Vol 24, No 2 (2020)
Published online: 2020-06-01

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Controversy over renin–angiotensin–aldosterone system (RAAS) inhibitors treatment in nephrology and cardiovascular diseases

Rafał Ł. Donderski1, Rafał Bednarski1, Jacek Manitius1
Arterial Hypertension 2020;24(2):45-55.


Drugs that act by inhibiting the renin–angiotensin–aldosterone system (RAAS), such as angiotensin-converting enzyme
inhibitors (ACE-Is) and angiotensin II receptor type 1 (AT1) blockers (ARBs), have been recognized as a basic
canon of nephroprotection for years. They are commonly used in monotherapy for glomerulonephritis with proteinuria.
At present, they are rarely used in combination therapy in a form of dual blockade of RAAS due to concern
about possible side effects. On the other hand, both ACE-Is and ARBs are also wrongly referred to as nephrotoxic
drugs. The significance of therapy with these drugs is seen in evoking acute kidney injury (AKI) or acceleration of
CKD. The aim of this article was to clarify the opinion on the relationship between ACE-Is or ARBs treatment and
AKI occurrence, and to attempt to reassess the role of dual RAAS blockade in the treatment of kidney diseases. The
principles of heart failure (HF) therapy with ACE-Is or ARBs and current data on the importance of RAAS dual
blockade in hypertension are also discussed.

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  1. Khan M, Fonarow G, Khan H, et al. Renin-angiotensin blockade in heart failure with preserved ejection fraction: a systematic review and meta-analysis. ESC Heart Fail. 2017; 4(4): 402–408.
  2. Chalmers J, MacMahon S. Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS): interpretation and implementation. J Hypertens Suppl. 2003; 21: S9–S14.
  3. Martínez-Milla J, García M, Urquía M, et al. Blockade of Renin–Angiotensin–Aldosterone System in Elderly Patients with Heart Failure and Chronic Kidney Disease: Results of a Single-Center, Observational Cohort Study. Drugs Aging. 2019; 36(12): 1123–1131.
  4. Gayat E, Hollinger A, Cariou A, et al. Impact of angiotensin-converting enzyme inhibitors or receptor blockers on post-ICU discharge outcome in patients with acute kidney injury. Intensive Care Med. 2018; 44(5): 598–605.
  5. Jones M, Tomson C. Acute kidney injury and ‘nephrotoxins’: mind your language. Clin Med (London). 2018; 18(5): 384–386.
  6. Tomson C, Tomlinson L. Stopping RAS Inhibitors to Minimize AKI. Clin J Am Soc Nephrol. 2019; 14(4): 617–619.
  7. Momoniat T, Ilyas D, Bhandari S. ACE inhibitors and ARBs: Managing potassium and renal function. Clev Clin J Med. 2019; 86(9): 601–607.
  8. Hiremath S, Kayibanda J, Chow B, et al. Drug discontinuation before contrast procedures and the effect on acute kidney injury and other clinical outcomes: a systematic review protocol. Syst Rev. 2018; 7(1).
  9. Coca SG, Garg AX, Swaminathan M, et al. Preoperative angiotensin-converting enzyme inhibitors and angiotensin receptor blocker use and acute kidney injury in patients undergoing cardiac surgery. Nephrol Dial Transplant. 2013; 28(11): 2787–2799.
  10. Whiting P, Morden A, Tomlinson L, et al. What are the risks and benefits of temporarily discontinuing medications to prevent acute kidney injury? A systematic review and meta-analysis. BMJ Open. 2017; 7(4): e012674.
  11. Hollmann C, Fernandes N, Biccard B. A Systematic Review of Outcomes Associated With Withholding or Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Before Noncardiac Surgery. Anest Analg. 2018; 127(3): 678–687.
  12. Bomback AS, Toto R. Dual Blockade of the Renin-Angiotensin-Aldosterone System: Beyond the ACE Inhibitor and Angiotensin-II Receptor Blocker Combination. Am J Hypertens. 2009; 22(10): 1032–1040.
  13. Ruggenenti P, Perna A, Remuzzi G, et al. ACE inhibitors to prevent end-stage renal disease: when to start and why possibly never to stop: a post hoc analysis of the REIN trial results. Ramipril Efficacy in Nephropathy. J Am Soc Nephrol. 2001; 12(12): 2832–2837.
  14. Jr JW. Effect of Blood Pressure Lowering and Antihypertensive Drug Class on Progression of Hypertensive Kidney DiseaseResults From the AASK Trial. JAMA. 2002; 288(19): 2421–2431.
  15. Ruggenenti P, Fassi A, Ilieva A, et al. Preventing Microalbuminuria in Type 2 Diabetes. N Engl J Med. 2004; 351(19): 1941–1951.
  16. Lewis E, Hunsicker L, Clarke W, et al. Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes. N Engl J Med. 2001; 345(12): 851–860.
  17. Brenner B, Cooper M, Zeeuw Dde, et al. Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy. N Engl J Med. 2001; 345(12): 861–869.
  18. Barnett A, Bain S, Bouter P, et al. Angiotensin-Receptor Blockade versus Converting–Enzyme Inhibition in Type 2 Diabetes and Nephropathy. N Engl J Med. 2004; 351(19): 1952–1961.
  19. Struthers A. The clinical implications of aldosterone escape in congestive heart failure. Eur J Heart Fail. 2004; 6(5): 539–545.
  20. Bomback A, Klemmer P. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol. 2007; 3(9): 486–492.
  21. Sato A, Hayashi K, Naruse M, et al. Effectiveness of Aldosterone Blockade in Patients With Diabetic Nephropathy. Hypertension. 2003; 41(1): 64–68.
  22. Rossing K, Schjoedt KJ, Jensen BR, et al. Enhanced Renoprotective Effects of Ultrahigh Doses of Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria. Kidney Int. 2005; 68(3): 1190–1198.
  23. Schmieder R, Klingbeil A, Fleischmann E, et al. Additional Antiproteinuric Effect of Ultrahigh Dose Candesartan: A Double-Blind, Randomized, Prospective Study. J Am Soc Nephrol. 2005; 16(10): 3038–3045.
  24. Adamczak M. Reversal of Glomerulosclerosis after High-Dose Enalapril Treatment in Subtotally Nephrectomized Rats. J Am Soc Nephrol. 2003; 14(11): 2833–2842.
  25. Donderski R, Manitius J. The role of aldosterone in kidney diseases and hypertension. Is it worth using mineralocorticoid receptor antagonists in clinical practice? Arterial Hypertension. 2019; 23(1): 1–7.
  26. Ruggenenti P. Dual renin–angiotensin system blockade for nephroprotection. Néphrol Thér. 2017; 13(Suppl 1): S43–S45.
  27. Čertíková Chábová VČ, Červenka L. The Dilemma of Dual Renin-Angiotensin System Blockade in Chronic Kidney Disease: Why Beneficial in Animal Experiments But Not in the Clinic? Physiol Res. 2017; 66(2): 181–192.
  28. Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual blockade of renin­angiotensin system in patients with hypertension, microalbuminuria, and non­insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ. 2000; 321(7274): 1440–1444.
  29. Mann J, Schmieder R, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008; 372(9638): 547–553.
  30. Parving HH, Brenner B, McMurray J, et al. Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes. N Engl J Med. 2012; 367(23): 2204–2213.
  31. Fried L, Emanuele N, Zhang J, et al. Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy. N Engl J Med. 2013; 369(20): 1892–1903.
  32. Rutkowski B, Tylicki L. Nephroprotective Action of Renin-Angiotensin-Aldosterone System Blockade in Chronic Kidney Disease Patients: The Landscape After ALTITUDE and VA NEPHRON-D Trails. J Ren Nutr. 2015; 25(2): 194–200.
  33. Palevsky P, Zhang J, Seliger S, et al. Incidence, Severity, and Outcomes of AKI Associated with Dual Renin-Angiotensin System Blockade. Clin J Am Soc Nephrol. 2016; 11(11): 1944–1953.
  34. Ponikowski P, Voors A, Anker S, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail. 2016; 18(8): 891–975.
  35. Effects of Enalapril on Mortality in Severe Congestive Heart Failure. N Engl J Med. 1987; 316(23): 1429–1435.
  36. Filippatos G, Farmakis D, Parissis J. Renal dysfunction and heart failure: things are seldom what they seem. Eur Heart J. 2013; 35(7): 416–418.
  37. Damman K, Valente M, Voors AA, et al. Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis. Eur Heart J. 2013; 35(7): 455–469.
  38. Sheerin N, Newton P, Macdonald P, et al. Worsening renal function in heart failure: The need for a consensus definition. Int J Cardiol. 2014; 174(3): 484–491.
  39. Damman K, Testani J. The kidney in heart failure: an update. Eur Heart J. 2015; 36(23): 1437–1444.
  40. Clark H, Krum H, Hopper I. Worsening renal function during renin-angiotensin-aldosterone system inhibitor initiation and long-term outcomes in patients with left ventricular systolic dysfunction. Eur J Heart Fail. 2013; 16(1): 41–48.
  41. Testani J, Kimmel S, Dries D, et al. Prognostic Importance of Early Worsening Renal Function After Initiation of Angiotensin-Converting Enzyme Inhibitor Therapy in Patients With Cardiac Dysfunction. Circ Heart Fail. 2011; 4(6): 685–691.
  42. Tykarski A, Filipiak KJ, Januszewicz A, et al. Zasady postępowania w nadciśnieniu tętniczym — 2019 rok. Wytyczne Polskiego Towarzystwa Nadciśnienia Tętniczego. Nadciśn Tętn Prakt. 2019; 5(1): 1–86.
  43. Grupa Robocza Europejskiego Towarzystwa Kardiologicznego (ESC) i Europejskiego Towarzystwa Nadciśnienia Tętniczego (ESH) do spraw postępowania w nadciśnieniu tętniczym. Wytyczne ESC/ESH dotyczące postępowania w nadciśnieniu tętniczym. Kardiol Pol. 2019; 77(2): 71–159.
  44. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020; 8(4): e21.
  45. Reynolds HR, Adhikari S, Pulgarin C, et al. Renin–Angiotensin–Aldosterone System Inhibitors and Risk of Covid-19. N Engl J Med. 2020; NEJMoa2008975.
  46. Mehra M, Desai S, Kuy S, et al. Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. N Engl J Med. 2020; NEJMoa2007621.
  47. Mancia G, Rea F, Ludergnani M, et al. Renin–Angiotensin–Aldosterone System Blockers and the Risk of Covid-19. N Engl J Med. 2020; NEJMoa2006923.
  48. Thomas G. Renin-angiotensin system inhibitors in COVID-19. Cleve Clin J Med. 2020.
  49. Statement of the European Society of Hypertension (ESH) on hypertension, Renin-Angiotensin System (RAS) blockers and COVID-19. https://www.eshonline.org/spotlights/esh-statement-covid-19/ (April 15th 2020).