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European Heart Journal Jan 2021This review covers the last 80 years of remarkable progress in the development of mineralocorticoid receptor (MR) antagonists (MRAs) from synthesis of the first... (Review)
Review
This review covers the last 80 years of remarkable progress in the development of mineralocorticoid receptor (MR) antagonists (MRAs) from synthesis of the first mineralocorticoid to trials of nonsteroidal MRAs. The MR is a nuclear receptor expressed in many tissues/cell types including the kidney, heart, immune cells, and fibroblasts. The MR directly affects target gene expression-primarily fluid, electrolyte and haemodynamic homeostasis, and also, but less appreciated, tissue remodelling. Pathophysiological overactivation of the MR leads to inflammation and fibrosis in cardiorenal disease. We discuss the mechanisms of action of nonsteroidal MRAs and how they differ from steroidal MRAs. Nonsteroidal MRAs have demonstrated important differences in their distribution, binding mode to the MR and subsequent gene expression. For example, the novel nonsteroidal MRA finerenone has a balanced distribution between the heart and kidney compared with spironolactone, which is preferentially concentrated in the kidneys. Compared with eplerenone, equinatriuretic doses of finerenone show more potent anti-inflammatory and anti-fibrotic effects on the kidney in rodent models. Overall, nonsteroidal MRAs appear to demonstrate a better benefit-risk ratio than steroidal MRAs, where risk is measured as the propensity for hyperkalaemia. Among patients with Type 2 diabetes, several Phase II studies of finerenone show promising results, supporting benefits on the heart and kidneys. Furthermore, finerenone significantly reduced the combined primary endpoint (chronic kidney disease progression, kidney failure, or kidney death) vs. placebo when added to the standard of care in a large Phase III trial.
Topics: Diabetes Mellitus, Type 2; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Spironolactone
PubMed: 33099609
DOI: 10.1093/eurheartj/ehaa736 -
British Journal of Pharmacology Jul 2022Mineralocorticoid receptor antagonists (MRAs) are key agents in guideline-oriented drug therapy for cardiovascular diseases such as chronic heart failure with reduced... (Review)
Review
Mineralocorticoid receptor antagonists (MRAs) are key agents in guideline-oriented drug therapy for cardiovascular diseases such as chronic heart failure with reduced ejection fraction and resistant hypertension. Currently available steroidal MRAs are efficacious in reducing morbidity and mortality; however, they can be associated with intolerable side effects including hyperkalaemia in everyday clinical practice. Recently, a new class of non-steroidal MRAs (including esaxerenone, AZD9977, apararenone, KBP-5074 and finerenone) have been developed with an improved benefit-risk profile and a novel indication for finerenone for diabetic kidney disease. To better understand the non-steroidal MRAs, this review provides information on the molecular pharmacology as well as relevant current preclinical and clinical data on cardiorenal outcomes. A comparative review of all compounds in the class is discussed with regard to clinical efficacy and safety as well as a perspective outlining their future use in clinical practice. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc.
Topics: Heart Failure; Humans; Hypertension, Renal; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Nephritis; Piperidines; Pyrazoles; Quinolines
PubMed: 34811750
DOI: 10.1111/bph.15747 -
American Journal of Kidney Diseases :... Nov 2022Mineralocorticoid receptor (MR) activation is involved in propagating kidney injury, inflammation, and fibrosis and in the progression of chronic kidney disease (CKD).... (Review)
Review
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.
Topics: Humans; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Aldosterone; Diabetes Mellitus, Type 2; Hyperkalemia; Mineralocorticoids; Renal Insufficiency, Chronic; Fibrosis; Inflammation
PubMed: 36057467
DOI: 10.1053/j.ajkd.2022.04.016 -
Steroids Feb 2000The physiology of mineralocorticoid action, particularly with respect to epithelial sodium transport, is well defined. A full understanding of the molecular basis of... (Review)
Review
The physiology of mineralocorticoid action, particularly with respect to epithelial sodium transport, is well defined. A full understanding of the molecular basis of mineralocorticoid action has however proven to be more elusive. In the last decade insights into structural and functional aspects of the mineralocorticoid receptor combined with emerging details of the components of the mediators of the sodium flux has resulted in a clearer picture. This review focuses on two aspects of these new developments; the mineralocorticoid receptor and putative aldosterone induced proteins.
Topics: Aldosterone; Animals; Humans; Ion Transport; Mineralocorticoids; Potassium; Receptors, Mineralocorticoid; Sodium
PubMed: 10639017
DOI: 10.1016/s0039-128x(99)00087-2 -
Anesthesiology Aug 2020The recent demonstration of the significant reduction in mortality in patients with septic shock treated with adjunctive glucocorticoids combined with fludrocortisone... (Review)
Review
The recent demonstration of the significant reduction in mortality in patients with septic shock treated with adjunctive glucocorticoids combined with fludrocortisone and the effectiveness of angiotensin II in treating vasodilatory shock have renewed interest in the role of the mineralocorticoid axis in critical illness. Glucocorticoids have variable interactions at the mineralocorticoid receptor. Similarly, mineralocorticoid receptor-aldosterone interactions differ from mineralocorticoid receptor-glucocorticoid interactions and predicate receptor-ligand interactions that differ with respect to cellular effects. Hyperreninemic hypoaldosteronism or selective hypoaldosteronism, an impaired adrenal response to increasing renin levels, occurs in a subgroup of hemodynamically unstable critically ill patients. The suggestion is that there is a defect at the level of the adrenal zona glomerulosa associated with a high mortality rate that may represent an adaptive response aimed at increasing cortisol levels. Furthermore, cross-talk exists between angiotensin II and aldosterone, which needs to be considered when employing therapeutic strategies.
Topics: Aldosterone; Clinical Trials as Topic; Critical Illness; Glucocorticoids; Humans; Hypoaldosteronism; Mineralocorticoids
PubMed: 32501957
DOI: 10.1097/ALN.0000000000003365 -
Endocrinology Apr 2022
Topics: Aldosterone; Glucocorticoids; Mineralocorticoids; Receptors, Mineralocorticoid
PubMed: 35148380
DOI: 10.1210/endocr/bqac016 -
Lancet (London, England) Apr 1999Hypertension with hypokalaemia and suppression of plasma renin activity is known as mineralocorticoid hypertension. Although mineralocorticoid hypertension accounts for... (Review)
Review
Hypertension with hypokalaemia and suppression of plasma renin activity is known as mineralocorticoid hypertension. Although mineralocorticoid hypertension accounts for a small number of patients labelled as having "essential" hypertension, it is a potentially reversible cause of high blood pressure. The most common cause of mineralocorticoid hypertension is probably primary aldosteronism; controlled posture studies to measure plasma renin activity and aldosterone concentrations, followed by adrenal imaging, will ensure the differential diagnosis between an aldosterone-producing adenoma and idiopathic adrenal hyperplasia in most cases. Three monogenic forms of mineralocorticoid hypertension have been described: glucocorticoid-suppressible hyperaldosteronism, Liddle's syndrome, and apparent mineralocorticoid excess, which have provided new insights into mineralocorticoid hormone action. Many patients with mineralocorticoid-based hypertension are now known to have normal serum potassium concentrations. Until the true prevalence of primary aldosteronism and monogenic forms of mineralocorticoid hypertension are defined, a high index of suspicion is needed in every hypertensive patient. Hypertensive patients with hypokalaemia, together with those with severe hypertension or a family history of hypertension or stroke, should be screened for mineralocorticoid excess.
Topics: Algorithms; Humans; Hyperaldosteronism; Hypertension; Hypokalemia; Mineralocorticoids; Prevalence
PubMed: 10218547
DOI: 10.1016/S0140-6736(98)06102-9 -
The Journal of Clinical Endocrinology... Apr 1996
Review
Topics: 11-beta-Hydroxysteroid Dehydrogenases; Addison Disease; Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Aldosterone; Animals; Child; Humans; Hydrocortisone; Hydroxysteroid Dehydrogenases; Mineralocorticoids
PubMed: 8636321
DOI: 10.1210/jcem.81.4.8636321 -
Seminars in Nephrology Nov 2006Mineralocorticoid hypertension is hypertension associated with the presence of hypokalemia, metabolic alkalosis, and suppression of plasma renin. Mineralocorticoid... (Review)
Review
Mineralocorticoid hypertension is hypertension associated with the presence of hypokalemia, metabolic alkalosis, and suppression of plasma renin. Mineralocorticoid hypertension represents only 10% of patients with essential hypertension. However, its recognition is important because it is a potentially reversible cause of hypertension. Primary hyperaldosteronism is the most common form of mineralocorticoid hypertension. It is current clinical practice to use the plasma aldosterone-renin ratio and the absolute plasma aldosterone level as screening tests. Confirmatory suppression tests and adrenal imaging are performed in appropriate patients. Three monogenic forms of mineralocorticoid hypertension have been identified including Liddle's syndrome, glucocorticoid-remediable hypertension, and apparent mineralocorticoid excess. In a number of patients with mineralocorticoid hypertension, hypokalemia can be a variable finding. This review highlights mineralocorticoid biology and important features of primary hyperaldosteronism and monogenic hypertension.
Topics: Alkalosis; Blood Pressure; Diagnosis, Differential; Humans; Hypertension; Hypokalemia; Mineralocorticoids; Prognosis
PubMed: 17275580
DOI: 10.1016/j.semnephrol.2006.10.004 -
Diabetologia Feb 2024The overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes related to multiple physiological systems, including the heart,... (Review)
Review
The overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes related to multiple physiological systems, including the heart, vasculature, adipose tissue and kidneys. The inhibition of the MR with classical MR antagonists (MRA) has successfully improved outcomes most evidently in heart failure. However, real and perceived risk of side effects and limited tolerability associated with classical MRA have represented barriers to implementing MRA in settings where they have been already proven efficacious (heart failure with reduced ejection fraction) and studying their potential role in settings where they might be beneficial but where risk of safety events is perceived to be higher (renal disease). Novel non-steroidal MRA have distinct properties that might translate into favourable clinical effects and better safety profiles as compared with MRA currently used in clinical practice. Randomised trials have shown benefits of non-steroidal MRA in a range of clinical contexts, including diabetic kidney disease, hypertension and heart failure. This review provides an overview of the literature on the systemic impact of MR overactivation across organ systems. Moreover, we summarise the evidence from preclinical studies and clinical trials that have set the stage for a potential new paradigm of MR antagonism.
Topics: Humans; Diabetic Nephropathies; Heart Failure; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Naphthyridines; Receptors, Mineralocorticoid
PubMed: 38127122
DOI: 10.1007/s00125-023-06031-1