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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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Apararenone in patients with diabetic nephropathy: results of a randomized, double-blind, placebo-controlled phase 2 dose-response study and open-label extension study.
Wada, T, Inagaki, M, Yoshinari, T, Terata, R, Totsuka, N, Gotou, M, Hashimoto, G
Clinical and experimental nephrology. 2021;(2):120-130
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Abstract
BACKGROUND We investigated the efficacy and safety of apararenone (MT-3995), a non-steroidal compound with mineralocorticoid receptor agonist activity, in patients with stage 2 diabetic nephropathy (DN). METHODS The study had two parts: a dose-response, parallel-group, randomized, double-blind, placebo-controlled, multicenter, phase 2, 24-week study and an open-label, uncontrolled, 28-week extension study. Primary and secondary endpoints were the 24-week percent change from baseline in urine albumin to creatine ratio (UACR) and 24- and 52-week UACR remission rates. Safety parameters were changes from baseline in estimated glomerular filtration rate (eGFR) and serum potassium at 24 and 52 weeks, and incidences of adverse events (AEs) and adverse drug reactions (ADRs). RESULTS In the dose-response period, 73 patients received placebo and 73, 74, and 73 received apararenone 2.5 mg, 5 mg, and 10 mg, respectively. As a percentage of baseline, mean UACR decreased to 62.9%, 50.8%, and 46.5% in the 2.5 mg, 5 mg, and 10 mg apararenone groups, respectively, at week 24 (placebo: 113.7% at week 24; all P < 0.001 vs placebo). UACR remission rates at week 24 were 0.0%, 7.8%, 29.0%, and 28.1% in the placebo and apararenone 2.5 mg, 5 mg, and 10 mg groups, respectively. eGFR tended to decrease and serum potassium tended to increase, but these events were not clinically significant. AE incidence increased with dose while ADR incidence did not. CONCLUSION The UACR-lowering effect of apararenone administered once daily for 24 weeks in patients with stage 2 DN was confirmed, and the 52-week administration was safe and tolerable. CLINICAL TRIAL REGISTRATION NCT02517320 (dose-response study) and NCT02676401 (extension study).
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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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Age-stratified comparison of clinical outcomes between medical and surgical treatments in patients with unilateral primary aldosteronism.
Nakamaru, R, Yamamoto, K, Akasaka, H, Rakugi, H, Kurihara, I, Yoneda, T, Ichijo, T, Katabami, T, Tsuiki, M, Wada, N, et al
Scientific reports. 2021;(1):6925
Abstract
Although adrenalectomy (ADX) is an established treatment for unilateral primary aldosteronism (uPA), the influence of age on the surgical outcomes is poorly understood. Therefore, we aimed to elucidate how age affects the clinical outcomes after treatments. We analyzed 153 older (≥ 65 years) and 702 younger patients (< 65 years) with uPA, treated either with ADX or mineralocorticoid receptor antagonist (MRA) in the Japan PA Study, and compared the estimated glomerular filtration rate (eGFR) or blood pressure over a 36-month period after treatments. ADX-treated patients showed severer biochemical indicators than MRA-treated patients. During 6 and 36 months, the eGFR decreased more prominently in older but not in younger patients with ADX than in those with MRA, which remained significant after adjustment with the inverse probability of treatment weighting (IPTW). There was a significant interaction between the age-groups and the treatment choices in the change of the eGFR with IPTW-adjusted analysis. The post-treatment dose of antihypertensive medication was lower in younger and higher in older patients with ADX than those with MRA. The clinical benefit of ADX differed between younger and older patients with uPA. These findings indicate the need for further validation on whether ADX can benefit older patients with uPA.
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Chronic kidney disease progression in patients with resistant hypertension subject to 2 therapeutic strategies: Intensification with loop diuretics vs aldosterone antagonists.
Verdalles, U, Goicoechea, M, García de Vinuesa, S, Torres, E, Hernández, A, Verde, E, Pérez de José, A, Luño, J
Nefrologia. 2020;(1):65-73
Abstract
INTRODUCTION Actualy, there are few data about glomerular filtration rate (eGFR) drop in patients with resistant hypertension and how diferent therapies can modify chronic kidney disease progression (CKD). OBJECTIVE To evaluate CKD progression in patients with resistant hypertension undergoing 2diferent therapies: treatment with spironolactone or furosemide. METHODS We included 30 patients (21M, 9W) with a mean age of 66.3±9.1 years, eGFR 55.8±16.5ml/min/1.73 m2, SBP 162.8±8.2 and DBP 90.2±6.2mmHg: 15 patients received spironolactone and 15 furosemide and we followed up them a median of 32 months (28-41). RESULTS The mean annual eGFR decrease was -2.8±5.4ml/min/1.73 m2. In spironolactone group was -2.1±4.8ml/min/1.73 m2 and in furosemide group was -3.2±5.6ml/min/1.73 m2, P<0.01. In patients received spironolactone, SBP decreased 23±9mmHg and in furosemide group decreased 16±3mmHg, P<.01. DBP decreased 10±8mmHg and 6±2mmHg, respectively (P<.01). Treatment with spironolactone reduced albuminuria from a serum albumin/creatine ratio of 210 (121-385) mg/g to 65 (45-120) mg/g at the end of follow-up, P<.01. There were no significant changes in the albumin/creatinine ratio in the furosemide group. The slower drop in kidney function was associated with lower SBP (P=.04), higher GFR (P=.01), lower albuminuria (P=.01), not diabetes mellitus (P=.01) and treatment with spironolactone (P=.02). Treatment with spironolactone (OR 2.13, IC 1.89-2.29) and lower albuminuria (OR 0.98, CI 0.97-0.99) maintain their independent predictive power in a multivariate model. CONCLUSION Treatment with spironolactone is more effective reducing BP and albuminuria in patients with resistant hypertension compared with furosemide and it is associated with a slower progression of CKD in the long term follow up.
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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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Spironolactone Use and Improved Outcomes in Patients With Heart Failure With Preserved Ejection Fraction With Resistant Hypertension.
Tsujimoto, T, Kajio, H
Journal of the American Heart Association. 2020;(23):e018827
Abstract
Background Resistant hypertension is a salt-retaining condition possibly attributable to inappropriate aldosterone secretion. Methods and Results This study was a secondary analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial. Patients with heart failure with preserved ejection fraction (HFpEF) with (n=1004) and without (n=2437) resistant hypertension were included. Resistant hypertension was defined as systolic blood pressure ≥130 mm Hg and/or diastolic blood pressure ≥80 mm Hg in a patient with hypertension, despite the concurrent use of a renin-angiotensin system blocker (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker), a calcium channel blocker, and a diuretic; or as those patients using ≥4 classes of antihypertensive medication. The primary outcome was a composite of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization. We analyzed hazard ratios (HRs) for outcomes with 95% CIs in the spironolactone group and compared them with the placebo group using Cox proportional hazard models. The risk of primary outcome events in patients with HFpEF with resistant hypertension was significantly lower in the spironolactone group than in the placebo group (HR, 0.70; 95% CI, 0.53-0.91; P=0.009), whereas the risk of primary outcome events in patients with HFpEF without resistant hypertension was not significantly different between the 2 groups (HR, 1.00; 95% CI, 0.83-1.20; P=0.97). There was a significant interaction between spironolactone use and resistant hypertension (P=0.03). Similar associations were also observed in patients with HFpEF from the Americas (United States, Canada, Brazil, and Argentina) only. Conclusions Spironolactone may be an effective add-on medication for patients with HFpEF with resistant hypertension taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, calcium channel blockers, and diuretics.