Pediatric Nephrology

, Volume 19, Issue 9, pp 956–961 | Cite as

Treatment strategies in patients with chronic renal disease: ACE inhibitors, angiotensin receptor antagonists, or both?

  • Karl F. HilgersEmail author
  • Jörg Dötsch
  • Wolfgang Rascher
  • Johannes F. E. Mann
Editorial Commentary


We discuss the evidence supporting the use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II type 1 receptor blockers (ARB), or the combination of both in children with chronic renal disease. Several large-scale, prospective, randomized studies with clinical end points have been performed in adult patients, but studies in children are relatively scarce. In adult patients with chronic renal diseases, ACEI clearly delay the progression of chronic non-diabetic renal diseases, and nephropathy in patients with type 1 diabetes. The benefits of ACEI are most apparent in glomerular diseases with marked proteinuria but extend also to kidney diseases with lower proteinuria. This notion is also supported by several smaller or retrospective trials in children. Therefore, ACEI should be given to children with chronic renal diseases, particularly if high blood pressure and/or proteinuria are present. In adults, large-scale trials have documented that ARB exert similar effects as ACEI but tend to exert fewer undesired side effects. Data on ARB in children with chronic renal disease are still very scarce, but these substances offer an alternative for patients who cannot tolerate ACEI due to unwarranted side effects. Combination therapy with ARB plus ACEI may be more effective than either drug class alone. However, we will need the results of further long-term prospective clinical studies, as well as a better understanding of the role of the AT2 receptor, before combination therapy can be widely recommended. A trial of ARB plus ACEI is justified in selected patients if blood pressure and/or proteinuria cannot adequately be lowered by ACEI or ARB alone.


Angiotensin-converting enzyme inhibitors Angiotensin II type 1 receptor blockers Chronic renal disease 


  1. 1.
    Hilgers KF, Mann JF (2002) ACE inhibitors versus AT(1) receptor antagonists in patients with chronic renal disease. J Am Soc Nephrol 13:1100–1108PubMedGoogle Scholar
  2. 2.
    Hilgers KF, Norwood VF, Gomez RA (1997) Angiotensin’s role in renal development. Semin Nephrol 17:492–501PubMedGoogle Scholar
  3. 3.
    Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ (1998) Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med 339:1285–1292CrossRefPubMedGoogle Scholar
  4. 4.
    Israili ZH, Hall WD (1992) Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med 117:234–242PubMedGoogle Scholar
  5. 5.
    Gasparo M de, Catt KJ, Inagami T, Wright JW, Unger T (2000) International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 52:415–472PubMedGoogle Scholar
  6. 6.
    Wolf G, Wenzel U, Burns KD, Harris RC, Stahl RA, Thaiss F (2002) Angiotensin II activates nuclear transcription factor-kappaB through AT1 and AT2 receptors. Kidney Int 61:1986–1995CrossRefPubMedGoogle Scholar
  7. 7.
    Anderson S, Rennke HG, Brenner BM (1986) Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat. J Clin Invest 77:1993–2000PubMedGoogle Scholar
  8. 8.
    Mann J, Ritz E (1987) Preservation of kidney function by use of converting-enzyme inhibitors for control of hypertension. Lancet II:622CrossRefGoogle Scholar
  9. 9.
    Milliner DS, Morgenstern BZ (1991) Angiotensin converting enzyme inhibitors for reduction of proteinuria in children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 5:587–590PubMedGoogle Scholar
  10. 10.
    Lewis EJ, Hunsicker LG, Bain RP, Rohde RD (1993) The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 329:1456–1462CrossRefPubMedGoogle Scholar
  11. 11.
    Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, Cheek D, Douglas-Baltimore JG, Gassman J, Glassock R, Hebert L, Jamerson K, Lewis J, Phillips RA, Toto RD, Middleton JP, Rostand SG (2002) Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 288:2421–2431CrossRefPubMedGoogle Scholar
  12. 12.
    Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P (1996) Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med 334:939–945CrossRefPubMedGoogle Scholar
  13. 13.
    Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, Scolari F, Schena FP, Remuzzi G (1999) Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 354:359–364CrossRefPubMedGoogle Scholar
  14. 14.
    The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia) (1997) Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 349:1857–1863PubMedGoogle Scholar
  15. 15.
    Jafar TH, Stark PC, Schmid CH, Landa M, Maschio G, Jong PE de, Zeeuw D de, Shahinfar S, Toto R, Levey AS (2003) Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis. Ann Intern Med 139:244–252PubMedGoogle Scholar
  16. 16.
    Wuhl E, Hadtstein C, Mehls O, Schaefer F (2004) Home, clinic, and ambulatory blood pressure monitoring in children with chronic renal failure. Pediatr Res 55:492–497CrossRefPubMedGoogle Scholar
  17. 17.
    Wuhl E, Mehls O, Schaefer F (2003) Antihypertensive efficacy of ramipril in children with chronic renal failure. Am J Hypertens 16:240ACrossRefGoogle Scholar
  18. 18.
    Oh J, Wunsch R, Turzer M, Bahner M, Raggi P, Querfeld U, Mehls O, Schaefer F (2002) Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure. Circulation 106:100–105CrossRefPubMedGoogle Scholar
  19. 19.
    Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S (2001) Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med 134:629–636PubMedGoogle Scholar
  20. 20.
    Brenner BM, Cooper ME, Zeeuw D de, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861–869CrossRefPubMedGoogle Scholar
  21. 21.
    Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851–860CrossRefPubMedGoogle Scholar
  22. 22.
    Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R, Remuzzi G (1998) Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). Ramipril Efficacy in Nephropathy. Lancet 352:1252–1256CrossRefPubMedGoogle Scholar
  23. 23.
    Lama G, Salsano ME, Pedulla’ M, Grassia C, Ruocco G (1997) Angiotensin converting enzyme inhibitors and reflux nephropathy: 2-year follow-up. Pediatr Nephrol 11:714–718CrossRefPubMedGoogle Scholar
  24. 24.
    Proesmans W, Van Dyck M (2004) Enalapril in children with Alport syndrome. Pediatr Nephrol 19:271–275CrossRefPubMedGoogle Scholar
  25. 25.
    Proesmans W, Knockaert H, Trouet D (2000) Enalapril in paediatric patients with Alport syndrome: 2 years’ experience. Eur J Pediatr 159:430–433CrossRefPubMedGoogle Scholar
  26. 26.
    Arbeiter K, Pichler A, Stemberger R, Mueller T, Ruffingshofer D, Vargha R, Balzar E, Aufricht C (2004) ACE inhibition in the treatment of children after renal transplantation. Pediatr Nephrol 19:222–226CrossRefPubMedGoogle Scholar
  27. 27.
    Franscini LM, Von Vigier RO, Pfister R, Casaulta-Aebischer C, Fossali E, Bianchetti MG (2002) Effectiveness and safety of the angiotensin II antagonist irbesartan in children with chronic kidney diseases. Am J Hypertens 15:1057–1063CrossRefPubMedGoogle Scholar
  28. 28.
    White CT, Macpherson CF, Hurley RM, Matsell DG (2003) Antiproteinuric effects of enalapril and losartan: a pilot study. Pediatr Nephrol 18:1038–1043CrossRefPubMedGoogle Scholar
  29. 29.
    Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T (2003) Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 361:117–124CrossRefPubMedGoogle Scholar
  30. 30.
    Veelken R, Hilgers KF, Mann JF (1998) The acute renal effects of angiotensin II receptor blockers. Nephrol Dial Transplant 13:1928–1929CrossRefPubMedGoogle Scholar
  31. 31.
    Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K (2003) Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 362:772–776CrossRefPubMedGoogle Scholar
  32. 32.
    Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, Cooper ME (2000) 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 321:1440–1444CrossRefPubMedGoogle Scholar
  33. 33.
    Ruilope LM, Aldigier JC, Ponticelli C, Oddou-Stock P, Botteri F, Mann JF (2000) Safety of the combination of valsartan and benazepril in patients with chronic renal disease. European Group for the Investigation of Valsartan in Chronic Renal Disease. J Hypertens 18:89–95CrossRefPubMedGoogle Scholar
  34. 34.
    Cohn JN, Tognoni G (2001) A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 345:1667–1675CrossRefPubMedGoogle Scholar
  35. 35.
    McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S, Pfeffer MA (2003) Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 362:767–771CrossRefPubMedGoogle Scholar
  36. 36.
    Laverman GD, Navis G, Henning RH, Jong PE de, Zeeuw D de (2002) Dual renin-angiotensin system blockade at optimal doses for proteinuria. Kidney Int 62:1020–1025CrossRefPubMedGoogle Scholar
  37. 37.
    Agarwal R (2001) Add-on angiotensin receptor blockade with maximized ACE inhibition. Kidney Int 59:2282–2289CrossRefPubMedGoogle Scholar
  38. 38.
    Scharer K (1999) Hypertension in children and adolescents. In: Malluche HH, Sawaya BP, Hakim RM, Sayegh MH (eds) Clinical nephrology, dialysis and transplantation. Deisenhofen, Dustri, pp 1–28Google Scholar
  39. 39.
    Wells T, Frame V, Soffer B, Shaw W, Zhang Z, Herrera P, Shahinfar S (2002) A double-blind, placebo-controlled, dose-response study of the effectiveness and safety of enalapril for children with hypertension. J Clin Pharmacol 42:870–880CrossRefPubMedGoogle Scholar
  40. 40.
    Soffer B, Zhang Z, Miller K, Vogt BA, Shahinfar S (2003) A double-blind, placebo-controlled, dose-response study of the effectiveness and safety of lisinopril for children with hypertension. Am J Hypertens 16:795–800CrossRefPubMedGoogle Scholar

Copyright information

© IPNA 2004

Authors and Affiliations

  • Karl F. Hilgers
    • 1
    • 4
    • 5
    Email author
  • Jörg Dötsch
    • 2
  • Wolfgang Rascher
    • 2
    • 4
  • Johannes F. E. Mann
    • 3
    • 4
  1. 1.Department of Medicine IVUniversity of Erlangen-NürnbergGermany
  2. 2.Department of PediatricsUniversity of Erlangen-NürnbergGermany
  3. 3.Department of Medicine VI, Schwabing General HospitalLudwig-Maximilians-UniversityMunichGermany
  4. 4.German Institute for High Blood Pressure ResearchHeidelbergGermany
  5. 5.Nephrology Research LaboratoryGermany

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