Renin Inhibitor Research Articles

Efficacy and safety of dual vs single renin-angiotensin-aldosterone system blockade in chronic kidney disease: An updated meta-analysis of randomized controlled trials.

Background:To lower albuminuria and to achieve blood pressure (BP) goals, dual renin–angiotensin–aldosterone system (RAAS) inhibitors are sometimes used in clinical practice for the treatment of CKD. However, the efficacy and safety of dual RAAS blockade therapy remains controversial.Methods:PubMed, EMBASE, and Cochrane Library were searched, and random effects model was used to calculate the effect sizes of eligible studies. Potential sources of heterogeneity were detected by meta-regression and subgroup analysis.Results:The present meta-analysis of 72 randomized controlled trials with 10,296 patients demonstrated that dual RAAS blockade therapy was superior to monotherapy in reducing the urine albumin excretion, urine protein excretion, and BP. These beneficial effects were related to the decrease of glomerular filtration rate, the increase of serum potassium level, and higher rates of hyperkalemia and hypotension. Meanwhile, these effects did not lead to improvements in short-term or long-term outcomes, including doubling of serum creatinine, acute kidney injury, end-stage renal disease, mortality, and hospitalization. Compared with the single therapy, angiotensin-converting enzyme inhibitor (ACEI) in combination with angiotensin-receptor blocker (ARB) was a better dual therapy than ACEI or ARB in combination with renin inhibitor or aldosterone receptor antagonist in decreasing urine albumin excretion, urine protein excretion and BP, and the combination was not associated with a lower glomerular filtration rate.Conclusion:Compared with the single therapy, ACEI in combination with ARB was a better dual therapy than ACEI or ARB in combination with renin inhibitor or aldosterone receptor antagonist. Although ACEI in combination with ARB was associated with higher incidences of hyperkalemia and hypotension, careful individualized management and potassium binders may further expand its application (PROSPERO number CRD42020179398).

Abstract P394: Angiotensin-(1-7) Attenuates Diastolic Dysfunction And Cardiac Remodeling In Murine Model Of Heart Failure With Preserved Ejection Fraction

Background: Heart failure with preserved ejection fraction (HFpEF) is a global public health epidemic that accounts for half of the heart failure cases. Various therapeutic approaches have been tested to block the activation of the Renin-Angiotensin System (RAS), including AT1R blockers (ARBs), Angiotensin-Converting Enzyme (ACE) inhibitors (ACEi), and direct renin inhibitors (DRIs) with modest to negligible benefits. The discovery of ACE2, a novel homolog of ACE, has advanced our understanding of the RAS. ACE2 is a monocarboxypeptidase that degrades Ang II into Ang-(1-7), which works via the activation of the Mas receptor. It has been well understood that the actions of Ang-(1-7) attenuate cardiac remodeling, production of ROS, and cardiac fibrosis. Objective: To determine the therapeutic role of Ang-(1-7) in HFpEF and identify the molecular mechanism related to its action. Methods and Results: To generate a murine model of HFpEF, male WT mice (n=24) were subjected to HFD in addition to eNOS inhibition with L-NAME (0.5 g l-1 in drinking water), as previously described. The control group (n=12) received chow diet and normal tap water. The murine model of HFpEF was validated using the non-invasive transthoracic echocardiography and invasive pressure-volume (PV) loop analyses, which exhibited diastolic dysfunction as well as cardiac hypertrophy. To evaluate the effects of Ang-(1-7) on HFpEF, animals were administered with either saline (n=12) or Ang-(1-7) (n=12) (24 μg/kg/day) for four weeks. Ang-(1-7) treatment improved diastolic function by reducing LVEDP (Ctrl: 8.267±1.254; HFD+L-NAME: 17.64±1.925; Ang-(1-7): 9.100±1.578) and Tau value (Ctrl: 7.365±0.5752; HFD+L-NAME: 9.224±0.3569; Ang-(1-7): 7.381±0.3041). Furthermore, Ang-(1-7) reduced cardiac hypertrophy by reducing the phosphorylation level of MAPK ERK 1/2 (Ctrl: 0.9074±0.1088; HFD+L-NAME: 1.212±0.1369; Ang-(1-7): 0.5615±0.1502) and increasing the phosphorylation level of AMPK (Ctrl: 0.1502±0.1502; HFD+L-NAME: 0.6127±0.06414; Ang-(1-7): 0.7852±0.1006). Ang-(1-7) treatment also reduces cardiomyocytes’ size and decreases interstitial fibrosis, as indicated by WGA and PSR staining. Conclusion: Ang-(1-7) treatment attenuated the development of HFD+L-NAME-induced HFpEF, reduced cardiac hypertrophy, and improved metabolic function.

MP53-20 RENOPROTECTIVE EFFECT OF DIRECT RENIN INHIBITOR (ALISKIREN) DURING ACUTE AND CHRONIC PARTIAL URETERAL OBSTRUCTION IN RAT SOLITARY KIDNEY

You have accessJournal of UrologyTrauma/Reconstruction/Diversion: Ureter (including Pyeloplasty) and Bladder Reconstruction (including fistula), Augmentation, Substitution, Diversion II (MP53)1 Sep 2021MP53-20 RENOPROTECTIVE EFFECT OF DIRECT RENIN INHIBITOR (ALISKIREN) DURING ACUTE AND CHRONIC PARTIAL URETERAL OBSTRUCTION IN RAT SOLITARY KIDNEY Mohamed Essam, Nashwa Barakat, Ahmed Elkashef, Amira Awadalla, A. E. Behery, and Mahmoud Abdel-Maboud Mohamed EssamMohamed Essam More articles by this author , Nashwa BarakatNashwa Barakat More articles by this author , Ahmed ElkashefAhmed Elkashef More articles by this author , Amira AwadallaAmira Awadalla More articles by this author , A. E. BeheryA. E. Behery More articles by this author , and Mahmoud Abdel-MaboudMahmoud Abdel-Maboud More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002083.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Obstructive uropathy is a major clinical problem that can result in permanent renal damage. The renoprotective effect of direct renin inhibitor (aliskiren) has been demonstrated in many experimental animal models mainly renal ischemia/reperfusion injury. Therefore, we studied the effect of aliskiren on the renal function during acute and chronic partial ureteral obstruction (PUO) in rat solitary kidney. METHODS: 60 male Sprague–Dawley rats were randomly allocated into 3 groups (20 rats each); sham, PUO and aliskiren groups. Right nephrectomy was performed in all groups. Rats in PUO and aliskiren groups were subjected to left PUO and received no treatment and aliskiren (10 mg/kg, orally, once per day till sacrification), respectively. Blood samples were then collected for biochemical measurements. 10 rats from each group were sacrificed after 2 weeks, while the remaining rats were sacrificed after 4 weeks. Left kidneys were harvested for histopathological examination, BCL-2, IL-6, TGF-β1, collagen I and fibronectin relative gene expression and assessment of glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) activity. RESULTS: After 2 and 4 weeks of PUO, aliskiren significantly recompensed the rise of serum creatinine (Scr) and blood urea nitrogen (BUN). Aliskiren also revealed significantly better histopathological results regarding cortical and medullary necrosis, regeneration and inflammatory cell infiltration (table 1). Aliskiren group showed significant up-regulation of BCL-2 and down-regulation of IL-6, TGF-β1, collagen I and fibronectin gene expression (table 2). Aliskiren also significantly increased GSH and SOD activity and reduced MDA and NO activity (table 2). Moreover, aliskiren administration for 4 weeks after PUO significantly yielded more renoprotective effect compared to its administration for 2 weeks. CONCLUSIONS: Aliskiren ameliorates the deterioration of the renal function during acute and chronic PUO in a solitary kidney. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e947-e947 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mohamed Essam More articles by this author Nashwa Barakat More articles by this author Ahmed Elkashef More articles by this author Amira Awadalla More articles by this author A. E. Behery More articles by this author Mahmoud Abdel-Maboud More articles by this author Expand All Advertisement Loading ...

Efficacy of Add-on Therapy with Carvedilol and the Direct Renin Inhibitor Aliskiren for Improving Cardiac Sympathetic Nerve Activity, Cardiac Function, Symptoms, Exercise Capacity and Brain Natriuretic Peptide in Patients with Dilated Cardiomyopathy.

Purpose/Method: Aliskiren is a direct renin inhibitor that has been reported to be effective for CHF, but the usefulness of combined therapy with carvedilol and aliskiren has not been reported. Forty-four patients with dilated cardiomyopathy (DCM) were randomized into a group receiving add-on therapy with carvedilol plus aliskiren and another group receiving carvedilol alone for 6 months. Nuclear imagings with 123I-Metaiodobenzylguanidine (MIBG) and 99mTc-Sestamibi were performed. Exercise capacity using a specific activity scale (SAS) and the New York Heart Association (NYHA) class were evaluated. Cardiac sympathetic nerve activity was evaluated by 123I-MIBG imaging, with the delayed heart-to-mediastinum activity ratio (H/M), delayed total defect score (TDS), and washout rate (WR). Results: Combined add-on therapy with carvedilol and aliskiren improved several parameters much more than carvedilol alone (p<0.05) with respect to TDS, ejection fraction (EF), NYHA, SAS on 6 months and the changes in TDS, EF, end-diastolic volume and brain natriuretic peptide (BNP). Conclusion: Add-on therapy with carvedilol and aliskiren is more effective than carvedilol alone for improving cardiac sympathetic nerve activity, cardiac function, symptoms, exercise capacity, and brain natriuretic peptide in patients with DCM.

The role of renin angiotensin system in the pathophysiology of rheumatoid arthritis.

In rheumatoid arthritis (RA) and osteoarthritis (OA), chronic inflammatory processes lead to progresive joint destruction. The renin-angiotensin system (RAS) is involved in the pathogenesis of RA and OA. The aim of this mini-review article is to summarize evidence on the role of RAS in RA and OA. A non-systematic search in Pubmed included terms as "rheumatoid arthritis", "renin angiotensin system", "osteopenia", "RANKL", "DKK-1", "MMP", "inflammation", "angiogenesis", "local renin-angiotensin system", "angiotensin converting enzyme", "AT2 receptor", "Ang-(1-7)", "VEGF", "angiotensine receptor blocker", "angiotensin converting enzyme inhibitors", "renin inhibitors". Both RAS axes, the classical one, formed by angiotensin converting enzyme (ACE), angiotensin (Ang) II and AT1 receptor (AT1R) and the counter-regulatory one, composed by ACE2, Ang-(1-7) and the Mas receptor, modulate inflammation and tissue damage. Ang II activates pro-inflammatory mediators and oxidative stress. Conversely, Ang-(1-7) exerts anti-inflammatory actions, decreasing cytokine release, leukocyte attraction, density of vessels, tissue damage and fibrosis. Angiogenesis facilitates inflammatory cells invasion, while osteopenia causes joint dysfunction. Up-regulated osteoclastogenisis and down-regulated osteoblastogeneses were associaed with the activation of the classical RAS axis. Three different pathways, RANKL, DKK-1 and MMPs are enhanced by classical RAS activation. The treatment of RA included methotrexate and corticosteroids, which can cause side effects. Studies with angiotensin receptor blockers (ARBs), angiotensin converting enzyme inhibitors (ACEi) and renin inhibitors have been conducted in experimental and clinical RA with promising results. The classical RAS activation is an important mechanism in RA pathogenesis and the benefit of ARB and ACEi administration should be further investigated.

Renoprotective effect of direct renin inhibitor (aliskiren) during partial ureteral obstruction

Partial ureteral obstruction (PUO) is a major clinical problem in the daily urologic practice that is treatable and often reversible. Renin-angiotensin system (RAS) is implicated in the pathophysiology of PUO as angiotensin II induces alterations in renal hemodynamics, apoptosis, inflammation and fibrosis

Systematic Review and Meta-Analysis of Renin-Angiotensin-Aldosterone System Blocker Effects on the Development of Cardiovascular Disease in Patients With Chronic Kidney Disease.

Background: Cardiovascular events are one of the most serious complications that increase the risk of mortality and morbidity in pre-dialysis and on-dialysis chronic kidney disease (CKD) patients. Activation of the renin–angiotensin–aldosterone system (RAAS) is considered to contribute to the development of cardiovascular events in these populations. Therefore, several kinds of RAAS blockers have been frequently prescribed to prevent cardiovascular events in patients with CKD; however, their effectiveness remains controversial. This systematic review focuses on whether RAAS blockers prevent cardiovascular events in patients with CKD. Method: PubMed were searched to retrieve reference lists of eligible trials and related reviews. Randomized prospective controlled trials that investigated the effects on cardiovascular events in CKD patients that were published in English from 2010 to 2020 were included. Results: Among 167 identified studies, 11 eligible studies (n = 8,322 subjects) were included in the meta-analysis. The meta-analysis showed that RAAS blockers significantly reduced cardiovascular events in on-dialysis patients with CKD [three studies; odds ratio (OR), 0.52; 95% confidence interval (CI), 0.36 to 0.74; p = 0.0003], but there was no significant difference in pre-dialysis patients with CKD because of the heterogeneity in each study (eight studies). We also investigated the effects of each kind of RAAS blocker on cardiovascular events in CKD patients. Among the RAAS blockers, mineralocorticoid receptor antagonists significantly decreased cardiovascular events in pre-dialysis or on-dialysis patients with CKD (four studies; OR, 0.60; 95%CI, 0.50 to 0.73, p < 0.0001). However, angiotensin receptor blockers did not show significant effects (four studies; OR, 0.65; 95%CI, 0.42 to 1.01; p = 0.0529). The effects of angiotensin converting enzyme inhibitors and direct renin inhibitors on cardiovascular events in patients with CKD could not be analyzed because there were too few studies. Conclusion: Mineralocorticoid receptor antagonists may decrease cardiovascular events in pre-dialysis or on-dialysis patients with CKD.

Pacific Dulse Protein: A Promising Source of Bioactive Peptides

Abstract Objectives Pacific dulse (Devaleraea mollis) is a protein-rich seaweed in the Pacific Northwest and increasingly being cultivated as food resource. Our previous work showed that dietary supplementation of dulse exerted beneficial metabolic effects to the high-fat fed mouse model. This study aims to evaluate the potential of the seaweed protein from dulse as a precursor for bioactive peptide (BAP) generation. Methods The potential of Pacific dulse protein as BAP precursor was assessed using in vitro and in silico approaches. Hydrolysates were prepared from the hydrated freeze-dried protein isolates which were digested using commercial proteases. These were used for the in vitro screening for antioxidant and anti-inflammatory activities as well as the inhibition of Angiotensin-converting enzyme 1 (ACE-1), Renin, and Dipeptidyl peptidase IV (DPPIV). Peptides in the hydrolysates that exhibit the highest activities were identified using de novo sequencing. Identified peptides were shortlisted based on their potential to be bioactive using Peptide Ranker and specific bioactivity scores were obtained using in silico platforms such as iDPPIV-SCM and PreAIP. To determine whether the consumption of the seaweed protein may help give rise to some bioactive peptides, annotated protein sequences of the seaweed material were obtained from UniProtKB and were subjected to in silico digestion using pepsin, chymotrypsin, and trypsin through BIOPEP. Bioactivity indices of the generated peptide fragments were recorded as predictive values. Results In silico digestion showed that dulse proteins can give rise to ACE-1, DPP-IV, and renin inhibitors, as well as antioxidant peptides. Hydrolysates exerted inhibitory effects on human ACE-1, DPPIV, and renin in vitro. ABTS radical scavenging assay and cellular antioxidant activity assay in human hepatocytes indicated the strong antioxidant potential of dulse BAP. Peptides identified through de novo sequencing had high predictive scores for DDPIV inhibition and anti-inflammatory potential. Conclusions Pacific dulse proteins is a promising precursor for the generation of BAPs that may exert beneficial health activities and support metabolic health improvement. Funding Sources Oregon State University Agricultural Research Foundation.

Synthesis and docking studies of renin inhibitors containing ester and amide derivatives of (3S, 4S)-4-amino-hydroxy acids with S3-S3’ renin binding site.

Synthesis and docking studies of renin inhibitors containing ester and amide derivatives of (3S, 4S)-4-amino-hydroxy acids with S3-S3’ renin binding site.

UTILIZATION OF ANTIHYPERTENSIVE DRUGS AS MONOTHERAPY AND COMBINED THERAPY IN BRAZIL: A POPULATION BASED STUDY

Objective: Our objective was to describe the use of antihypertensive drugs in Brazil with a focus on the combination of two drugs. Design and method: Secondary data analysis from the National Survey on Access Use and Promotion of Rational Use of Medicines (PNAUM 2014), a nationwide cross-sectional population-based study, focused on the use of medicines in Brazil with a total of 41,433 interviews. The sample consists of all antihypertensive drugs cited as used to treat hypertension. The I Brazilian Positioning about Combination of Antihypertensive Drugs 2013 was used as a criteria to identify the combinations as Preferential: ACEI (Angiotensin-converting enzyme inhibitors) + CCB (Calcium channel blockers), ACEI + Diuretic, ARB (Angiotensin II receptor blockers) + CCB (dihydropyridine derivates), ARB + Diuretic; Acceptable: Diuretic + BB (beta-Blockers), CCB (dihydropyridine derivates) + BB, CCB + Diuretic, RI (Renin inhibitor)+ Diuretic, RI + CCB, Diuretic Thiazide + Potassium-sparing Agent; Less usual: ACEI + BB, ARB + BB and Unusual combinations: CCB (non-dihydropyridine derivates) + BB, ACEI + ARB, ACEI + RI, ARB + RI, Antiadrenergic agents, centrally acting + BB. The Statistical Analysis System (SAS) version 9.4 was used. Results: A total of 45 antihypertensive drugs was related. Diuretics (47.2% 95%CI 45.5–48.8), ACEI (38.1% 95%CI 36.4–39.8) and ARB (37.1% 95%CI 35.5–38.7) were the most used drugs, regardless the treatment as monotherapy or combined therapy. As monotherapy the three classes cited was the most used, however in a different percentage: ACEI (37.1% 95%CI 35.0–39.4), ARB (28.1% 95%CI 26.1–30.2) and Diuretics (14.5% 95%CI 12.9–16.1). Considering people under therapy with two drugs and the I Brazilian Positioning about Combination of Antihypertensive Drugs criteria, the preferential combinations represented 66.3% (95%CI 63.8–68.8), acceptable 19.2% (95%CI 17.1–21.2), less usual 10.1% (95%CI 8.5–11.8), unusual combinations 1.4% (95% CI 0.9–1.9) and other combinations 3.0% (95%CI 1.9–4.1). The most preferential combinations were ARB + Diuretic 30.3% (95%CI 27.8–32.8) and ACEI + Diuretic 28.0% (95%CI 25.5–30.5). In general, Brazil is using antihypertensives according to the guidelines of hypertension. Conclusions: In general, Brazil is using antihypertensives according to the guidelines of hypertension.

The effect of neprilysin and renin inhibition on the renal dysfunction following ischemia-reperfusion injury in the rat.

The natriuretic peptide (NP) system counter‐regulates the renin‐angiotensin system (RAS), so enhancing the activity of natriuretic peptides (NPs) may be beneficial in conditions when RAS is activated such as ischemia‐reperfusion injury (IRI). Neprilysin is the key enzyme responsible for the degradation of NPs. The effects of neprilysin inhibition or the combination of neprilysin inhibition and RAS inhibition on renal IRI‐induced renal dysfunction have not been investigated yet. To investigate this, rats underwent sham surgery or bilateral IRI for 20 min. G‐Als, G‐Scb, and G‐Als+Scb underwent similar protocol but received aliskiren (renin inhibitor), sacubitril (neprilysin inhibitor) or a combination of both pre‐ and post‐IRI, respectively. IRI caused significant alterations in all renal functional parameters, markers of acute renal injury, pro‐inflammatory and pro‐fibrotic cytokines, and histological features. All these alterations were significantly attenuated in G‐Als, G‐Scb, and G‐Als+Scb. The attenuations in the alterations in serum creatinine, creatinine clearance, and histological features were larger in G‐Als+Scb compared to either G‐Als or G‐Scb. We conclude that RAS blockade by a renin inhibitor (aliskiren) or neprilysin inhibition by sacubitril separately led to significant attenuation in the renal IRI‐induced renal dysfunction. The combination of aliskiren and sacubitril was more effective than either one alone.

CoMSIA Study on Renin Inhibitors as Antihypertensives: SAR and 3D QSAR

CoMSIA Study on Renin Inhibitors as Antihypertensives: SAR and 3D QSAR

Computational guided designing of novel Renin inhibitors

Computational guided designing of novel Renin inhibitors

Managing patients with diabetes and chronic kidney disease

In late 2020, the nonprofit organization Kidney Disease: Improving Global Outcomes (KDIGO) published a clinical practice guideline in the Annals of Internal Medicine on management of patients with diabetes and chronic kidney disease (CKD). The new guidance focuses on comprehensive care needs, glycemic monitoring and targets, and educational and integrated care approaches. “The 2020 KDIGO clinical practice guideline on diabetes management incorporates recent kidney outcome data to provide specific recommendations on use of glucose-lowering agents to mitigate kidney and cardiovascular risk,” said Joshua J. Neumiller, PharmD, CDCES, FADCES, FASCP, vice-chair and Allen I. White Distinguished Associate Professor in the College of Pharmacy and Pharmaceutical Sciences at Washington State University in Pullman. “Recommendations from KDIGO complement current guidance from the endocrine and cardiology communities, but provides a succinct resource related to the specific care needs of patients with diabetes and CKD. Particularly important to pharmacists is the guideline's discussion of risk mitigation strategies and important counseling points to optimize patient safety,” said Neumiller. Patients with diabetes and CKD often have other comorbidities and a higher cardiovascular burden, so a comprehensive management approach is needed. KDIGO recommends use of an ACE inhibitor (ACEi) or an ARB in patients with diabetes, hypertension, and albuminuria, with these medications titrated to the highest approved dose that is tolerated. Use may also be considered in patients with diabetes, albuminuria, and normal blood pressure. Only one of these agents should be used at a time, as combination therapy with an ACEi and an ARB or one of these agents with a direct renin inhibitor may be potentially harmful. Close monitoring of blood pressure, potassium levels, and serum creatinine is needed within 2 to 4 weeks of initiation of therapy or when there is a dose increase. KDIGO recommends that hyperkalemia be managed by implementing measures to reduce potassium levels (e.g., moderating potassium intake, initiating diuretics) rather than by decreasing or discontinuing the ACEi or ARB immediately. In addition, KDIGO recommends continuation of the ACEi or ARB unless creatinine levels increase by more than 30%. The ACEi or ARB dose should be reduced or withdrawn in patients who develop symptomatic hypotension, uncontrolled hyperkalemia (despite interventions), and acute kidney injury. The guideline discusses tobacco cessation as part of the comprehensive care plan, with patients encouraged to avoid using any tobacco products and to reduce their exposure to secondhand smoke. A section on lifestyle intervention is also included, and clinicians are encouraged to review those recommendations in the full publication. KDIGO recommends that A1C levels be used to monitor glycemic control in patients with diabetes and CKD, with an individualized target ranging from <6.5% to <8.0% for those not treated with dialysis. Assessment twice per year is reasonable, but assessments as often as 4 times per year may be needed if glycemic targets are not met or after a change in antihyperglycemic therapy. For antihyperglycemic therapy, KDIGO recommends metformin in combination with a sodium–glucose cotransporter-2 inhibitor for patients with type 2 diabetes, CKD, and an eGFR of 30 mL/min/1.73 m2 or greater. If patients do not reach their individualized glycemic target or are unable to use those medications, the guideline recommends use of a glucagon-like peptide-1 receptor agonist as the next preferred agent. Other antihyperglycemic agents are also listed with a figure (i.e., Figure 4) that helps guide appropriate selection based on patient and provider preferences (e.g., weight loss, avoid injections, avoid hypoglycemia, potent glucose lowering needed), comorbidities (e.g., high-risk atherosclerotic cardiovascular disease, heart failure), eGFR (e.g., dialysis), and cost. KDIGO recognizes that data on use of newer agents in patients with type 1 diabetes and CKD receiving insulin are sparse and makes no special recommendations for these patients. KDIGO discusses the importance of both a self-management education program and a team-based integrated approach to care. The self-education program should consider local context, cultures, and availability of resources and be tailored to individual preferences and learning styles. These programs can be delivered one-on-one or as a group-based model. The team-based approach should include both physician and nonphysician personnel and focus on regular assessments, control of multiple risk factors, and self-management to protect kidney function and reduce the risk for complications.

Role of Blood Pressure Management in Stroke Prevention: A Systematic Review and Network Meta-Analysis of 93 Randomized Controlled Trials.

Background and Purpose The present study aimed to compare the efficacy and tolerability of different blood pressure (BP)-lowering strategies. Methods Randomized controlled trials that compared various antihypertensive treatments and stroke outcomes were included. Eligible trials were categorized into three scenarios: single or combination antihypertensive agents against placebos; single or combination agents against other agents; and different BP-lowering targets. The primary efficacy outcome was the risk reduction pertaining to strokes. The tolerability outcome was the withdrawal of drugs, owing to drug-related side effects (PROSPERO registration number CRD42018118454 [20/12/2018]). Results The present study included 93 trials (average follow-up duration, 3.3 years). In the pairwise analysis, angiotensin-converting enzyme inhibitors (ACEis) and beta-blockers (BBs) were inferior to calcium channel blockers (CCBs) (odds ratio [OR], 1.123; 95% confidence interval [CI], 1.008 to 1.252) (OR, 1.261; 95% CI, 1.116 to 1.425) for stroke prevention, BB was inferior to angiotensin II receptor blockers (ARB) (OR, 1.361; 95% CI, 1.142 to 1.622), and diuretics were superior to ACEi (OR, 0.871; 95% CI, 0.771 to 0.984). The combination of ACEi+CCB was superior to ACEi+diuretic (OR, 0.892; 95% CI, 0.823 to 0.966). The network meta-analysis confirmed that diuretics were superior to BB (OR, 1.34; 95% CI, 1.11 to 1.58), ACEi+diuretic (OR, 1.47; 95% CI, 1.02 to 2.08), BB+CCB (OR, 2.05; 95% CI, 1.05 to 3.79), and renin inhibitors (OR, 1.87; 95% CI, 1.25 to 2.75) for stroke prevention. Regarding the tolerability profile, the pairwise analysis revealed that ACEi was inferior to CCB and less tolerable, compared to the other treatments. Conclusions Monotherapy using diuretics, CCB, or ARB, and their combinations could be employed as first-line treatments for stroke prevention in terms of efficacy and tolerability.

Comparative risk of new‐onset hyperkalemia for antihypertensive drugs in patients with diabetic nephropathy: A Bayesian network meta‐analysis

Several randomised controlled trials (RCTs) have evaluated the risk of hyperkalemia of antihypertensive drugs on diabetic nephropathy, yet the results are conflicting. We searched MEDLINE, Embase, The Cochrane Library, and Web of Science for RCTs investigating the risk of antihypertensive drugs on hyperkalemia in diabetic nephropathy from inception to May 31, 2020. Direct comparative meta-analysis showed that the proportion of patients with hyperkalemia was significantly higher in the ARB, aldosterone antagonist, renin inhibitor group than in the placebo group. Moreover, the risk of hyperkalemia in the ARB group was higher than that in the CCB group. Network meta-analysis showed the risk of hyperkalemia in the ARB, aldosterone antagonist, and renin inhibitor group was higher than in the placebo group, but there was no statistical difference between the CCB, ACEI, β blocker, endothelin inhibitor, and diuretic groups than in the placebo group. The possibility of antihypertensive drugs in risk of hyperkalemia being the worst treatment was aldosterone antagonist (98.8%), followed by ARB (73.8%), renin inhibitor (63.8%), diuretic (53.1%), ACEI (46.9%), β blocker (36.8%), endothelin inhibitor (35.2%), placebo (27.1%), and finally CCB (14.3.1%). Therefore, aldosterone antagonist seems worse than other antihypertensive drugs in the risk of hyperkalemia in patients with diabetic nephropathy.

Repurposing of renin inhibitors as SARS-COV-2 main protease inhibitors: A computational study

The COVID-19 pandemic has urged for the repurposing of existing drugs for rapid management and treatment. Renin inhibitors down regulation of ACE2, which is an essential receptor for SARS-CoV-2 infection that is responsible for COVID-19, in addition to their ability to act as protease inhibitors were encouraging aspects for their investigation as possible inhibitors of main protease of SARS-CoV-2 via computational studies. A Pharmacophore model was generated using the newly released SARS-COV-2 main protease inhibitors. Virtual screening was performed on renin inhibitors, and Drug likeness filter identified remikiren and 0IU as hits. Molecular docking for both compounds showed that the orally active renin inhibitor remikiren (Ro 42–5892) of Hoffmann–La Roche exhibited good molecular interaction with Cys145 and His41 in the catalytic site of SARS-CoV-2 main protease. Molecular dynamics simulation suggested that the drug is stable in the active site of the enzyme.

Deep neural network modeling based virtual screening and prediction of potential inhibitors for renin protein

Renin enzyme plays an essential role in the Renin-Angiotensin System (RAS), and it is involved in the pathogenesis of hypertension and several other cardiovascular diseases (CVDs). Inhibition of renin is an effective way to intervene with the pathogenesis of these diseases. Docking-based virtual screening, 3D-Quantitative Structure-Activity Relationship (3D-QSAR), and structure-based drug design are the most frequently used strategies towards discovering novel inhibitors targeting renin. In this study, we have developed a 2D fingerprint-based Deep Neural Network (DNN) classifier for virtual screening and a DNN-QSAR model for biological activity prediction. The resulting hits from the DNN-QSAR model were then subjected to the molecular docking to identify further top hits. Molecular Dynamics (MD) simulation was conducted to get a better insight into the binding mode of identified hits. We have discovered six compounds from the Maybridge chemical database with the predicted IC50 values ranging from 24.2 nM to 83.6 nM. To the best of our knowledge, this is the first study that used a cascaded DNN model to identify potential lead compounds for the inhibition of renin target. Through the results presented in this study, we provide evidence of the DNN method being a useful approach to identify new chemical entities/novel lead compounds that may overcome the limitation of existing conventional strategies used in drug discovery research. Communicated by Ramaswamy H. Sarma

For adults with primary hypertension, how do renin inhibitors compare with angiotensin-converting enzyme (ACE) inhibitors?

For adults with primary hypertension, how do renin inhibitors compare with angiotensin-converting enzyme (ACE) inhibitors?

Role of renin blocker (Aliskiren) on Cisplatin induced-nephrotoxicity in rats

Aliskiren (ALSK), being a direct renin inhibitor, is known for its additional benefit of renoprotection under several pathological conditions. On the other hand, Cisplatin (CP) is one of the most preferred chemotherapeutic agent; however, its clinical utility is limited owing to nephrotoxicity as its primary side effect. This study was aimed to investigate the protective role of ALSK against CP-induced nephrotoxicity in rats. Male Wistar rats were randomly divided into four groups of six animals each. They included vehicle treated normal control, CP (7.5 mg/kg), ALSK (25 mg/kg), and ALSK + CP treated groups. ALSK was orally administered for 2 weeks while CP was administered through the i.p. route on the 10th day to the respective groups. Blood and kidney samples were collected for the estimation of renal function, histology, the determination of oxidative stress, and the measurement of pro-inflammatory cytokines and markers of apoptosis. The results demonstrated that CP significantly elevated the levels of serum creatinine (Cr), blood urea nitrogen (BUN), and uric acid (UA) while it suppressed the renal markers of oxidative stress including glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) and increased malondialdehyde (MDA) content. In addition, CP up-regulated the markers of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α in the kidney and induced apoptosis by activating caspase cascade, which was observed as elevated levels of caspase-3 and −9. Two weeks of continuous treatment of ALSK 25 mg/kg significantly decreased the levels of serum Cr, BUN, UA and ameliorated histological damage in CP-treated animals. ALSK increased the antioxidant defense (increased renal GSH, SOD, and CAT levels while MDA content was suppressed) against CP. ALSK also significantly decreased the levels of IL-1β, IL-6, and TNF-α and prevented apoptosis by reversing the increased levels of caspase-3 and −9 by CP. Therefore, it may be concluded that ALSK has a protective role against CP-induced nephrotoxicity in rats.