Severe Acute Respiratory Syndrome Coronavirus 2, COVID-19, and the Renin-Angiotensin System: Pressing Needs and Best Research Practices.

The coronavirus disease 2019 (COVID-19) pandemic is associated with significant morbidity and mortality throughout the world, predominantly due to lung and cardiovascular injury. The virus responsible for COVID-19-severe acute respiratory syndrome coronavirus 2-gains entry into host cells via ACE2 (angiotensin-converting enzyme 2). ACE2 is a primary enzyme within the key counter-regulatory pathway of the renin-angiotensin system (RAS), which acts to oppose the actions of Ang (angiotensin) II by generating Ang-(1-7) to reduce inflammation and fibrosis and mitigate end organ damage. As COVID-19 spans multiple organ systems linked to the cardiovascular system, it is imperative to understand clearly how severe acute respiratory syndrome coronavirus 2 may affect the multifaceted RAS. In addition, recognition of the role of ACE2 and the RAS in COVID-19 has renewed interest in its role in the pathophysiology of cardiovascular disease in general. We provide researchers with a framework of best practices in basic and clinical research to interrogate the RAS using appropriate methodology, especially those who are relatively new to the field. This is crucial, as there are many limitations inherent in investigating the RAS in experimental models and in humans. We discuss sound methodological approaches to quantifying enzyme content and activity (ACE, ACE2), peptides (Ang II, Ang-[1-7]), and receptors (types 1 and 2 Ang II receptors, Mas receptor). Our goal is to ensure appropriate research methodology for investigations of the RAS in patients with severe acute respiratory syndrome coronavirus 2 and COVID-19 to ensure optimal rigor and reproducibility and appropriate interpretation of results from these investigations.

Association of outpatient use of renin-angiotensin-aldosterone system blockers on outcomes of acute respiratory illness during the COVID-19 pandemic: a cohort study.

OBJECTIVES: Evaluate the associations between patients taking ACE inhibitors and angiotensin receptor blockers (ARBs) and their clinical outcomes after an acute viral respiratory illness (AVRI) due to COVID-19. DESIGN: Retrospective cohort. SETTING: The USA; 2017-2018 influenza season, 2018-2019 influenza season, and 2019-2020 influenza/COVID-19 season. PARTICIPANTS: People with hypertension (HTN) taking an ACEi, ARB or other HTN medications, and experiencing AVRI. MAIN OUTCOME MEASURES: Change in hospital admission, intensive care unit (ICU) or coronary care unit (CCU), acute respiratory distress (ARD), ARD syndrome (ARDS) and all-cause mortality, comparing COVID-19 to pre-COVID-19 influenza seasons. RESULTS: The cohort included 1 059 474 episodes of AVRI (653 797 filled an ACEi or ARB, and 405 677 other HTN medications). 58.6% were women and 72.9% with age ≥65. The ACEi/ARB cohort saw a larger increase in risk in the COVID-19 influenza season than the other HTN medication cohort for four out of five outcomes, with an additional 1.5 percentage point (pp) increase in risk of an inpatient stay (95% CI 1.2 to 1.9 pp) and of ICU/CCU use (95% CI 0.3 to 2.7 pp) as well as a 0.7 pp (0.1 to 1.2 pp) additional increase in risk of ARD and 0.9 pp (0.4 to 1.3 pp) additional increase in risk of ARDS. There was no statistically significant difference in the absolute risk of death (-0.2 pp, 95% CI -0.4 to 0.1 pp). However, the relative risk of death in 2019/2020 versus 2017/2018 for the ACEi/ARB group was larger (1.40 (1.36 to 1.44)) than for the other HTN medication cohort (1.24 (1.21 to 1.28)). CONCLUSIONS: People with AVRI using ACEi/ARBs for HTN had a greater increase in poor outcomes during the COVID-19 pandemic than those using other medications to treat HTN. The small absolute magnitude of the differences likely does not support changes in clinical practice.

Expression of ACE2 in the Intact and Acutely Injured Kidney.

Background: The actions of angiotensin-converting enzyme 2 (ACE2) oppose those of the renin-angiotensin-aldosterone system. ACE2 may be a cytoprotectant in some tissues. This study examined ACE2 expression in models of AKI. Methods: ACE2 mRNA and protein expression and ACE2 activity were assessed in murine ischemic AKI. Renal ACE2 mRNA expression was evaluated in LPS-induced AKI in wild-type (C57BL/6J) mice, in heme oxygenase-1+/+ and heme oxygenase-1-/- mice, and after unilateral ureteral obstruction (UUO) in wild-type mice. The effect of sex and age on renal ACE2 protein expression was also assessed. Results: In ischemic AKI, ACE2 mRNA and protein expression and ACE2 activity were reduced as compared with such indices in the intact kidney. In ischemic AKI, ACE2, which, in health, is prominently expressed in the tubular epithelium, especially proximal tubules, is decreased in expression in these segments. Decreased ACE2 expression in AKI did not reflect reduced GFR, because ACE2 mRNA expression was unaltered after UUO. LPS induced renal ACE2 mRNA expression in wild-type mice, but this effect did not occur in heme oxygenase-1-deficient mice. In ischemic and LPS-induced AKI, renal expression of the Mas receptor was increased. In the intact kidney, renal ACE2 protein expression decreased in female mice as compared with male mice, but was unaltered with age. Conclusion: We conclude that renal ACE2 expression is decreased in ischemic AKI, characterized by decreased GFR and abundant cell death, but is upregulated in LPS-induced AKI, an effect requiring heme oxygenase-1. Determining the significance of ACE2 expression in experimental AKI merits further study. We suggest that understanding the mechanism underlying ACE2 downregulation in AKI may offer insights relevant to COVID-19: ACE2 expression is downregulated after ACE2 mediates SARS-CoV-2 cellular entry; such downregulation is proinflammatory; and AKI commonly occurs and determines outcomes in COVID-19.

Telehealth versus face-to-face visits: A comprehensive outpatient perspective-based cohort study of patients with kidney disease.

BACKGROUND: Telenephrology has become an important health care delivery modality during the COVID-19 pandemic. However, little is known about patient perspectives on the quality of care provided via telenephrology compared to face-to-face visits. We aimed to use objective data to study patients' perspectives on outpatient nephrology care received via telenephrology (phone and video) versus face-to-face visits. METHODS: We retrospectively studied adults who received care in the outpatient Nephrology & Hypertension division at Mayo Clinic, Rochester, from March to July 2020. We used a standardized survey methodology to evaluate patient satisfaction. The primary outcome was the percent of patients who responded with a score of good (4) or very good (5) on a 5-point Likert scale on survey questions that asked their perspectives on access to their nephrologist, relationship with care provider, their opinions on the telenephrology technology, and their overall assessment of the care received. Wilcoxon rank sum tests and chi-square tests were used as appropriate to compare telenephrology versus face-to-face visits. RESULTS: 3,486 of the patient encounters were face-to-face, 808 phone and 317 video visits. 443 patients responded to satisfaction surveys, and 21% of these had telenephrology encounters. Established patients made up 79.6% of telenephrology visits and 60.9% of face-to-face visits. There was no significant difference in patient perceived access to health care, satisfaction with their care provider, or overall quality of care between patients cared for via telenephrology versus face-to-face. Patient satisfaction was also equally high. CONCLUSIONS: Patient satisfaction was equally high amongst those patients seen face-to-face or via telenephrology.

Clinical research during the COVID-19 pandemic: The role of virtual visits and digital approaches.

Clinical trials are a fundamental tool in evaluating the safety and efficacy of new drugs, medical devices, and health system interventions. Clinical trial visits generally involve eligibility assessment, enrollment, intervention administration, data collection, and follow-up, with many of these steps performed during face-to-face visits between participants and the investigative team. Social distancing, which emerged as one of the mainstay strategies for reducing the spread of SARS-CoV-2, has presented a challenge to the traditional model of clinical trial conduct, causing many research teams to halt all in-person contacts except for life-saving research. Nonetheless, clinical research has continued during the pandemic because study teams adapted quickly, turning to virtual visits and other similar methods to complete critical research activities. The purpose of this special communication is to document this rapid transition to virtual methodologies at Clinical and Translational Science Awards hubs and highlight important considerations for future development. Looking beyond the pandemic, we envision that a hybrid approach, which implements remote activities when feasible but also maintains in-person activities as necessary, will be adopted more widely for clinical trials. There will always be a need for in-person aspects of clinical research, but future study designs will need to incorporate remote capabilities.

COVID-19 and Sex Differences: Mechanisms and Biomarkers.

Men are consistently overrepresented in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and coronavirus disease 2019 (COVID-19) severe outcomes, including higher fatality rates. These differences are likely due to gender-specific behaviors, genetic and hormonal factors, and sex differences in biological pathways related to SARS-CoV-2 infection. Several social, behavioral, and comorbid factors are implicated in the generally worse outcomes in men compared with women. Underlying biological sex differences and their effects on COVID-19 outcomes, however, have received less attention. The present review summarizes the available literature regarding proposed molecular and cellular markers of COVID-19 infection, their associations with health outcomes, and any reported modification by sex. Biological sex differences characterized by such biomarkers exist within healthy populations and also differ with age- and sex-specific conditions, such as pregnancy and menopause. In the context of COVID-19, descriptive biomarker levels are often reported by sex, but data pertaining to the effect of patient sex on the relationship between biomarkers and COVID-19 disease severity/outcomes are scarce. Such biomarkers may offer plausible explanations for the worse COVID-19 outcomes seen in men. There is the need for larger studies with sex-specific reporting and robust analyses to elucidate how sex modifies cellular and molecular pathways associated with SARS-CoV-2. This will improve interpretation of biomarkers and clinical management of COVID-19 patients by facilitating a personalized medical approach to risk stratification, prevention, and treatment.

SARS-CoV-2 Infection and COVID-19 During Pregnancy: A Multidisciplinary Review.

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has been associated with worse outcomes in several patient populations, including the elderly and those with chronic comorbidities. Data from previous pandemics and seasonal influenza suggest that pregnant women may be at increased risk for infection-associated morbidity and mortality. Physiologic changes in normal pregnancy and metabolic and vascular changes in high-risk pregnancies may affect the pathogenesis or exacerbate the clinical presentation of COVID-19. Specifically, SARS-CoV-2 enters the cell via the angiotensin-converting enzyme 2 (ACE2) receptor, which is upregulated in normal pregnancy. Upregulation of ACE2 mediates conversion of angiotensin II (vasoconstrictor) to angiotensin-(1-7) (vasodilator) and contributes to relatively low blood pressures, despite upregulation of other components of the renin-angiotensin-aldosterone system. As a result of higher ACE2 expression, pregnant women may be at elevated risk for complications from SARS-CoV-2 infection. Upon binding to ACE2, SARS-CoV-2 causes its downregulation, thus lowering angiotensin-(1-7) levels, which can mimic/worsen the vasoconstriction, inflammation, and pro-coagulopathic effects that occur in preeclampsia. Indeed, early reports suggest that, among other adverse outcomes, preeclampsia may be more common in pregnant women with COVID-19. Medical therapy, during pregnancy and breastfeeding, relies on medications with proven safety, but safety data are often missing for medications in the early stages of clinical trials. We summarize guidelines for medical/obstetric care and outline future directions for optimization of treatment and preventive strategies for pregnant patients with COVID-19 with the understanding that relevant data are limited and rapidly changing.