Blockade Of System Research Articles

Finerenone and Cardiorenal Outcomes by History of Cardiovascular Disease in Patients with Type 2 Diabetes: Fidelity Analyses

Patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) are at risk of cardiovascular complications. FIDELITY (prespecified pooled analysis of FIDELIO-DKD [NCT02540993] and FIGARO-DKD [NCT02545049]) evaluated finerenone (a selective, nonsteroidal mineralocorticoid receptor antagonist) in patients with CKD and T2D. Cardiovascular and kidney outcomes were compared in primary and secondary prevention populations. Patients with T2D, and either urine albumin-to-creatinine ratio (UACR [mg/g])≥30–<300 and estimated glomerular filtration rate (eGFR [mL/min/1.73m2])≥25–≤90, or UACR≥300–≤5,000 and eGFR≥25, treated with optimized renin–angiotensin system blockade, were randomized to finerenone or placebo. Cardiovascular outcomes (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or heart failure hospitalization) and kidney outcomes (kidney failure, sustained eGFR decrease≥57% or kidney death) were categorized by prior atherosclerotic cardiovascular disease (CVD). Investigator-reported adverse events (AEs) were assessed. 5,935/13,026 of eligible patients had a history of CVD. Finerenone lowered the risk of the cardiovascular outcome vs placebo (HR=0.86; 95%CI=0.78-0.95; 3.0-year median follow-up), with no treatment modification by CVD history (HR=0.83 [95%CI=0.74-0.94] in patients with CVD; HR=0.91 [95%CI=0.78-1.06] in patients without CVD; Pinteraction=0.375). The effect of finerenone on the kidney outcome (HR=0.77; 95%CI=0.67-0.88) was not modified by CVD (HR=0.71 [95%CI=0.57-0.88] and HR=0.81 [95%CI=0.68-0.97] in patients with and without CVD history, respectively; Pinteraction=0.325). AEs did not differ between CVD subgroups, with a low incidence of hyperkalemia-related treatment discontinuation that was more frequent in the finerenone group but similar between CVD subgroups. Finerenone reduced the risk of cardiovascular and kidney outcomes in patients with CKD and T2D vs placebo, irrespective of CVD history.

Blockade of endocannabinoid system by oxytocin attenuates memory deficits in oxycodone-treated rats.

Oxycodone is a highly prescribed opioid and its abuse has been rampant. Accumulating evidence shows that the cannabinoid CB1 receptor (CB1R) plays a key role in mediating rewarding effects to opioids. However, the downstream signalling of CB1R induced by oxycodone remains unclear. The neuropeptide oxytocin is well known as a potential remedy for drug addiction. Thus, our study aims to explore the mechanism of oxycodone-induced learning and memory deficits underlying the endocannabinoid system (ECS) and the effect of oxytocin. Rats were intraperitoneally injected with oxycodone once a day for eight consecutive day. Novel object recognition, resident-intruder and Morris Water Maze tests were employed to assess the cognitive, social and spatial memory of the rats after oxycodone withdrawal. The (co-)expression of CB1R, cyclin-dependent kinase 5 (Cdk5), regulatory protein p25, tau and phosphorylated tau was measured 1day after the last behavioural test. The histopathological staining and synaptic density in the hippocampus were observed as well. We found that oxycodone upregulated the expression of p-GSK3β, co-expression of p-Cdk5 and p25 through CB1R. This finding was accompanied by elevation of pSer396, pSer404 in the tau, and reduction of the number of neurons, dendritic spines and synaptic density in the hippocampus. Furthermore, i.c.v. treatment with oxytocin ameliorates memory deficits in oxycodone-treated rats through inhibition of the ECS. We propose further studies on the clinical use of this neuropeptide, which may potentially cure drug addiction.

Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece.

Alport syndrome (AS) is the most frequent monogenic inherited glomerulopathy and is also genetically and clinically heterogeneous. It is caused by semi-dominant pathogenic variants in the X-linked COL4A5 (NM_000495.5) gene or recessive variants in the COL4A3/COL4A4 (NM_000091.4/NM_000092.4) genes. The disease manifests in early childhood with persistent microhematuria and can progress to proteinuria and kidney failure in adolescence or early adulthood if left untreated. On biopsy, pathognomonic features include alternate thinning, thickening and lamellation of the glomerular basement membrane (GBM), in the presence of podocyte foot process effacement. Although previous studies indicate a prevalence of AS of about 1/50,000, a recent publication reported a predicted rate of pathogenic COL4A5 variants of 1/2320. We herewith present 98 patients (40 M/58 F) from 26 Greek families. We are selectively presenting the families segregating the X-linked form of AS with pathogenic variants in the COL4A5 gene. We found 21 different pathogenic variants, 12 novel: eight glycine and one proline substitutions in the collagenous domain, one cysteine substitution in the NC1 domain, two premature termination of translation codons, three splicing variants, one 5-bp insertion/frameshift variant, one indel-frameshift variant and four gross deletions. Notably, patients in six families we describe here and three families we reported previously, carried the COL4A5-p.G624D substitution, a founder defect encountered all over Europe which is hypomorphic with mostly milder symptomatology. Importantly, on several occasions, the correct genetic diagnosis reclassified patients as patients with AS, leading to termination of previous immunosuppressive/cyclosporine A therapy and a switch to angiotensin converting enzyme inhibitors (ACEi). With the understanding that all 98 patients span a wide range of ages from infancy to late adulthood, 15 patients (11 M/4 F) reached kidney failure and 11 (10 M/1 F) received a transplant. The prospects of avoiding lengthy diagnostic investigations and erroneous medications, and the advantage of delaying kidney failure with very early administration of renin-angiotensin-aldosterone system (RAAS) blockade, highlights the importance of timely documentation of AS by genetic diagnosis.

Abstract 13023: Exercise Training Potentiates Diuretic Benefits on Mechanism of Arterial Pressure Control in Hypertensive Postmenopausal Rats: Role of Inflammatory and Redox Balance

Introduction: Thiazide diuretic is a classic drug used to treat elevated arterial pressure (AP). However, their neuroinflammatory effects are limited when compared with other therapies. Objective: To compare the effect of hydrochlorothiazide (HCTZ) alone or combined with concurrent exercise training (aerobic+resistance, CET) on mechanisms of AP control and on inflammatory and redox balance in hypertensive postmenopausal rats. Methods: Female spontaneously hypertensive rats were distributed into sedentary (S) and ovariectomized groups: sedentary (OS), sedentary treated with HCTZ (OSH), trained (OT) and trained treated with HCTZ (OTH). HCTZ treatment (30 mg/kg) and CET (40-60% maximal capacity, 3 days/wk) were conducted for 8wks. AP was directly recorded at rest and after vasopressor system blockade (vasopressin antagonist, losartan and hexamethonium). Inflammation and oxidative stress were evaluated in cardiac tissue. Results: Trained groups presented higher exercise tests performance. Systolic (OT:178±18 and OTH:178±17 vs. OS:205±15) and mean AP (mmHg) (OTH:153±17 vs. OS:176±16) were reduced in trained groups. CET promoted an increase in both bradycardic and tachycardic responses of baroreflex sensitivity and a reduction in AP variability indexes in relation to OS group. After sympathetic blockade, AP (mmHg) reduction was higher in OS group (-75.7±19.2 vs. S:-53.2±12.6 and OTH:-49.8±12.4). In addition, IL-10 (OTH vs. OS and OSH) and IL-10/TNF-alpha ratio (OTH vs. S, OS, OSH and OT) were higher in OTH group. OS group showed increased NAPDHoxidase and reduced catalase (vs. S); however, these changes were not observed in OTH group. Negative correlation was observed between sympathetic vascular modulation and IL/TNF-alpha ratio (p&lt;0.001, r:-0.6). Conclusions: We concluded that CET alone or combined with HCTZ are more efficient approaches than HCTZ to reduce AP and improve AP control of circulation. Specifically, the combination HCTZ plus CET induces additional positive adaptations on physical, autonomic, inflammatory and redox balance. These results highlight the key role of exercise in the management of HTN, probably impacting on the quality of life and reducing the residual risk in post menopause. Grants: FAPESP (2019/06277-0).

A prespecified exploratory analysis from FIDELITY examined finerenone use and kidney outcomes in patients with chronic kidney disease and type 2 diabetes

In FIDELITY, a prespecified pooled analysis of the FIDELIO-DKD and FIGARO-DKD studies, finerenone was found to improve cardiorenal outcomes in patients with type 2 diabetes, a urine albumin-to-creatinine ratio of 30-5000 mg/g, an estimated glomerular filtration rate (eGFR) of 25 ml/min per 1.73 m2 or more and also receiving optimized renin-angiotensin system blockade treatment. This present analysis focused on the efficacy and safety of finerenone on kidney outcomes. Among 13,026 patients with a median follow-up of three years, finerenone significantly reduced the hazard of a kidney composite outcome (time to kidney failure, sustained 57% or more decrease in eGFR from baseline, or kidney death) by 23% versus placebo (hazard ratio, 0.77; 95% confidence interval, 0.67-0.88), with a three-year absolute between-group difference of 1.7% (95% confidence interval, 0.7-2.6). Hazard ratios were directionally consistent for a prespecified baseline eGFR and urine albumin-to-creatinine ratio categories (Pinteraction = 0.62 and Pinteraction = 0.67, respectively), although there was a high degree of uncertainty in the 30-300 mg/g subgroup. Finerenone significantly reduced the hazard of end-stage kidney disease (ESKD) by 20% versus placebo (0.80; 0.64-0.99). Adverse events were similar between treatment arms, although hyperkalemia leading to treatment discontinuation occurred significantly more frequently with finerenone versus placebo (2.4% vs 0.8% and 0.6% vs 0.3% in patients with eGFR less than 60 vs. greater than or equal to 60 ml/min per 1.73 m2, respectively). Thus, finerenone improved kidney outcomes, reduced the hazard of ESKD, and is well tolerated in patients with chronic kidney disease and type 2 diabetes.

Enhanced Cardiorenal Protective Effects of Combining SGLT2 Inhibition, Endothelin Receptor Antagonism and RAS Blockade in Type 2 Diabetic Mice.

Treatments with sodium-glucose 2 cotransporter inhibitors (SGLT2i) or endothelin receptor antagonists (ERA) have shown cardiorenal protective effects. The present study aimed to evaluate the cardiorenal beneficial effects of the combination of SGLT2i and ERA on top of renin-angiotensin system (RAS) blockade. Type 2 diabetic mice (db/db) were treated with different combinations of an SGLT2i (empagliflozin), an ERA (atrasentan), and an angiotensin-converting enzyme inhibitor (ramipril) for 8 weeks. Vehicle-treated diabetic mice and non-diabetic mice were included as controls. Weight, blood glucose, blood pressure, and kidney and heart function were monitored during the study. Kidneys and heart were collected for histological examination and to study the intrarenal RAS. Treatment with empagliflozin alone or combined significantly decreased blood glucose compared to vehicle-treated db/db. The dual and triple therapies achieved significantly greater reductions in diastolic blood pressure than ramipril alone. Compared to vehicle-treated db/db, empagliflozin combined with ramipril or in triple therapy significantly prevented GFR increase, but only the triple combination exerted greater protection against podocyte loss. In the heart, empagliflozin alone or combined reduced cardiac isovolumetric relaxation time (IVRT) and left atrium (LA) diameter as compared to vehicle-treated db/db. However, only the triple therapy was able to reduce cardiomyocyte area. Importantly, the add-on triple therapy further enhanced the intrarenal ACE2/Ang(1-7)/Mas protective arm of the RAS. These data suggest that triple therapy with empagliflozin, atrasentan and ramipril show synergistic cardiorenal protective effects in a type 2 diabetic mouse model.

Effect of dual blockade of renin-angiotensin system on renal nephrin and vascular endothelial growth factor – A expression in diabetic-hypertensive rats

Objectives: The effects of early renin-angiotensin system (RAS) blockade using angiotensin-converting enzyme (ACE) inhibitor lisinopril and/or angiotensin receptor blocker valsartan on renal nephrin and vascular endothelial growth factor (VEGF)-A gene expression were investigated in diabetic-hypertensive rats. Materials and Methods: Diabetes and hypertension were induced in adult Wistar rats using streptozotocin (45 mg/kg, i.p.) and Nω-nitro-L-arginine methyl ester (60 mg/kg/12 h) for 4 consecutive days. Experimental animals were allocated into six groups (n = 6): normal control, diabetic control, diabetic-hypertensive control and lisinopril-, valsartan- and combination-treated diabetic-hypertensive groups (5 mg/kg/drug/day, p.o., for 21 days). Blood glucose, blood pressure, body weight, kidney weight to body weight ratio, serum albumin, creatinine, total protein and urea were measured and recorded every week. Nephrin and VEGF-A gene expression were measured using real-time polymerase chain reaction. Renal nephrin protein was measured using ELISA as well as nephrin immunostaining. Results: Blood pressure was significantly decreased by all treatments (P ≤ 0.05). All treatments normalised serum albumin and urea. Serum creatinine significantly decreased, while total protein significantly increased (P ≤ 0.05). Nephrin gene expression had a non-significant decrease in diabetic-hypertensive rats, yet it was statistically increased with individual treatments (P ≤ 0.05) and normalised with combined treatment. Renal nephrin protein significantly decreased in diabetic-hypertensive rats, normalised by lisinopril and significantly increased by valsartan and combined treatments (P ≤ 0.05). VEGF-A expression significantly increased in diabetic-hypertensive rats and significantly decreased with lisinopril and valsartan monotherapy and normalised with combined treatment (P ≤ 0.05). Immunostaining of nephrin also showed an obvious increase in the case of combined treatment. Conclusion: Early dual blockade of RAS in diabetic-hypertensive rats protected against renal damage and improved renal nephrin and VEGF-A gene expression as well as renal nephrin protein expression.

Blockade of the renin-angiotensin system as a therapeutic target of NAFLD: results of an experimental model of hypercholesterolemia

Abstract Background/Introduction Non-alcoholic fatty liver disease (NAFLD) is often associated with metabolic syndrome (MS) and its components, including systemic arterial hypertension (SAH). In a recently published meta-analysis, the estimated prevalence of SAH in patients with NAFLD was 39.34%. Recently published observational studies have shown that the presence of NAFLD is independently associated with an increased risk of identifying SAH. Therefore, we can infer that we will often have to treat SAH in patients with NAFLD and that potential beneficial effects of the antihypertensive drug, in this context, may influence the choice of the respective drug. Purpose To evaluate the effects of olmesartan in an animal model of NAFLD (hypercholesterolemic rabbits). Methods 34 rabbits divided into 3 groups: control group (CG) n=13, olmesartan group (OG) n=12 and normal control group (NCG) n=9. The NCG received standard chow for laboratory rabbits, the CG and OG received standard chow plus 1% cholesterol. The OG was medicated with olmesartan 1 mg/kg/day throughout the study period (8 weeks), and the three groups were euthanised in the eighth week. Serum levels of glucose, total cholesterol, triglycerides, creatinine, aspartate aminotransferase (AST) and alanine aminotransferase were evaluated at baseline and euthanasia, and liver tissue samples were taken in the euthanasia from the three groups. Haematoxylin-eosin stained slides were analysed based on the histological scoring system for NAFLD, Gomori,s trichrome stained slides were used for further evaluation of fibrosis, and immunostained slides with antibodies anti-nitric oxide synthase inducible (iNOS) for hepatic oxidative stress analysis. Results The steatosis (p=0.013), lobular inflammation (p&amp;lt;0.001), ballooning (p=0.039), and fibrosis (p=0.015) scores were significantly lower in the OG compared to the CG. Similarly, NAFLD activity scores were significantly lower in OG compared to CG. The hepatic expression of iNOS was significantly lower in OG than CG (P=0.001). The serum variables results suggest no direct effect of olmesartan in any of them. Conclusion(s) Olmesartan significantly attenuated hepatic oxidative stress, the development of steatosis, lobular inflammation, ballooning, fibrosis and steatohepatitis. Therefore, it suggests that olmesartan may be considered a potentially suitable option for hypertensive patients with NAFLD. Funding Acknowledgement Type of funding sources: None.

Comparative effectiveness of sacubitril/valsartan versus angiotensin converting enzyme inhibitors/angiotensin receptor blockers in de novo heart failure patients

Abstract Introduction Effective use of pharmacological therapy in de novo heart failure (HF) patients is key for slowing down the progression of HF. Randomised clinical trials have shown sacubitril/valsartan (sac/val), providing superior benefit over renin angiotensin system (RAS) blockade with angiotensin converting enzyme inhibitors (ACEi) in patients with HF with reduced ejection fraction (HFrEF) including de novo HF patients. However, real world evidence is scarce. Purpose To compare the rate of all-cause hospitalisations in a real world de novo HFrEF US patient population after initiating sac/val or initiating or continuing RAS blockade with ACEi or angiotensin receptor blockers (ARB) within one year of index date. Methods This retrospective, non-interventional cohort study included adult de novo HFrEF patients (left ventricular ejection fraction ≤40%), from the Optum Electronic Health Records, from Jan 2016 to Mar 2020 (study period: Dec 2013–Mar 2021) who were prescribed sac/val or ACEi/ARB within 30 days of a new HF diagnosis. Patients either with any history of HF in the prior two years or with prior sac/val treatment were excluded. Index date was defined as the first prescription of sac/val or ACEi/ARB after a new HF diagnosis (≤30 days prior to index). One-to-two greedy propensity score matching was used to balance the study arms on demographics and clinical covariates (medications, LVEF, selected comorbidities). Negative binomial models were used to compare the primary endpoint between treatment groups and across subgroups of interest. The primary endpoint was the rate of all-cause hospitalisations within one year from index. Treatment groups were stratified by age, sex, race, ethnicity, history of myocardial infarction, comorbidities and prior ACEi/ARB treatment. Statistical analyses were conducted using R and SAS software. Results Prior to matching, 3,290 patients were initiated on sac/val, 47,678 on ACEi/ARB and post-matching there were 3,290 patients on sac/val and 6,580 patients on ACEi/ARB. Patients with prior ACEi/ARB treatment in both the groups were 1,597 and 2,806, respectively. Mean age was 63.5 in sac/val and 63.7 years in ACEi/ARB groups. After propensity-score matching, the annual rate (per person-year) of all-cause hospitalisation was lower in sac/val compared with ACEi/ARB group, with incidence rate ratio (IRR) of 0.81 (95% confidence interval [CI]: 0.74–0.90) ≤1 year from index. Similarly, in the ACEi/ARB treatment naïve subgroup, sac/val treatment led to 20% reduction in the primary endpoint (IRR: 0.80, 95% CI: 0.69–0.92) compared with ACEi/ARB. Amongst subgroups, results were consistent for most, with significant reduction seen in all-cause hospitalisation rates with sac/val treatment vs. ACEi/ARB. Conclusion Treatment with sac/val vs. ACEi or ARB significantly reduced the risk of all-cause hospitalisations in this real-world study supporting the first-line use of sac/val in treating de novo HFrEF patients. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis Pharma AG

Evaluation of non-linear heart rate variability using multi-scale multi-fractal detrended fluctuation analysis in mice: Roles of the autonomic nervous system and sinoatrial node.

Nonlinear analyses of heart rate variability (HRV) can be used to quantify the unpredictability, fractal properties and complexity of heart rate. Fractality and its analysis provides valuable information about cardiovascular health. Multi-Scale Multi-Fractal Detrended Fluctuation Analysis (MSMFDFA) is a complexity-based algorithm that can be used to quantify the multi-fractal dynamics of the HRV time series through investigating characteristic exponents at different time scales. This method is applicable to short time series and it is robust to noise and nonstationarity. We have used MSMFDFA, which enables assessment of HRV in the frequency ranges encompassing the very-low frequency and ultra-low frequency bands, to jointly assess multi-scale and multi-fractal dynamics of HRV signals obtained from telemetric ECG recordings in wildtype mice at baseline and after autonomic nervous system (ANS) blockade, from electrograms recorded from isolated atrial preparations and from spontaneous action potential recordings in isolated sinoatrial node myocytes. Data demonstrate that the fractal profile of the intrinsic heart rate is significantly different from the baseline heart rate in vivo, and it is also altered after ANS blockade at specific scales and fractal order domains. For beating rate in isolated atrial preparations and intrinsic heart rate in vivo, the average fractal structure of the HRV increased and multi-fractality strength decreased. These data demonstrate that fractal properties of the HRV depend on both ANS activity and intrinsic sinoatrial node function and that assessing multi-fractality at different time scales is an effective approach for HRV assessment.

Hypertension Management in Patients with Chronic Kidney Disease.

Hypertension and chronic kidney disease are closely linked. Patients with chronic kidney disease have hypertension almost universally and uncontrolled hypertension accelerates the decline in kidney function. The pathophysiology of hypertension in chronic kidney disease is complex, but is largely related to reduced nephron mass, sympathetic nervous system overactivation, involvement of the renin-angiotensin-aldosterone system, and generalized endothelial dysfunction. Consensus guidelines for blood pressure targets have adopted a blood pressure <120/80 mm Hg in native chronic kidney disease and <130/80 mm Hg in kidney transplant recipients. Guidelines also strongly advocate for renin-angiotensin-aldosterone system blockade as the first-line therapy.

The Association of Renin-Angiotensin System Blockades and Mortality in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease and Acute Respiratory Failure: A Retrospective Cohort Study.

BackgroundAcute respiratory failure (ARF) is a common cause of admission to the intensive care unit (ICU) for patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). There is still a lack of effective interventions and treatments. ACE inhibitors (ACEI)/ angiotensin II receptor blockers (ARB) were effective in COPD patients. We aimed to study the effect of ACEI/ARB use on AECOPD combined with ARF and evaluate the effect of in-hospital continuation of medication.MethodsWe included patients with AECOPD and ARF from the Medical Information Bank for Intensive Care (MIMIC-III) database. MIMIC III is a large cohort database from Boston, USA. Patients were divided into two groups according to the use of ACEI/ARB before admission. Propensity score matching (PSM) was used to reduce potential bias between the two groups. Cox regression and Kaplan-Meier curves compared 30-day mortality in ACEI/ARB users and non-users. We also defined and analyzed the use of in-hospital ACEI/ARB. Multiple models were used to ensure the robustness of the findings. Subgroup analysis was used to analyze the variability between groups.ResultsA total of 544 patients were included in the original study. After PSM, 256 patients were included in the matched cohort. Multivariate Cox regression showed 30-day mortality was significantly lower in ACEI/ARB users compared with controls (HR = 0.50, 95% CI: 0.29–0.86, p= 0.013). In PSM and inverse probability-weighted models, the results are stable Continued in-hospital use of ACEI/ARB remains effective (HR 0.40, 95% CI 0.22–0.74, p = 0.003). Kaplan-Meier showed a significant difference in survival between the two groups.ConclusionThis study found that pre-hospital ACEI/ARB use was associated with reduced mortality in patients with AECOPD and ARF.

Up-Date on Diabetic Nephropathy.

Diabetes is one of the leading causes of kidney disease. Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease (ESKD) worldwide, and it is linked to an increase in cardiovascular (CV) risk. Diabetic nephropathy (DN) increases morbidity and mortality among people living with diabetes. Risk factors for DN are chronic hyperglycemia and high blood pressure; the renin-angiotensin-aldosterone system blockade improves glomerular function and CV risk in these patients. Recently, new antidiabetic drugs, including sodium–glucose transport protein 2 inhibitors and glucagon-like peptide-1 agonists, have demonstrated additional contribution in delaying the progression of kidney disease and enhancing CV outcomes. The therapeutic goal is regression of albuminuria, but an atypical form of non-proteinuric diabetic nephropathy (NP-DN) is also described. In this review, we provide a state-of-the-art evaluation of current treatment strategies and promising emerging treatments.

Multimodal Blockade of the Renin-Angiotensin System Is Safe and Is a Potential Cancer Treatment for Cats.

Simple SummaryAs activation of the renin-angiotensin system (RAS) promotes cancer cell growth, medications that inhibit RAS activation could reduce cancer progression. However, studies in people in which RAS has been inhibited by a single treatment have not been consistently beneficial, possibly as RAS can be activated by many different cellular pathways. Multiple treatments have been used to more consistently block RAS in people, but such multimodal treatments have never previously been evaluated in veterinary species. In the present study, the safety of multimodal RAS inhibition using a combination of five treatments was assessed in six cats with cancer. Cats were treated for 8 weeks and none of the cats developed low blood pressure, evidence of kidney or liver disease, or significant adverse effects. Of the six cats enrolled in the study, one cat was withdrawn from the study due to difficulties administering the medications and another cat died of an unrelated cause. Two cats were euthanatized due to cancer progression during the study period while two cats completed the 8-week treatment period. The study showed that a multimodal blockade of RAS has the potential to be a safe and cost-effective treatment for cancer in cats.The role of the renin-angiotensin system (RAS) in cancer growth and progression is well recognized in humans. However, studies on RAS inhibition with a single agent have not shown consistent anticancer effects, potentially due to the neoplastic cells utilizing alternative pathways for RAS activation. To achieve more complete RAS inhibition, multimodal therapy with several medications that simultaneously block multiple steps in the RAS has been developed for use in humans. In the present study, the safety of multimodal RAS inhibition using atenolol, benazepril, metformin, curcumin, and meloxicam was assessed in six cats with squamous cell carcinomas. Cats were treated for 8 weeks, with blood pressure measured and blood sampled five times during the treatment period. None of the cats developed hypotension, azotemia, or increased serum liver enzyme concentrations. The packed cell volume of one cat decreased to just below the reference range during treatment. One cat was reported to have increased vomiting, although this occurred infrequently. One cat was withdrawn from the study due to difficulties administering the medications, and another cat died of an unrelated cause. Two cats were euthanatized during the study period due to cancer progression. Two cats completed the 8-week study period. One was subsequently euthanized due to cancer progression while the other cat is still alive 32 weeks after entering the study and is still receiving the multimodal blockade of the RAS. This is the first evaluation of multimodal blockade of the RAS in veterinary species. The study showed that the treatment is safe, with only mild adverse effects observed in two treated cats. Due to the small number of cats, the efficacy of treatment could not be evaluated. However, evidence from human studies suggests that a multimodal blockade of RAS could be a safe and cost-effective treatment option for cancer in cats.

Sodium-Glucose Cotransporter-2 Inhibitor and Glucagon-Like Peptide-1 Receptor Agonist Combination Therapy in Type 2 Diabetes: Protocol for a Kidney End Points Real-world Study (COMBi-KID Study).

BackgroundSodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are both considered to be part of standard care in the management of glycemia in type 2 diabetes. Recent trial evidence has indicated benefits on primary kidney end points for individual drugs within each medication class. Despite the potential benefits of combining SGLT2is and GLP-1RAs for glycemia management, according to national and international guideline recommendations, there is currently limited data on kidney end points for this drug combination.ObjectiveThe aims of the study are to assess the real-world effects of combination SGLT2i and GLP-1RA therapies for diabetes management on kidney end points, glycemic control, and weight in people with type 2 diabetes who are being treated with renin-angiotensin system blockade medication.MethodsThis retrospective cohort study will use the electronic health records of people with type 2 diabetes that are registered with general practices covering over 15 million people in England and Wales and are included in the Oxford-Royal College of General Practitioners Research and Surveillance Centre network. A propensity score–matched cohort of prevalent new users of SGLT2is and GLP-1RAs and those who have been prescribed SGLT2is and GLP-1RAs in combination will be identified. They will be matched based on drug histories, comorbidities, and demographics. A repeated-measures, multilevel, linear regression analysis will be performed to compare the mean change (from baseline) in estimated glomerular filtration rate at 12 and 24 months between those who switched to combined therapy and those continuing monotherapy with an SGLT2i or GLP-1RA. The secondary end points will be albuminuria, serum creatinine level, glycated hemoglobin level, and BMI. These will also be assessed for change at the 12- and 24-month follow-ups.ResultsThe study is due to commence in March 2022 and is expected to be complete by September 2022.ConclusionsOur study will be the first to assess the impact of combination SGLT2i and GLP-1RA therapy in type 2 diabetes on primary kidney end points from a real-world perspective.International Registered Report Identifier (IRRID)PRR1-10.2196/34206

Progress in the management of patients with diabetes and chronic kidney disease.

Diabetic kidney disease is the most common cause of chronic kidney disease (CKD) and end-stage kidney disease in the world. Risk factor modification, glucose control, and renin-angiotensin-aldosterone system blockade have remained the standard of care for 2 decades. New therapeutic agents have emerged in recent years, demonstrating kidney and cardiovascular benefits, and herein we review recent clinical trials on this topic. After the publication of several cardiovascular outcome trials for sodium-glucose cotransporter 2 inhibitors (SGLT-2i), new trials have focused ON primary kidney-specific outcomes demonstrating safety and benefits among patients with proteinuric CKD; patients with or without diabetes, and heart failure with preserved ejection fraction (HFpEF) respectively. Similarly, nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs) and glucagon-like-peptide 1 receptor agonists (GLP-1 RAs) have improved cardiovascular and kidney outcomes. Recently, clinical practice guidelines have also been updated to reflect this new evidence. In summary, SGLT-2i, GLP-1 RAs, and ns-MRAs have demonstrated cardiovascular and kidney benefits, including all-cause and cardiovascular mortality, progression to end-stage kidney disease, and hospitalizations for heart failure exacerbation among diverse patient population.

Effects of sodium-glucose cotransporter-2 inhibitors and aldosterone antagonists, in addition to renin-angiotensin system antagonists, on major adverse kidney outcomes in patients with type 2 diabetes and chronic kidney disease: A systematic review and network meta-analysis.

To compare the efficacy of sodium-glucose cotransporter-2 (SGLT2) inhibitors, nonsteroidal mineralocorticoid receptor antagonists (MRAs), selective aldosterone antagonists and nonselective aldosterone antagonists, on top of renin-angiotensin-aldosterone system (RAAS) blockade, in reducing kidney-specific composite events, cardiovascular outcomes, and other events of special interest in participants with type 2 diabetes (T2D) and chronic kidney disease (CKD). PubMed, EMBASE and CENTRAL were searched for studies published up to January 20, 2022. Randomized clinical trials enrolling participants with T2D and CKD were included, in which SGLT2 inhibitors, nonsteroidal MRAs, selective aldosterone antagonists and nonselective aldosterone antagonists were compared with either each other, or with placebo or no treatment. A network meta-analysis using a Bayesian approach was performed. The primary outcome was a kidney-specific composite event. Secondary outcomes included death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, and all-cause mortality. We also examined blood pressure and safety outcomes of interest, including acute kidney injury, hyperkalaemia, hyponatraemia, and volume reduction events. All research was conducted according to a protocol registered in the PROSPERO database (CRD42022307113). This meta-analysis of 17 trials randomizing 22 981 participants found SGLT2 inhibitors (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.52 to 0.73) and nonsteroidal MRAs (OR 0.76, 95% CI 0.66 to 0.88) were associated with significantly lower kidney-specific composite events than the control groups. Nonsteroidal MRAs (OR 0.78, 95% CI 0.66 to 0.92) and SGLT2 inhibitors (OR 0.57, 95% CI 0.45 to 0.72) were associated with greater reductions in hospitalization for heart failure than the control groups. SGLT2 inhibitors were associated with a lower risk of hospitalization for heart failure events compared with nonsteroidal MRAs (OR 0.73, 95% CI 0.55-0.97). SGLT2 inhibitors were associated with a reduction in cardiovascular death (OR 0.80, 95% CI 0.65 to 0.98) and all-cause mortality (OR 0.79, 95% CI 0.66 to 0.93) compared with the control groups. When compared to the control groups, both nonsteroidal MRAs (weighted mean difference [WMD] -10.96, 95% CI -20.49 to -1.46) and SGLT2 inhibitors (WMD -3.50, 95% CI -6.01 to -1.013) were linked with lower systolic blood pressure, nonsteroidal MRAs (OR 2.27, 95% CI 2.02 to 2.56) and nonselective aldosterone antagonists (OR 3.22, 95% CI 1.43 to 7.66) were associated with an increased risk of hyperkalaemia, nonsteroidal MRAs were linked with an increased risk of hyponatraemia (OR 16.56, 95% CI 2.78 to 455.19), and SGLT2 inhibitors were associated with an increased risk of volume reduction events (OR 1.28, 95% CI 1.06 to 1.56). SGLT2 inhibitors were ranked the best for our primary and secondary outcomes. Confidence in the evidence was often high or moderate. In this network meta-analysis, the use of SGLT2 inhibitors or nonsteroidal MRAs, combined with RAAS blockade, was associated with a reduction in kidney-specific composite events and hospitalization for heart failure events in patients with T2D and CKD compared to placebo or no treatment. SGLT2 inhibitors were associated with a lower risk of hospitalization for heart failure events compared with nonsteroidal MRAs. Use of SGLT2 inhibitors was associated with lower mortality than placebo or no treatment.

Heart Failure in Cardiac Rehabilitation: A REVIEW AND PRACTICAL CONSIDERATIONS.

Exercise cardiac rehabilitation (CR) represents an evidence-based therapy for patients with heart failure with reduced ejection fraction (HFrEF) and this article provides a concise review of the relevant exercise testing and CR literature, including aspects unique to their care. A hallmark feature of HFrEF is exercise intolerance (eg, early-onset fatigue). Drug therapies for HFrEF target neurohormonal pathways to blunt negative remodeling of the cardiac architecture and restore favorable loading conditions. Guideline drug therapy includes β-adrenergic blocking agents; blockade of the renin-angiotensin system; aldosterone antagonism; sodium-glucose cotransport inhibition; and diuretics, as needed. Various assessments are used to quantify exercise capacity in patients with HFrEF, including peak oxygen uptake measured during an exercise test and 6-min walk distance. The mechanisms responsible for the exercise intolerance include abnormalities in ( a ) central transport (chronotropic response, stroke volume) and ( b ) the diffusion/utilization of oxygen in skeletal muscles. Cardiac rehabilitation improves exercise capacity, intermediate physiologic measures (eg, endothelial function and sympathetic nervous system activity), health-related quality of life (HRQoL), and likely clinical outcomes. The prescription of exercise in patients with HFrEF is generally similar to that for other patients with cardiovascular disease; however, patients having undergone an advanced surgical therapy do present with features that require attention. Few patients with HFrEF enroll in CR and as such, many miss the derived benefits, including improved exercise capacity, a likely reduction in risk for subsequent clinical events (eg, rehospitalization), improved HRQoL, and adoption of disease management strategies.

Treatment potential in APOL1-associated nephropathy.

More than 5 million African-Americans, and millions more in Africa and worldwide, possess apolipoprotein L1 gene (APOL1) high-risk genotypes with an increased risk for chronic kidney disease. This manuscript reviews treatment approaches for slowing the progression of APOL1-associated nephropathy. Since the 2010 discovery of APOL1 as a cause of nondiabetic nephropathy in individuals with sub-Saharan African ancestry, it has become apparent that aggressive hypertension control, renin-angiotensin system blockade, steroids and conventional immunosuppressive agents are suboptimal treatments. In contrast, APOL1-mediated collapsing glomerulopathy due to interferon treatment and HIV infection, respectively, often resolve with cessation of interferon or antiretroviral therapy. Targeted therapies, including APOL1 small molecule inhibitors, APOL1 antisense oligonucleotides (ASO) and inhibitors of APOL1-associated inflammatory pathways, hold promise for these diseases. Evolving therapies and the need for clinical trials support the importance of increased use of APOL1 genotyping and kidney biopsy. APOL1-associated nephropathy includes a group of related phenotypes that are driven by the same two genetic variants in APOL1. Clinical trials of small molecule inhibitors, ASO, and inflammatory pathway inhibitors may improve outcomes in patients with primary forms of APOL1-associated nephropathy.

INCIDENCE AND UPDATES MANAGEMENT OF DIABETIC RETINOPATHY

One of the biggest causes of vision loss in the globe is diabetic retinopathy (DR), a consequence of diabetes. Despite significant attempts to lower the prevalence of vision impairment, DR continues to grow. There is damage to the vascular endothelial cells as the first pathophysiology of DRcells and a decrease in pericytes. As a result of the hypoxic reactions that follow, vascular endothelialvascular endothelial growth factor (VEGF) The most effective treatment available right nowControlling blood sugar levels is the key to preventing diabetic retinopathy and diabetic macular edema (DME). Superior in every way Laser therapy, anti-VEGF therapy, steroid therapy, and vitrectomy are all necessary treatments in these situations. Photocoagulation of the retinal pigment epithelium There is strong evidence that non-proliferative diabetic retinopathy (NPDR) is a viable treatment option.results that can be used to keep DR from progressing further. Furthermore, laser therapy has proven to be effective.For example, grid and subthreshold diode laser micropulse photocoagulation (SDM) for DME has been used.reported. In cases of vitreous hemorrhage or tractional retinal detachment in PDR patients, vitrectomy has been undertaken. There has also been significant interest in the ability of anti-VEGF medication to slow the progression of PDR from DME patients. Even with these therapies, many individuals with DR are still at risk of losing their eyesight and developing potentially dangerous side effects.. In the most advanced stages of DR, laser photocoagulation and vitrectomy are effective treatments for preventing severe vision loss. Both approaches, however, have their limitations. Evidence from preclinical and clinical studies shows that targeting renin-angiotensin system inhibition, vascular endothelial growth factor, and renin-angiotensin system blockade can reduce cardiovascular disease risk.the growth hormone, corticosteroids and protein kinase C.DR may be treated with these methodsMethodsThe study between January 2017 and November 2020 total number of patients 2968, Retrospective three year analysis.ResultsIncidence of referable retinopathy was independently associated with known duration of diabetes, age at diagnosis, and use of insulin treatment. For participants needing insulin treatment with a duration of diabetes of 10 years or more, cumulative incidence of referable retinopathy at one and three years was 9.61 and 30.99 per 1000 people, respectively.