Daniel Leisman, MD, MSCR
Resident Physician, PGY-2
Massachusetts General Hospital
Boston, Massachusetts
Disclosure information not submitted.
Arnav Mehta, MD, PhD
Post-Doctoral Fellow
Broad Institute, United States
Disclosure information not submitted.
Nir Hacohen, PhD
Co-Director, Cell Circuits Program
Broad Institute, United States
Disclosure information not submitted.
Michael Filbin, MD, MS
Director, Clinical Research in Emergency Medicine
Massachusetts General Hospital, United States
Disclosure information not submitted.
Marcia Goldberg, MD
Director of Research, Division of Infectious Disease
Massachusetts General Hospital, United States
Disclosure information not submitted.
Title: Renin-Angiotensin System Markers and Non-Pulmonary Organ Injury in Severe COVID-19 Pneumonia
Introduction: The renin-angiotensin system (RAS) is not well characterized over the course of severe COVID-19 illness. We hypothesized RAS markers would be associated with non-pulmonary organ injury in critically ill COVID-19.
Methods: This single-center observational cohort enrolled COVID-19 patients requiring respiratory support at ED presentation. On Day 0, 3, and 7, blood was drawn and clinical data recorded. Proximity extension assays measured plasma renin, ACE2, and renin-receptor, as well as >40 markers of endothelial, alveolar, cardiac, and renal injury. Multivariable mixed-effects models compared markers over time in mechanical ventilation (MV) vs. supplemental oxygen (SO2) patients. Multivariable proportional odds models assessed associations with 28-day clinical status: death, persistent mechanical ventilation, or recovery.
Results: Of 225 patients, 74 (33%) received MV at Day 0. At Day 0, MV patients had similar levels of renin (fold-difference: 0.91 [CI: 0.78-1.06], p=0.24), renin receptor (0.93 [0.87-0.99], p=0.039), and ACE2 (0.95 [0.79-1.13], p=0.55) vs. SO2 patients. However, by Day 3, MV patients had significantly higher renin (1.71 [1.47-2.00], p< 0.0001), renin receptor (1.19 [1.11-1.27], p< 0.0001), and ACE2 (1.38 [1.16-1.64], p=0.0003). Differences persisted at Day 7 (overall pinteraction< 0.0001 for all). Renin was highly correlated with heart and kidney injury markers including cystatin C (R: 0.57, p< 0.0001), creatinine (R: 0.54, p< 0.0001), KIM-1 (0.49, p< 0.0001), and troponin (R: 0.38, p< 0.0001). Similar patterns were seen for renin receptor and ACE2. The three RAS markers showed correlations with endothelial, but not with alveolar, injury markers. Whereas Day 0 RAS markers were not associated with clinical status at Day 28, Day 3 levels were associated with significantly worse 28-day clinical status: renin OR: 1.86 [CI: 1.14-3.03], p=0.0130; renin receptor: 4.01 [1.28-12.53], p=0.0169; ACE2: 1.64 [1.08-2.51], p=0.0218.
Conclusions: Mechanically ventilated COVID-19 patients initially have RAS marker levels similar to non-critically ill severe COVID-19. Over time, critically ill patients develop higher RAS markers that are associated with non-pulmonary organ injury and worse 28-day outcome. RAS disturbances may contribute to later, rather than early, severe COVID-19 disease course.