Skip to main navigation menu Skip to main content Skip to site footer

Viewpoint

Vol. 150 No. 4950 (2020)

The renin-angiotensin-aldosterone system inhibitors in COVID-19: from acidosis to ventilation and immunity

DOI
https://doi.org/10.4414/smw.2020.20444
Cite this as:
Swiss Med Wkly. 2020;150:w20444
Published
11.12.2020

References

  1. Esler M, Esler D. Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic? J Hypertens. 2020;38(5):781–2. doi:.https://doi.org/10.1097/HJH.0000000000002450
  2. Kuster GM, Pfister O, Burkard T, Zhou Q, Twerenbold R, Haaf P, et al. SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19? Eur Heart J. 2020;41(19):1801–3. doi:.https://doi.org/10.1093/eurheartj/ehaa235
  3. Watkins J. Preventing a covid-19 pandemic. BMJ. 2020;368:m810. doi:.https://doi.org/10.1136/bmj.m810
  4. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med. 2020;382(17):1653–9. doi:.https://doi.org/10.1056/NEJMsr2005760
  5. Fang L, Karakiulakis G, Roth M. Antihypertensive drugs and risk of COVID-19? - Authors’ reply. Lancet Respir Med. 2020;8(5):e32–3. doi:.https://doi.org/10.1016/S2213-2600(20)30159-4
  6. Liao WH, Suendermann C, Steuer AE, Pacheco Lopez G, Odermatt A, Faresse N, et al. Aldosterone deficiency in mice burdens respiration and accentuates diet-induced hyperinsulinemia and obesity. JCI Insight. 2018;3(14):e99015. doi:.https://doi.org/10.1172/jci.insight.99015
  7. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239–42. doi:.https://doi.org/10.1001/jama.2020.2648
  8. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–62. doi:.https://doi.org/10.1016/S0140-6736(20)30566-3
  9. Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091. doi:.https://doi.org/10.1136/bmj.m1091
  10. Abbatecola AM, Antonelli-Incalzi R. COVID-19 Spiraling of Frailty in Older Italian Patients. J Nutr Health Aging. 2020;24(5):453–5. doi:.https://doi.org/10.1007/s12603-020-1357-9
  11. de Abajo FJ, Rodríguez-Martín S, Lerma V, Mejía-Abril G, Aguilar M, García-Luque A, et al.; MED-ACE2-COVID19 study group. Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study. Lancet. 2020;395(10238):1705–14. doi:.https://doi.org/10.1016/S0140-6736(20)31030-8
  12. Whelton PK, Carey RM, Aronow WS, Casey DE, Jr, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):e13–115. doi:.https://doi.org/10.1161/HYP.0000000000000065
  13. Glezen WP, Greenberg SB, Atmar RL, Piedra PA, Couch RB. Impact of respiratory virus infections on persons with chronic underlying conditions. JAMA. 2000;283(4):499–505. doi:.https://doi.org/10.1001/jama.283.4.499
  14. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G ; Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342(3):145–53. doi:.https://doi.org/10.1056/NEJM200001203420301
  15. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al.; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861–9. doi:.https://doi.org/10.1056/NEJMoa011161
  16. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020;367(6485):1444–8. doi:.https://doi.org/10.1126/science.abb2762
  17. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020;367(6483):1260–3. doi:.https://doi.org/10.1126/science.abb2507
  18. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11(8):875–9. doi:.https://doi.org/10.1038/nm1267
  19. Jia HP, Look DC, Shi L, Hickey M, Pewe L, Netland J, et al. ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia. J Virol. 2005;79(23):14614–21. doi:.https://doi.org/10.1128/JVI.79.23.14614-14621.2005
  20. Li XC, Zhang J, Zhuo JL. The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res. 2017;125(Pt A):21–38. doi:.https://doi.org/10.1016/j.phrs.2017.06.005
  21. Yuan YM, Luo L, Guo Z, Yang M, Ye RS, Luo C. Activation of renin-angiotensin-aldosterone system (RAAS) in the lung of smoking-induced pulmonary arterial hypertension (PAH) rats. J Renin Angiotensin Aldosterone Syst. 2015;16(2):249–53. doi:.https://doi.org/10.1177/1470320315576256
  22. Bobulescu IA, Moe OW. Na+/H+ exchangers in renal regulation of acid-base balance. Semin Nephrol. 2006;26(5):334–44. doi:.https://doi.org/10.1016/j.semnephrol.2006.07.001
  23. Keidar S, Gamliel-Lazarovich A, Kaplan M, Pavlotzky E, Hamoud S, Hayek T, et al. Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients. Circ Res. 2005;97(9):946–53. doi:.https://doi.org/10.1161/01.RES.0000187500.24964.7A
  24. Henger A, Tutt P, Riesen WF, Hulter HN, Krapf R. Acid-base and endocrine effects of aldosterone and angiotensin II inhibition in metabolic acidosis in human patients. J Lab Clin Med. 2000;136(5):379–89. doi:.https://doi.org/10.1067/mlc.2000.110371
  25. Reeh PW, Steen KH. Tissue acidosis in nociception and pain. Prog Brain Res. 1996;113:143–51. doi:.https://doi.org/10.1016/S0079-6123(08)61085-7
  26. Menk AV, Scharping NE, Moreci RS, Zeng X, Guy C, Salvatore S, et al. Early TCR Signaling Induces Rapid Aerobic Glycolysis Enabling Distinct Acute T Cell Effector Functions. Cell Rep. 2018;22(6):1509–21. doi:.https://doi.org/10.1016/j.celrep.2018.01.040
  27. Abdelaal Ahmed Mahmoud A, Campbell M, Blajeva M. Can ACE-I Be a Silent Killer While Normal Renal Functions Falsely Secure Us? Case Rep Anesthesiol. 2018;2018:1852016. doi:.https://doi.org/10.1155/2018/1852016
  28. Schmidt ME, Varga SM. The CD8 T Cell Response to Respiratory Virus Infections. Front Immunol. 2018;9:678. doi:. https://doi.org/10.3389/fimmu.2018.00678
  29. Wiesel M, Walton S, Richter K, Oxenius A. Virus-specific CD8 T cells: activation, differentiation and memory formation. APMIS. 2009;117(5-6):356–81. doi:.https://doi.org/10.1111/j.1600-0463.2009.02459.x
  30. Bosticardo M, Ariotti S, Losana G, Bernabei P, Forni G, Novelli F. Biased activation of human T lymphocytes due to low extracellular pH is antagonized by B7/CD28 costimulation. Eur J Immunol. 2001;31(9):2829–38. doi:.https://doi.org/10.1002/1521-4141(200109)31:9<2829::AID-IMMU2829>3.0.CO;2-U
  31. Calcinotto A, Filipazzi P, Grioni M, Iero M, De Milito A, Ricupito A, et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 2012;72(11):2746–56. doi:.https://doi.org/10.1158/0008-5472.CAN-11-1272
  32. Fischer B, Müller B, Fischer KG, Baur N, Kreutz W. Acidic pH inhibits non-MHC-restricted killer cell functions. Clin Immunol. 2000;96(3):252–63. doi:.https://doi.org/10.1006/clim.2000.4904
  33. Xie D, Zhu S, Bai L. Lactic acid in tumor microenvironments causes dysfunction of NKT cells by interfering with mTOR signaling. Sci China Life Sci. 2016;59(12):1290–6. doi:.https://doi.org/10.1007/s11427-016-0348-7
  34. Walton ZE, Patel CH, Brooks RC, Yu Y, Ibrahim-Hashim A, Riddle M, et al. Acid Suspends the Circadian Clock in Hypoxia through Inhibition of mTOR. Cell. 2018;174(1):72–87.e32. doi:.https://doi.org/10.1016/j.cell.2018.05.009
  35. Welbourne TC. Acidosis activation of the pituitary-adrenal-renal glutaminase I axis. Endocrinology. 1976;99(4):1071–9. doi:.https://doi.org/10.1210/endo-99-4-1071
  36. May RC, Kelly RA, Mitch WE. Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism. J Clin Invest. 1986;77(2):614–21. doi:.https://doi.org/10.1172/JCI112344
  37. Simon D, Luke RG. Polymorphonuclear leucocytosis and lymphopenia in acute renal failure and metabolic acidosis in the rat. Clin Sci Mol Med. 1973;45(3):397–402. doi:.https://doi.org/10.1042/cs0450397
  38. Tan L, Wang Q, Zhang D, Ding J, Huang Q, Tang YQ, et al. Correction: Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Transduct Target Ther. 2020;5(1):61. doi:.https://doi.org/10.1038/s41392-020-0159-1
  39. Teijaro JR, Walsh KB, Cahalan S, Fremgen DM, Roberts E, Scott F, et al. Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell. 2011;146(6):980–91. doi:.https://doi.org/10.1016/j.cell.2011.08.015
  40. Ahmadpoor P, Rostaing L. Why the immune system fails to mount an adaptive immune response to a COVID-19 infection. Transpl Int. 2020;33(7):824–5. doi:.https://doi.org/10.1111/tri.13611
  41. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135(23):2033–40. doi:.https://doi.org/10.1182/blood.2020006000
  42. Etulain J, Negrotto S, Carestia A, Pozner RG, Romaniuk MA, D’Atri LP, et al. Acidosis downregulates platelet haemostatic functions and promotes neutrophil proinflammatory responses mediated by platelets. Thromb Haemost. 2012;107(1):99–110. doi:.https://doi.org/10.1160/TH11-06-0443
  43. Bernstein KE, Khan Z, Giani JF, Cao DY, Bernstein EA, Shen XZ. Angiotensin-converting enzyme in innate and adaptive immunity. Nat Rev Nephrol. 2018;14(5):325–36. doi:.https://doi.org/10.1038/nrneph.2018.15
  44. Kahn JS, McIntosh K. History and recent advances in coronavirus discovery. Pediatr Infect Dis J. 2005;24(11, Suppl):S223–7, discussion S226. doi:.https://doi.org/10.1097/01.inf.0000188166.17324.60
  45. Egan BM, Li J, Hutchison FN, Ferdinand KC. Hypertension in the United States, 1999 to 2012: progress toward Healthy People 2020 goals. Circulation. 2014;130(19):1692–9. doi:.https://doi.org/10.1161/CIRCULATIONAHA.114.010676
  46. Burnier M, Egan BM. Adherence in Hypertension. Circ Res. 2019;124(7):1124–40. doi:.https://doi.org/10.1161/CIRCRESAHA.118.313220
  47. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2002;25(1):213–29. doi:.https://doi.org/10.2337/diacare.25.1.213
  48. American Diabetes Association. Standards of Medical Care in Diabetes-2020 Abridged for Primary Care Providers. Clin Diabetes. 2020;38(1):10–38. doi:.https://doi.org/10.2337/cd20-as01
  49. Karet FE. Mechanisms in hyperkalemic renal tubular acidosis. J Am Soc Nephrol. 2009;20(2):251–4. doi:.https://doi.org/10.1681/ASN.2008020166
  50. Oussalah A, Gleye S, Clerc Urmes I, Laugel E, Callet J, Barbé F, et al. Long-Term ACE Inhibitor/ARB Use Is Associated with Severe Renal Dysfunction and Acute Kidney Injury in Patients with severe COVID-19: Results from a Referral Center Cohort in the North East of France. Clin Infect Dis. 2020;ciaa677. doi:.https://doi.org/10.1093/cid/ciaa677
  51. Kendrick J, Chonchol M, You Z, Jovanovich A. Lower serum bicarbonate is associated with an increased risk of acute kidney injury. J Nephrol. 2020. doi:.https://doi.org/10.1007/s40620-020-00747-8
  52. Wesson DE, Simoni J. Acid retention during kidney failure induces endothelin and aldosterone production which lead to progressive GFR decline, a situation ameliorated by alkali diet. Kidney Int. 2010;78(11):1128–35. doi:.https://doi.org/10.1038/ki.2010.348
  53. Atkins JL. Effect of sodium bicarbonate preloading on ischemic renal failure. Nephron. 1986;44(1):70–4. doi:.https://doi.org/10.1159/000183915
  54. Bavishi C, Maddox TM, Messerli FH. Coronavirus Disease 2019 (COVID-19) Infection and Renin Angiotensin System Blockers. JAMA Cardiol. 2020;5(7):745–7. doi:.https://doi.org/10.1001/jamacardio.2020.1282
  55. Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436(7047):112–6. doi:.https://doi.org/10.1038/nature03712
  56. Gu H, Xie Z, Li T, Zhang S, Lai C, Zhu P, et al. Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus. Sci Rep. 2016;6(1):19840. doi:.https://doi.org/10.1038/srep19840
  57. Sodhi CP, Nguyen J, Yamaguchi Y, Werts AD, Lu P, Ladd MR, et al. A Dynamic Variation of Pulmonary ACE2 Is Required to Modulate Neutrophilic Inflammation in Response to Pseudomonas aeruginosa Lung Infection in Mice. J Immunol. 2019;203(11):3000–12. doi:.https://doi.org/10.4049/jimmunol.1900579
  58. Reynolds HR, Adhikari S, Pulgarin C, Troxel AB, Iturrate E, Johnson SB, et al. Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19. N Engl J Med. 2020;382(25):2441–8. doi:.https://doi.org/10.1056/NEJMoa2008975
  59. Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19. N Engl J Med. 2020;382(25):2431–40. doi:.https://doi.org/10.1056/NEJMoa2006923
  60. Reiffel JA. Propensity Score Matching: The ‘Devil is in the Details’ Where More May Be Hidden than You Know. Am J Med. 2020;133(2):178–81. doi:.https://doi.org/10.1016/j.amjmed.2019.08.055
  61. Kitterer D, Schwab M, Alscher MD, Braun N, Latus J. Drug-induced acid-base disorders. Pediatr Nephrol. 2015;30(9):1407–23. doi:.https://doi.org/10.1007/s00467-014-2958-5
  62. Tanaka T, Tsutamoto T, Sakai H, Fujii M, Yamamoto T, Horie M. Comparison of the effects of efonidipine and amlodipine on aldosterone in patients with hypertension. Hypertens Res. 2007;30(8):691–7. doi:.https://doi.org/10.1291/hypres.30.691
  63. Bauer JH, Sunderrajan S, Reams G. Effects of calcium entry blockers on renin-angiotensin-aldosterone system, renal function and hemodynamics, salt and water excretion and body fluid composition. Am J Cardiol. 1985;56(16):H62–7. doi:.https://doi.org/10.1016/0002-9149(85)90546-6
  64. Bozkurt B, Kovacs R, Harrington B. Joint HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19. J Card Fail. 2020;26(5):370. doi:.https://doi.org/10.1016/j.cardfail.2020.04.013