And/or Angiotensin Receptor Blockers Research Articles

#2041 Analysis of current real-world management of IgAN in five European countries

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. Due to the often progressive nature of IgAN, patients generally face a poor prognosis if the condition is not appropriately controlled. Current treatment recommendations focus on disease management through the use of optimised supportive care, including use of an angiotensin-converting enzyme inhibitor (ACEi) and/or angiotensin receptor blocker (ARB). A physician questionnaire and patient chart review was conducted to investigate the real-world management of IgAN in five European countries. Method Between 21 December 2022 and 6 February 2023, physicians from France, Germany, Italy, Spain and the UK completed a questionnaire on IgAN management, and patient charts from their centres were analysed. Physicians included had to spend >40% of their time in a clinical setting, and have been in practice between 2 and 40 years. Physicians had to have ≥50 CKD stage 1–4 patients under their management, including ≥4 non-dialysis IgAN patients. Patient charts included in the analysis were required to be from patients ≥12 years of age, diagnosed with IgAN and not on dialysis, with an estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m2. Results A total of 261 physicians answered the questionnaire on IgAN management and completed chart audits on 473 of their most recently seen patients. Charts included in the audit were predominantly from male (71%), Caucasian (78%) patients. The mean age of patients was 47 years and 76% were in CKD stage 3 or later. At referral, 66% of patients were receiving an ACEi and/or ARB, 21% were receiving another antihypertensive agent and 6% were taking a sodium-glucose cotransporter 2 inhibitor (SGLT2i). Most patients (88%) had undergone ≥1 kidney biopsy. At the time of initial biopsy, average eGFR was 51.0 mL/min/1.73 m2 and proteinuria was 2.7 g/day. Of patients who had a biopsy, 73% had a mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T) and crescents (C) (MEST-C) score available. Due to biopsy results, 29% of patients initiated systemic steroids and 10% started an SGLT2i. On average, IgAN patients are prescribed five medications, with the number of medications increasing with age. The large majority of patients (92%) were taking an ACEi and/or ARB at the time of the most current visit; prescriptions with an ACEi and/or ARB included combination with an SGLT2i only (36%), with a systemic steroid only (10%), and with both an SGLT2i and a systemic steroid (5%). Less than half (41%) of patients were prescribed an ACEi and/or ARB alone. An ACEi and/or ARB were considered first-line therapy by 81% of physicians. Systemic steroids and SGLT2is were largely thought of as later line treatment options. The majority of physicians (66%) believed that their patients were completely adherent to their treatment regimen. Notably, over one-third (35%) of patients were on second-line therapy or later, with drivers of treatment change including increased proteinuria (31%), decreased eGFR (26%) and side effect management (15%). Over half (54%) of physicians were not completely satisfied with their patients’ overall response to treatment. Physicians anticipated that 74% of their patients would eventually progress to dialysis. Conclusion Many treating physicians are not satisfied with current treatment options for IgAN, with increasing levels of proteinuria, eGFR decline and side effects driving treatment change. Overall, this study indicates that there is a need for more effective and safe treatments for IgAN to prevent disease progression and improve prognosis.

Age at onset of type 1 diabetes between puberty and 30 years old is associated with increased diabetic nephropathy risk

Diabetic nephropathy is a critical complication of patients with type 1 diabetes, while epidemiological studies were scarce among Asian countries. We conducted a cross-sectional study to identify factors associated with diabetic nephropathy by questionnaires, using student’s t-test, chi-square test, and multivariable logistic regression. Among 898 participants, 16.7% had diabetic nephropathy. Compared with non-diabetic nephropathy patients, the patients with diabetic nephropathy had significantly higher percentage with onset age of type 1 diabetes between puberty and under 30 years old (female ≥ 12 or male ≥ 13 years old to 29 years old), longer diabetes duration, having family history of diabetes and diabetic nephropathy, accompanied with hypertension, hyperlipidemia, or coronary artery disease (CAD). Compared with patients with onset age before puberty, the odds of diabetic nephropathy occurrence increased to 1.61 times in patients with onset age between puberty and under 30 years old (p = 0.012) after adjusting diabetes duration. Age of diabetes onset between puberty and under 30 years old, diabetes duration, HbA1c, hospital admission within 3 years, diabetic retinopathy, hypertension, systolic blood pressure (SBP), triglyceride levels, and use of angiotensin converting enzyme inhibitor (ACEI) and/or angiotensin receptor blockers (ARB) were independent factors associated with diabetic nephropathy Screening for proteinuria is important in daily clinical practice and should be part of diabetes self-management education for patients with type 1 diabetes.

THE RENIN ANGIOTENSIN SYSTEM BLOCKADE DOES NOT SIGNIFICANTLY REDUCE THE RISK OF CARDIOVASCULAR EVENTS IN DIALYSIS PATIENTS: A META-ANALYSIS OF 5 RCTS

Objective: Angiotensin-converting-enzyme-inhibitors (ACEIs) and/or angiotensin-receptor-blockers (ARBs) are recommended by guidelines as first-line therapies for the management of hypertension in the general population. However, the cardioprotective benefit of these agents among patients on chronic dialysis remains uncertain. This meta-analysis aimed to explore the effect of ACEIs/ARBs on cardiovascular events in this high-risk patient population. Design and method: We searched Medline/PubMed and Cochrane database of clinical trials from inception through February 2022 to identify randomized controlled trials (RCTs) comparing the effect of ACEIs/ARBs relative to placebo or no add-on treatment in patients receiving dialysis. RCTs were eligible in quantitative data synthesis, if they were assessing fatal or non-fatal cardiovascular events as a primary efficacy endpoint. Results: We identified 5 RCTs including a total of 1,582 dialysis patients. As compared with placebo or no add-on treatment, the use of ACEIs/ARBs was not associated with a significantly lower risk of cardiovascular events [risk ratio (RR): 0.79; 95% confidence interval (CI): 0.57-1.11; I2 = 73%, P = 0.005]. Furthermore, there was no benefit of ACEIs/ARBs on cardiovascular mortality (RR: 0.82; 95% CI: 0.59-1.14; I2 = 6%, P = 0.37) and all-cause mortality (RR: 0.86; 95% CI: 0.64-1.15; I2 = 44%, P = 0.13). These results were consistent, when the included RCTs were stratified into subgroups according to the hypertension status and ethnicity of patients, sample size, duration of follow-up and method quality. Conclusions: The present meta-analysis showed that among patients on dialysis, the use of ACEIs/ARBs is not associated with a significantly lower risk of cardiovascular events and all-cause mortality as compared with placebo or no add-on treatment.

Steroid- and immunosuppressant-based protocol of Henoch-Schönlein purpura nephritis without angiotensin inhibitors in the acute phase.

The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest initially using angiotensin-converting-enzyme inhibitors (ACE-Is) and/or angiotensin receptor blockers (ARBs) to treat Henoch-Schönlein purpura nephritis (HSPN). However, these guidelines might overlook the potential benefits of aggressive therapy. Therefore, we evaluated the efficacy of an HSPN protocol that primarily uses steroids and immunosuppressants, without ACE-Is or ARBs. We determine treatment intensity based on International Study of Kidney Diseases in Children (ISKDC) grading. Fifty-one patients were treated with our protocol that primarily uses steroids and immunosuppressants. ACE-Is and ARBs were not used in the acute phase, including before renal biopsy. We evaluated the proteinuria disappearance rate, duration to proteinuria disappearance, and estimated glomerular filtration rate (eGFR) at the time of last observation and compared them to those in previous reports. Proteinuria disappeared in 49 patients (96%) within a median of 5 months. The median eGFR was 116.0 mL/min/1.73 m2 at the time of last observation. Six of 51 patients had acute kidney injury (eGFR<90 mL/min/1.73 m2) before treatment, but all recovered during the observation period (median 52 months). Our steroid- and immunosuppressant-based protocol without ACE-Is or ARBs in the acute phase of HSPN had almost equivalent efficacy to that in previous studies that used ACE-Is and/or ARBs with steroids and immunosuppressants.

Efficacy and safety of sodium glucose cotransporter 2 inhibitors plus standard care in diabetic kidney disease: A systematic review and meta-analysis

IntroductionMany people with type 2 diabetes progress to end-stage diabetic kidney disease (DKD) despite blockade of the renin-angiotensin system, suggesting the need for innovative treatment options for DKD. To capture the findings of recent studies, we performed an updated systematic review and meta-analysis of the efficacy and safety of sodium glucose co-transporter 2 (SGLT2) inhibitors combined with standard care involving angiotensin converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) on the development and progression of DKD in people with type 2 diabetes compared with standard care alone. MethodsThe Cochrane Library, MEDLINE, EMBASE, PubMed and clinical trials registers were systematically searched for randomized controlled trials published before 1 September 2022. Primary outcomes were urine albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). Secondary outcomes were glycated hemoglobin (HbA1c) and systolic blood pressure (SBP). Relative risk was calculated for adverse events. ResultsEight studies enrolling 5512 participants were included. In the meta-analysis (n = 1327), SGLT2 inhibitors were associated with a statistically significant reduction in UACR (weighted mean difference [WMD] -105.61 mg/g, 95 % CI -197.25 to −13.98, I2 = 99 %, p = 0.02). There was no statistically significant difference in relation to eGFR (n = 1375; WMD -0.23 mL/min/1.73m2, 95 % CI -4.34 to 3.89, I2 = 94 %, p = 0.91). ConclusionsSGLT2 inhibitors in addition to standard care including ACE inhibitors and/or ARBs significantly reduced albuminuria, HbA1c and SBP when compared to standard care alone, supporting their routine use in people with type 2 diabetes.

IgA Nephropathy Patient Baseline Characteristics in the Sparsentan PROTECT Study

Sparsentan is a novel single-molecule dual endothelin angiotensin receptor antagonist with hemodynamic and anti-inflammatory properties and is not an immunosuppressant. The ongoing phase 3 PROTECT trial examines sparsentan in adults with IgA nephropathy (IgAN). The PROTECT trial (NCT03762850) is a multicenter, international, randomized, double-blind, parallel-group, active-controlled study. The efficacy and safety of sparsentan versus the active control irbesartan is being evaluated in adults with biopsy-proven IgAN and proteinuria≥1.0 g/d despite maximized treatment with an angiotensin-converting enzyme inhibitor (ACEi) and/or angiotensin receptor blocker (ARB) for at least 12 weeks. Blinded and aggregated baseline characteristics are reported descriptively and compared to contemporary phase 3 trials with patients with IgAN. The primary analysis population includes 404 patients who were randomized and received study drug (median age, 46 years). Enrolled patients were from Europe (53%), Asia Pacific (27%), and North America (20%). Baseline median urinary protein excretion was 1.8 g/d. The range of estimated glomerular filtration rate (eGFR) was broad with the largest proportion of patients (35%) in chronic kidney disease (CKD) stage 3B. Before transitioning to study medication, mean systolic/diastolic blood pressure was 129/82 mmHg, with the majority of patients (63.4%) receiving the maximum labeled ACEi or ARB dose. Patients in Asian versus non-Asian regions included a higher percentage of females, had lower blood pressures, and included lower proportions of patients with a history of hypertension and baseline antihypertensive treatment. Patient enrollment in PROTECT, with differing racial backgrounds and across CKD stages, will allow for important characterization of the treatment effect of sparsentan in patients with IgAN with proteinuria at high risk of kidney failure.

Systematic review and meta-analysis of the clinical outcomes of ACEI/ARB in East-Asian patients with COVID-19.

SARS-CoV-2 invades human cells and leads to COVID-19 by direct associating with angiotensin converting enzyme 2 (ACE2) receptors, the level of which may be increased by treatment with angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs). This meta-analysis aimed to explore the impact of ACEI/ARB treatment on the clinical outcomes of patients with COVID-19 infections among population in the East-Asia region. We collected clinical data published from January 2000 to May 2022 in the English databases including PubMed, Embase, and the Cochrane Library. Two reviewers independently screened and identified studies that met the prespecified criteria. Review Manager 5.3 software was used to perform the meta-analysis. A total of 28 articles were included in this analysis. The results showed that patients who were prescribed with ACEI/ARB had a shorter duration of hospital stay [MD = -2.37, 95%CI (-3.59, -1.14), P = 0.000 2] and a lower mortality rate [OR = 0.61, 95% CI (0.52, 0.70), P<0.000 01] than patients who were not on ACEI/ARB. Furthermore, there was no statistically significant difference in disease severity [OR = 0.99, 95% CI (0.83, 1.17), P = 0.90] between individuals receiving ACEI/ARB or not. This meta-analysis suggested that the use of ACEI/ARB was not associated with adverse clinical outcomes in East-Asian Covid-19 patients and a reduced mortality and shorter duration of hospital stay among East-Asian population (especially for female subjects) was found. Thus, ACEI/ARB should be continued in patients infected by Covid-19.

Effect of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on cardiovascular outcomes in dialysis patients: a systematic review and meta-analysis.

Angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) are recommended by guidelines as first-line antihypertensive therapies in the general population or in patients with earlier stages of kidney disease. However, the cardioprotective benefit of these agents among patients on dialysis remains uncertain. We searched the MEDLINE, PubMed and Cochrane databases from inception through February 2022 to identify randomized controlled trials (RCTs) comparing the efficacy of ACEIs/ARBs relative to placebo or no add-on treatment in patients receiving dialysis. RCTs were eligible if they assessed fatal or non-fatal cardiovascular events as a primary efficacy endpoint. We identified five RCTs involving 1582 dialysis patients. Compared with placebo or no add-on treatment, the use of ACEIs/ARBs was not associated with a significantly lower risk of cardiovascular events {risk ratio [RR] 0.79 [95% confidence interval (CI) 0.57-1.11]}. Furthermore, there was no benefit in cardiovascular mortality [RR 0.82 (95% CI 0.59-1.14)] and all-cause mortality [RR 0.86 (95% CI 0.64-1.15)]. These results were consistent when the included RCTs were stratified by subgroups, including hypertension, ethnicity, sample size, duration of follow-up and quality. The present meta-analysis showed that among patients on dialysis, the use of ACEIs/ARBs is not associated with a significantly lower risk of cardiovascular events and all-cause mortality as compared with placebo or no add-on treatment.

RAAS Inhibition & 1 Year Mortality Post LVAD Implantation: A Meta-Analysis

<h3>Purpose</h3> Several single center retrospective studies have suggested a potential benefit with renin angiotensin aldosterone system inhibitors (RAASi) in patients with left ventricular assist devices (LVADs). Their effect on mortality in this population, however, has not been well described. <h3>Methods</h3> We previously reported a reduction in one-year mortality with RAASi at our center. To better define this potential relationship, we performed a meta-analysis of all studies evaluating the use of angiotensin-converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB) in LVAD patients and report their effect on mortality. We searched the PubMED database, for all relevant single and multi-center studies, regardless of publication year, using the key words LVAD, ACE and ARB. Publications utilizing registry data were excluded to avoid double counting patients. <h3>Results</h3> 4 studies met inclusion criteria with a total of 1,222 patients, of whom 36% were on RAASi (n=440). Adjusted effect measures were included in the analysis. The primary outcome was the overall mortality incidence using pooled HR to represent the overall effect size. Random-effects using DerSimonian and Laird model was used to calculate effect sizes due to anticipated high degree of heterogeneity (figure 1a). Sensitivity analysis was performed using the leave-one-out method with calculating the effect size after omitting each study at a time (figure 1b). Publication bias was deferred as less than 10 studies were included in the analysis. Our results showed borderline no mortality benefits for RAASi in LVAD patients with pooled HR of 0.41 (CI 0.17-1.02) albeit with a high degree of heterogeneity noted (I2 = 90.77%). <h3>Conclusion</h3> There is considerable heterogeneity in the literature examining outcomes of RAASi use in LVAD patients. Our meta-analysis suggests an unclear mortality benefit of RAASi use in LVAD patients at one year.

Long-term outcome of targeted therapy of underlying conditions in patients with early persistent atrial fibrillation and heart failure: data of the RACE 3 trial.

AimsThe Routine vs. Aggressive risk factor driven upstream rhythm Control for prevention of Early persistent atrial fibrillation (AF) in heart failure (HF) (RACE 3) trial demonstrated that targeted therapy of underlying conditions improved sinus rhythm maintenance at 1 year. We now explored the effects of targeted therapy on the additional co-primary endpoints; sinus rhythm maintenance and cardiovascular outcome at 5 years.Methods and resultsPatients with early persistent AF and mild-to-moderate stable HF were randomized to targeted or conventional therapy. Both groups received rhythm control therapy according to guidelines. The targeted group additionally received four therapies: angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers (ARBs), statins, mineralocorticoid receptor antagonists (MRAs), and cardiac rehabilitation. The presence of sinus rhythm and cardiovascular morbidity and mortality at 5-year follow-up were assessed. Two hundred and sixteen patients consented for long-term follow-up, 107 were randomized to targeted and 109 to conventional therapy. At 5 years, MRAs [76 (74%) vs. 10 (9%) patients, P < 0.001] and statins [81 (79%) vs. 59 (55%), P < 0.001] were used more in the targeted than conventional group. Angiotensin-converting enzyme inhibitors/ARBs and physical activity were not different between groups. Sinus rhythm was present in 49 (46%) targeted vs. 43 (39%) conventional group patients at 5 years (odds ratio 1.297, lower limit of 95% confidence interval 0.756, P = 0.346). Cardiovascular mortality and morbidity occurred in 20 (19%) in the targeted and 15 (14%) conventional group patients, P = 0.353.ConclusionIn patients with early persistent AF and HF superiority of targeted therapy in sinus rhythm maintenance could not be preserved at 5-year follow-up. Cardiovascular outcome was not different between groups.Trial registration numberClinicaltrials.gov NCT00877643.

The Crosstalk between SARS-CoV-2 Infection and the RAA System in Essential Hypertension-Analyses Using Systems Approach.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for the coronavirus disease of 2019 (COVID-19) pandemic, has affected and continues to affect millions of people across the world. Patients with essential arterial hypertension and renal complications are at particular risk of the fatal course of this infection. In our study, we have modeled the selected processes in a patient with essential hypertension and chronic kidney disease (CKD) suffering from COVID-19, emphasizing the function of the renin-angiotensin-aldosterone (RAA) system. The model has been built in the language of Petri nets theory. Using the systems approach, we have analyzed how COVID-19 may affect the studied organism, and we have checked whether the administration of selected anti-hypertensive drugs (angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs)) may impact the severity of the infection. Besides, we have assessed whether these drugs effectively lower blood pressure in the case of SARS-CoV-2 infection affecting essential hypertensive patients. Our research has shown that neither the ACEIs nor the ARBs worsens the course infection. However, when assessing the treatment of hypertension in the active SARS-CoV-2 infection, we have observed that ARBs might not effectively reduce blood pressure; they may even have the slightly opposite effect. On the other hand, we have confirmed the effectiveness of arterial hypertension treatment in patients receiving ACEIs. Moreover, we have found that the simultaneous use of ARBs and ACEIs averages the effects of taking both drugs, thus leading to only a slight decrease in blood pressure. We are a way from suggesting that ARBs in all hypertensive patients with COVID-19 are ineffective, but we have shown that research in this area should still be continued.

Serum potassium changes due to concomitant ACEI/ARB and spironolactone therapy: A systematic review and meta-analysis.

DisclaimerIn an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.PurposeTo provide evidence of serum potassium changes in individuals taking angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) concomitantly with spironolactone compared to ACEI/ARB therapy alone.MethodsPubMed, Embase, Scopus, and Web of Science were searched for studies including exposure to both spironolactone and ACEI/ARB therapy compared to ACEI/ARB therapy alone. The primary outcome was serum potassium change over time. Main effects were calculated to estimate average treatment effect using random effects models. Heterogeneity was assessed using Cochran’s Q and I 2. Risk of bias was assessed using the revised Cochrane risk of bias tool.ResultsFrom the total of 1,225 articles identified, 20 randomized controlled studies were included in the meta-analysis. The spironolactone plus ACEI/ARB group included 570 patients, while the ACEI/ARB group included 547 patients. Treatment with spironolactone and ACEI/ARB combination therapy compared to ACEI/ARB therapy alone increased the mean serum potassium concentration by 0.19 mEq/L (95% CI, 0.12-0.26 mEq/L), with intermediate heterogeneity across studies (Q statistic = 46.5, P = 0.004; I 2 = 59). Sensitivity analyses showed that the direction and magnitude of this outcome did not change with the exclusion of individual studies, indicating a high level of reliability. Reporting risk of bias was low for 16 studies (80%), unclear for 3 studies (15%) and high for 1 study (5%).ConclusionTreatment with spironolactone in combination with ACEI/ARB therapy increases the mean serum potassium concentration by less than 0.20 mEq/L compared to ACEI/ARB therapy alone. However, serum potassium and renal function must be monitored in patients starting combination therapy to avoid changes in serum potassium that could lead to hyperkalemia.

The Impact of Angiotensin Converting Enzyme Inhibition and/or Angiotensin Receptor Blockade on Tissue Expression of the SARS‐CoV‐2 Receptor ACE2 in Mice

The angiotensin‐converting enzyme 2 (ACE2) is an established receptor and entry point for the novel SARS‐CoV‐2 coronavirus, as the spike protein on the viral envelope binds the ACE2 receptor. Published histological profiling revealed ACE2 to be highly expressed on human lung alveolar epithelial cells and on enterocytes of the small intestine, as well as on arterial and venous endothelial cells. Given the widespread abundance of ACE2 across tissues, there has been much speculation regarding whether ACE inhibitors (ACEi) and/or Angiotensin Receptor Blockers (ARB) might alter tissue ACE2 expression and thereby change the risk of transmission or development of severe complications. Therefore, the aim of this ongoing study is to measure the impact of ACEi and ARB singly and in combination versus placebo control on tissue distribution of ACE2 in male and female mice.A factorial design was employed with the following exposures: ACEi (lisinopril, 10 mg/kg/day), ARB (losartan, 10 mg/kg/day), both drugs, or water control. Drugs were delivered via drinking water. C57BL/6J Mice were 8 weeks of age at the start of the experiment. After 21 days of treatment, four mice (two males and two females) from each treatment group were euthanized, followed by perfusion and tissue collection. 12 more untreated mice were combined with the placebo group to increase the sample size of this reference group to 16 (8 males, 8 females). ACE2 protein abundance in brain, kidney, liver, lung, and small intestine was measured by ELISA (Abcam) and normalized to BCA‐measured total protein. Two‐way ANOVA was performed to test for differences in ACE2 levels by organ or sex among untreated mice; Mann‐Whitney tests were performed to compare each drug treatment group to the control group.Among untreated mice, ACE2 levels differed by organ (p < 0.01), but there were no differences between males and females for a given organ (p = 0.20). Males and females were combined for subsequent analyses. After 21 days of treatment, ACEi, ARB, and the combination therapy lowered ACE2 tissue abundance compared to untreated mice in the brain (ACEi p = 0.04; ARB p = 0.04; ACEi+ARB p = 0.01), kidney (ACEi p = 0.03; ARB p = 0.02; ACEi+ARB p = 0.02), and lung (ACEi p = 0.01; ARB p = 0.01; ACEi+ARB p = 0.01). ACEi, but not ARB or combination therapy, lowered ACE2 tissue abundance in the liver (p = 0.02). None of the treatments changed ACE2 tissue abundance in the small intestine.These results indicate that ACEi, ARB, or combination therapy reduces levels of ACE2, the SARS‐CoV‐2 receptor, in key tissues affected by the virus, including lung, kidney, and brain. An ongoing validation study will evaluate ACE2 protein and gene expression at earlier time points, as well as after discontinuation of treatment. These results will provide valuable insight into the risk or potential benefit of starting or stopping ACEi, ARB, or combination therapy during the COVID‐19 pandemic.

Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin Receptor Blockers (ARB) Are Protective Against ICU Admission and Mortality for Patients With COVID-19 Disease

Introduction: Corona Virus disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. The aim of this study was to investigate the impact of being on an Angiotensin-Converting Enzyme Inhibitors (ACEI) and/or Angiotensin Receptor Blockers (ARB) on hospital admission, on the following COVID-19 outcomes: disease severity, ICU admission, and mortality.Methods: The charts of all patients consecutively diagnosed with COVID-19 from the 24th of February to the 16th of June of the year 2020 in Jaber Al-Ahmed Al-Sabah hospital in Kuwait were checked. All related patient information and clinical data was retrieved from the hospitals electronic medical record system. The primary outcome was COVID-19 disease severity defined as the need for Intensive Care Unit (ICU) admission. Secondary outcome was mortality.Results: A total of 4,019 COVID-19 patients were included, of which 325 patients (8.1%) used ACEI/ARB, users of ACEI/ARB were found to be significantly older (54.4 vs. 40.5 years). ACEI/ARB users were found to have more co-morbidities; diabetes (45.8 vs. 14.8%) and hypertension (92.9 vs. 13.0%). ACEI/ARB use was found to be significantly associated with greater risk of ICU admission in the unadjusted analysis [OR, 1.51 (95% CI: 1.04–2.19), p = 0.028]. After adjustment for age, gender, nationality, coronary artery disease, diabetes and hypertension, ICU admission was found to be inversely associated with ACEI use [OR, 0.57 (95% CI: 0.34–0.88), p = 0.01] and inversely associated with mortality [OR, 0.56 (95% CI: 0.33–0.95), p = 0.032].Conclusion: The current evidence in the literature supports continuation of ACEI/ARB medications for patients with co-morbidities that acquire COVID-19 infection. Although, the protective effects of such medications on COVID-19 disease severity and mortality remain unclear, the findings of the present study support the use of ACEI/ARB medication.

Phenotypic spectrum and antialbuminuric response to angiotensin converting enzyme inhibitor and angiotensin receptor blocker therapy in pediatric Dent disease.

BackgroundTo characterize the phenotypic spectrum and assess the antialbuminuric response to angiotensin converting enzyme (ACE) inhibitor and/or angiotensin receptor blocker (ARB) therapy in a cohort of children with Dent disease.MethodsThe patients’ clinical findings, renal biopsy results, genetic and follow‐up data were analyzed retrospectively. Mutations in CLCN5 or OCRL were detected by next‐generation sequencing or Sanger sequencing.ResultsOf 31 Dent disease boys, 24 carried CLCN5 and 7 carried OCRL mutations. Low molecular weight proteinuria and albuminuria were detected in all cases. Nephrotic‐range proteinuria and severe albuminuria were identified in 52% and 62% of cases, respectively; by 7 years of age, 6 patients had hematuria and nephrotic‐range proteinuria, and 7 patients had hematuria and moderate to severe albuminuria. In addition to disease‐related renal features, patients with Dent‐1 disease also presented with congenital cataract (1/9) and developmental delay (2/7). Seventeen of 31 patients underwent renal biopsy. Glomerular changes included mild glomerular lesions, mesangial proliferative glomerulonephritis and focal segmental glomerular sclerosis. Thirteen of the 31 patients had follow‐up records and received ACE inhibitor and/or ARB treatment for more than 3 months. After a median 1.7 (range 0.3–8.5) years of treatment, a reduction in the urinary microalbumin‐to‐creatinine ratio was observed in 54% of children.ConclusionsHematuria with nephrotic‐range proteinuria or moderate to severe albuminuria was common in Dent disease patients. Extrarenal manifestations were observed in Dent‐1 patients, which extends the phenotypic spectrum. In addition, ACE inhibitors and ARBs are well tolerated, and they are partially effective in controlling albuminuria.

The effects of losartan versus beta-blockers on cardiovascular protection in marfan syndrome: A systematic review and meta-analysis

Variable effects of beta-blockers (BB) and/or angiotensin receptor blockers (ARB) were reported to retard aortic root growth in Marfan syndrome (MFS). This study aimed to compare the effects of BB therapy and ARB-related therapies on cardiovascular protection in MFS. Studies of randomized control trials comparing the efficacy of only-BB and ARB-related (only-ARB or ARB-plus-BB) therapies for MFS published before July 31, 2018 in PubMed, Embase, and the Cochrane Library were selected. The outcomes included changes in aortic growth and cardiovascular events. Eight trials involving 1381 patients were included. Patients received only-BB and ARB-related therapies did not differ significantly in changes in aortic growth (aortic root diameter: standardized mean difference [SMD]=0.04, 95% confidence interval [CI]: -0.11-0.19, p=0.63) or cardiovascular events (aortic dissection: Peto odds ratio [OR]=1.67, 95% CI: 0.42-6.72, p=0.47; aortic surgery: risk ratio=0.97, 95% CI: 0.66-1.41, p=0.86; death: Peto OR=2.78, 95% CI: 0.39-19.82, p=0.31). Subgroup analysis revealed that ARB-plus-BB therapy exhibited nonsignificantly better outcomes than only-BB therapy (aortic root diameter: SMD=0.11, 95% CI: -0.22-0.45, p=0.52; ascending aorta diameter: SMD=0.10, 95% CI: -0.07-0.27, p=0.26; aortic surgery: Peto OR = 1.10, 95% CI: 0.75-1.61, p=0.62). For cardiovascular protection in MFS, only-ARB therapy is not inferior to only-BB therapy. Moreover, the outcomes of ARB-plus-BB therapy seemed to be favourable to those of only-BB therapy.

Steroid- and immunosuppressant-based protocol of Henoch-Schönlein purpura nephritis without angiotensin inhibitors in the acute phase: case series with correlation to histology.

The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest initially using angiotensin-converting-enzyme inhibitors (ACE-Is) and/or angiotensin receptor blockers (ARBs) to treat Henoch-Schönlein purpura nephritis (HSPN). However, these guidelines might overlook the potential benefits of aggressive therapy. Therefore, we evaluated the efficacy of an HSPN protocol that primarily uses steroids and immunosuppressants, without ACE-Is or ARBs. We determine treatment intensity based on International Study of Kidney Diseases in Children (ISKDC) grading. Fifty-one patients were treated with our protocol that primarily uses steroids and immunosuppressants. ACE-Is and ARBs were not used in the acute phase, including before renal biopsy. We evaluated the proteinuria disappearance rate, duration to proteinuria disappearance, and estimated glomerular filtration rate (eGFR) at the time of last observation and compared them to those in previous reports. Proteinuria disappeared in 49 patients (96%) within a median of 5 months. The median eGFR was 116.0 mL/min/1.73 m2 at the time of last observation. Six of 51 patients had acute kidney injury (eGFR <90 mL/min/1.73 m2) before treatment, but all recovered during the observation period (median 52 months). Our steroid- and immunosuppressant-based protocol without ACE-Is or ARBs in the acute phase of HSPN had almost equivalent efficacy to that in previous studies that used ACE-Is and/or ARBs with steroids and immunosuppressants.

Corticosteroid therapy in IgA nephropathy with minimal proteinuria and high renal pathological score: A single‑center cohort study.

Currently, there is no clear evidence that advocates the widespread use of corticosteroids for the treatment of immunoglobulin A nephropathy (IgAN) with minimal proteinuria (<1g/day). The recent Kidney Disease: Improving Global Outcomes Clinical Practice Guideline recommends supportive corticosteroid treatment. In the present study, 45IgAN patients with high renal pathological scores and minimal proteinuria were enrolled. The patients were randomly divided into two groups. The treatment group received methylprednisolone tablets in addition to angiotensin‑converting‑enzyme inhibitor (ACE‑I) and/or angiotensin‑receptor blocker (ARB) treatment. The control group only received ACE‑I and/or ARB treatment. In the treatment group, a single dose of 1mg/kg (maximum 60mg/day) methylprednisolone tablets was given daily followed by gradually decreasing dosage. The follow‑up time of the patients was 3years. In addition, the underlying mechanisms were investigated. The results indicated that there was a significant reduction in the amount of urinary proteins in the treatment group compared with the control group. At the end of the follow‑up, the endpoint event rate of moderate or severe proteinuria and decrease in estimated glomerular filtration rate (eGFR) in the treatment group was significantly lower than the control group. Furthermore, higher levels of serum cytokines, interleukin (IL)‑4, IL‑17, transforming growth factor‑β1 and IL‑21, were detected in patients with IgAN compared with a group of healthy controls. There was no significant difference in IFN‑γ expression between the IgAN and healthy control groups. Furthermore, the expression of Janus kinase (Jak)1, Jak3, signal transducer and activator of transcription (STAT)3 and STAT6 was significantly upregulated in patients with IgAN compared with healthy controls. However, the expression levels of STAT5 and chaperone protein, C1GALT1 specific chaperone1, in IgAN patients were significantly reduced compared with healthy controls. In addition, there was no significant difference in the expression of Jak2, tyrosine kinase 2, STAT1 and STAT4 between the two groups. In conclusion, for IgAN patients with minimal proteinuria and high renal pathological score corticosteroid therapy is likely to be effective. The dysregulation of serum cytokine levels in these patients with IgAN may have a role in the pathogenesis and progression of disease, which is associated with the activation of the JAK/STAT signaling pathway.

Effects of mineralocorticoid receptor antagonists on the progression of diabetic nephropathy.

Aims/IntroductionWe aimed to evaluate the potential benefits and adverse effects of adding a mineralocorticoid receptor antagonist (MRA) to angiotensin‐converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB), as standard treatment in patients with diabetic nephropathy.Materials and MethodsWe scanned the Embase, PubMed and Cochrane Central Register of Controlled Trials databases for human clinical trials published in English until June 2016, evaluating renal outcomes in patients with diabetic nephropathy.ResultsA total of 18 randomized controlled trials involving 1,786 patients were included. Compared with ACEI/ARB alone, co‐administration of MRA and ACEI/ARB significantly reduced urinary albumin excretion and the urinary albumin–creatinine ratio (mean difference −69.38, 95% confidence intervals −103.53 to −35.22, P < 0.0001; mean difference −215.74, 95% confidence intervals −409.22 to −22.26, P = 0.03, respectively). A decrease of blood pressure was also found in the co‐administration of MRA and ACEI/ARB groups. However, we did not observe any improvement in the glomerular filtration rate. There was a significant increase in the risk of hyperkalemia on the addition of MRA to ACEI/ARB treatment (relative risk 3.74, 95% confidence intervals 2.30–6.09, P < 0.00001).ConclusionsThese findings suggest that co‐administration of MRA and ACEI/ARB has beneficial effects on renal outcomes with increasing the incidence of hyperkalemia.

The prevalence of albuminuria among diabetic patients in a primary care setting in Singapore.

Microalbuminuria is an early sign of kidney damage. The prevalence of microalbuminuria in Singapore has been reported to be 36.0%-48.5%. However, the prevalence of microalbuminuria reported in these studies was determined with one urine sample using a qualitative urine test. The aim of this study was to determine the prevalence of micro- and macroalbuminuria using a more stringent criterion of two positive quantitative urine albumin-creatinine ratio (ACR) tests. We conducted a cross-sectional study of patients with type 2 diabetes mellitus (T2DM) who were followed up at a primary care clinic in Singapore. Patients were diagnosed to have albuminuria if they had two positive ACR tests within a seven-month period. A total of 786 patients with T2DM met the study's inclusion criteria. 55.7% were already on an angiotensin-converting enzyme inhibitor (ACEI) and/or angiotensin receptor blocker (ARB). The prevalence rates of micro- and macroalbuminuria were 14.2% and 5.7%, respectively. Patients with albuminuria were more likely to have hypertension (odds ratio [OR] 3.47, 95% confidence interval [CI] 1.55-7.80). Diabetics with poorer diabetic control (OR 1.88, 95% CI 1.26-2.79), and higher systolic (OR 1.69, 95% CI 1.14-2.49) and diastolic (OR 1.96, 95% CI, 1.20 to 3.22) blood pressures were more likely to have albuminuria. In the present study, the prevalence of microalbuminuria is significantly lower than that previously reported in Singapore. The presence of hypertension, poor diabetic control and suboptimal blood pressure control are possible risk factors for albuminuria in patients with T2DM.