Skip to main content

Advertisement

Log in

Renal effects of dual renin–angiotensin–aldosterone system blockade in patients with diabetic nephropathy

  • Nephrology - Review
  • Published:
International Urology and Nephrology Aims and scope Submit manuscript

Abstract

Evidence from recent studies indicates that in patients with diabetic nephropathy combined therapy with ACE inhibitors (ACEI) and AT1-receptor antagonists (ARB) results in more complete blockade of the renin–angiotensin–aldosterone system (RAS) than monotherapy, and reduces proteinuria. Most of these trials, however, had short follow-up, included a small number of patients, and were heterogeneous, so the opportunity to start this treatment in these patients remains unclear. This review summarizes the results of these studies, describing the renal effects of dual RAS blockade in both type 1 and type 2 diabetic patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Pfeffer MA, McMurray JJ, Velazquez EJ et al (2003) Valsartan in acute myocardial infarction trial investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 349:1893–1906. doi:10.1056/NEJMoa032292

    Article  PubMed  CAS  Google Scholar 

  2. ONTARGET Investigators, Yusuf S, Teo KK, Pogue J et al (2008) Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 358:1547–1559. doi:10.1056/NEJMoa0801317

    Article  PubMed  CAS  Google Scholar 

  3. Cohn JN, Tognoni G (2001) Valsartan heart failure trial investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 345:1667–1675. doi:10.1056/NEJMoa010713

    Article  PubMed  CAS  Google Scholar 

  4. McMurray JJ, Ostergren J, Swedberg K et al (2003) CHARM Investigators and Committees. 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 362:767–771. doi:10.1016/S0140-6736(03)14283-3

    Article  PubMed  CAS  Google Scholar 

  5. Carey RM, Siragy HM (2003) The intrarenal renin–angiotensin system and diabetic nephropathy. Trends Endocrinol Metab 14:274–281. doi:10.1016/S1043-2760(03)00111-5

    Article  PubMed  CAS  Google Scholar 

  6. Paul M, Poyan Mehr A, Kreutz R (2006) Physiology of local renin–angiotensin systems. Physiol Rev 86:747–803. doi:10.1152/physrev.00036.2005

    Article  PubMed  CAS  Google Scholar 

  7. Cooper ME (2001) Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. Diabetologia 44:1957–1972. doi:10.1007/s001250100000

    Article  PubMed  CAS  Google Scholar 

  8. Lewis EJ, Hunsicker LG, Bain RP et al (1993) The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The collaborative study group. N Engl J Med 329:1456–1462. doi:10.1056/NEJM199311113292004

    Article  PubMed  CAS  Google Scholar 

  9. Brenner BM, Cooper ME, de Zeeuw D (2001) RENAAL study investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861–869. doi:10.1056/NEJMoa011161

    Article  PubMed  CAS  Google Scholar 

  10. Lewis EJ, Hunsicker LG, Clarke WR et al (2001) Collaborative study group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851–860. doi:10.1056/NEJMoa011303

    Article  PubMed  CAS  Google Scholar 

  11. Parving HH, Lehnert H, Bröchner-Mortensen J et al (2001) Irbesartan in patients with type 2 diabetes and microalbuminuria study group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345:870–878. doi:10.1056/NEJMoa011489

    Article  PubMed  CAS  Google Scholar 

  12. Juillerat L, Nussberger J, Ménard J et al (1990) Determinants of angiotensin II generation during converting enzyme inhibition. Hypertension 16:564–572

    PubMed  CAS  Google Scholar 

  13. van den Meiracker AH, Man in ‘t Veld AJ, Admiraal PJ et al (1992) Partial escape of angiotensin converting enzyme (ACE) inhibition during prolonged ACE inhibitor treatment: does it exist and does it affect the antihypertensive response? J Hypertens 10:803–812. doi:10.1097/00004872-199208000-00015

    PubMed  Google Scholar 

  14. Roig E, Perez-Villa F, Morales M et al (2000) Clinical implications of increased plasma angiotensin II despite ACE inhibitor therapy in patients with congestive heart failure. Eur Heart J 21:53–57. doi:10.1053/euhj.1999.1740

    Article  PubMed  CAS  Google Scholar 

  15. Ritz E (2003) Chymase: a potential culprit in diabetic nephropathy? J Am Soc Nephrol 14:1952–1954. doi:10.1097/01.ASN.0000076125.12092.C6

    Article  PubMed  Google Scholar 

  16. Wolf G, Ziyadeh FN, Thaiss F et al (1997) Angiotensin II stimulates expression of the chemokine RANTES in rat glomerular endothelial cells. Role of the angiotensin type 2 receptor. J Clin Invest 100:1047–1058. doi:10.1172/JCI119615

    Article  PubMed  CAS  Google Scholar 

  17. Cao Z, Kelly DJ, Cox A et al (2000) Angiotensin type 2 receptor is expressed in the adult rat kidney and promotes cellular proliferation and apoptosis. Kidney Int 58:2437–2451. doi:10.1046/j.1523-1755.2000.00427.x

    Article  PubMed  CAS  Google Scholar 

  18. Cao Z, Bonnet F, Candido R et al (2002) Angiotensin type 2 receptor antagonism confers renal protection in a rat model of progressive renal injury. J Am Soc Nephrol 13:1773–1787. doi:10.1097/01.ASN.0000019409.17099.33

    Article  PubMed  CAS  Google Scholar 

  19. Wolf G (2002) “The road not taken”: role of angiotensin II type 2 receptor in pathophysiology. Nephrol Dial Transplant 17:195–198. doi:10.1093/ndt/17.2.195

    Article  PubMed  CAS  Google Scholar 

  20. Ma LJ, Fogo AB (2001) Angiotensin as inducer of plasminogen activator inhibitor-1 and fibrosis. Contrib Nephrol 135:161–170. doi:10.1159/000060164

    Article  PubMed  CAS  Google Scholar 

  21. Ma L, Fogo AB (2001) Role of angiotensin II in glomerular injury. Semin Nephrol 21:544–553. doi:10.1053/snep.2001.26793

    Article  PubMed  CAS  Google Scholar 

  22. Russo D, Pisani A, Balletta MM et al (1999) Additive antiproteinuric effect of converting enzyme inhibitor and losartan in normotensive patients with IgA nephropathy. Am J Kidney Dis 33:851–856. doi:10.1016/S0272-6386(99)70416-6

    Article  PubMed  CAS  Google Scholar 

  23. Russo D, Minutolo R, Pisani A et al (2001) Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy. Am J Kidney Dis 38:18–25. doi:10.1053/ajkd.2001.25176

    Article  PubMed  CAS  Google Scholar 

  24. Laverman GD, Navis G, Henning RH et al (2002) Dual renin–angiotensin system blockade at optimal doses for proteinuria. Kidney Int 62:1020–1025. doi:10.1046/j.1523-1755.2002.00536.x

    Article  PubMed  CAS  Google Scholar 

  25. Luno J, Barrio V, Goicoechea M et al (2002) Effects of dual blockade of the renin–angiotensin system in primary proteinuric nephropathies. Kidney Int 82:S47–S52. doi:10.1046/j.1523-1755.62.s82.10.x

    Article  CAS  Google Scholar 

  26. Fernandez-Juárez G, Barrio V, de Vinuesa SG et al (2006) Dual blockade of the renin–angiotensin system in the progression of renal disease: the need for more clinical trials. J Am Soc Nephrol 17:S250–S254. doi:10.1681/ASN.2006080922

    Article  PubMed  CAS  Google Scholar 

  27. Nakao N, Yoshimura A, Morita H et al (2003) Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 361:117–124. doi:10.1016/S0140-6736(03)12229-5

    Article  PubMed  CAS  Google Scholar 

  28. Kunz R, Friedrich C, Wolbers M et al (2008) Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med 148:30–48

    PubMed  Google Scholar 

  29. Kunz R, Wolbers M, Glass T et al (2008) The COOPERATE trial: a letter of concern. Lancet 371:1575–1576. doi:10.1016/S0140-6736(08)60681-9

    Article  PubMed  Google Scholar 

  30. Jacobsen P, Andersen S, Jensen BR et al (2003) Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy. J Am Soc Nephrol 14:992–999. doi:10.1097/01.ASN.0000054495.96193.BF

    Article  PubMed  CAS  Google Scholar 

  31. Jacobsen P, Andersen S, Rossing K et al (2002) Dual blockade of the renin–angiotensin system in type 1 patients with diabetic nephropathy. Nephrol Dial Transplant 17:1019–1024. doi:10.1093/ndt/17.6.1019

    Article  PubMed  CAS  Google Scholar 

  32. Jacobsen P, Andersen S, Rossing K et al (2003) Dual blockade of the renin–angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy. Kidney Int 63:1874–1880. doi:10.1046/j.1523-1755.2003.00940.x

    Article  PubMed  CAS  Google Scholar 

  33. Mogensen CE, Neldam S, Tikkanen I et al (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 321:1440–1444. doi:10.1136/bmj.321.7274.1440

    Article  PubMed  CAS  Google Scholar 

  34. Andersen NH, Poulsen PL, Knudsen ST et al (2005) Long-term dual blockade with candesartan and lisinopril in hypertensive patients with diabetes: the CALM II study. Diabetes Care 28:273–277. doi:10.2337/diacare.28.2.273

    Article  PubMed  CAS  Google Scholar 

  35. Rossing K, Christensen PK, Jensen BR et al (2002) Dual blockade of the renin–angiotensin system in diabetic nephropathy: a randomized double-blind crossover study. Diabetes Care 25:95–100. doi:10.2337/diacare.25.1.95

    Article  PubMed  CAS  Google Scholar 

  36. Rossing K, Jacobsen P, Pietraszek L et al (2003) 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 26:2268–2274. doi:10.2337/diacare.26.8.2268

    Article  PubMed  CAS  Google Scholar 

  37. Kim MJ, Song JH, Suh JH et al (2003) Additive antiproteinuric effect of combination therapy with ACE inhibitor and angiotensin II receptor antagonist: differential short-term response between IgA nephropathy and diabetic nephropathy. Yonsei Med J 44:463–472

    PubMed  CAS  Google Scholar 

  38. Kuriyama S, Tomonari H, Tokudome G et al (2002) Antiproteinuric effects of combined antihypertensive therapies in patients with overt type 2 diabetic nephropathy. Hypertens Res 25:849–855. doi:10.1291/hypres.25.849

    Article  PubMed  CAS  Google Scholar 

  39. Cetinkaya R, Odabas AR, Selcuk Y (2004) Anti-proteinuric effects of combination therapy with enalapril and losartan in patients with nephropathy due to type 2 diabetes. Int J Clin Pract 58:432–435. doi:10.1111/j.1368-5031.2004.00004.x

    Article  PubMed  CAS  Google Scholar 

  40. Tütüncü NB, Gürlek A, Gedik O (2001) Efficacy of ACE inhibitors and ATII receptor blockers in patients with microalbuminuria: a prospective study. Acta Diabetol 38:157–161. doi:10.1007/s592-001-8073-2

    Article  PubMed  Google Scholar 

  41. Hebert LA, Falkenhain ME, Nahman NS et al (1999) Combination ACE inhibitor and angiotensin II receptor antagonist therapy in diabetic nephropathy. Am J Nephrol 19:1–6. doi:10.1159/000013417

    Article  PubMed  CAS  Google Scholar 

  42. Fujisawa T, Ikegami H, Ono M et al (2005) Combination of half doses of angiotensin type 1 receptor antagonist and angiotensin-converting enzyme inhibitor in diabetic nephropathy. Am J Hypertens 18:13–17. doi:10.1016/j.amjhyper.2004.08.001

    Article  PubMed  CAS  Google Scholar 

  43. Bakris GL, Weir MR (2000) Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med 160:685–693. doi:10.1001/archinte.160.5.685

    Article  PubMed  CAS  Google Scholar 

  44. Apperloo AJ, De Zeeuw D, De Jong PE (1997) A short-term antihypertensive treatment-induced fall in glomerular filtration rate predicts long-term stability of renal function. Kidney Int 51:793–797. doi:10.1038/ki.1997.111

    Article  PubMed  CAS  Google Scholar 

  45. Covic A, Gusbeth-Tatomir P, Goldsmith DJA (2007) Current dilemmas in inhibiting the renin–angiotensin system: do not forget real life. Int Urol Nephrol 39:571–576. doi:10.1007/s11255-007-9211-0

    Article  PubMed  Google Scholar 

  46. Siamopoulos KC, Kalaitzidis RG (2008) Inhibition of renin–angiotensin system and chronic kidney disease. Int Urol Nephrol. doi:10.1007/s11255–008-9424-x

  47. Saklayen MG, Gyebi LK, Tasosa J et al (2008) Effects of additive therapy with spironolactone on proteinuria in diabetic patients already on ACE inhibitor or ARB therapy: results of a randomized, placebo-controlled, double-blind, crossover trial. J Investig Med 56:714–719

    PubMed  CAS  Google Scholar 

  48. van den Meiracker AH, Baggen RG, Pauli S et al (2006) Spironolactone in type 2 diabetic nephropathy: effects on proteinuria, blood pressure and renal function. J Hypertens 24:2285–2292

    Article  PubMed  CAS  Google Scholar 

  49. Schjoedt KJ, Rossing K, Juhl TR et al (2006) Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney Int 70:536–542

    PubMed  CAS  Google Scholar 

  50. Schjoedt KJ, Rossing K, Juhl TR et al (2005) Beneficial impact of spironolactone in diabetic nephropathy. Kidney Int 68:2829–2836. doi:10.1111/j.1523-1755.2005.00756.x

    Article  PubMed  CAS  Google Scholar 

  51. Rossing K, Schjoedt KJ, Smidt UM et al (2005) Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study. Diabetes Care 28:2106–2112. doi:10.2337/diacare.28.9.2106

    Article  PubMed  CAS  Google Scholar 

  52. Furumatsu Y, Nagasawa Y, Tomida K et al (2008) Effect of renin–angiotensin–aldosterone system triple blockade on non-diabetic renal disease: addition of an aldosterone blocker, spironolactone, to combination treatment with an angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker. Hypertens Res 31(1):59–67. doi:10.1291/hypres.31.59

    Article  PubMed  CAS  Google Scholar 

  53. Parving HH, Persson F, Lewis JB et al (2008) AVOID study investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 358:2433–2446. doi:10.1056/NEJMoa0708379

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. Dalla Vestra.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dalla Vestra, M., Simioni, N. & Masiero, A. Renal effects of dual renin–angiotensin–aldosterone system blockade in patients with diabetic nephropathy. Int Urol Nephrol 41, 119–126 (2009). https://doi.org/10.1007/s11255-008-9490-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11255-008-9490-0

Keywords

Navigation