Angiotensin Receptor Blockade Research Articles

Combining angiotensin receptor blockade and enzyme replacement therapy for vascular disease in mucopolysaccharidosis type I

Vascular involvement in the genetic disorder mucopolysaccharidosis type I (MPS I) has features of atherosclerotic disease near branch points of arterial vasculature, such as intimal thickening with disruption of the internal elastic lamina, and proliferation of macrophages and myofibroblasts. Inflammatory pathways are implicated in the pathogenesis of vascular disease in MPS I animal models, evidenced by cytokines like CD18 and TGF-β within arterial plaques. The angiotensin II-mediated inflammatory pathway is well studied in human atherosclerotic coronary artery disease. Recent work indicates treatment with the angiotensin receptor blocker losartan may improve vascular MPS I disease in mouse models. Here, we combined losartan with the standard therapy for MPS I, enzyme replacement therapy (ERT), to measure effects on cytokines in serum and aortic vasculature. Each treatment group (losartan, ERT, and their combination) equally normalized levels of cytokines that were largely differential between normal and mutant mice. Some cytokines, notably CD30 ligand, Eotaxin-2, LIX, IL-13, IL-15, GM-CSF, MCP-5, MIG, and CCL3 showed elevations in mice treated with ERT above normal or mutant levels; these elevations were reduced or absent in mice that received losartan or combination therapy. The observations suggest that losartan may impact inflammatory cascades due to MPS I and may also blunt inflammation in combination with ERT.

Retraction Note: Mechanisms Involved in Superiority of Angiotensin Receptor Blockade over ACE Inhibition in Attenuating Neuropathic Pain Induced in Rats

Retraction Note: Mechanisms Involved in Superiority of Angiotensin Receptor Blockade over ACE Inhibition in Attenuating Neuropathic Pain Induced in Rats

#4321 ACTION3 PHASE 3 STUDY: EVALUATING A NOVEL THERAPEUTIC STRATEGY OF A CCR2 INHIBITOR (DMX-200) WITH ANGIOTENSIN RECEPTOR BLOCKADE IN FSGS

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is a disease of podocytes. Complications include nephrotic syndrome and progressive kidney failure. FSGS is a condition with high unmet need and there is no approved treatment. The angiotensin II receptor type 1 (AT1R) and chemokine receptor 2 (CCR2) are G protein coupled receptors that form functional heteromers. Simultaneous antagonism of these receptors suggested synergistic renoprotective effects in preclinical and early phase clinical studies of proteinuric kidney disease. DMX-200 (repagermanium) is a C-C chemokine receptor type 2 (CCR2) inhibitor that, when administered concurrently with an angiotensin II receptor blocker (ARB), is designed to inhibit recruitment of monocytes implicated in the inflammatory chemokine environment of chronic disease. In a Phase 2a open-label study of 27 patients with proteinuric chronic kidney disease, 25% of patients achieved > 50% reduction in uPCR with combined use of DMX-200 and irbesartan. A Phase 2a placebo-controlled cross-over study in 8 patients with primary FSGS receiving stable dose of irbesartan demonstrated evidence of promising efficacy with clinically relevant reduction in uPCR of 17% with DMX-200 compared with placebo. These encouraging data suggest that treatment with DMX-200 may result in clinically meaningful reduction in proteinuria when added to ARB in patients with glomerular diseases such as FSGS. Proteinuria reduction is a positive prognostic sign for preserving kidney function. The observations from earlier trials have led to the initiation of an international randomised double-blind, placebo-controlled Phase 3 clinical trial (ACTION3) to further evaluate the efficacy of DMX-200 in patients with FSGS receiving an ARB. Method Eligible patients are adults (18-80 years) with biopsy-proven primary FSGS, genetic FSGS or FSGS of undetermined cause (FSGS-UC), and uPCR of >1.5g/g based on 24hr urine collection and eGFR of ≥25 ml/min/1.73 m2. Blood pressure ≤160/100 mmHg and BMI ≤40kg/m2. Patients with secondary FSGS or those treated with strong immunomodulatory agents (other than corticosteroids) are excluded. All patients are required to receive concomitant ARB treatment at a dose of at least 50% of the maximum approved dose according to the relevant product label. Patients receiving ACE-inhibitors are required to switch to an ARB. Other background therapies such as SGLT-2 inhibitors and mineralocorticoid receptor antagonists are permitted if receiving a stable dose in the 3 months prior to screening. Patients are randomized in a 1:1 ratio to DMX-200 (120 mg twice daily) or placebo. The primary objective is to evaluate the efficacy of DMX-200 on reduction in PCR after 35 weeks of treatment and eGFR slope after 104 weeks of treatment. Secondary objectives are safety and tolerability of DMX-200 and to evaluate the effect of DMX-200 on response criteria and composite endpoint of worsening kidney function. Exploratory objectives include assessment of changes in inflammatory biomarkers such as MCP-1 and the pharmacokinetic profile of DMX-200. Two interim analyses (IA) are planned, first planned IA for futility will be performed by an Independent Data Monitoring Committee after the first ​72 randomized patients (36 patients per group) complete 35 weeks ​of treatment. A second IA will be performed once approximately​ 144 enrolled patients complete 35 weeks ​of treatment.​ The final analysis will be performed once approximately 286 patients complete 104 weeks of treatment. The study is currently open in 11 countries at approximately 75 investigational sites and will be expanded to include more countries and sites subject to a successful first interim analysis. Results ACTION3 is a trial in progress and is expected to be completed in 2026. Conclusion ACTION3 is a Phase 3 randomized, placebo-controlled efficacy and safety trial which evaluates the novel approach of combining an investigational CCR2 inhibitor, DMX-200, with angiotensin receptor blockade in patients with FSGS.

PS-R04-9: REVERSIBLE ACUTE RENAL INJURY IN MALIGNANT HYPERTENSION DURING LONG-TERM FOLLOW-UP

Background: Malignant hypertension is a disease characterized by severe hypertension and multi-organ damage. Although mortality and renal prognosis have improved with antihypertensive therapy, progression to end-stage renal disease remains a leading cause of morbidity and mortality. Case presentation: A 37-year-old man with a history of untreated hypertension and proteinuria was referred to our hospital with complaints of right paralysis. He was diagnosed with left putaminal hemorrhage and treated with conservative blood pressure reduction management. He was also complicated with severe hypertension (blood pressure 231/146 mmHg), acute renal failure (BUN 39 mg/dl, serum creatinine 4.01 mg/dl, urinary protein 2.848 g/gCre), and heart failure with preserved ejection fraction (BNP 373 pg/ml). Initial evaluation demonstrated hyperreninemia (32.6 ng/ml/hr) with hyperaldosteronism (125 pg/ml), consistent with malignant hypertension. Secondary hypertension, such as primary aldosteronism, Cushing's syndrome, pheochromocytoma, and renal artery stenosis was excluded by further examination. His renal size was mildly atrophic assessed by CT scan, suggesting a history of chronic kidney disease. At first, we gradually decreased blood pressure with antihypertensive agents except for angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blockade (ARB) so as not to induce exacerbation of renal function via glomerular ischemia. In the long-term, he was treated to achieve a tight blood pressure control to systolic blood pressure of 100–110 mmHg with the combination of ACE inhibitor, calcium channel blocker, and alpha/beta blocker. Although his clinical course showed gradual recovery of renal function, our conservative approach successfully induced renal function recovery over six months of follow-up (BUN 27 mg/dl, serum creatinine 2.26 mg/dl, urinary protein 0.154 g/gCre). Discussion: Previous reports suggest that malignant nephrosclerosis may recover slowly if the blood pressure is tightly controlled during the follow-up. From a long-term perspective, tight blood pressure control with inhibition of the renin-angiotensin-aldosterone system, which is a critical factor of the pathogenesis in malignant hypertension, may provide beneficial effects on the renal prognosis of malignant hypertension.

Angiotensin receptor blockade and stereotactic body radiation therapy for early stage lung cancer ARB & SBRT for early stage lung cancer

ABSTRACT Stereotactic body radiotherapy (SBRT) demonstrates excellent local control in early stage lung cancer, however a quarter of patients develop recurrence or distant metastasis. Transforming growth factor-beta (TGF-β) supports metastasis and treatment resistance, and angiotensin receptor blockade (ARB) indirectly suppresses TGF-β signaling. This study investigates whether patients taking ARBs while undergoing SBRT for early stage lung cancer exhibited improved overall survival (OS) or recurrence free survival (RFS) compared to patients not taking ARBs. This was a single institution retrospective analysis of 272 patients treated with SBRT for early stage lung cancer between 2009 and 2018. Patient health data was abstracted from the electronic medical record. OS and RFS were assessed using Kaplan–Meier method. Log-rank test was used to compare unadjusted survival between groups. Univariable and multivariable Cox proportional hazard regression models were used to estimate hazard ratios (HRs). Of 247 patients analyzed, 24 (10%) patients took ARBs for the duration of radiotherapy. There was no difference in mean age, median tumor diameter, or median biologic effective dose between patients taking ARBs or not. Patients taking ARBs exhibited increased OS (ARB = 96.7 mo.; no ARB = 43.3 mo.; HR = 0.25 [95% CI: 0.10 to 0.62, P = .003]) and increased RFS (median RFS, ARB = 64.3 mo.; No ARB = 35.1 mo.; HR = 0.26 [95% CI: 0.10 to 0.63, P = .003]). These effects were not seen in patients taking angiotensin converting enzyme inhibitors (ACEIs) or statins. ARB use while undergoing SBRT for early stage lung cancer may increase OS and RFS, but ACEI use does not show the same effect.

Abstract 11532: Cardiac Complications in Polyarteritis Nodosa: A Case of Multi-Vessel Coronary Occlusion Treated With 4-Vessel Coronary Artery Bypass Grafting

Polyarteritis nodosa (PAN) is a necrotizing vasculitis causing intimal proliferation, luminal narrowing, thrombosis, ischemia, and even infarction. Coronary manifestations are rare, though recent evidence suggests coronary disease may progress rapidly causing significant morbidity and mortality. We report a case of multi-vessel occlusive coronary artery disease (CAD) in a patient with systemic PAN, successfully managed with 4-vessel coronary artery bypass grafting (CABG). An obese 53-year-old male with hypertension, hyperlipidemia, and tobacco use presented with episodic epigastric pain. Serial troponins and EKGs did not suggest cardiac ischemia. Cardiac MRI showed concentric LV hypertrophy with preserved systolic function without signs of infiltrative disease or fibrosis. Abdominal CT demonstrated splenic infarction, luminal narrowing of the celiac axis, and abdominal aortic and bilateral iliac artery aneurysms. MRA revealed inflammation of the celiac, splenic, and common hepatic arteries. CT angiography revealed beading of the superior mesenteric artery and celiac trunk, indicative of vasculitis. C3 and C4 levels were elevated. Polyarteritis nodosa was felt to be his unifying diagnosis. Prior to initiating cyclophosphamide, he returned with severe epigastric pain prompting admission. Endoscopy was negative. Coronary CT showed extensive calcification. Angiography revealed multi-vessel occlusive disease patterned with ectasia. He underwent 4-vessel CABG revascularization with LIMA-LAD and SVG-OM-LPDA-RPDA. After surgery, he began prednisone, dual anti-platelet, statin, beta-blocker, and angiotensin receptor blockade with rheumatology follow-up for optimal timing of cyclophosphamide initiation. For patients with systemic inflammatory conditions, recognition of atypical anginal events is crucial as typical identifiers of atherosclerosis may not be obvious. Bypass is definitive therapy, as stenting arteritic vessels may result in neo-endothelization. Clinicians must recognize increased risk of CAD while offering appropriate primary and secondary interventions such as screening imaging and knowledge of disease distribution for appropriate graft choice.

Angiotensin receptor blockade is associated with increased risk of giant cell arteritis.

Angiotensin II is implicated in GCA pathology. We examined whether the use of angiotensin receptor blockers (ARBs) is associated with GCA risk compared with angiotensin-converting enzyme inhibitors (ACEis) or other antihypertensives. We performed a matched cohort study including adults who were initiators of antihypertensives in UK primary care data between 1995 and 2019. Treatment-naïve individuals without prior GCA or PMR were categorized into three groups-ARB initiators, ACEi initiators, or other antihypertensive initiators (beta-blockers, calcium channel blockers, diuretics or alpha-adrenoceptor blockers)-and followed for up to 5 years. Incident GCA was defined using validated Read codes, with age of onset ≥50 years and two or more glucocorticoid prescriptions. Inverse probability-weighted Cox models were used to model outcome risk, adjusting for lifestyle parameters, comorbidities and comedications. Among >1 million new starters of antihypertensives (81 780 ARBs, 422 940 ACEis and 873 066 other antihypertensives), the incidence rate of GCA per 10 000 patient-years was 2.73 (95% CI 2.12, 3.50) in the ARB group, 1.76 (95% CI 1.25, 2.39) in the ACEi group and 1.90 (95% CI 1.37, 2.56) in the other antihypertensives group. The hazard of GCA was higher in ARB initiators [hazard ratio (HR) 1.55; 95% CI 1.16, 2.06] than initiators of ACEis, but similar between initiators of other antihypertensives and ACEis (HR 1.08; 95% CI 0.87, 1.35). Initiation of ARBs is associated with a higher risk of GCA compared with ACEis or other antihypertensives. Mechanistic studies of angiotensin receptor biology will provide further clarity for our findings.

Application of Angiotensin Receptor-Neprilysin Inhibitor in Chronic Kidney Disease Patients: Chinese Expert Consensus.

Chronic kidney disease (CKD) is a global public health problem, and cardiovascular disease is the most common cause of death in patients with CKD. The incidence and prevalence of cardiovascular events during the early stages of CKD increases significantly with a decline in renal function. More than 50% of dialysis patients die from cardiovascular disease, including coronary heart disease, heart failure, arrhythmia, and sudden cardiac death. Therefore, developing effective methods to control risk factors and improve prognosis is the primary focus during the diagnosis and treatment of CKD. For example, the SPRINT study demonstrated that CKD drugs are effective in reducing cardiovascular and cerebrovascular events by controlling blood pressure. Uncontrolled blood pressure not only increases the risk of these events but also accelerates the progression of CKD. A co-crystal complex of sacubitril, which is a neprilysin inhibitor, and valsartan, which is an angiotensin receptor blockade, has the potential to be widely used against CKD. Sacubitril inhibits neprilysin, which further reduces the degradation of natriuretic peptides and enhances the beneficial effects of the natriuretic peptide system. In contrast, valsartan alone can block the angiotensin II-1 (AT1) receptor and therefore inhibit the renin–angiotensin–aldosterone system. These two components can act synergistically to relax blood vessels, prevent and reverse cardiovascular remodeling, and promote natriuresis. Recent studies have repeatedly confirmed that the first and so far the only angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan can reduce blood pressure more effectively than renin–angiotensin system inhibitors and improve the prognosis of heart failure in patients with CKD. Here, we propose clinical recommendations based on an expert consensus to guide ARNI-based therapeutics and reduce the occurrence of cardiovascular events in patients with CKD.

Abstract 543: Inhibition Of Renin-angiotensin System Failed To Suppress Beta-aminopropionitrile-induced Thoracic Aortopathies In Mice

Objective: Cross-linking of elastin and collagen fibers is a vital process in aortic development. Pharmacological inhibition of aortic cross-linking by β-aminopropionitrile (BAPN) leads to thoracic aortopathies, such as thoracic aortic aneurysm and dissection, in mice. Although the renin angiotensin system (RAS) contributes to several types of thoracic aortopathies, it remains unclear whether inhibition of the RAS protects against aortopathy formation caused by the impairment of elastin and collagen cross-linking in mice. Approach and Results: Either vehicle or losartan (15 mg/kg/d, AT1 receptor blocker) were administered through osmotic pumps for 4 weeks in male C57BL/6J mice (3-4-weeks-old, n=30/group). BAPN (0.5% wt/vol) was given through drinking water to induce aortopathies. Losartan increased plasma renin concentrations significantly compared to vehicle-infused mice, indicating effective blockade of at1 receptors. However, losartan did not suppress BAPN-induced aortic rupture and dilatation. Since losartan is a surmountable inhibitor, we also tested the effects of irbesartan, an insurmountable inhibitor of AT1 receptor blocker, on BAPN-induced aortopathy formation (50 mg/kg/day, diet, n=30/group). Despite the significant increase of plasma renin concentrations, irbesartan did not ameliorate aortic rupture and dilatation in BAPN-administered mice. Thus, BAPN-induced thoracic aortopathies were refractory to angiotensin receptor blockade. We next inhibited angiotensinogen, the unique substrate for angiotensin II, using an antisense oligonucleotide targeting angiotensinogen (AGT-ASO). AGT-ASO decreased plasma angiotensinogen concentrations, while aortic death and dilatations were not attenuated. Since hepatocytes are the major source of angiotensinogen, BAPN-induced thoracic aortopathy formation was also examined in mice with hepatocyte-specific angiotensinogen deletion. Although plasma angiotensinogen concentrations displayed 90% reduction compared to wild type littermates, aortic rupture and aneurysm formation were not suppressed. Conclusion: Inhibition of the RAS does not attenuate BAPN-induced thoracic aortopathy formation in mice.

Additive antiproteinuric effect of pentoxifylline in patients with diabetic nephropathy under angiotensin receptor blockade: A short-term, randomized, and controlled trial

Additive antiproteinuric effect of pentoxifylline in patients with diabetic nephropathy under angiotensin receptor blockade: A short-term, randomized, and controlled trial

Medical Management of Patients With Heart Failure and Reduced Ejection Fraction.

Treatment options for patients with heart failure (HF) with reduced ejection fraction (HFrEF) have expanded considerably over the past few decades. Whereas neurohormonal modulation remains central to the management of patients with HFrEF, other pathways have been targeted with drugs that have novel mechanisms of action. The angiotensin receptor-neprilysin inhibitors (ARNIs) which enhance levels of compensatory molecules such as the natriuretic peptides while simultaneously providing angiotensin receptor blockade have emerged as the preferred strategy for inhibiting the renin angiotensin system. Sodium glucose cotransporter 2 (SGLT2) inhibitors which were developed as hypoglycemic agents have been shown to improve outcomes in patients with HF regardless of their diabetic status. These agents along with beta blockers and mineralocorticoid receptor antagonists are the core medical therapies for patients with HFrEF. Additional approaches using ivabradine to slow heart rate in patients with sinus rhythm, the hydralazine/isosorbide dinitrate combination to unload the heart, digoxin to provide inotropic support and vericiguat to augment cyclic guanosine monophosphate production have been shown in well-designed trials to have beneficial effects in the HFrEF population and are used as adjuncts to the core therapies in selected patients. This review provides an overview of the medical management of patients with HFrEF with focus on the major developments that have taken place in the field. It offers prospective of how these drugs should be employed in clinical practice and also a glimpse into some strategies that may prove to be useful in the future.

Effect of Angiotensin receptor blockade on Plasma Osmolality and Neurohumoral Responses to High Environmental Temperature in Rats Fed a High Salt Diet

Plasma osmolality (pOsmol) and neurohumoral signals play important roles in the pathophysiology of cardiovascular diseases. Our study investigated the effect of high environmental temperature (HET) on neurohumoral responses and pOsmol in rats fed a high salt diet (HSD), with and without angiotensin II receptor blockade (ARB), using telmisartan. Fifty-six male 8-week old Sprague-Dawley rats (95-110g) were randomly assigned into seven groups of 8 rats. These included control rats (I) fed with 0.3% NaCl diet (normal diet, ND); salt-loaded rats (II) fed with 8% NaCl (high salt) diet; ND rats (III) exposed to HET (38.5±0.5oC ) 4 hours daily per week; rats (IV) fed with 8% NaCl diet and exposed to HET daily. Others included rats (V) fed with 8% NaCl diet and treated with telmisartan (30mg/kg); ND rats (VI) exposed to HET and treated with telmisartan; rats (VI) fed with 8% NaCl diet, exposed to HET and treated with telmisartan. Plasma angiotensin II, aldosterone, vasopressin and norepinephrine (NE) concentrations were determined by ELISA technique; pOsmol from plasma K+, Na+ and Urea. HSD combined with HET in rats synergistically increased pOsmol (P<0.001) with an associated non-synergistic rise in fluid intake (P<0.001), fluid balance (P<0.001), plasma angiotensin II (P<0.01) and aldosterone (P<0.05), NE (P<0.001) and vasopressin (P<0.05) concentrations compared to control. Telmisartan did not alter pOsmol in all the treated-rats, but normalized fluid intake levels and plasma vasopressin in the rats exposed to either HSD or HEt alone. Prolonged exposure of rats to hot environment exacerbated the effect of excess dietary salt on pOsmol, with no effect on angiotensin II-mediated neurohumoral responses

Effect of Angiotensin receptor blockade on Plasma Osmolality and Neurohumoral Responses to High Environmental Temperature in Rats Fed a High Salt Diet.

Plasma osmolality (pOsmol) and neurohumoral signals play important roles in the pathophysiology of cardiovascular diseases. Our study investigated the effect of high environmental temperature (HET) on neurohumoral responses and pOsmol in rats fed a high salt diet (HSD), with and without angiotensin II receptor blockade (ARB), using telmisartan. Fifty-six male 8-week old Sprague-Dawley rats (95-110g) were randomly assigned into seven groups of 8 rats. These included control rats (I) fed with 0.3% NaCl diet (normal diet, ND); salt-loaded rats (II) fed with 8% NaCl (high salt) diet; ND rats (III) exposed to HET (38.5±0.5oC ) 4 hours daily per week; rats (IV) fed with 8% NaCl diet and exposed to HET daily. Others included rats (V) fed with 8% NaCl diet and treated with telmisartan (30mg/kg); ND rats (VI) exposed to HET and treated with telmisartan; rats (VI) fed with 8% NaCl diet, exposed to HET and treated with telmisartan. Plasma angiotensin II, aldosterone, vasopressin and norepinephrine (NE) concentrations were determined by ELISA technique; pOsmol from plasma K+, Na+ and Urea. HSD combined with HET in rats synergistically increased pOsmol (P<0.001) with an associated non-synergistic rise in fluid intake (P<0.001), fluid balance (P<0.001), plasma angiotensin II (P<0.01) and aldosterone (P<0.05), NE (P<0.001) and vasopressin (P<0.05) concentrations compared to control. Telmisartan did not alter pOsmol in all the treated-rats, but normalized fluid intake levels and plasma vasopressin in the rats exposed to either HSD or HEt alone. Prolonged exposure of rats to hot environment exacerbated the effect of excess dietary salt on pOsmol, with no effect on angiotensin II-mediated neurohumoral responses.

Single, Double and Triple Blockade of RAAS in Alport Syndrome: Different Tools to Freeze the Evolution of the Disease.

Background: The goal of the treatment of Alport syndrome (AS) is to delay the progression of kidney damage. The current standard of care is the use of Renin Angiotensin Aldosterone System (RAAS) blockers: angiotensin-converting enzyme inhibition (ACEi), angiotensin receptor blockade, and, recently, spironolactone (SP). Aim of the study: the purpose of this retrospective study is to evaluate the efficacy (reduction of proteinuria and changes of glomerular function) and safety of a sequential introduction of RAAS blockers up to a triple RAAS blockade in pediatric proteinuric patients with AS. Methods: in this retrospective study (1995 to 2019), we evaluated proteinuria values in AS patients, during the 12 months following the beginning of a new RAAS blocker, up to a triple blockade. ACEi was always the first line of treatment; then ARB and SP were sequentially added if uPCR increased by 50% from the basal level in 2 consecutive samples during a 3-months observation period, or when uPCR ratio was >2 mg/mg. Results: 26 patients (mean age at treatment onset was 10.55 ± 5.02 years) were enrolled. All patients were on ACEi, 14/26 were started on a second drug (6/14 ARB, 8/14 SP) after a mean time of 2.2 ± 1.7 years, 7/26 were on triple RAAS blockade after a further period of 5.5 ± 2.3 years from the introduction of a second drug. Repeated Measure Anova analysis of log-transformed data shows that the reduction of uPCR values after Time 0 from the introduction of the first, second and third drug is highly significant in all three cases (p values = 0.0016, 0.003, and 0.014, respectively). No significant changes in eGFR were recorded in any group, apart from a 15-year-old boy with X-linked AS, who developed kidney failure. One patient developed mild hyperkaliemia, and one gynecomastia and symptomatic hypotension. No life-threatening events were recorded. Conclusions: double and triple RAAS blockade is an effective and safe strategy to reduce proteinuria in children with AS. Nevertheless, we suggest monitoring eGFR and Kaliemia during follow-up.

Abstract P260: SARS-Cov-2 Spike Protein S1-Mediated Endothelial Injury And Pro-Inflammatory State Is Amplified By Dihydrotestosterone And Prevented By Mineralocorticoid Antagonism

Objectives: Men are disproportionately affected by the coronavirus disease-2019 (COVID-19) and experience higher mortality as compared to women. Endothelial dysfunction has been proposed as a major inciting factor of pro-inflammatory and thrombotic changes in COVID-19 infection. The vascular effects of androgen signaling and inflammatory cytokines in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated endothelial damage are not defined. Methods: Here, we determined the effects of SARS-CoV-2 spike protein-mediated endothelial damage under conditions of exposure to androgens and TNF-α. We tested the therapeutic effects of approved drugs: angiotensin receptor blockade by valsartan and mineralocorticoid receptor antagonism by spironolactone. Circulating endothelial injury markers VCAM-1 and E-selectin were measured in the plasma from men and women diagnosed with COVID-19. Results: Exposure of endothelial cells (ECs) in vitro to androgen dihydrotestosterone (DHT) exacerbated spike protein S1-mediated endothelial injury transcripts for cell adhesion molecules E-selectin, VCAM-1, and ICAM-1 and anti-fibrinolytic PAI-1 (P&lt;0.05), as well as increased THP-1 monocyte adhesion to ECs (P=0.032). Spironolactone dramatically reduced DHT+S1-induced endothelial activation. Pre-treatment of ECs with valsartan did not increase endothelial activation by S1. TNF-α exacerbated S1-induced EC activation and spironolactone abrogated this effect. Analysis of plasma from patients hospitalized with COVID-19 showed concordant higher VCAM-1 in men as compared to women. Conclusions: Androgen exposure promoted spike protein-mediated endothelial injury by increasing markers of inflammation and thrombosis. A beneficial therapeutic effect of the FDA-approved drug spironolactone was observed, supporting a rationale for further evaluation as an adjunct treatment in COVID-19.

Primary membranous glomerulonephritis with negative serum PLA2R in haemophilia A successfully managed with rituximab \u2013 case report and review of the literature

BackgroundHepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause a wide range of glomerular pathologies. In people with haemophilia, transfusion-associated infections with these viruses are common and definitive pathological diagnosis in this population is complicated by the difficulty of safely obtaining a renal biopsy. Membranous nephropathy (MN) is a common cause of adult onset nephrotic syndrome occurring in both primary and secondary forms. Primary MN is associated with podocyte autoantibodies, predominantly against phospholipase A2 receptor (PLA2R). Secondary disease is often associated with viral infection; however, infrequently with HIV or HCV. Distinguishing these entities from each other and other viral glomerular disease is vital as treatment strategies are disparate.Case presentationWe present the case of a 48-year-old man with moderate haemophilia A and well-controlled transfusion-associated HCV and HIV coinfection who presented with sudden onset nephrotic range proteinuria. Renal biopsy demonstrated grade two membranous nephropathy with associated negative serum PLA2R testing. Light and electron microscopic appearances were indeterminant of a primary or secondary cause. Given his extremely stable co-morbidities, treatment with rituximab and subsequent angiotensin receptor blockade was initiated for suspected primary MN and the patient had sustained resolution in proteinuria over the following 18 months. Subsequent testing demonstrated PLA2R positive glomerular immunohistochemistry despite multiple negative serum results.ConclusionsPursuing histological diagnosis is important in complex cases of MN as the treatment strategies between primary and secondary vary significantly. Serum PLA2R testing alone may be insufficient in the presence of multiple potential causes of secondary MN.

Untying the Gordian knot of sex and heart failure therapy

Untying the Gordian knot of sex and heart failure therapy

Renin Angiotensin System Inhibition as treatment for Covid-19?

Renin Angiotensin System Inhibition as treatment for Covid-19?

Inhibition of the Renin-Angiotensin System Reduces Gene Expression of Inflammatory Mediators in Adipose Tissue Independent of Energy Balance.

Obesity is a growing health problem worldwide. The renin-angiotensin system (RAS) is present in adipose tissue, and evidence suggests that it is involved in both diet-induced obesity and the inflammation associated with obesity. The present experiments determined the effect of (1) different angiotensin-converting enzyme (ACE) inhibitors (captopril, perindopril, enalapril) and angiotensin receptor blockers (ARBs: telmisartan, losartan) on adiposity of mice fed a high-fat diet for 28 days (2); acute treatment with the ACE-inhibitor captopril on gene expression of inflammatory markers in mice fed a high-fat diet (HFD); and (3) short-term (2 days) and chronic (28 days) treatment of ACE-inhibition on energy expenditure (EE) and energy balance in mice fed HFD ad libitum (AL), as well as receiving HFD limited to the amount of calories eaten by controls (pair-fed (PF) group). Body weight, food intake, adiposity and plasma leptin were lower in ACE inhibitor or ARB-treated groups over 28 days compared with HFD untreated mice. Short-term treatment with captopril led to increased EE relative to the level in the PF group. After 28 days, EE was lower in both captopril-treated and PF mice compared with AL, but the effect was greater in the captopril-treated group. Adiponectin was elevated in captopril-treated mice, but not in PF mice, after both 2 and 28 days. Additionally, acute RAS blockade in HFD-fed mice reduced mRNA expression for MCP-1, IL-6, TLR4, and leptin in adipose tissue relative to values in untreated groups. These data demonstrate that ACE inhibition and angiotensin receptor blockade reduce food intake to produce weight loss and suggest that the anti-inflammatory effects of ACE inhibition may be independent of weight loss.

MO246ESTIMATING DELAY IN TIME TO ESKD FOR TREATMENT EFFECTS ON PROTEINURIA IN IGA NEPHROPATHY AND FSGS*

Abstract Background and Aims Reduction in proteinuria is associated with lower risk of end-stage kidney disease (ESKD) in IgA nephropathy (Thompson et al, 2019) and focal segmental glomerulosclerosis (FSGS) (Troost et al, 2017). Sparsentan, a dual endothelin receptor and angiotensin II receptor antagonist, is in phase 3 clinical trials in IgA nephropathy (PROTECT) and FSGS (DUPLEX), that are powered to detect a treatment benefit on proteinuria-based endpoints versus standard of care angiotensin receptor blockade (irbesartan). In this study, we aim to estimate the delay in time to ESKD conferred by the hypothesized treatment effect of sparsentan on proteinuria in these phase 3 trials; for PROTECT, a 30% reduction in urine protein to creatine ratio (UP/C) vs irbesartan in IgA nephropathy patients, and for DUPLEX, 30% more patients achieving the new FSGS Partial Remission Endpoint (UP/C &amp;lt;1.5 g/g associated with a 40% reduction in UP/C) versus irbesartan. Methods We analysed individual patient level data from two UK registries: the first is provided by Leicester General Hospital, UK and consists of IgAN patients, and the second is the UK National Registry of Rare Kidney Disease (RaDaR) Nephrotic Syndrome cohort, with access provided by the University of Bristol, UK, including FSGS patients. IgAN patients with urine total protein value ≥1.0 g/day or UP/C ≥1.0 g/g and eGFR &amp;gt;30 mL/min at the initiation of renin-angiotensin system blockade (RASB) were identified, as were patients with primary or genetic FSGS with UP/C ≥1.5 g/g and eGFR ≥30 mL/min. The time to ESKD (eGFR &amp;lt;15 mL/min, initiation of dialysis, transplantation) or death from any cause over the patient follow-up period was analysed using accelerated failure time modelling; Weibull, Log Logistic and Log Normal distributions were applied with the fitted survivor function reported from the model with the lowest AIC. The time gained for a given reduction in risk in ESKD/death and 5-year survival was estimated under proportional hazards. Results A 30% reduction in proteinuria in IgAN patients confers a 50% lower risk of ESKD, extending the median time to ESKD by 10.7 years, from 12.4 to 23.1 years; 5-year ESKD free survival rate is also increased, from 77.7% to 88.1%. Similarly, ongoing analysis in FSGS patients indicates 30% more patients achieving the FSGS Partial Remission Endpoint confers lower risk for ESKD and increase in 5-year ESKD free survival. Conclusion The data from the Leicester General Hospital, UK and RaDaR provide invaluable insight into the longer-term natural history of IgAN and FSGS patients and time to ESKD. Therapeutic interventions that reduce proteinuria and the risk of ESKD can confer important and clinically meaningful extensions in the time patients are alive and free from ESKD.