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 