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Novelties in Therapy of Chronic Heart Failure.
Doimo, S, Pavan, D
Heart failure clinics. 2021;(2):255-262
Abstract
In recent decades, considerable advances have been made in the treatment of heart failure. The main target of heart failure therapy is the inhibition of the sympathetic nervous system and renin-angiotensin-aldosterone system. The angiotensin receptor blockers represent a breakthrough in the treatment of heart failure with a demonstrated effect on reduction of cardiovascular events. However, new perspectives derive from latest drugs developed for diabetes, iron deficiency, and hyperkalemia. New frontiers are also opened to the development of neurohormonal therapies, antagonists of inflammatory mediators, inotropic agents, and cell-based treatments.
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Cardiovascular Protection With Sodium-Glucose Cotransporter-2 Inhibitors and Mineralocorticoid Receptor Antagonists in Chronic Kidney Disease: A Milestone Achieved.
Sarafidis, P, Papadopoulos, CE, Kamperidis, V, Giannakoulas, G, Doumas, M
Hypertension (Dallas, Tex. : 1979). 2021;(5):1442-1455
Abstract
Chronic kidney disease (CKD) and cardiovascular disease are intimately linked. They share major risk factors, including age, hypertension, and diabetes, and common pathogenetic mechanisms. Furthermore, reduced renal function and kidney injury documented with albuminuria are independent risk factors for cardiovascular events and mortality. In major renal outcome trials and subsequent meta-analyses in patients with CKD, ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin II receptor blockers) were shown to effectively retard CKD progression but not to significantly reduce cardiovascular events or mortality. Thus, a high residual risk for cardiovascular disease progression under standard-of-care treatment is still present for patients with CKD. In contrast to the above, several outcome trials with SGLT-2 (sodium-glucose cotransporter-2) inhibitors and MRAs (mineralocorticoid receptor antagonists) clearly suggest that these agents, apart from nephroprotection, offer important cardioprotection in this population. This article discusses existing evidence on the effects of SGLT-2 inhibitors and MRAs on cardiovascular outcomes in patients with CKD that open new roads in cardiovascular protection of this heavily burdened population.
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Hyperkalemia with RAAS inhibition: Mechanism, clinical significance, and management.
Hundemer, GL, Sood, MM
Pharmacological research. 2021;:105835
Abstract
Renin-angiotensin-aldosterone system (RAAS) inhibitors are evidence-based treatments for a number of conditions including hypertension, diabetes mellitus, chronic kidney disease, and congestive heart failure. Among the most common adverse effects of RAAS inhibitors is hyperkalemia which results from either reduced secretion of aldosterone or increased resistance to aldosterone. Many of the conditions for which RAAS inhibitors are recommended further amplify the risk for hyperkalemia in and of themselves. RAAS inhibitor-related hyperkalemia is associated with an increased risk for cardiovascular events, hospitalizations, and death. Yet discontinuation of RAAS inhibitors for patients with chronic kidney disease and congestive heart failure is also associated with an increased risk for cardiovascular events, hospitalizations, and death. Therefore, clinicians are often left to struggle with the dilemma of the best management approach to RAAS inhibitor-related hyperkalemia. The ideal solution involves pharmacotherapies that are safe and effective in mitigating hyperkalemia and allow patients to continue to receive the beneficial effects from RAAS inhibitors. In this regard, modern pharmacologic agents such as patiromer and zirconium cyclosilicate are providing a mechanism whereby physicians are better equipped to maintain their patients on RAAS inhibitors.
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Prevention and management of hyperkalemia in patients treated with renin-angiotensin-aldosterone system inhibitors.
Weinstein, J, Girard, LP, Lepage, S, McKelvie, RS, Tennankore, K
CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2021;(48):E1836-E1841
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Mineralcorticoid receptor blockers in chronic kidney disease.
Erraez, S, López-Mesa, M, Gómez-Fernández, P
Nefrologia. 2021;(3):258-275
Abstract
There are many experimental data supporting the involvement of aldosterone and mineralcorticoid receptor (MR) activation in the genesis and progression of chronic kidney disease (CKD) and cardiovascular damage. Many studies have shown that in diabetic and non-diabetic CKD, blocking the renin- angiotensin-aldosterone (RAAS) system with conversion enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs) decreases proteinuria, progression of CKD and mortality, but there is still a significant residual risk of developing these events. In subjects treated with ACEi or ARBs there may be an aldosterone breakthrough whose prevalence in subjects with CKD can reach 50%. Several studies have shown that in CKD, the aldosterone antagonists (spironolactone, eplerenone) added to ACEi or ARBs, reduce proteinuria, but increase the risk of hyperkalemia. Other studies in subjects treated with dialysis suggest a possible beneficial effect of antialdosteronic drugs on CV events and mortality. Newer potassium binders drugs can prevent / decrease hyperkalemia induced by RAAS blockade, and may reduce the high discontinuation rates or dose reduction of RAAS-blockers. The nonsteroidal MR blockers, with more potency and selectivity than the classic ones, reduce proteinuria and have a lower risk of hyperkalemia. Several clinical trials, currently underway, will determine the effect of classic MR blockers on CV events and mortality in subjects with stage 3b CKD and in dialysis patients, and whether in patients with type 2 diabetes mellitus and CKD, optimally treated and with high risk of CV and kidney events, the addition of finerenone to their treatment produces cardiorenal benefits. Large randomized trials have shown that sodium glucose type 2 cotransporter inhibitors (SGLT2i) reduce mortality and the development and progression of diabetic and nondiabetic CKD. There are pathophysiological arguments, which raise the possibility that the triple combination ACEi or ARBs, SGLT2i and aldosterone antagonist provide additional renal and cardiovascular protection.
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Mineralocorticoid receptor antagonists in heart failure patients with chronic kidney disease: why, when, and how?
Kassem, H, Chatila, K
Current opinion in nephrology and hypertension. 2020;(2):258-263
Abstract
PURPOSE OF REVIEW Congestive heart failure (CHF) and chronic kidney disease (CKD) often coexist. However, and despite their established benefits, the use of mineralcorticoid receptor antagonists (MRAs) in patients with both comorbidities is inconsistent. This review will focus on the role of aldosterone in CHF, as well as timing, selection, and management of MRAs in CHF patients with CKD. RECENT FINDINGS Aldosterone in CHF patients contributes to worsening sodium retention, hypokalemia, metabolic alkalosis, cardiac fibrosis, and CKD progression. MRAs are beneficial in CHF patients with CKD despite the adverse events of hyperkalemia and acute kidney injury. MRAs were previously studied in patients with CKD stage III but were recently found to be safe in end-stage kidney disease (ESKD) patients. New nonsteroidal MRAs are more selective for the mineralocorticoid receptor and have a better side effect profile. The use of potassium lowering agents, such as patriomer, helps maintain normokalemia in patients with CKD who are treated with MRAs. SUMMARY It is recommended to use MRAs in CHF patients with normal potassium levels and a glomerular filtration rate of more than 30 ml/min. Their use is also safe in ESKD patients. In nondialysis advanced CKD patients, they may need to be combined to medications such as patiromer. New nonsteroidal MRAs are currently being studied.
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New mineralocorticoid receptor antagonists: update on their use in chronic kidney disease and heart failure.
Capelli, I, Gasperoni, L, Ruggeri, M, Donati, G, Baraldi, O, Sorrenti, G, Caletti, MT, Aiello, V, Cianciolo, G, La Manna, G
Journal of nephrology. 2020;(1):37-48
Abstract
Aldosterone is a mineralocorticoid hormone with a well-known effect on the renal tubule leading to water retention and potassium reabsorption. Other major effects of the hormone include the induction of proinflammatory activity that leads to progressive fibrotic damage of the target organs, heart and kidney. Blocking the aldosterone receptor therefore represents an important pharmacological strategy to avoid the clinical conditions deriving from heart failure (CHF) and chronic kidney disease (CKD). However, steroidal mineralocorticoid receptor antagonists (MRA) have a low safety profile, especially in CKD patients due to the high incidence of hyperkalemia. A new generation of nonsteroidal MRA has recently been developed to obtain a selective receptor block avoiding side-effects like hyperkalemia and thereby making the drugs suitable for administration to CKD patients. This review summarizes the results of published preclinical and clinical studies on the nonsteroidal MRA, apararenone esaxerenone and finerenone. The trials showed a better safety profile with maintained drug efficacy compared with steroidal MRA. For this reason, nonsteroidal MRA represent an interesting new therapeutic approach for the prevention of CHF and CKD progression. Some basic research findings also yielded interesting results in acute clinical settings such as myocardial infarction and acute kidney injury.
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The New Biology of Diabetic Kidney Disease-Mechanisms and Therapeutic Implications.
Lytvyn, Y, Bjornstad, P, van Raalte, DH, Heerspink, HL, Cherney, DZI
Endocrine reviews. 2020;(2):202-31
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Abstract
Diabetic kidney disease remains the most common cause of end-stage kidney disease in the world. Despite reductions in incidence rates of myocardial infarction and stroke in people with diabetes over the past 3 decades, the risk of diabetic kidney disease has remained unchanged, and may even be increasing in younger individuals afflicted with this disease. Accordingly, changes in public health policy have to be implemented to address the root causes of diabetic kidney disease, including the rise of obesity and diabetes, in addition to the use of safe and effective pharmacological agents to prevent cardiorenal complications in people with diabetes. The aim of this article is to review the mechanisms of pathogenesis and therapies that are either in clinical practice or that are emerging in clinical development programs for potential use to treat diabetic kidney disease.
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[Antifibrotic renal role of mineralcorticoid receptor antagonists].
Ocello, A, La Rosa, S, Fiorini, F, Randone, S, Maccarrone, R, Battaglia, G, Granata, A
Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia. 2019;(4)
Abstract
Cardiovascular and renal diseases are one of the main health problems in all industrialized countries. Their incidence is constantly increasing due to the aging of the population and the greater prevalence of obesity and type 2 diabetes. Clinical evidence suggests that aldosterone and the activation of mineralocorticoid receptors (MR) have a role in the pathophysiology of cardiovascular and renal diseases. Moreover, clinical studies demonstrate the benefits of mineralocorticoid receptor antagonists (MRAs) on mortality and progression of heart and kidney disease. In addition to renal effects on body fluid homeostasis, aldosterone has multiple extrarenal effects including the induction of inflammation, vascular rigidity, collagen formation and stimulation of fibrosis. Given the fundamental role of MR activation in renal and cardiac fibrosis, effective and selective blocking of the signal with MRAs can be used in the clinical practice to prevent or slow down the progression of heart and kidney diseases. The aim of the present work is to review the role of MRAs in light of the new evidence as well as its potential use as an antifibrotic in chronic kidney disease (CKD). The initial clinical results suggest that MRAs are potentially useful in treating patients with chronic kidney disease, particularly in cases of diabetic nephropathy. We don't yet have efficacy and safety data on the progression of kidney disease up to the end stage (ESRD) and filling this gap represents an important target for future trials.
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Optimally managing hyperkalemia in patients with cardiorenal syndrome.
Wang, AY
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2019;(Suppl 3):iii36-iii44
Abstract
Renin-angiotensin-aldosterone system inhibitors (RAASi) are now a standard treatment in most patients with cardiovascular disease, especially in those with heart failure (HF). The European Society of Cardiology and the American College of Cardiology/American Heart Association gave a Class IA recommendation for the use of RAASi in the treatment of Classes II-IV symptomatic HF with reduced ejection fraction (HFREF), based on their strong clinical benefits of lowering all-cause mortality and HF hospitalizations in these subjects. However, RAASi therapy or adding mineralocorticoid receptor antagonists in subjects receiving background angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be associated with an increased risk of hyperkalemia (HK), especially in those with reduced kidney function. As a result, a significant proportion of these subjects either have RAASi dose reduced or more often discontinued when they develop HK. Discontinuation of RAASi in patients hospitalized with HFREF was associated with higher postdischarge mortality and rehospitalization rates, while optimal dosing of RAASi significantly reduced median hospital stays, outpatient visits and related costs. Thus, effective treatment is required to lower potassium level and maintain normokalemia in subjects with HF and reduced kidney disease who develop or are at risk of HK, thus enabling them to continue their RAASi therapy and maximize benefits from RAASi. In this review, we provide an up-to-date review of the prevalence and significance of HK in patients with cardiorenal syndrome, as well as their optimal management of HK with recent novel therapies.