IMPORTANCE OF THE FIELD: The renin-angiotensin-aldosterone system (RAAS) is a 
key regulator of blood pressure (BP), as well as volume and electrolytes, in 
both hypertensive and normotensive individuals. Inappropriate activation of the 
RAAS is important in hypertension-induced cardiovascular disease (CVD) and 
chronic kidney disease (CKD). Renin is the rate-limiting step in the RAAS 
cascade, which makes direct renin inhibitors (DRIs) an attractive target for 
RAAS suppression and treatment of hypertension. Current regimens using either 
angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker 
(ARB) result in feedback upregulation of renin and aldosterone breakthrough, 
which contribute to incomplete suppression of the RAAS. Thereby, aliskiren - 
alone or in combination - might offer a novel therapeutic intervention to 
improve suppression of the RAAS, with potential to translate to improved CVD and 
CKD outcomes.
AREAS COVERED IN THIS REVIEW: Herein, we present the current state of knowledge 
of DRIs in the preclinical and clinical realm and their antihypertensive 
efficacy in relation to cardiovascular and renal risk. Recent clinical trials 
(2007 - 2009) support the efficacy of aliskiren, and studies suggest the 
potential for improved CVD and CKD outcomes.
WHAT THE READER WILL GAIN: An understanding of the mechanism of action of DRIs 
and a perspective of recent clinical trials.
TAKE HOME MESSAGE: The DRI aliskiren is an effective antihypertensive agent that 
preliminary data suggests has a beneficial effect in CVD and CKD. Combination of 
aliskiren with an ACEi or ARB may be better tolerated than the ACEi-ARB 
combination. Future work is needed to further quantify aliskiren's impact on 
hard CVD and CKD end points.