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1.
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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2.
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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3.
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.
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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.
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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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8.
Initiation, Continuation, Switching, and Withdrawal of Heart Failure Medical Therapies During Hospitalization.
Bhagat, AA, Greene, SJ, Vaduganathan, M, Fonarow, GC, Butler, J
JACC. Heart failure. 2019;(1):1-12
Abstract
Patients with worsening heart failure with reduced ejection fraction (HFrEF) spend a large proportion of time in the hospital and other health care facilities. The benefits of guideline-directed medical therapy (GDMT) in the outpatient setting have been shown in large randomized controlled trials. However, the decision to initiate, continue, switch, or withdraw HFrEF medications in the inpatient setting is often based on multiple factors and subject to significant variability across providers. Based on available data, in well-selected, treatment-naïve patients who are hemodynamically stable and clinically euvolemic after stabilization during hospitalization for HF, elements of GDMT can be safely initiated. Inpatient continuation of GDMT for HFrEF appears safe and well-tolerated in most hemodynamically stable patients. Hospitalization is also a potential time for switching from an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker to sacubitril/valsartan therapy in eligible patients, and is the subject of ongoing study. Therapy withdrawal or need for dose reduction is rarely required, but if needed identifies a particularly at-risk group of patients with progressive HF. If recurrent intolerance to neurohormonal blockers is observed, these patients should be evaluated for advanced HF therapies. There is an enduring need for using the teachable moment of HFrEF hospitalization for optimal initiation, continuation, and switching of GDMT to improve post-discharge patient outcomes and the quality of chronic HFrEF care.
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9.
Change in renal function associated with drug treatment in heart failure: national guidance.
Clark, AL, Kalra, PR, Petrie, MC, Mark, PB, Tomlinson, LA, Tomson, CR
Heart (British Cardiac Society). 2019;(12):904-910
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Abstract
Inhibitors of the renin-angiotensin-aldosterone (RAAS) system are cornerstones of the management of patients with heart failure with reduced left ventricular ejection fraction (HFrEF). However, RAAS inhibitors may cause decline in renal function and/or hyperkalaemia, particularly during initiation and titration, intercurrent illness and during worsening of heart failure. There is very little evidence from clinical trials to guide the management of renal dysfunction. The Renal Association and British Society for Heart Failure have collaborated to describe the interactions between heart failure, RAAS inhibitors and renal dysfunction and give clear guidance on the use of RAAS inhibitors in patients with HFrEF. During initiation and titration of RAAS inhibitors, testing renal function is mandatory; a decline in renal function of 30% or more can be acceptable. During intercurrent illness, there is no evidence that stopping RAAS inhibitor is beneficial, but if potassium rises above 6.0 mmol/L, or creatinine rises more than 30%, RAAS inhibitors should be temporarily withheld. In patients with fluid retention, high doses of diuretic are needed and a decline in renal function is not an indication to reduce diuretic dose: if the patient remains congested, more diuretics are required. If a patient is hypovolaemic, diuretics should be stopped or withheld temporarily. Towards end of life, consider stopping RAAS inhibitors. RAAS inhibition has no known prognostic benefit in heart failure with preserved ejection fraction. Efforts should be made to initiate, titrate and maintain patients with HFrEF on RAAS inhibitor treatment, whether during intercurrent illness or worsening heart failure.
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The Mechanisms of Actions of Aldosterone and its Antagonists in Cardiovascular Disease.
Pantelidis, P, Sideris, M, Viigimaa, M, Avranas, K, Deligkaris, P, Zografou, I, Lovic, D
Current pharmaceutical design. 2018;(46):5491-5499
Abstract
BACKGROUND Aldosterone, through its actions on Mineralcorticosteroid Receptors (MR), controls fluid and electrolyte balance, but also exerts various direct deleterious actions on the vasculature. A number of aldosterone antagonists have been manufactured to reverse these effects. OBJECTIVE A comprehensive review of the underlying mechanisms of the actions of aldosterone and its antagonists in cardiovascular disease. METHOD The relevant studies indexed in PubMed, Scopus and Google Scholar databases, published from 2003 to May 2018 were identified and reported. RESULTS Aldosterone binds to MR, activating them as intracellular transcription factors. Moreover, aldosterone, through its actions on MR, as well as on another not fully explored class of receptors, triggers several signaling pathways that produce rapid, non-genomic actions. In the vasculature, all these changes favor the establishment of inflammation and cardiovascular dysfunction, which, in turn, lead to or exacerbate various cardiovascular diseases. Mineralcorticosteroid Antagonists (MRA) are compounds that antagonize the action of aldosterone on MR. Spironolactone was the first steroidal MRA to be commercially used. It showed beneficial clinical results, but also a number of adverse effects. The next generation of steroidal MRA, exhibited lower potency but did not induce many of these adverse reactions, due to their high selectivity for MR. The third generation of MRA compromises the newly introduced non-steroidal MRA, which have a completely different chemical structure, they induce different and more drastic changes to MR, they are much more specific and currently under clinical trials. CONCLUSION New MRA, which block the aldosterone induced pathways in the vasculature, hold promising results for the treatment of cardiovascular disease.