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Review: Renal protection by inhibition of the renin-angiotensin-aldosterone system

Division of Renal Diseases and Hypertension, University of Colorado at Denver Health Sciences Center, Denver, Colorado, USA, Tomas.Berl@ uchsc.edu

Renin-angiotensin-aldosterone system (RAAS) inhibition exerts a renoprotective effect independent of blood pressure reduction. Many studies using an end-point of proteinuria compared the effects of angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) monotherapy with combination ACE-I/ARB therapy. Despite methodological limitations, most studies suggest that combination therapy provides a greater antiproteinuric effect than monotherapy, perhaps because of more prolonged and complete RAAS inhibition. COOPERATE and ONTARGET used more robust end-points to study renoprotective effects. In COOPERATE, combination therapy resulted in significantly longer times to doubling serum creatinine or developing end-stage renal disease than trandolapril or losartan monotherapy. However, a secondary ONTARGET finding was that combination therapy significantly increased the risk for renal dysfunction compared with ramipril or telmisartan alone. Eventually, the VA NEPHRON-D trial should provide definitive data relating to patients with diabetic nephropathy. Results of AVOID suggest the renoprotective benefits of combination therapy extend to the direct renin inhibitors (DRI). In AVOID, combination therapy with aliskiren, a DRI, and losartan resulted in 20% greater protein excretion decrement than losartan monotherapy. Future trials should examine higher RAAS inhibitor doses, facilitate differentiation of renoprotective and antihypertensive effects of RAAS blockade, and use end-points that robustly demonstrate renoprotective effects.

Key Words: angiotensin-converting enzyme inhibitor • angiotensin receptor blocker • combination therapy • direct renin inhibitor • monotherapy • proteinuria

References

• Remuzzi G., Benigni A., Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 2006;116:288-96.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Peterson JC, Adler S., Burkart JM et al. Blood pressure control, proteinuria, and the progression of renal disease: the Modification of Diet in Renal Disease Study. Ann Intern Med 1995;123:754-62.[Abstract/Free Full Text]
• De Zeeuw D., Remuzzi G., Parving HH et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004;65:2309-20.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Atkins RC, Briganti EM, Lewis JB et al. Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. Am J Kidney Dis 2005;45:281-7.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Lea J., Greene T., Hebert L. et al. The relationship between magnitude of proteinuria reduction and risk of end-stage renal disease: results of the African American study of kidney disease and hypertension. Arch Intern Med 2005;165:947-53.[Abstract/Free Full Text]
• Laverman GD, Navis G., Henning RH, de Jong PE, De Zeeuw D. Dual renin-angiotensin system blockade at optimal doses for proteinuria. Kidney Int 2002;62:1020-5.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Hou FF, Xie D., Zhang X. et al. Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: a randomized controlled study of benazepril and losartan in chronic renal insufficiency. J Am Soc Nephrol 2007;18:1889-98.[Abstract/Free Full Text]
• Hollenberg NK, Parving HH, Viberti G. et al. Albuminuria response to very high-dose valsartan in type 2 diabetes mellitus. J Hypertens 2007;25:1921-6.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Bianchi S., Bigazzi R., Campese VM Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int 2006;70:2116-23.[Web of Science][Medline] [Order article via Infotrieve]
• Kunz R., Friedrich C., Wolbers M., Mann JFE. Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin-angiotensin system on proteinuria in renal disease. Ann Intern Med 2008;148:30-48.[Abstract/Free Full Text]
• Mogensen CE, Neldam S., Tikkanen I. et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000;321:1440-4.[Abstract/Free Full Text]
• Jacobsen P., Andersen S., Jensen BR, Parving HH Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy. J Am Soc Nephrol 2003;14:992-9.[Abstract/Free Full Text]
• Jacobsen P., Andersen S., Rossing K., Jensen BR, Parving HH Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy. Kidney Int 2003;63:1874-80.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Luno J., Barrio V., Goicoechea MA et al. Effects of dual blockade of the renin-angiotensin system in primary proteinuric nephropathies. Kidney Int 2002;62(suppl 82):47-52.[CrossRef][Medline] [Order article via Infotrieve]
• Campbell R., Sangalli F., Perticucci E. et al. Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies. Kidney Int 2003;63:1094-103.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Nakao N., Yoshimura A., Morita H., Takada M., Kayano T., Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003;361:117-24.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-59.[Abstract/Free Full Text]
• Segura J., Praga M., Campo C., Rodicio JL, Ruilope LM Combination is better than monotherapy with ACE inhibitor or angiotensin receptor antagonist at recommended doses. J Renin Angiotensin Aldosterone Syst 2003;4:43-7.[Abstract/Free Full Text]
• Rossing K., Jacobsen P., Pietraszek L., Parving HH Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy: a randomized double-blind crossover trial. Diabetes Care 2003;26:2268-74.[Abstract/Free Full Text]
• Rutkowski P., Tylicki L., Renke M., Korejwo G., Zdrojewski Z., Rutkowski B. Low-dose dual blockade of the renin-angiotensin system in patients with primary glomerulonephritis. Am J Kidney Dis 2004;43:260-8.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Esnault VLM, Ekhlas A., Delcroix C., Moutel MG, Nguyen JM Diuretic and enhanced sodium restriction results in improved antiproteinuric response to RAS blocking agents. J Am Soc Nephrol 2005;16:474-81.[Abstract/Free Full Text]
• Heeg JE, de Jong PE, van der Hem GK, De Zeeuw D. Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril. Kidney Int 1989;36:272-9.[Web of Science][Medline] [Order article via Infotrieve]
• Buter H., Hemmelder MH, Navis G., de Jong PE, De Zeeuw D. The blunting of the antiproteinuric efficacy of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide. Nephrol Dial Transplant 1998;13:1682-5.[Abstract/Free Full Text]
• Doulton TWR, He FJ, MacGregor GA Systematic review of combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade in hypertension. Hypertension 2005;45:880-6.[Abstract/Free Full Text]
• Schmieder RE, Klingbeil AU, Fleischmann EH, Veelken R., Delles C. Additional antiproteinuric effect of ultrahigh dose candesartan: a double-blind, randomized, prospective study. J Am Soc Nephrol 2005;16:3038-45.[Abstract/Free Full Text]
• Forclaz A., Maillard M., Nussberger J., Brunner HR, Burnier M. Angiotensin II receptor blockade: is there truly a benefit of adding an ACE inhibitor? Hypertension 2003;41:31-6.[Abstract/Free Full Text]
• Linas SL Are two better than one? Angiotensin-converting enzyme inhibitors plus angiotensin receptor blockers for reducing blood pressure and proteinuria in kidney disease. Clin J Am Soc Nephrol 2008;3(suppl 1):S17-23.[Abstract/Free Full Text]
• Bidani A. Controversy about COOPERATE ABPM trial data. Am J Nephrol 2006;26:629, 632.[Web of Science]
• Kunz R., Wolbers M., Glass T., Mann JF The COOPERATE trial: a letter of concern. Lancet 2008;371:1575-6.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Mann JF, Schmieder RE, McQueen M. et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-53.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• VA NEPHRON-D Study. www.clinicaltrials.gov/ct2/show/NCT00555217. Accessed April 7, 2008.
• Staessen JA, Li Y., Richart T. Oral renin inhibitors. Lancet 2006;368:1449-56.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Uresin Y., Taylor AA, Kilo C. et al. Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension. J Renin Angiotensin Aldosterone Syst 2007;8:190-8.[Abstract/Free Full Text]
• Oparil S., Yarows SA, Patel S., Fang H., Zhang J., Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet 2007;370:221-9.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 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;73:1419-25.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Parving HH, Persson F., Lewis JB, Lewis EJ, Hollenberg NK, for the AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008;358:2433-46.[Abstract/Free Full Text]

Journal of Renin-Angiotensin-Aldosterone System, Vol. 10, No. 1, 1-8 (2009)
DOI: 10.1177/1470320309102747


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This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Berl, T. Search for Related Content PubMed PubMed Citation Articles by Berl, T. Social Bookmarking                         What's this?