What Is Considered a High Renin Level

Renin-angiotensin-aldosterone system inhibitors

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September 19, 2021

Summary

Renin-angiotensin-aldosterone system (RAAS) inhibitors are a group of drugs that act by inhibiting the renin-angiotensin-aldosterone system (RAAS) and include angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin-receptor blockers (ARBs), and direct renin inhibitors. ACE inhibitors and ARBs are commonly used in the treatment of patients with hypertension, heart failure with reduced ejection fraction, and certain types of chronic kidney disease, as well as patients who have had a myocardial infarction. They are particularly important in the treatment of hypertensive diabetic patients, as they prevent the development of diabetic nephropathy. A common side effect of ACE inhibitors is a bradykinin-induced cough, which may necessitate switching to an alternative therapy (e.g., ARBs), while angioedema and hyperkalemia may occur with both ARBs and ACE inhibitor use. Direct renin inhibitors may be considered in hypertensive patients if ACE inhibitors or ARBs are not well tolerated; however, they should never be used in combination with other RAAS inhibitors.

Overview

The renin-angiotensin-aldosterone system (RAAS)

• Drops in blood pressure reduce renal perfusion.
• If the pressure in the renal artery falls by more than 10–15 mmHg , proteolytic renin is released from the juxtaglomerular apparatus → renin converts angiotensinogen to angiotensin I → ACE cleaves C-terminal peptides on angiotensin I, converting it to angiotensin II → increases the blood pressure in two ways: vasoconstriction and stimulation of the release of aldosterone , which increases the retention of water and sodium
• For more information, see "Renin-angiotensin-aldosterone system" in "Adrenal gland."

Angiotensin-converting enzyme inhibitors (ACE inhibitors)

• Drug names: enalapril, lisinopril , ramipril, captopril , benazepril
• Indications
  • Arterial hypertension
  • Diabetes mellitus (type I and type II) with ^{[1] [2]}
    • Nephroprotective indications , such as:
      • Arterial hypertension
      • Microalbuminuria and proteinuria (especially ≥ 300 mg/g )
    • Coronary heart disease
  • Heart failure with reduced ejection fraction ^[3]
    • Survival benefit (the exact mechanisms are poorly understood)
    • Any murmur that decreases with amyl nitrite has an etiology that is treatable with ACE inhibitors.
  • History of myocardial infarction ^[4]
  • Nondiabetic chronic kidney disease with proteinuria
  • Scleroderma-associated hypertensive crisis (even if creatinine is elevated)

Angiotensin-receptor blocker (ARBs, sartans)

• Drug names: valsartan , candesartan , losartan , irbesartan
• Indications: same as ACE inhibitors , mostly used as second-line treatment if ACE inhibitors are not tolerated

Direct renin inhibitors

Pharmacodynamics

ACE inhibitors

• Mechanism of action: inhibition of ACE → ↓ conversion of angiotensin I to angiotensin II
• Main effects
  • ↓ Angiotensin II
    • ↓ Vasoconstriction → ↓ blood p ressure
    • ↓ Secretion of aldosterone → ↓ reabsorption of Na⁺ and water → ↓ blo o d pressure
    • Dilation of efferent arteriole → ↑ renal plasma flow → ↓ GFR → ↓ filtration fraction
    • ↑ Renin secretion (due to lack of feedback inhibition) → ↑ angiotensin I
  • ↓ Breakdown of bradykinin → ; ↑ production of arachidonic acid metabolites → ↑ vasodilation → ↓ blood pressure
• Other effects
  • ↓ Proteinuria and ↓ progression of proteinuric chronic kidney disease : ↓ intraglomerular hydrostatic pressure attenuates thickening and sclerosis of the GBM
  • ↓ Preload and afterload → ↓ cardiac remodeling ; after acute myocardial infarction or in chronic hypertensive disease

ARBs

• Mechanism of action: inhibition of angiotensin II receptor type 1 ( AT₁ receptor )
• Main effects
  • ↓ Vasoconstriction → ↓ blood pressure
  • ↓ Secretion of aldosterone → ↓ reabsorption of Na⁺ and water → ↓ blood pressure
  • ↑ Renin secretion (compensatory) → ↑ angiotensin I → ↑ angiotensin II
• Other effects

Direct renin inhibitors

• Mechanism of action: direct inhibition of renin → ↓ conversion of angiotensinogen into angiotensin I → ↓ angiotensin I and angiotensin II → ↓ angiotensin II → ↓ vasoconstriction
• Main effects
  • ↓ Blood pressure
  • ↓ Secretion of aldosterone → ↓ reabsorption of Na ⁺ and water → further ↓ blood pressure

a LES ki REN : LESS REN in with aliskiren.

Adverse effects

ACE inhibitors

• Increase in bradykinin concentration , which can lead to:
  • Dry cough ( can be treated by discontinuing ACE inhibitor , consider switching to ARB ) ^{[6] [7]}
  • Bradykinin-mediated angioedema due to increased vascular permeability and vasodilation
• Hypotension
• ↓ GFR (with ↑ creatinine) : can cause acute kidney injury in patients with preexisting renal hypoperfusion (e.g., renal artery stenosis, hypovolemia, heart failure) ^[8]
• Hyperkalemia
• Proteinuria
• Pemphigus vulgaris (unknown mechanism) ^[9]
• Teratogenicity: renal malformations
• Leukopenia
• Rash
• Taste changes

Side effects of CAPTOPRIL: Cough, Angioedema, Pemphigus vulgaris, Teratogenicity, hypOtension, high Potassium, Renal failure, Increased creatinine, Low GFR.

ARBs

• Angioedema
• Hyperkalemia
• ↓ GFR (with ↑ creatinine )
• Hypotension
• Teratogenicity
• Leukopenia
• Rash

Direct renin inhibitors

Acute kidney injury is a potential side effect of all types of RAAS inhibitors, especially in patients with preexisting kidney disease or in combination with NSAIDs

We list the most important adverse effects. The selection is not exhaustive.

Contraindications

Contraindications for ACE inhibitors and ARBs

• Absolute contraindications
  • Hypersensitivity
  • C1 esterase inhibitor deficiency (due to predisposition to angioedema)
  • Pregnancy : risk of harm to the fetus (e.g., renal impairment, renal malformations, oligohydramnios, placental insufficiency) ^[1]
  • Breastfeeding
• Relative contraindications
  • Aortic stenosis
  • Renal dysfunction , consider altering dose if GFR < 60 mL/min ^{[10] [11]}
  • Bilateral renal artery stenosis or a solitary kidney : GFR is already decreased and further reduction may lead to acute kidney injury.
  • Drug interactions: See "Interactions" below.

Normally, angiotensin II constricts efferent vessels, increasing the GFR. ACE inhibitors antagonize the conversion of angiotensin I to angiotensin II , reducing the GFR.

Contraindications for direct renin inhibitors

• Hypersensitivity
• Pregnancy
• Current treatment with ACE inhibitors or ARBs
• Drug interactions: See "Interactions" below.

We list the most important contraindications. The selection is not exhaustive.

Interactions

ACE inhibitors and ARBs ^[12]

• Other antihypertensive drugs → ↑ hypotensive effect
• NSAIDs → ↓ antihypertensive effect
• Potassium-sparing diuretics ; or other drugs that increase potassium level: ↑ hyperkalemia
• ↑ Level of lithium due to ↓ renal elimination
• Allopurinol: ↑ risk of immunological reactions or leukopenia ^{[13] [14]}

Direct renin inhibitors ^[15]

• P-glycoprotein inhibitors ; ( e.g., ketoconazole, verapamil ; , clarithromycin, erythromycin, amiodarone): ↑ aliskiren level
• ACE inhibitors or ARBs → ↑ hyperkalemia ^[16]

Do not combine direct renin inhibitors with ACE inhibitors or ARBs, especially in patients with diabetes or preexisting kidney disease.

Additional considerations

References

1. Standards of Medical Care in Diabetes 2016. http://care.diabetesjournals.org/content/suppl/2015/12/21/39.Supplement_1.DC2/2016-Standards-of-Care.pdf. Updated: January 1, 2016. Accessed: February 22, 2017.
2. Roett MA, Liegl S, Jabbarpour Y. Diabetic nephropathy - the family physician's role. Am Fam Physician. 2012; 85 (9): p.883-889.
3. Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of Enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991; 325 (5): p.293-302. doi: 10.1056/nejm199108013250501 . | Open in Read by QxMD
4. Franzosi MG, Santoro E, Zuanetti G, et al. Indications for ACE inhibitors in the early treatment of acute myocardial infarction : systematic overview of individual data from 100 000 Patients in randomized trials. Circulation. 1998; 97 (22): p.2202-2212. doi: 10.1161/01.cir.97.22.2202 . | Open in Read by QxMD
5. Haymore BR, Yoon J, Mikita CP, Klote MM, DeZee KJ. Risk of angioedema with angiotensin receptor blockers in patients with prior angioedema associated with angiotensin-converting enzyme inhibitors: a meta-analysis. Ann Allergy Asthma Immunol .. 2008; 101 (5): p.495-499. doi: 10.1016/s1081-1206(10)60288-8 . | Open in Read by QxMD
6. Karlberg BE. Cough and inhibition of the renin-angiotensin system.. J Hypertens Suppl. 1993; 11 (3): p.S49-52.
7. Yılmaz İ. Angiotensin-Converting Enzyme Inhibitors Induce Cough.. Turkish thoracic journal. 2019; 20 (1): p.36-42. doi: 10.5152/TurkThoracJ.2018.18014 . | Open in Read by QxMD
8. Navis G, Faber HJ, de Zeeuw D, de Jong PE. ACE Inhibitors and the Kidney. Drug Saf. 1996; 15 (3): p.200-211. doi: 10.2165/00002018-199615030-00005 . | Open in Read by QxMD
9. Ayatollahi A, Toossi P, Younespour S, Robati R. Serum angiotensin converting enzyme in pemphigus vulgaris. Indian J Dermatol. 2014; 59 (4): p.348. doi: 10.4103/0019-5154.135478 . | Open in Read by QxMD
10. Use of angiotensin converting-enzyme inhibitors and angiotensin receptor blockers in CKD. https://www2.kidney.org/professionals/kdoqi/guidelines_bp/guide_11.htm. Updated: January 1, 2004. Accessed: April 11, 2018.
11. Bicket DP. Using ACE inhibitors appropriately. Am Fam Physician. 2002; 66 (3): p.461-469.
12. Shionoiri H. Pharmacokinetic drug interactions with ACE inhibitors. Clin Pharmacokinet. 1993; 25 (1): p.20-58. doi: 10.2165/00003088-199325010-00003 . | Open in Read by QxMD
13. Polónia J. Interaction of antihypertensive drugs with anti-inflammatory drugs. Cardiology. 1997; 88 (3): p.47-51. doi: 10.1159/000177507 . | Open in Read by QxMD
14. Stamp LK, Chapman PT. Gout and its comorbidities: implications for therapy. Rheumatology. 2012; 52 (1): p.34-44. doi: 10.1093/rheumatology/kes211 . | Open in Read by QxMD
15. Vaidyanathan S, Jarugula V, Dieterich HA, Howard D, Dole WP. Clinical pharmacokinetics and pharmacodynamics of Aliskiren. Clin Pharmacokinet. 2008; 47 (8): p.515-531. doi: 10.2165/00003088-200847080-00002 . | Open in Read by QxMD
16. Harel Z, Gilbert C, Wald R, et al. The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis. BMJ. 2012; 344 : p.e42. doi: 10.1136/bmj.e42 . | Open in Read by QxMD

What Is Considered a High Renin Level

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