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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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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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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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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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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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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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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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New pharmacological strategies for protecting kidney function in type 2 diabetes.
Muskiet, MHA, Wheeler, DC, Heerspink, HJL
The lancet. Diabetes & endocrinology. 2019;(5):397-412
Abstract
Type 2 diabetes is the leading cause of impaired kidney function, albuminuria, and renal replacement therapy globally, thus placing a large burden on health-care systems. Current treatment strategies rely on intensive glucose lowering as well as strict blood pressure control through blockade of the renin-angiotensin-aldosterone system. Such approaches might slow decline in kidney function, but many patients progress to end-stage kidney failure despite optimal therapy. In recent clinical trials, new-generation glucose-lowering drug classes, the sodium-glucose co-transporter-2 inhibitors and agents that target the incretin pathway, have been shown to improve kidney outcomes in patients with type 2 diabetes. Other new approaches, which have been developed on the basis of an improved understanding of the mechanisms that contribute to kidney damage in the context of diabetes, include use of drugs that block endothelin receptors (eg, atrasentan) and non-steroidal mineralocorticoid receptors (eg, finerenone). In this Review, we provide an overview of recent clinical data relevant to these new therapeutic approaches for management of kidney disease in the context of type 2 diabetes.
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Potassium-lowering agents for the treatment of nonemergent hyperkalemia: pharmacology, dosing and comparative efficacy.
Bridgeman, MB, Shah, M, Foote, E
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2019;(Suppl 3):iii45-iii50
Abstract
Hyperkalemia represents a common and potentially life-threating electrolyte abnormality, a complication frequently observed in patients with heart failure, kidney disease, diabetes or in those receiving drug therapies influencing the renin-angiotensin-aldosterone system. Elevated serum potassium levels are often the result of impaired urinary potassium elimination, inadequate or reduced cellular potassium uptake, severe heart failure, use of medications influencing potassium levels in the circulation, or, more commonly, a combination of these factors. Strategies for the treatment of nonemergent hyperkalemia include the use of cation-exchange resins, polymers or other novel mechanisms of potassium trapping, including sodium polystyrene sulfonate, patiromer and sodium zirconium cyclosilicate. These agents differ in their pharmacology and mechanism of action, clinical efficacy, including onset and extent of potassium-lowering effect, dosage and administration, and potential safety and adverse effect profiles. In this review, an evaluation of these characteristics, including clinical evidence and safety concerns, in the management of nonemergent hyperkalemia will be explored.