Clinical and Experimental Nephrology

, Volume 12, Issue 1, pp 33–40

Dual blockade of the rennin–angiotensin system versus maximal recommended dose of angiotensin II receptor blockade in chronic glomerulonephritis

  • Urara Mori-Takeyama
  • Shinya Minatoguchi
  • Ichijirou Murata
  • Hisayoshi Fujiwara
  • Yoko Ozaki
  • Michiya Ohno
  • Hiroshi Oda
  • Hiroshige Ohashi
Original Article



Proteinuria and hypertension are predictors of poor renal outcome in chronic glomerulonephritis (CGN). At the same level of blood pressure (BP) control, we evaluated which is superior, dual blockade of the rennin–angiotensin system (RAS) with both angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II type 1 (AT-1) receptor blockade (ARB) or single blockade of ARB to reduce proteinuria and to preserve renal function in patients with CGN.


In this prospective, parallel, open study of 86 patients with CGN, we compared the effects on proteinuria and renal functions of 36 months with comparable blood pressure (BP) control achieved by candesartan cilexetil (candesartan, 4–12 mg/day) or benazepril hydrochrolide (benazepril, 2.5–10 mg/day) with candesartan (4 mg/day). Aiming at BP 125/75 mmHg or less, the dose of candesartan (single blockade) or benazepril (dual blockade) was increased.


Dual blockade decreased proteinuria more than single blockade with ARB (−42.3 vs. −60.5%, P < 0.01). Renal plasma flow (RPF) and glomerular filtration fraction (GFR) did not change significantly in either group. The filtration fraction (FF) decreased dual blockade more than single blockade (−1.7 vs. −19.0%, P < 0.05). Decreased FF was associated with the reduction of proteinuria (P < 0.05). Six percent of patients with dual blockade were not able to continue the study because of a dry cough.


Long-term dual blockade decreased proteinuria more than single blockade with ARB. Although ARB and ACEI have a glomerular size-selective function for proteinuria, a greater antiproteinuric effect may depend on renal hemodynamics, especially FF. Increased levels of bradykinin after ACEI can decrease FF and ameliorate proteinuria. Dry cough is a significant adverse effect of ACE inhibitor.


Candesartan Benazepril Dual blockade Chronic glomerulonephritis Proteinuria Renal function 


  1. 1.
    Mashio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, et al. Effect of angiotensin-converting-enzyme inhibitor benazepril on chronic renal insufficiency. N Engl J Med. 1996;334:939–45.CrossRefGoogle Scholar
  2. 2.
    Remuzzi G, Ruggenenti P, Perico N. Chronic renal disease: renoprotective benefits of rennin–angiotensin system inhibition. Ann Intern Med. 2002;136:604–15.PubMedGoogle Scholar
  3. 3.
    Weir MR. Progressive renal and cardiovascular disease: optimal treatment strategies. Kidney Int. 2002;62:1482–92.PubMedCrossRefGoogle Scholar
  4. 4.
    Yu HT. Progression of chronic renal failure. Arch Intern Med. 2003;163:1417–29.PubMedCrossRefGoogle Scholar
  5. 5.
    Gansevoort RT, Sluiter WJ, Hemmelder MH, de Jong PE, et al. Antiproteinuric effect of blood-pressure-lowerling agents: a meta-analysis of comparative trials. Nephrol Dial Transplant. 1995;10:1963–74.PubMedGoogle Scholar
  6. 6.
    Hilgers KF, Mann JF. ACE inhibitors versus AT(1) rexeptor antagonists in patients with chronic renal disease. J Am Soc Nephrol. 2002;13:1100–8.PubMedGoogle Scholar
  7. 7.
    Taal M, Brennner B. Combination ACE inhibitor and ARB therapy: additional benefit in renoprotection. Curr Opin Nephrol Hypertens. 2002;11:377–81.PubMedCrossRefGoogle Scholar
  8. 8.
    Russo D, Pisani A, Balletta MM, De Nicola L, Savino FA, Andreucci M, et al. Additive antiproteinuric effect on converting enzyme inhibitor and losartan in normotensive patients with IgA nephropathy. Am J Kidney Dis. 1999;33:851–6.PubMedGoogle Scholar
  9. 9.
    Ruilope LM, Aldigier JC, Ponticelli C, Oddou-Stock P, Batteri F, Mann JF. Safety of the combination of valsartan and benazepril in patients with chronic renal disease. European group fot the investigation of valsartan in chronic renal disease. J Hypertens. 2000;18:89–95.PubMedGoogle Scholar
  10. 10.
    Laverman GD, Navis G, Henning RH, de Jong PE, de Zeeuw D. Dual rennin–angiotensin system blockade at optimal doses for proteinuria. Kidney Int. 2002;62:1020–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T, et al. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomized controlled trial. Lancet 2003;361:117–24.PubMedCrossRefGoogle Scholar
  12. 12.
    Campbell R, Sangalli F, Perticucci, Aros C, Viscarra C, Perna A, et al. Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies. Kidney Int. 2003;63:1094–103.PubMedCrossRefGoogle Scholar
  13. 13.
    Thurmann JM, Schrier RW. Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on blood pressure and the kidney. Am J Med. 2003;114:588–98.CrossRefGoogle Scholar
  14. 14.
    Kincaid-Smith P, Fairely KF, Packham D. Dual blockade of the rennin–angiotensin system compared with a 50% increase in the dose of angiotensin-converting enzyme inhibitor: effects on proteinuria and blood pressure. Nephrol Dial Transplant. 2004;19:2272–4.PubMedCrossRefGoogle Scholar
  15. 15.
    Russo D, Minutolo R, Pisani A, Esposito R, Signoriello G, Andreucci M, et al. Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy. Am J Kidney Dis. 2001;38:18–25.PubMedGoogle Scholar
  16. 16.
    Iodice C, Balletta M, Minutolo R, Giannattasio P, Tuccillo S, Bellizzi V, et al. Maximal suppression of rennin–angiotensin system in nonproliferative glomerulonephritis. Kidny Int. 2003;63:2214–21.CrossRefGoogle Scholar
  17. 17.
    Keilani T, Danesh F, Schlueter W, Molteni A, Batlle D. A subdepressor low dose of rampril lowers urinary protein excretion without increasing plasma potassium. Am J Kidney Dis. 1999;33:450–7.PubMedGoogle Scholar
  18. 18.
    Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophisiology. Ann Intern Med. 1992;117:234–42.PubMedGoogle Scholar
  19. 19.
    Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The seventh report of the joint national committee on prevention, evaluation and treatment of high blood pressure: the JNC 7 report. JAMA. 2003;289:2560–71.PubMedCrossRefGoogle Scholar
  20. 20.
    Guideline Committee. 2003 European society of hypertension–European society of cardiology guidelines for the management of arterial hypertension. J Hypertens. 2003;21:10011–1053.Google Scholar
  21. 21.
    Remuzzi G, Ruggenenti P, Perico N. Chronic renal disease: renoprotective benefits of rennin–angiotensin system inhibition. Ann Intern Med. 2002;136:604–15.PubMedGoogle Scholar
  22. 22.
    Ichikawa I. Will angiotensin II receptor antagonists be renoprotective in humans. Kidney Int. 1996;50:684–92.PubMedCrossRefGoogle Scholar
  23. 23.
    Lafayette RA, Mayer G, Park SK, Meyer TW. Angiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass. J Clin Invest. 1922;90:766.Google Scholar
  24. 24.
    Kakinuma Y, Kawamura T, Bills T, Yoshioka T, Ichikawa T, Fogo A. Blood pressure-independent effect of angiotensin inhibition on the glomerular and non-glomerular vascular lesions of chronic renal failure. Kidney Int. 1992;42:46.PubMedCrossRefGoogle Scholar
  25. 25.
    Zoja C, Donadelli R, Coma D, Testa D, Facchinetti D, Maffi R, et al. The renoprotective properties of angiotensin-converting enzyme inhibitors in a chronic model of membranous nephropathy are soley due to the inhibition of angiotensin II: evidence based on comparative studies with a receptor antagonist. Am J Kidney Dis. 1997;29:254.PubMedGoogle Scholar
  26. 26.
    Ots M, Mackenzie HS, Troy JL, Rennke HG, Brenner BM. Effects of combination therapy with enalapril and losartan on the rate of progression of renal injury in rats with 5/6 renal mass ablation. J Am Soc Nephrol. 1998;9:224.PubMedGoogle Scholar
  27. 27.
    Hutchison FN, Cui X, Webster SK. The antiproteinuric action on angiotensin -converting enzyme in dependent on kinin. J Am Soc Nephrol. 1995;6:1216–22.PubMedGoogle Scholar
  28. 28.
    Bascands J, Schanstra JP. Bradykinin and renal fibrosis: have we ACE’d it? J Am Soc Nephrol. 2004;15:2504–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Okada H, Watanabe Y, Kikuta T, Kobayashi T, Kannno Y, Suguya T, et al. Bradykinin decreases plasminogen activator inhibitor-1 expression and facilitates matrix degradation in the renal tubulointerstium under angiotensin converting enzyme blockade. J Am Soc Nephrol. 2004;15:2404–13.PubMedCrossRefGoogle Scholar
  30. 30.
    Nath KA. Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis. 1992;1:1–17.Google Scholar
  31. 31.
    Woo KS, Nicholls MG. High prevalence of persistent cough with angiotensin converting enzyme inhibitors in Chinese. Br J Clin Pharmacol. 1995;40:141–4.PubMedGoogle Scholar
  32. 32.
    Bakris GL, Weir MR, Secic M, Cambell B, Weis-McNulty A. Differential effects of calcium antagonist subclasses on markers of nephropathy progression. Kidney Int. 2004;65:1991–2002.PubMedCrossRefGoogle Scholar
  33. 33.
    Schieppati A, Remuzzi G. The future renoprotection: frustration and promises. Kidney Int. 2003;64:1947–55.PubMedCrossRefGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2008

Authors and Affiliations

  • Urara Mori-Takeyama
    • 1
  • Shinya Minatoguchi
    • 1
  • Ichijirou Murata
    • 1
  • Hisayoshi Fujiwara
    • 1
  • Yoko Ozaki
    • 2
  • Michiya Ohno
    • 2
  • Hiroshi Oda
    • 2
  • Hiroshige Ohashi
    • 2
  1. 1.Second Department of Internal MedicineGifu UniversityGifuJapan
  2. 2.Division of NephrologyGifu Prefectural Gifu HospitalGifuJapan

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