mineralocorticoid receptor antagonist
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Author(s):  
Tatsufumi Oka ◽  
Yusuke Sakaguchi ◽  
Koki Hattori ◽  
Yuta Asahina ◽  
Sachio Kajimoto ◽  
...  

Background: Real-world evidence about mineralocorticoid receptor antagonist (MRA) use has been limited in chronic kidney disease, particularly regarding its association with hard renal outcomes. Methods: In this retrospective cohort study, adult chronic kidney disease outpatients referred to the department of nephrology at an academic hospital between January 2005 and December 2018 were analyzed. The main inclusion criteria were estimated glomerular filtration rate ≥10 and <60 mL/min per 1.73 m 2 and follow-up ≥90 days. The exposure of interest was MRA use, defined as the administration of spironolactone, eplerenone, or potassium canrenoate. The primary outcome was renal replacement therapy initiation, defined as the initiation of chronic hemodialysis, peritoneal dialysis, or kidney transplantation. A marginal structural model using inverse probability of weighting was applied to account for potential time-varying confounders. Results: Among a total of 3195 patients, the median age and estimated glomerular filtration rate at baseline were 66 years and 38.4 mL/min per 1.73 m 2 , respectively. During follow-up (median, 5.9 years), 770 patients received MRAs, 211 died, and 478 started renal replacement therapy. In an inverse probability of weighting-weighted pooled logistic regression model, MRA use was significantly associated with a 28%-lower rate of renal replacement therapy initiation (hazard ratio, 0.72 [95% CI, 0.53–0.98]). The association between MRA use and renal replacement therapy initiation was dose-dependent ( P for trend <0.01) and consistent across patient subgroups. The incidence of hyperkalemia (>5.5 mEq/L) was somewhat higher in MRA users but not significant (hazard ratio, 1.14 [95% CI, 0.88–1.48]). Conclusions: MRA users showed a better renal prognosis across various chronic kidney disease subgroups in a real-world chronic kidney disease population.


2022 ◽  
pp. 106002802110595
Author(s):  
Allissa Long ◽  
Marissa Salvo

Objective: To describe the pharmacology, clinical and safety evidence, and relevance to clinical practice of finerenone. Data Sources: A literature search was conducted utilizing PubMed, MEDLINE, and clinicaltrials.gov with search terms of “finerenone” and “BAY94-8862.” Study Selection and Data Extraction All available studies with human participants in English were considered. Studies were included if they investigated drug pharmacology, efficacy, and safety information. Data Synthesis In addition to standard of care with a renin-angiotensin system inhibitor (RASi), finerenone lowered the risk of kidney disease progression (17.8% vs 21.1%) in patients with type 2 diabetes mellitus and chronic kidney disease compared to placebo. Similarly, finerenone reduced cardiovascular risk in patients with type 2 diabetes mellitus and chronic kidney disease compared to placebo (12.4% vs 14.2%). Relevance to Patient Care and Clinical Practice It is anticipated that finerenone will be added to therapy after a RASi and a sodium-glucose cotransporter-2 inhibitor, as tolerated, based on adverse events and potassium levels. Conclusions Finerenone offers a unique approach to further delay the progression of chronic kidney disease in patients with type 2 diabetes mellitus. It also provides another option for patients who cannot tolerate RASi or sodium-glucose cotransporter-2 inhibitors.


Author(s):  
R. Rodrigues-Díez Raul ◽  
Antonio Tejera-Muñoz ◽  
Vanesa Esteban ◽  
B. Steffensen Lasse ◽  
Raquel Rodrigues-Díez ◽  
...  

Background: CCN2 (cellular communication network factor 2) is a matricellular protein involved in cell communication and microenvironmental signaling responses. CCN2 is known to be overexpressed in several cardiovascular diseases, but its role is not completely understood. Methods: Here, CCN2 involvement in aortic wall homeostasis and response to vascular injury was investigated in inducible Ccn2 -deficient mice, with induction of vascular damage by infusion of Ang II (angiotensin II; 15 days), which is known to upregulate CCN2 expression in the aorta. Results: Ang II infusion in CCN2-silenced mice lead to 60% mortality within 10 days due to rapid development and rupture of aortic aneurysms, as evidenced by magnetic resonance imaging, echography, and histological examination. Ccn2 deletion decreased systolic blood pressure and caused aortic structural and functional changes, including elastin layer disruption, smooth muscle cell alterations, augmented distensibility, and increased metalloproteinase activity, which were aggravated by Ang II administration. Gene ontology analysis of RNA sequencing data identified aldosterone biosynthesis as one of the most enriched terms in CCN2-deficient aortas. Consistently, treatment with the mineralocorticoid receptor antagonist spironolactone before and during Ang II infusion reduced aneurysm formation and mortality, underscoring the importance of the aldosterone pathway in Ang II–induced aorta pathology. Conclusions: CCN2 is critically involved in the functional and structural homeostasis of the aorta and in maintenance of its integrity under Ang II–induced stress, at least, in part, by disruption of the aldosterone pathway. Thus, this study opens new avenues to future studies in disorders associated to vascular pathologies.


2021 ◽  
Author(s):  
Yong Wu ◽  
Huan Yang ◽  
Sujuan Xu ◽  
Ming Cheng ◽  
Jie Gu ◽  
...  

Inflammatory response and renal fibrosis are the hallmarks of chronic kidney disease (CKD). However, the specific mechanism of aldosterone-induced renal injury in the progress of CKD requires elucidation. Emerging evidence has demonstrated that absent in melanoma 2 (AIM2)-mediated inflammasome activation and endoplasmic reticulum stress (ERS) play a pivotal role in the renal fibrosis. Here, we investigated whether overexpression or deficiency of AIM2 affects ERS and fibrosis in aldosterone-infused renal injury. Interestingly, we found that AIM2 was markedly expressed in the diseased proximal tubules from human and experimental chronic kidney disease. Mechanically, overactivation of AIM2 aggravated aldosterone-induced ERS and fibrotic changes in vitro while knockdown of AIM2 blunted these effects in vivo and vitro. By contrast, AIM2 deficiency ameliorated renal structure and function deterioration, decreased proteinuria levels and lower systolic blood pressure in vivo; silencing of AIM2 blocked inflammasome-mediated signaling pathway, relieved ERS and fibrotic changes in vivo. Furthermore, mineralocorticoid receptor antagonist eplerenone and ERS inhibitor tauroursodeoxycholic acid (TUDCA) had nephroprotective effects on the basis of AIM2 overactivation in vitro while they failed to produce a more remarkable reno-protective effect on the treatment of AIM2 silence in vitro. Notably, the combination of TUDCA with AIM2 knockdown significantly reduced proteinuria levels in vivo. Additionally, immunofluorescence assay identified that apoptosis-associated speck-like protein (ASC) recruitment and Gasdermin-D (GSDMD) cleavage respectively occurred in the glomeruli and tubules in vivo. These findings establish a crucial role for AIM2 inflammasome in aldosterone-induced renal injury, which may provide a novel therapeutic target for the pathogenesis of CKD.


Author(s):  
Murray Epstein ◽  
Roberto Pecoits-Filho ◽  
Catherine Clase ◽  
Manish Sood ◽  
Csaba Kovesdy

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Christian Basile ◽  
Ilaria Fucile ◽  
Maria Virginia Manzi ◽  
Federica Ilardi ◽  
Anna Franzone ◽  
...  

Abstract Aims Aortic stenosis (AS) is a very common valve disease and is associated with high mortality once it becomes symptomatic. Arterial hypertension (HT) has a high prevalence among patients with AS leading to worst left ventricle remodelling and faster degeneration of the valve. HT also seems to interfere with the assessment of the severity of AS leading to an underestimation of the real degree of stenosis. Treatment of HT in AS has historically been associated with reluctance due to both the lack of clear guidelines and the fear of adverse effects, but the most recent evidence shows as several drugs that can be used. Methods The pathophysiology of the combination of AS and HT is the association of a first fixed mechanical obstruction of the aortic root and a second obstruction due to systemic vascular resistance. Consequently, a decrease in systemic vascular resistance through, for example, the administration of vasodilators could theoretically cause a drop in systemic pressure due to the fixed mechanical obstruction given by the stenosis which prevents an increase in cardiac output. This theory was the basis for avoiding vasodilators in patients with AS. Results There is a unanimous opinion on maintaining blood pressure values of 130–139 mmHg of systolic and 70–90 mmHg of diastolic, but there is not the same agreement on which drugs to adopt to achieve the aforementioned values. Renin-Angiotensin-Aldosterone system inhibitors are certainly the first-line treatment thanks to their cardioprotective, plaque stabilizing, and antiarrhythmic effect since they are also associated with increased survival rates and greater left ventricular mass reduction in patients after surgical or transcatheter aortic valve replacement for severe AS. If blood pressure is not yet controlled, the addition of a beta-blocker should be considered: metoprolol has the greatest literature, showing not only an improvement in haemodynamic and metabolic performance but also a reduction in mortality in patients who already presented with coronary artery disease. Mineralocorticoid receptor antagonist can be used, among them eplerenone has been studied and can be useful to relieve symptoms of patients with a flare-up of heart failure by reducing the preload, provided that a close fluid and echocardiographic monitoring is implemented. Conclusions The use of phosphodiesterase 5 inhibitors can improve the haemodynamic status of patients with aortic stenosis and reduce the level of left ventricular hypertrophy, as well as improve pulmonary circulation and exercise tolerability of patients with AS, however it should be considered that in other studies sildenafil was associated with a worse clinical outcome. Calcium channel blocker are one the most used medications in patients with HT, but their use was associated with a 7-fold relative risk of all-cause mortality independent of known confounders and was also associated with an adverse effect on treadmill exercise and higher risk of all-cause mortality in patients with AS.


Hypertension ◽  
2021 ◽  
Vol 78 (6) ◽  
pp. 1809-1817
Author(s):  
Andrea V. Haas ◽  
Li En Yee ◽  
Yan E. Yuan ◽  
Yin H. Wong ◽  
Paul N. Hopkins ◽  
...  

Salt sensitivity of blood pressure is associated with increased cardiovascular morbidity and mortality. A diplotype in the β2AR gene (rs1042713, rs1042714) and single nucleotide polymorphisms in ESR2 (rs10144225), SGK1 (rs2758151), and AGT (rs2493134) genes are all independently associated with salt sensitivity of blood pressure and all but AGT are associated with increased aldosterone levels and/or activity. We sought to determine whether individuals who carried a double hit risk phenotype—a risk allele associated with increased aldosterone secretion (either β2AR or ESR2 ) and a risk allele associated with amplification of aldosterone’s effects ( SGK1 ) would result in more significant SSBP compared with individuals homozygous for a single risk allele. Data were obtained from the Hypertension Pathotypes cohort where individuals completed 7 days of restricted sodium and liberal sodium diets. We defined 3 genetic combinations: β2AR/SGK, ESR2/SGK , and AGT/SGK. Multivariate regression analyses found a significantly higher salt sensitivity of blood pressure as the number of risk allele pairs increased in both the β2AR/SGK (β=5.46; P <0.001) and ESR2/SGK ( β =4.87; P 0.01). In addition, the number of risk allele pairs was associated with serum aldosterone levels for β2AR/SGK and ESR2/SGK . On the other hand, there was no association between the number of risk allele pairs with salt sensitivity of blood pressure nor aldosterone levels in the AGT/SGK combination. In conclusion, genetic combinations of β2AR/SGK1 and ESR2 / SGK1 are associated with greater salt sensitivity of blood pressure and plasma aldosterone concentrations. Hypertensive combination risk homozygotes may be candidates for mineralocorticoid receptor antagonist therapy—gene-driven, personalized medicine.


2021 ◽  
Author(s):  
Vin-Cent Wu ◽  
Shuo-Meng Wang ◽  
Kuo-How Huang ◽  
Yao-Chou Tsai ◽  
Chieh-Kai Chan ◽  
...  

OBJECTIVE: Long-term outcomes (especially mortality and/or major cardiovascular events [MACE]) of the unilateral primary aldosteronism (uPA) patients who underwent medical or surgery targeted treatment, relative to those with essential hypertension (EH), have been scarcely reported. DESIGN and SETTINGS: Using the prospectively designed observational TAIPAI cohort, we identified 858 uPA cases among 1220 primary aldosteronism (PA) patients and another 1210 EH controls. EXPOSURES Operated uPA patients were grouped via their 1-year post-therapy statuses. RESULTS PASO clinical complete success (hypertension-remission) was achieved in 272 (49.9%) of 545 surgically-treated uPA patients. After follow-up for 6.3±4.0 years, both hypertension-remissive (HR, 0.54, p< 0.001) and not-cured (HR, 0.61, p< 0.001) uPA patients showed a lower risk of all-cause mortality than that of EH controls; whereas the not-cured group had a higher risk of incident MACE (sub-hazard ratio (sHR), 1.41, p= 0.037) but similar atrial fibrillation (Af) and congestive heart failure (CHF). Mineralocorticoid receptor antagonist (MRA)-treated uPA patients had higher risks of MACE (sHR, 1.38, p= 0.033), Af (sHR,1.62, p= 0.049) and CHF (sHR, 1.44, p= 0.048) than those of EH controls, with mortality as a competing risk. Using inverse probability of treatment-weighted matching and counting adrenalectomy as a time-varying factor, treatment with adrenalectomy was associated with lower risks of all-cause mortality (HR 0.57; p= 0.035), MACE (HR 0.67; p= 0.037) and CHF (HR 0.49; p= 0.005) compared to those of MRA therapy. CONCLUSIONS : Adrenalectomy, independent of post-surgical hypertension remission, was associated with lower all-cause mortality of uPA patients, compared to that of EH patients. We further documented a more beneficial effect of adrenalectomy over MRA treatment on long-term mortality, MACE, and CHF in uPA patients.


2021 ◽  
Vol 20 (7) ◽  
pp. 3068
Author(s):  
O. A. Osipova ◽  
E. V. Gosteva ◽  
T. P. Golivets ◽  
O. N. Belousova ◽  
O. A. Zemlyansky ◽  
...  

Aim. To compare the effect of 12-month pharmacotherapy with a betablocker (BB) (bisoprolol and nebivolol) and a combination of BB with a mineralocorticoid receptor antagonist (bisoprolol+eplerenone, nebivolol+eplerenone) on following fibrosis markers: matrix metalloproteinases 1 and 9 (MMP-1, MMP-9) and tissue inhibitor of MMP-1 (TIMP-1) in patients with heart failure with mid-range ejection fraction (HFmrEF) of ischemic origin.Material and methods. The study included 135 patients, including 40 (29,6%) women and 95 (70,4%) men aged 45-60 years (mean age, 53,1±5,7 years). Patients were randomized into subgroups based on pharmacotherapy with BB (bisoprolol or nebivolol) and their combination with eplerenone. The enzyme-linked immunosorbent assay was used to determine the level of MMP-1, MMP-9, TIMP-1 (ng/ml) using the commercial test system “MMP-1 ELISA”, “MMP-9 ELISA”, “Human TIMP-1 ELISA” (“Bender Medsystems “, Austria).Results. In patients with HFmrEF of ischemic origin, there were following downward changes in serum level of myocardial fibrosis markers, depending on the therapy: bisoprolol  — MMP-1 decreased by 35% (p<0,01), MMP-9  — by 56,3% (p<0,001), TIMP-1  — by 17,9% (p<0,01); nebivolol  — MMP-1 decreased by 45% (p<0,001), MMP-9  — by 57,1% (p<0,001), TIMP-1  — by 30,1% (p<0,01); combination of bisoprolol with eplerenone  — MMP-1 decreased by 43% (p<0,001), MMP-9  — by 51,2% (p<0,001), TIMP-1  — by 25,1% (p<0,01); combination of nebivolol with eplerenone  — MMP-1 decreased by 53% (p<0,001), MMP-9 — by 64,3% (p<0,001), TIMP-1 — by 39% (p<0,01). In patients with NYHA class I HFmrEF after 12-month therapy, the decrease in MMP-1 level was 39,9% (p<0,01), MMP-9  — 57,5% (p<0,001). In class II, the decrease in MMP-1 level was 47% (p<0,001), MMP-9 — 49,7% (p<0,001). A significant decrease in TIMP-1 level was revealed in patients with class I by 29% (p<0,01), in patients with class II by 27,1% (p<0,01) compared with the initial data.Conclusion. A significant decrease in the levels of myocardial fibrosis markers (MMP-1, MMP-9, TIMP-1) was demonstrated in patients with HFmrEF of ischemic origin receiving long-term pharmacotherapy. The most pronounced effect was determined in patients with NYHA class I HF.


2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Aya Saiki ◽  
Michio Otsuki ◽  
Daisuke Tamada ◽  
Tetsuhiro Kitamura ◽  
Kosuke Mukai ◽  
...  

Abstract Purpose Excessive aldosterone secretion causes a high risk of cardio-cerebrovascular events. Mineralocorticoid receptor antagonist (MRA) is 1 of the treatment strategies for primary aldosteronism (PA). However, current MRA treatment is insufficient because MRA-treated patients with suppressed plasma renin activity (PRA) &lt; 1 ng/mL/h still had a higher risk of cardiovascular disease than those with unsuppressed PRA. This is a prospective interventional study to determine the effects of an increase in MRA dosage on blood pressure (BP) control and urinary albumin excretion (UAE) in MRA-treated PA patients. Methods Thirty-four PA patients were recruited, and 24 patients (6 male, 18 female) completed this study. Serum potassium concentration was assessed every two months to adjust the dosage of MRA safely for 6 months. The primary outcomes were the changes in BP and UAE between baseline and 6 months. Results Systolic BP (SBP) and log10UAE decreased significantly as the daily dose of MRA increased. Diastolic BP (DBP) tended to decrease. We divided the PA patients into two groups (baseline PRA &lt; 1 ng/mL/h and baseline PRA ≥ 1 ng/mL/h) according to PRA. In the group with baseline PRA &lt; 1 ng/mL/h but not that with baseline PRA ≥ 1 ng/mL/h, SBP, DBP and log10UAE after 6 months were significantly lower than those at baseline. Conclusions The increase in MRA dosage improved BP and UAE in PA patients with suppressed PRA.


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