Role of aliskiren in cardio-renal protection and use in hypertensives with multiple risk factors

Abstract

The renin-angiotensin-aldosterone system (RAAS) is an important mediator of blood pressure (BP) and volume regulation in both normotensive and hypertensive persons and is a major contributor to hypertension-related target organ damage. The concept of renin inhibition for managing hypertension by blocking the RAAS pathway at its point of activation is very attractive since the renin-angiotensinogen reaction is the first and rate-limiting step in the generation of angiotensin II (Ang II). Aliskiren, the first in a new class of orally effective direct renin inhibitors (DRIs), is approved for the treatment of hypertension. It is effective in reducing BP in the general population of hypertensive patients and in special patient groups such as obese persons, and has a tolerability and safety profile similar to placebo. Aliskiren has renoprotective, cardioprotective and anti-atherosclerotic effects in animal models that appear to be independent of BP lowering. It reduces proteinuria in diabetic patients and has favorable neurohumoral effects in patients with symptomatic heart failure. Additional outcome trials are needed to establish the role of this novel class of antihypertensive medication in the therapeutic armamentarium.

Figure 1

Proteolytic and non-proteolytic activation of prorenin. A renin inhibitor will increase the amount of nonproteolytically activated prorenin. Such a drug binds to prorenin when it is in its open active conformation. Once bound, the prosegment cannot regain its original “closed” position, and thus prorenin will now be recognized by antibodies directed against the active site, although of course it is incapable of generating angiotensin (Ang) I from angiotensinogen (Aog). Because of the high affinity of the renin inhibitor, prorenin will stay in the “open” conformation, and thus the equilibrium will shift into the direction of the open conformation. Eventually, all prorenin will be in the open conformation. Reproduced with permission From Danser AH, Deinum J. Renin, prorenin and the putative (pro)renin receptor. Hypertension. 2005;46:1069–1076. Copyright © 2005 Lippincott Williams & Wilkins.

Figure 2

Schematic representation of the renin-angiotensin-aldosterone system. ACE, angiotensin-converting enzyme; Ang, angiotensin (roman numerals refer to the nomenclature for the peptide; numbers in parentheses refer to the amino acid positions in the peptide relative to Ang I, which has 10 amino acids); AT1, angiotensin II type I receptor; AT2, angiotensin II type 2 receptor. Adapted from Reudelhuber TL. Renin. In: Oparil S, Weber MA (eds). Hypertension, 2nd ed. A Companion to Brenner and Rector’s The kidney. Philadelphia: Elsevier, 2005, p. 89–94. Copyright © 2005 Elsevier.

Figure 3

Urinary albumin/creatinine ratio in diabetic patients with micro- or macroalbuminuria treated with aliskiren for 28 days followed by 28 days washout. Reproduced with permission from Persson F, Rossing P, Schjoedt KJ, et al. Time course of the antiproteinuric and antihypertensive effects of direct renin inhibition in type 2 diabetes. Kidney Int. 2008;73:1419–1425. Copyright © 2008 Nature Publishing Group.

Figure 4

The percentage changes from baseline in the urinary albumin-to-creatinine ratio (▪ aliskiren; Δ placebo). Reproduced with permission from Parving HH, Persson F, Lewis JB, et al. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358:2433–2446. Copyright © 2008 Massachusetts Medical Society. All rights reserved.