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Renin-angiotensin system

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The renin-angiotensin system is a "blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin I; angiotensin II; and angiotensinase."[1]

Components and physiology

For links to more information, see: Renin-angiotensin system: Subtopics

"Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system."[1]

Angiotensin-converting enzyme 2 is a newly recognized component of the renin-angiotensin system.[2]

Medications that affect the renin-angiotensin system

Several classes of medications affect the renin-angiotensin system. Angioedema may occur with inhibition of the system.[3]

Aldosterone antagonists

Aldosterone antagonists may reduce proteinuria according to a systematic review by the Cochrane Collaboration.[4]

Direct renin inhibitors

Aliskiren is an oral direct renin inhibitor that according to a randomized controlled trial may have "renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy."[5]

Angiotensin-converting enzyme inhibitors

For more information, see: Angiotensin-converting enzyme inhibitor.

Angiotensin-converting enzyme inhibitors are medications used for the treatment of hypertension and heart failure.

Angiotensin II receptor antagonists

For more information, see: Angiotensin II receptor antagonist.

Angiotensin II receptor antagonists are medications that antagonize the angiotensin II type 1 receptor and are used for the treatment of hypertension and heart failure.

Clinical significance

Blocking the renin-angiotensin system can help treatment of heart failure and chronic kidney disease.

An observational study suggests blocking the renin-angiotensin system may prevent dementia.[6]

Combining classes of medications to block the renin-angiotensin system at multiple points can be dangerous.[7]

Heart failure

Randomized controlled trials have investigated combining the latter two classes together for a synergistic effect, but have usually found increased adverse effects that outweigh beneficial reduction of proteinuria (see summary Table).[8][9]

Trials of combining angiotensin-converting enzyme inhibitors with angiotensin II receptor antagonists[10][11][12][13][14]
Trial Year Patients Findings
Valsartan Heart Failure Trial[10] 2001 New York Heart Association class II-IV heart failure "Valsartan significantly reduces the combined end point of mortality and morbidity and improves clinical signs and symptoms in patients with heart failure, when added to prescribed therapy. However, the post hoc observation of an adverse effect on mortality and morbidity in the subgroup receiving valsartan, an ACE inhibitor, and a beta-blocker raises concern about the potential safety of this specific combination"[10]
CHARM-Added[11] 2003 New York Heart Association class II-IV heart failure and left-ventricular ejection fraction 40% or lower"[11] "The addition of candesartan to ACE inhibitor and other treatment leads to a further clinically important reduction in relevant cardiovascular events in patients."[11]
VALIANT[12] 2003 myocardial infarction with left ventricular systolic dysfunction or heart failure "Valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after myocardial infarction. Combining valsartan with captopril increased the rate of adverse events without improving survival."
ONTARGET[13][14] 2008 vascular disease or high-risk diabetes "Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema. The combination of the two drugs was associated with more adverse events without an increase in benefit."[13] "Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal outcomes."[14]

Chronic kidney disease

Inhibition of the renin-angiotensin system can benefit chronic kidney disease.[9]

Combining classes of medications to block the renin-angiotensin system at multiple points can be dangerous.[7] A safer approach may be to add a nondihydropyridine calcium channel blockers to monotherapy against the renin-angiotensin system according to multiple trials by one investigator[15][16][17][18] and has not been replicated by other investigators.[19]

Combining aldosterone antagonists with angiotensin II receptor antagonists or angiotensin-converting enzyme inhibitors may slow the progression of chronic kidney disease according to a meta-analysis by the Cochrane Collaboration.[4]

An initial randomized controlled trial of patients with hypertension and diabetes mellitus type 2 with nephropathy found reduced albuminuria by combining aliskiren (an oral direct renin inhibitor) with losartan (an angiotensin II receptor antagonist).[5]

In contrast, combining telmisartan (angiotensin II receptor antagonists) and ramipril (angiotensin-converting enzyme inhibitors) reduces proteinuria greater than monotherapy, overall renal outcomes are worse.[14]


  1. 1.0 1.1 Anonymous (2018), Renin-angiotensin system (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. Boehm M, Nabel EG (November 2002). "Angiotensin-converting enzyme 2--a new cardiac regulator". N. Engl. J. Med. 347 (22): 1795–7. DOI:10.1056/NEJMcibr022472. PMID 12456857. Research Blogging.
  3. Makani H, Messerli FH, Romero J, Wever-Pinzon O, Korniyenko A, Berrios RS et al. (2012). "Meta-Analysis of Randomized Trials of Angioedema as an Adverse Event of Renin-Angiotensin System Inhibitors.". Am J Cardiol. DOI:10.1016/j.amjcard.2012.03.034. PMID 22521308. Research Blogging.
  4. 4.0 4.1 Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF (2009). "Aldosterone antagonists for preventing the progression of chronic kidney disease.". Cochrane Database Syst Rev (3): CD007004. DOI:10.1002/14651858.CD007004.pub2. PMID 19588415. Research Blogging.
  5. 5.0 5.1 Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK (June 2008). "Aliskiren combined with losartan in type 2 diabetes and nephropathy". N. Engl. J. Med. 358 (23): 2433–46. DOI:10.1056/NEJMoa0708379. PMID 18525041. Research Blogging.
  6. Ellul J, Archer N, Foy CM, et al (March 2007). "The effects of commonly prescribed drugs in patients with Alzheimer's disease on the rate of deterioration". J. Neurol. Neurosurg. Psychiatr. 78 (3): 233–9. DOI:10.1136/jnnp.2006.104034. PMID 17012333. Research Blogging.
  7. 7.0 7.1 Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A et al. (2004). "Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study.". N Engl J Med 351 (6): 543-51. DOI:10.1056/NEJMoa040135. PMID 15295047. Research Blogging.
  8. McMurray JJ (April 2008). "ACE inhibitors in cardiovascular disease--unbeatable?". N. Engl. J. Med. 358 (15): 1615–6. DOI:10.1056/NEJMe0801925. PMID 18378521. Research Blogging.
  9. 9.0 9.1 Kunz R, Friedrich C, Wolbers M, Mann JF (January 2008). "Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease". Ann. Intern. Med. 148 (1): 30–48. PMID 17984482[e]
  10. 10.0 10.1 10.2 Cohn JN, Tognoni G (December 2001). "A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure". N. Engl. J. Med. 345 (23): 1667–75. PMID 11759645[e]
  11. 11.0 11.1 11.2 11.3 McMurray JJ, Ostergren J, Swedberg K, et al (September 2003). "Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial". Lancet 362 (9386): 767–71. DOI:10.1016/S0140-6736(03)14283-3. PMID 13678869. Research Blogging.
  12. 12.0 12.1 Pfeffer MA, McMurray JJ, Velazquez EJ, et al (November 2003). "Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both". N. Engl. J. Med. 349 (20): 1893–906. DOI:10.1056/NEJMoa032292. PMID 14610160. Research Blogging. ACP Journal Club
  13. 13.0 13.1 13.2 Yusuf S, Teo KK, Pogue J, et al (April 2008). "Telmisartan, ramipril, or both in patients at high risk for vascular events". N. Engl. J. Med. 358 (15): 1547–59. DOI:10.1056/NEJMoa0801317. PMID 18378520. Research Blogging.
  14. 14.0 14.1 14.2 14.3 Mann JF, Schmieder RE, McQueen M, et al (August 2008). "Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial". Lancet 372 (9638): 547–53. DOI:10.1016/S0140-6736(08)61236-2. PMID 18707986. Research Blogging. ACP Journal Club
  15. Bakris GL (1990). "Effects of diltiazem or lisinopril on massive proteinuria associated with diabetes mellitus.". Ann Intern Med 112 (9): 707-8. PMID 2159250[e]
  16. Bakris GL, Barnhill BW, Sadler R (1992). "Treatment of arterial hypertension in diabetic humans: importance of therapeutic selection.". Kidney Int 41 (4): 912-9. PMID 1325010[e]
  17. Bakris GL, Copley JB, Vicknair N, Sadler R, Leurgans S (1996). "Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy.". Kidney Int 50 (5): 1641-50. PMID 8914031[e]
  18. Bakris GL, Weir MR, DeQuattro V, McMahon FG (1998). "Effects of an ACE inhibitor/calcium antagonist combination on proteinuria in diabetic nephropathy.". Kidney Int 54 (4): 1283-9. DOI:10.1046/j.1523-1755.1998.00083.x. PMID 9767545. Research Blogging.
  19. Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V et al. (2004). "Preventing microalbuminuria in type 2 diabetes.". N Engl J Med 351 (19): 1941-51. DOI:10.1056/NEJMoa042167. PMID 15516697. Research Blogging. Review in: ACP J Club. 2005 May-Jun;142(3):65