key: cord-0810021-90d21ck7 authors: Wong, Sunnie Y.; Brubaker, Aleah L.; Wang, Aileen X.; Taiwo, Adetokunbo A.; Melcher, Marc L. title: What Solid Organ Transplant Healthcare Providers should know about Renin‐Angiotensin‐Aldosterone System Inhibitors and COVID‐19 date: 2020-05-23 journal: Clin Transplant DOI: 10.1111/ctr.13991 sha: 09b2036eba6ba6a828fecc57c7ba7ff7ff7d9dcf doc_id: 810021 cord_uid: 90d21ck7 The data on the outcomes of solid organ transplant recipients who have contracted coronavirus disease 2019 (COVID‐19) are still emerging. Kidney transplant recipients are commonly prescribed renin‐angiotensin‐aldosterone system (AAS) inhibitors given the prevalence of hypertension, diabetes, and cardiovascular disease. As the angiotensin‐converting enzyme 2 (ACE2) facilitates the entry of coronaviruses into target cells, there have been hypotheses that preexisting use of Renin‐Angiotensin‐Aldosterone System (RAAS) inhibitors may increase the risk of developing severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. Given the common use of RAAS inhibitors among solid organ transplant recipients, we sought to review the RAAS cascade, the mechanism of SARS‐CoV‐2 entry, and pertinent data related to the effect of RAAS inhibitors on ACE2 to guide management of solid organ transplant recipients during the COVID‐19 pandemic. At present there is no clear evidence to support the discontinuation of RAAS inhibitors in solid organ transplant recipients during the COVID‐19 pandemic. The current coronavirus disease 2019 pandemic is associated with unprecedented morbidity and mortality 1 , and recent publications in the transplant literature report varying rates of mortality from 6-28% [2] [3] [4] [5] . Early reports from China and Italy have shown that co-existing conditions, including diabetes mellitus, hypertension, congestive heart failure, and coronary artery disease, are more common among patients who developed severe symptoms of COVID-19 [6] [7] [8] [9] . Conventional medical management of these comorbidities often includes the use of Renin-Angiotensin-Aldosterone System (RAAS) inhibitors. Interestingly, coronaviruses interact with angiotensin-converting enzyme 2 (ACE2) to facilitate entry into target cells 10 , raising concerns in several published commentaries that preexisting use of RAAS inhibitors may increase the risk of developing severe manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [11] [12] [13] [14] . Citing preclinical studies that demonstrated the correlation between increased levels of circulating ACE2 and RAAS inhibitors, some in the medical community suggested preemptive discontinuation of RAAS inhibitors during COVID-19, as these medications might theoretically promote viral entry 12 . Given the common use of RAAS inhibitors among solid organ transplant recipients with cardiovascular disease or polycythemia, we sought to review the RAAS cascade, the mechanism of SARS-CoV-2 entry, and pertinent data related to the effect of RAAS inhibitors on ACE2 to guide management of solid organ transplant recipients during the COVID-19 pandemic. The RAAS is a cascade of vasoactive peptides that orchestrate key physiological processes, including blood pressure regulation, fluid and electrolyte balance, and cardiac and renal function 15, 16 . In the classical view of the cascade, renin cleaves angiotensinogen and generates angiotensin (Ang) I, which is cleaved by angiotensin-converting enzyme (ACE), generating Ang II ( Figure 1A ). Ang II is the active form of angiotensin that binds to receptors in the adrenal cortex, releasing aldosterone. Ang II also induces arterial vasoconstriction and promotes fibrosis. A parallel pathway mediated by ACE2, a homolog of ACE, generates Ang (1-9) from Ang I and Ang (1-7) from Ang II ( Figure 1B ). Ang (1-7) This article is protected by copyright. All rights reserved has organ-protective properties which oppose the vasoconstrictive, inflammatory, sodium retaining, and remodeling properties of Ang II. While ACE2 is predominantly a membrane-bound enzyme, its membrane anchor can be cleaved by a disintegrin and metalloprotease 17 (ADAM17), releasing ACE2 into blood, urine, and other body fluids. Membrane-bound ACE2 (found on pneumocytes) along with transmembrane protease serine 2 (TMPRSS2) is required to facilitate SARS-CoV-2 entry into target cells 17 . On the other hand, soluble ACE2 has been shown to significantly block early stages of SAR-CoV-2 infections in in vitro experiments and represents a potential therapeutic intervention 18 ( Figure 2 ). Although ACE2 shares significant homology with ACE (40% identity and 61% similarity), its substrate-binding pocket site is distinct from ACE; therefore, classical ACE inhibitors (ACEi) do not directly affect ACE2 enzymatic activity 19 . In addition, ACEi use may be protective as it reduces Ang II which increases alveolar permeability and would potentiate acute lung injury. Several animal studies have reported mixed findings on the effect of ACEi on ACE2 mRNA expression or enzymatic activity in cardiac 20-23 and renal tissues 24 . In comparison, angiotensin II type I receptor blockers (ARBs) more consistently upregulate ACE2 mRNA or protein level in cardiac tissue 20,25-27 and renal vasculatures 28 , though the effect varies across study models and requires high doses of ARBs. The upregulation of ACE2 by ARBs may be protective against lung injury via Ang-(1-7), a vasodilatory peptide 29 . In contrast, there are very few studies in humans to assess the effect of RAAS inhibitors on ACE2 expression [30] [31] [32] [33] [34] [35] . It is important to note that all these studies reported the level of ACE2 activity in blood or urine, as quantifying membrane-bound ACE2 in vivo in human cardiac and kidney tissue would be technically challenging and invasive. There is no evidence to support that soluble ACE2 is a reliable surrogate for membrane-bound ACE2. Interestingly, membrane-bound ACE2 protein expression was found to be decreased in human autopsy hearts that were positive for SARS-CoV during the Toronto SARS outbreak in 2009 36 . Hypothetically, if the animal data can be extrapolated This article is protected by copyright. All rights reserved to humans, increased membrane-bound ACE2 in human myocardium associated with pre-existing use of RAAS inhibitors may be potentially protective against COVID19-associated myocarditis. Kidney transplant recipients with cardiovascular disease and post-transplant erythrocytosis are commonly prescribed ACEi and ARB 37, 38 . Studies on RAAS blockade in kidney transplant patients have been mixed with regards to patient and graft survival [39] [40] [41] [42] [43] [44] [45] . Interestingly, a rare condition that calls for the use of ARB post-transplant is antibody-mediated rejection related to angiotensin II type I receptor (AT1R), a G protein-coupled receptor expressed at the endothelial cell surface 46 from Italy found a 25% mortality rate 5 . Contrary to these higher mortality rates a single center cohort study out of Spain found a 6% mortality rate among 33 patients infected with COVID-19 from the This article is protected by copyright. All rights reserved onset of the pandemic to mid-April of 2020 54 This article is protected by copyright. All rights reserved An interactive web-based dashboard to track COVID-19 in real time COVID-19 infection in kidney transplant recipients Preliminary data on outcomes of SARS-CoV-2 infection in a Spanish single centre cohort of kidney recipients Covid-19 and Kidney Transplantation Early experience with COVID-19 in kidney transplantation Clinical features of patients infected with 2019 novel coronavirus in Wuhan Clinical Characteristics of Coronavirus Disease 2019 in China Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy Comorbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic? Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Drugs and the renin-angiotensin system in covid-19 Accepted Article This article is protected by copyright. All rights reserved Mechanisms of disease: local renin-angiotensin-aldosterone systems and the pathogenesis and treatment of cardiovascular disease Renin-angiotensin-aldosterone system and progression of renal disease SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2 A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2 Enalapril attenuates downregulation of Angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat Combination renin-angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implications for future therapeutic directions Myocardial infarction increases ACE2 expression in rat and humans Differential regulation of renal angiotensin-converting enzyme (ACE) and ACE2 during ACE inhibition and dietary sodium restriction in healthy rats The effects of different angiotensin II type 1 receptor blockers on the regulation of the ACE-AngII-AT1 and ACE2-Ang(1-7)-Mas axes in pressure overload-induced cardiac remodeling in male mice Olmesartan attenuates the development of heart failure after experimental autoimmune myocarditis in rats through the modulation of ANG 1-7 mas receptor Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirusinduced lung injury Evidence against a major role for angiotensin converting enzyme-related carboxypeptidase (ACE2) in angiotensin peptide metabolism in the human coronary circulation Soluble angiotensin-converting enzyme 2 in human heart failure: relation with myocardial function and clinical outcomes Angiotensin converting enzyme 2 activity and human atrial fibrillation: increased plasma angiotensin converting enzyme 2 activity is associated with atrial fibrillation and more advanced left atrial structural remodelling Plasma ACE2 Activity Predicts Mortality in Aortic Stenosis and Is Associated With Severe Myocardial Fibrosis Elevated plasma angiotensin converting enzyme 2 activity is an independent predictor of major adverse cardiac events in patients with obstructive coronary artery disease Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS Management of cardiovascular disease in renal transplant recipients All rights reserved 38 Blood pressure, antihypertensive treatment, and graft survival in kidney transplant patients No improvement of patient or graft survival in transplant recipients treated with angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers: a collaborative transplant study report Renin-Angiotensin System Blockade and Long-term Clinical Outcomes in Kidney Transplant Recipients: A Metaanalysis of Randomized Controlled Trials Angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist therapy is associated with prolonged patient and graft survival after renal transplantation The Effect of Renin-angiotensin System Inhibitors on Kidney Allograft Survival: A Systematic Review and Meta-analysis. N Effects of ACE inhibitors on long-term outcome of renal transplant recipients: a randomized controlled trial Short-and long-term outcomes with reninangiotensin-aldosterone inhibitors in renal transplant recipients: A meta-analysis of randomized controlled trials The influence of non-HLA antibodies directed against angiotensin II type 1 receptor (AT1R) on early renal transplant outcomes Non-HLA agonistic anti-angiotensin II type 1 receptor antibodies induce a distinctive phenotype of antibody-mediated rejection in kidney transplant recipients Role of angiotensin II type 1 receptor-activating antibodies in solid organ transplantation Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection Coronaviruses and immunosuppressed patients. The facts during the third epidemic COVID-19 in long-term liver transplant patients: preliminary experience from an Italian transplant centre in Lombardy COVID-19 in kidney transplant recipients Identification of Kidney Transplant Recipients with Coronavirus Disease Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in renal transplantation between 1990 and 2002 in Spain Case report of COVID-19 in a kidney transplant recipient: Does immunosuppression alter the clinical presentation? Neprilysin inhibitorangiotensin II receptor blocker combination (sacubitril/valsartan): rationale for adoption in SARS-CoV-2 patients High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells