Is There Added Value to Adding ARB to ACE Inhibitors in the Management of CKD? Debbie L. Cohen and Raymond R. Townsend Renal, Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania The role of the renin-angiotensin-aldo- sterone-system (RAAS) in processes that lead to heart disease, stroke, and kidney failure took a great leap forward when it became possible to antagonize this sys- tem. This work began with the peptides saralesin and teprotide, which, although available only intravenously (thus only short term), nonetheless provided proof of concept that the RAAS exerted a sig- nificant role in the regulation of BP and the mediation of target-organ damage. Thereafter, the first orally active angio- tensin-converting enzyme (ACE) inhibi- tor, captopril, appeared in the summer of 1981. This drug made long-term clinical trials feasible in humans. In the interven- ing years, it has become clear that, in ad- dition to BP regulation, the RAAS partic- ipates in inflammatory, thrombotic, and other vasculotoxic processes, which ulti- mately mediate target-organ damage at- tributable to atherosclerosis. As a result, the RAAS is a pivotal target for manipu- lation in primary and secondary preven- tion efforts to reduce the devastating ef- fects of heart attack, heart failure, stroke, and further reduction in kidney function, particularly when increased amounts of urinary protein are present. The complexity of the RAAS contin- ues to unfold despite more than 100 yr of recognition of importance of the system by Tigerstedt and Bergman. 1 Currently, it is possible to block the system in three places. These places are at the level of ACE itself, by competitive blockade of the angiotensin II receptor site and through direct inhibition of renin activ- ity. Another point of blockade includes interruption of aldosterone (whose pro- duction and secretion are stimulated by angiotensin II) effect through selective mineralocorticoid blockade. We do not address further the addition of aldoste- rone or renin inhibitors to dual therapy with ACE inhibitor and angiotensin II receptor blocker (ARB) treatment. A substantial portfolio of human clin- ical trials, first in heart failure 2 ; followed by type 1 diabetic nephropathy 3 ; and then extending to coronary artery dis- ease, patients with high cardiovascular risk, general hypertension, and second- ary stroke prevention attest to the benefit of ACE inhibitor and ARB drugs when applied to patients with these diseases. It was soon noted that there is “ACE es- cape” in some patients 4 in which both angiotensin II and aldosterone levels re- turn to pretreatment values despite the presence of suppressed ACE activity. When the ARB class was introduced in spring of 1995 with the approval of losar- tan, an oft-repeated question arose pon- dering whether additional benefit would evidence when an ARB was added to an existing ACE inhibitor treatment regi- men. Arguing from the ACE escape phe- nomenon, the rationale for blocking rogue angiotensin II produced by chy- mases and other non–ACE inhibitor– suppressible systems provided clinical plausibility for benefit from dual RAAS blockade. In the rest of this clinical com- mentary, we focus our thoughts on as- pects of this important clinical query with respect to patients with chronic kid- ney disease (CKD). CKD affects millions of adults in the United States. Progressive loss of kidney Published online ahead of print. Publication date available at www.jasn.org. Correspondence: Dr. Debbie L. Cohen, Renal, Elec- trolyte and Hypertension Division, Department of Medicine, University of Pennsylvania, 1 Founders Building, 3400 Spruce Street, Philadelphia, PA 19104. Phone: 215-615-0794; Fax: 215-615-0349; E-mail: debbie.cohen@uphs.upenn.edu Copyright  2009 by the American Society of Nephrology ABSTRACT Antagonism of the rennin-angiotensin-aldosterone-system (RAAS) decreases BP and reduces proteinuria in chronic kidney disease. BP is decreased approximately 5 mmHg when angiotensin II blockers are added to angiotensin-converting enzyme (ACE) inhibitors and is less than typically seen when other agents are added to existing ACE inhibitor regimens. Dual RAAS blockade results in additional reduc- tion in proteinuria. Clinically insignificant increases in hyperkalemia and modest decreases in GFR occur. Data regarding long-term preservation of renal function are lacking. We suggest dual RAAS blockade be used in patients with chronic kidney disease with residual proteinuria on maximal ACE inhibitor or angiotensin II blocker therapy, anticipating additional data with ongoing trials. J Am Soc Nephrol 20: 1666 –1668, 2009. doi: 10.1681/ASN.2008040381 CLINICAL COMMENTARY www.jasn.org 1666 ISSN : 1046-6673/2008-1666 J Am Soc Nephrol 20: 1666–1668, 2009