, Mineralocorticoid Receptor Antagonists; NR, not reported; qd, once daily; SPL, Spironolactone; WRF, worsening renal function.

Composite outcome of all-cause mortality or CHF admission.

For patients with eGRF 30–49 mL/min/1.73 m2.

Results are reported only for thefinerenone 10 and 20 mg doses.

Composite outcome of drug discontinuation due to persistent hyperkalemia (>5.5 mmol/l), persistent creatinine levels >3.0 mg/dl, anaphylactic reaction, drug intolerance, or gynecomastia.

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higher incidence of hyperkalemia (K+> 5.5 mmol/l) and WRF (defined as doubling of serum creatinine from baseline) leading to permanent drug discontinuation (HR 3.80; 95% CI 2.24–6.45 and HR 2.12; 95% CI 1.41–3.19 for the eGFR groups of 45–60 and 30–45 mL/min/1.73m2re- spectively). Based on these data, for every 100 patients treated with spironolactone, the authors would expect to prevent 9 occurrences of the primary composite outcome but provoke 27 drug discontinuations for adverse events among patients with an eGFR<45 ml/min/1.73m2 and 8 drug discontinuations in those with an eGFR >60 ml/min/

1.73m2. The authors suggested that spironolactone use in patients with HFpEF and eGFR <45 ml/min/1.73m2should only be considered when close laboratory monitoring is possible.

2.3. RCTs - MRA and acute CHF

ATHENA-HF (Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure) trial was a prospective, multicen- ter, double-blind clinical trial (Butler et al., 2017). The authors tested the hypothesis that addition of high-dose spironolactone (100 mg), compared with placebo or spironolactone≤25 mg (standard of care), would result in greater symptomatic relief in patients presenting with acutely decompensated CHF. The study enrolled patients with eGFR

≥30 mL/min/1.73m2. High-dose spironolactone was well tolerated but did not improve the primary outcome (change in NT-proBNP levels from baseline to 96 h), the secondary efficacy outcomes (clinical con- gestion score, dyspnea assessment, net urine output, net weight change, diuretic dosage at discharge, in-hospital worsening CHF, and a compos- ite of all-cause mortality, all-cause readmission, or outpatient worsen- ing CHF a day-30) or the secondary safety outcomes (hyperkalemia and changes in renal function during the 96-h treatment period).

In the ATHENA-HF trial, 50% of patients had CKD and approximately 20% of them had an eGFR in the 30–45 mL/min/1.73m2range (Greene et al., 2019). There was no significant difference in the primary or sec- ondary end points between the spironolactone and standard of care arms across eGFR subgroups (P-value for interaction was not significant for all outcomes tested). No relevant changes in serum potassium or creatinine levels were detected from baseline to 96 h/discharge in the high-dose spironolactone and the standard of care groups across all eGFR strata (P-value for interaction was not significant). The authors concluded that use of spironolactone was safe in the hospital in patients with moderate CKD, even at high doses.

2.4. Registry data

In this section, we present registry data on outcomes with MRAs in patients with CKD. We report only propensity-matched cohorts or stud- ies attempting to account for baseline differences between the MRA users and non-users.

The Alabama Heart Failure Project included 1140 patients with HFrEF (LVEF <45%) and moderate-advanced CKD (eGFR <45 mL/min/

1.73m2). A total of 207 patients treated with spironolactone were com- pared with 933 patients who were not treated with an MRA using pro- pensity score - adjusted hazard ratios (aHR) (Inampudi et al., 2014).

Patients on spironolactone had a higher one-year risk of all-cause read- mission (HR 1.36; 95% CI 1.13–1.63,p= 0.001). This risk was highest among the 106 patients with stage 5 CKD (eGFR <15 ml/min/1.73m2) (HR 4.75; 95% CI 1.84–12.28, P-value for interaction = 0.003).

The Korean Heart Failure Registry studied the relationship between spironolactone use and all-cause mortality in 1035 patients with acute systolic heart failure and severe renal dysfunction (defined as GFR < 45 ml/min/1.73m2). A subgroup of 105 patients with acutely de- compensated CHF on spironolactone were propensity score-matched with 105 patient who did not receive an MRA (Oh et al., 2015). There was no statistically significant difference in all-cause mortality (HR 0.63; 95% CI 0.35–1.13,p= 0.12) or rehospitalization rates (40% vs.

36%,p= 0.72) between the two groups, after adjusting for other heart

failure risk factors. Overall, the clinical benefit of spironolactone was preserved in CKD stage 3b patients but not in CKD stage 4 or 5.

In the Norwegian Heart Failure Registry, the effect of spironolactone on all-cause mortality was studied using 170 propensity score-matched pairs of patients with CHF and CKD (defined as eGFR <60 mL/min/

1.73m2). A lower incidence of all-cause mortality at two years was ob- served in the spironolactone group compared with no treatment (HR 0.59, 95% CI 0.37 to 0.92,p= 0.02). A decrease in eGFR was seen in spironolactone-treated patients (from 46 to 41 mL/min/1.73m2; p< 0.001) but not in the control group (Stubnova, Os, Grundtvig, Atar,

& Waldum-Grevbo, 2017).

In a retrospective cohort study including all patients followed at the McGill University heart failure clinic, the authors compared 314 patients on spironolactone (121 with CKD) or eplerenone with 1116 patients who did not receive an MRA (408 with CKD), using propensity score- adjusted Cox proportional hazards models (Mavrakanas, Giannetti, Sapir-Pichhadze, & Alam, 2020). All patients were receiving an ACEI or an Angiotensin II receptor blocker (ARB). The MRA had to be discontinued in 30% of patients with CKD and 35% of patients without CKD (p= 0.39). In this cohort, there was no difference between the two groups in the incidence of a composite outcome of death from any cause, myocardial infarction, or hospital admission for decompen- sated CHF. The effect of MRAs on this outcome was not affected by CKD status (P-value for interaction = 0.27). The safety renal outcome, defined as hyperkalemia >6 mmol/l or any doubling of serum creatinine in patients not yet on dialysis, occurred more frequently in MRA users without CKD than MRA users with CKD (P-value for interaction = 0.02). The authors concluded that MRAs could be safely prescribed in patients with CHF and CKD who were already treated with an ACEI or an ARB.

2.5. Ongoing trials

SPIRO-CKD (Spironolactone in Chronic Kidney Disease) trial (NCT02502981) is an ongoing multicentre, prospective, randomized, open-label, blinded end point clinical trial that will compare the effect of spironolactone to chlorthalidone on left ventricular mass (LVM) (Hayer et al., 2017). The trial plans to enrol patients without history of CHF or diabetes mellitus and a preserved LVEF (≥50%). Recruitment of 154 patients had been completed by December 2016 but the results of this trial have not yet been reported.

3. MRAs for the prevention of worsening nephropathy in patients with CKD

Patients with diabetes mellitus are at increased risk of developing kidney disease, then gradually progress to end-stage renal disease (ESRD) (Collins et al., 2014;de Boer et al., 2014). Albuminuria is consid- ered a surrogate marker for hard renal and CV endpoints and control of albuminuria is an important preventive strategy in this population (de Zeeuw et al., 2004;Schmieder et al., 2011).Table 3summarizes the evidence on how MRAs have been used to control albuminuria and prevent progression of CKD.

3.1. RCTs

ARTS-DN (Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy) was thefirst multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2b study to comparefinerenone (at the initial dose of 1.25 mg daily titrated up to 20 mg) with placebo in patients with type 2 diabetes and a urinary albu- min to creatinine ratio (UACR)≥30 mg/g (Bakris et al., 2015;Ruilope et al., 2014). All patients were already treated with an ACEI or an ARB.

A total of 1501 patients were screened and 821 patients received at least one dose offinerenone or placebo. Upon randomization, 37% of patients had very high albuminuria, defined as a UACR≥300 mg/g.

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A significant decrease in UACR was detected with all doses offinerenone compared with placebo at 90 days: UACR ratio in thefinerenone to pla- cebo group of 0.79 (90% CI, 0.68–0.91;p= 0.004), 0.76 (90% CI, 0.65–0.88;p= 0.001), 0.67 (90% CI, 0.58–0.77;p< 0.001), and 0.62 (90% CI, 0.54–0.72; p < 0.001) with the dose of 7.5, 10, 15 and 20 mg offinerenone, respectively.

In ARTS-DN, the overall incidence of hyperkalemia, defined as a serum potassium in the 5.5–6.0 mmol/l range, was 1.6%. In the subgroup of patients with stage 3 CKD, there were no cases of hyperkalemia with the 10 mgfinerenone dose, but hyperkalemia was observed in 6.3% of patients who received the 20 mg dose. A drop in eGFR of at least 30%

at any time post-baseline was observed at a similar rate across the fourfinerenone dose (4.2–7.0%) and the placebo group (5.4%). In addi- tion, there was no difference between the study groups in the incidence of an eGFR drop of≥40% or≥57% (equivalent to a doubling in serum creatinine levels) by day 60. In conclusion,finerenone in patients with diabetic nephropathy, in addition to ACEIs or ARBs, improved protein- uria compared with placebo. However, long-term effects on CKD pro- gression or antifibrotic and anti-inflammatory properties have not been evaluated due to the short duration of the study.

PRIORITY (Proteomic Prediction and Renin Angiotensin Aldosterone System Inhibition Prevention Of Early Diabetic nephRopathy In TYpe 2 Diabetic Patients With Normoalbuminuria) was an investigator- initiated, prospective, double-blind, randomized, placebo-controlled, multicenter study in people with diabetes, an eGFR >45 mL/min/

1.73m2and normal urine albumin excretion (Tofte et al., 2020). A uri- nary proteomic risk classifier (CKD273) was used to classify patients

at high or low risk for kidney disease. A total of 216 patients (12%) were classified in the high-risk group. They were randomized to receive spironolactone at the dose of 25 mg (102 patients) or placebo (107 pa- tients). No significant difference was detected in the incidence of microalbuminuria between the two study groups: 25% with spironolactone versus 33% with placebo (HR 0.81, 95% CI 0.49–1.34;

p= 0.41). Hyperkalemia, defined as serum K+> 5.5 mmol/l, was ob- served in 13% versus 4% in the two groups, respectively.

Several smaller randomized studies with a cross-over or a parallel group design have been conducted in patients with diabetic nephropa- thy (defined as a UACR≥30 mg/g) who were also treated with an ACEI or an ARB. These studies were summarized in a systematic review:

eight studies enrolled a total of 404 patients, with spironolactone (at the dose of 25-50 mg) in seven of them and eplerenone (at the dose of 50-100 mg) in one study (Mavrakanas, Gariani, & Martin, 2014).

Combined treatment (with an MRA and an ACEI or an ARB) was com- pared with ACEI or ARB monotherapy and was associated with reduced albuminuria levels by 23 to 61% and better blood pressure control at the expense of a higher incidence of hyperkalemia, raising the dropout rate up to 17%.

A Cochrane meta-analysis of randomized trials included 1549 pa- tients from 27 studies who were treated with an MRA (either spironolactone or eplerenone) or placebo, on the top of an ACEI or an ARB, in patients with mild to moderate CKD (Bolignano, Palmer, Navaneethan, & Strippoli, 2014). Combined treatment was associated with a significant reduction in 24-h proteinuria (standardized mean dif- ference of−0.61, 95% CI−1.08 to−0.13, outcome assessed by 11 Table 3

Renal outcomes with MRAs in patients with CKD.

Reference Treatment groups Proteinuria

assessment Patients (number)

Effect on proteinuria eGFR change Hyperkalemia

Non-Diabetic Kidney Disease

Edwards et al. (2012) SPL 25 vs. placebo UACR (mg/mmol)

115 −3.2 vs. -0.6 mg/mmol (p< 0.05) −3 mL/min/1.73m2with SPL from baseline (p< 0.01)

2/56 in both groups Bianchi, Bigazzi, and

Campese (2006)

SPL 25 qd vs. no MRA

UPCR (g/g) 165 Absolute change with SPL at 1 y:

from 2.1 to 0.9 g/g (p< 0.001)

With SPL at 1 y: from 62 to 59 mL/min/1.73m2(p< 0.05)

4/83 vs. 2/82 Guney et al. (2009) SPL 25 qd

(Before/after)

UPCR (g/g) 24 from 2.4 to 1.7 g/g with SPL at 6 months (p< 0.01)

With SPL at 1 y: from 63 to 58 mL/min/1.73m2(p> 0.05)

NR Furumatsu et al. (2008) SPL 25 qd vs. no

MRA

UPCR (g/g) 32 1.4 ± 0.3 to 0.6 ± 0.1 with SPL at 1 y (p< 0.05)

With SPL at 1 y: from 92 to

79 mL/min (p> 0.05) 2/15 in SPL group$ Diabetic Kidney Disease

Bakris et al. (2015) FNR 1.25–20 qd vs placebo

UACR (mg/g)

823 UACR ratio at 90 days 0.76 (90% CI 0.65–0.88)

with FNR 10 mg at day 90:

−1.3 mL/min/1.73m2

No episodes Epstein et al. (2006) EPL 50–100 vs.

placebo

UACR (mg/g)

268 UACR−50% from baseline vs. no change with placebo (p< 0.001)

With EPL 100 mg at 12 wks: from 75 to 66 mL/min/1.73m2

7/177 vs. 3/88 (p= 0.38) Chrysostomou, Pedagogos,

MacGregor, and Becker (2006)#

ACEI ± ARB ± SPL 25

24 h urine protein (g)

41 +1% vs.−48% from baseline at 6 months (p= 0.004)

With SPL at 6 months: from 59 to

56 mL/min 1/10 patients in the

ACEI+SPL group††

van den Meiracker et al.

(2006)

SPL 25–50 qd vs.

placebo

UACR (mg/mmol)

59 UACR−44% vs. +14% from baseline at 1 y (p= 0.002)

−13 vs−5 mL/min/1.73m2at 1y (p= 0.004)

5/29 vs. 1/30 Mehdi, Adams-Huet, Raskin,

Vega, and Toto (2009)

SPL 25 qd vs.

losartan 100 qd vs.

placebo

UACR (mg/g)

81 −34% at 1 y with SPL vs. placebo (95% CI−51% to−11%,p= 0.007)

No change from baseline with SPL vs. losartan vs. placebo (p= 0.80)

14/27 (SPL) vs. 2/27 (placebo) (p< 0.001)††

Kato et al. (2015) SPL 25 qd vs. no MRA

UACR (mg/g)

52 −33% from baseline with SPL (95%

CI−22 to−54)

−3.2 mL/min/1.73m2vs. control at 8 wks (p= 0.05)

NR At high risk for Diabetic Kidney Disease

Tofte et al. (2020) SPL 25 qd vs.

placebo

UACR (mg/g)

209 Progression to microalbuminuria:

25% vs. 33%; HR 0.81 (95% CI 0.49–1.34)

Progression to stage 3 CKD: 32%

vs. 14%; HR 2.88 (95% CI 1.56–5.30)

13% vs. 4%

Doses are shown in mg. Estimated glomerularfiltration (eGFR) values are shown in as mL/min/1.73m2. Chronic kidney disease (CKD) stage 3 was defined as an eGFR of 30–59 mL/min/

1.73 m2. Potassium (K+) values are shown in mmol/l. Hyperkalemia was defined as K+> 5.5 mmol/l, unless cited otherwise. The two treatment strategies are compared for their effect on proteinuria unless stated otherwise.

ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; CI, confidence interval; CKD, chronic kidney disease; EPL, Eplerenone; FNR, Finerenone; HR, hazard ratio; MRA, mineralocorticoid receptor antagonist; NR, not reported; SPL, Spironolactone; UACR, urine albumin to creatinine ratio; UPCR, urine protein to creatinine ratio; wks, weeks;

y, year.

# The study also included patients with non-diabetic kidney disease. Results for the ACEI vs. ACEI + SPL groups are shown.

$ Hyperkalemia was defined as K+> 5.0 mmol/l.

Results are for creatinine clearance (in ml/min).

The study tested seven different doses of FNR. In this Table, only the results with the 10 mg dose are shown.

†† Hyperkalemia was defined as K+> 6.0 mmol/l.

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studies with high heterogeneity). Spironolactone use was associated with a higher risk of hyperkalemia [relative risk (RR) 2.0, 95% CI 1.3–3.2]. There was no difference between the study groups in eGFR decline (mean difference−2.6 mL/min/1.73m2, 95% CI -5.7 to 0.5) or progression to ESRD (RR 3.0, 95% CI 0.3–27.7). In a more recent meta- analysis, MRAs were associated with a statistically significant drop in eGFR from baseline compared with placebo: mean difference of

−2.8 mL/min/1.73m2, 95% CI−4.0 to−1.7 (Alexandrou et al., 2019).

However, this eGFR change may represent an initial drop due to hemo- dynamic factors and a nephroprotective effect in the long run cannot be formally ruled out due to the short follow-up in most studies.

3.2. Registries

Blankenburg et al. conducted a retrospective cohort study using the PharMetrics Plus United States claims database from 2006 to 2015 (Blankenburg, Kovesdy, Fett, Griner, & Gay, 2020). Patients with type 2 diabetes and CKD treated with spironolactone (N= 5465) were matched 1:1 with non-users for selected baseline characteristics, in- cluding CKD stage and time interval from diagnosis of diabetes. Preva- lence of CKD stage 3, 4, and 5 was 39%, 7%, and 12%, respectively.

Spironolactone users had higher prevalence of CV disease, edema, and proteinuria at baseline. Use of ACEIs or ARBs was more common among spironolactone users (56% and 40%) versus non-users (52%

and 33%) (p< 0.001 for both medication classes). A total of 2630 pa- tients (48%) discontinued spironolactone within 6 months from initia- tion (non-persistent users). Compared with non-users, a larger proportion of spironolactone-treated patients experienced progression to a more advanced CKD stage at one year (18% versus 30%), acute kid- ney injury (34% versus 51%), and hyperkalemia (17% versus 30%). The authors attributed worse outcomes with spironolactone to higher co- morbidity burden among users compared with non-users.

Yang et al. studied the long-term effects of spironolactone in patients with or without diabetes and CKD (stage 3 or 4), using the Taiwan health insurance database (Yang, Kor, & Hsieh, 2018). They compared 693 spironolactone users with 1386 non-users. A lower incidence of ESRD was observed among spironolactone users (HR 0.66, 95% CI 0.51–0.84) but spironolactone was associated with higher risk of hospi- talization due to hyperkalemia (HR 3.17, 95% CI 2.41–4.17), compared with non-users (p < 0.001 for both outcomes). In a subgroup analysis among patients with moderate to severe CKD, the spironolactone bene- fit on ESRD progression was consistent across most patient subgroups (male sex, presence of hypertension, patients without diabetes, or not treated with an ACEI or ARB). There was no significant difference in CV events, hospitalization for CHF, and all-cause mortality between the two groups.

3.3. Ongoing trials

Two RCTs are currently ongoing withfinerenone and are both parts of a phase III program designed to assess the efficacy and safety of finerenone in patients with CKD and type 2 diabetes.

FIDELIO-DKD (NCT02540993) is a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial (Bakris et al., 2019). Patients with an eGFR of 25–75 ml/min/1.73m2and a UACR of 30–5000 mg/g have been enrolled. They are treated withfinerenone at the dose of 10 mg daily (or 20 mg in patients with an eGFR

≥60 ml/min/1.73 m2) or matching placebo. The study has randomized 5674 patients, of which 88.4% and 54.9% had an eGFR <60 or < 45 mL/min/1.73 m2, respectively, whereas 87.4% of them presented very high albuminuria (defined as a UACR≥300 mg/g). The primary out- come is a composite of time tofirst occurrence of kidney failure, sustained decrease of eGFR≥40% from baseline for at least 4 weeks, or renal death. Kidney failure is defined as either the occurrence of ESRD (defined as initiation of maintenance dialysis for at least 90 days or

kidney transplantation) or an eGFR <15 mL/min/1.73 m2for at least 4 weeks. Results are expected in 2020.

FIGARO-DKD (NCT02545049) is a randomized trial with similar de- sign with FIDELIO-DKD (Ruilope et al., 2019). Inclusion criteria and treatment groups are the same with FIDELIO-DKD. The primary out- come is a composite of CV death, nonfatal myocardial infarction, nonfa- tal stroke, or hospitalization for CHF. The study has randomized 7354 patients, with a median UACR of 312 mg/g. More than 60% have pre- served renal function (eGFR≥60 mL/min/1.73m2). Patients with HFrEF and NYHA stage II–IV have been excluded. Results are expected in 2021.

Secondary endpoints that are common in both trials include all- cause hospital admission, all-cause mortality, change in UACR from baseline at 4 months, and a composite endpoint of occurrence of kidney failure, sustained decrease in eGFR≥57% from baseline for at least 4 weeks, or renal death.

4. Use of potassium binders in association with MRAs in patients with CKD

The important adverse effects of MRAs, namely hyperkalemia, cur- rently limit their use in advanced CKD. However, new potassium binders, including patiromer and zirconium cyclosilicate, may be able to adequately control potassium levels and facilitate the use of MRA among these patients.

In the AMBER randomized trial, patients with resistant hyperten- sion, an eGFR between 25 and 45 ml/min/1.73m2, and serum potassium between 4.3 and 5.1 mmol/l were randomized to receive either patiromer (at the dose of 8.4 g daily) or placebo in addition to open label spironolactone (up to 50 mg daily) and their baseline anihypert- ensive agents (Agarwal et al., 2019). The primary efficacy endpoint was the difference between the two groups in the proportion of patients who remained on spironolactone by week 12. Patiromer enabled more patients to remain on spironolactone compared with placebo: 86% vs 66% (between group difference of 19.5%, 95% CI 10.0–29.0%, p< 0.001). Results were consistent in the subgroup of patients who also had heart failure at baseline (Rossignol, Fay, Girerd, & Zannad, 2020). Therefore, use of patiromer or other potassium binders may re- duce the risk of hyperkalemia among patients with advanced CKD who receive an MRA.

Other therapeutic strategies, such as point of care or home potas- sium monitoring, may increase safety of MRAs in patients with advanced CKD and merit further investigation (Rossignol et al., 2020).

5. MRAs in patients with kidney failure on maintenance dialysis 5.1. RCTs

Thefirst randomized trial with MRAs in patients on hemodialysis (HD) was a 6-month pilot study that enrolled 50 patients and examined safety of spironolactone at the dose of 25 mg daily (Matsumoto et al., 2009). There was no significant increase in potassium levels from baseline at 2 and 6 months, respectively (p< 0.05). The same group conducted thefirst open-label, randomized trial evaluating the inci- dence of CV and cerebrovascular events in patients with ESRD on main- tenance HD. A total of 309 patients were randomized to receive spironolactone 25 mg daily in addition to standard of care or standard of care alone and were followed-up for 3 years (Matsumoto et al., 2014). The composite outcome of death or hospitalization for CV or ce- rebrovascular events was observed in 5.7% of patients in the spironolactone group and 12.5% of patients in the control group (aHR 0.38, 95% CI 0.17–0.83;p= 0.02). The incidence of death from any cause was significantly lower in the spironolactone group (6.4%) com- pared with the control group (19.7%) (aHR 0.34, 95% CI 0.16–0.69;

p= 0.003). Gynecomastia or breast pain was reported in 16 patients treated with spironolactone (10.2%), while only three patients (1.9%)

C. Cosimato, T. Agoritsas and T.A. Mavrakanas Pharmacology & Therapeutics 219 (2021) 107701

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