Renin, angiotensin, aldosterone and you

There’s no escaping the kidneys in pharmacy.  Their significance in drug elimination, blood pressure and salt and fluid balance is undeniable.  

Renin is produced by juxtaglomerular cells in the afferent arteriole in response to decreased pressure in the kidney.  Renin is also responsible for the initial rate limiting step in the production of angiotensin.  Angiotensin-converting enzyme (ACE) facilitates the final step in the production of the active angiotensin II and is also responsible for the metabolism of certain peptides, such as bradykinin.

ACE-inhibitors (ACE-i) and angiotensin receptor blockers (ARB) reduce the effects of angiotensin II, which is responsible for vasoconstriction and aldosterone and sodium retention, to decrease the blood pressure and pressure within the kidney through different mechanisms.  ACE-i block ACE; however there are other pathways for the production of angiotensin leading to “ACE escape”.  ARBs would block angiotensin at its site of action, thereby bypassing the risk of “ACE escape”.  Both classes of medications can lead to increases in renin due to sustained lower pressures within the glomerulus.

Though increased bradykinin is the cause of the notorious ACE-i induced dry cough, it also provides added vasodilation.  A recent meta-analysis looking at mortality data from 20 trials utilizing an ACE-i or an ARB compared with a control showed that ACE-i offered a 10% mortality decrease compared with ARBs and the control drug or placebo.  The meta-analysis excluded patients who had heart disease or kidney disease, where RAAS inhibition has already been shown to have significant added benefits.  

The analysis shows that there is a clear mortality benefit to using an ACE-i in patients with hypertension without other comorbidities that would indicate RAAS inhibition.  If a patient is unable to take an ACE-i, there is no added mortality benefit to using an ARB over another antihypertensive.

Aliskiren, or Tekturna, is a direct renin inhibitor, the newest class of RAAS inhibitors.   Researchers hypothesized that using aliskiren in combination with an ACE-i or an ARB would improve outcomes by targeting RAAS through two mechanisms.  The “Aliskiren trial in type 2 diabetes using cardio-renal endpoints” studying aliskiren with an ACE-i or and ARB in diabetics was stopped early in December due to futility as well as increased risk of renal impairment, hypotension, and hypokalemia.  Prior to this in 2008, the TARGET study had also shown lack of benefit with combining an ACE-i and an ARB in patients with vascular disease or diabetes with organ damage.

The Food and Drug Administration, FDA, has recently placed a warning on aliskiren against its use in combination with an ACE-i or an ARB in patients with diabetes or moderate to severe renal impairment. 

While both an ACE-i or an ARB has clear benefit in patients with kidney disease or heart failure, ACE-i are superior to ARBs in mortality benefit in patients with hypertension alone.  Combining an ACE-i with an ARB or aliskiren should be avoided.

References:

Atlas SA.  The renin-angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition.  Journal of Managed Care Pharmacy 2007; 13(8): S9-S20.

van Vark LC, Bertrand M, Akkerhuis KM et al.  Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158 998 patients.  European Heart Journal 2012; DOI:10.1093/eurheartj/ehs075. Available at: http://eurheartj.oxfordjournals.org

Lowes R. No aliskiren with ACE inhibitors, ARBs in some patients: FDA.  theheart.org April 20, 2012.  Available at http://www.theheart.org/article/1388139.do