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Renin-Angiotensin System Blockade In The Coronavirus Disease 2019 Pandemic

  • Cohen, Jordana B1, 1
  • South, Andrew M2, 3, 4, 5
  • Shaltout, Hossam A4, 5, 4, 6
  • Sinclair, Matthew R7, 8
  • Sparks, Matthew A7, 9
  • 1 University of Pennsylvania, USA , (United States)
  • 2 Section of Nephrology, USA , (United States)
  • 3 Winston Salem, USA , (United States)
  • 4 Wake Forest School of Medicine, USA , (United States)
  • 5 Cardiovascular Sciences Center, USA , (United States)
  • 6 University of Alexandria, Egypt , (Egypt)
  • 7 Duke University School of Medicine, USA , (United States)
  • 8 Duke Clinical Research Institute, USA , (United States)
  • 9 Renal Section, USA , (United States)
Published Article
Clinical Kidney Journal
Oxford University Press
Publication Date
Feb 02, 2021
DOI: 10.1093/ckj/sfab026
PMCID: PMC7929063
PubMed Central


In the early months of the coronavirus disease 2019 (COVID-19) pandemic, a hypothesis emerged suggesting that pharmacologic inhibitors of the renin-angiotensin system (RAS) may increase COVID-19 severity. This hypothesis was based on the role of angiotensin-converting enzyme 2 (ACE2), a counter-regulatory component of the RAS, as the binding site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), allowing viral entry into host cells. Extrapolations from prior evidence led to speculation that upregulation of ACE2 by RAS blockade may increase the risk of adverse outcomes from COVID-19. However, counterarguments pointed to evidence of potential protective effects of ACE2 and RAS blockade with regard to acute lung injury, as well as substantial risks from discontinuing these commonly used and important medications. Here we provide an overview of classic RAS physiology and the crucial role of ACE2 in systemic pathways affected by COVID-19. Additionally, we critically review the physiologic and epidemiologic evidence surrounding the interactions between RAS blockade and COVID-19. We review recently published trial evidence and propose important future directions to improve upon our understanding of these relationships.

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