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Dual Renin-Angiotensin-Aldosterone System Inhibition for the Treatment of Diabetic Kidney Disease: Adverse Effects and Unfulfilled Promise

  • Microvascular Complications—Nephropathy (T Isakova, Section Editor)
  • Published:
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Abstract

Diabetic nephropathy (DN) is a major complication of diabetes mellitus (DM) affecting individuals with type 1 or type 2 DM and is the leading cause of chronic kidney disease and end-stage kidney disease (ESKD) in the USA. Estimates of disease burden are projected to increase, with prevalence of nearly one in five adults by 2050. The role of renin-angiotensin-aldosterone system (RAAS) inhibition in delaying the progression of DN utilizing angiotensin-converting enzyme inhibitors or angiotensin receptor blockers has been well established in multiple controlled trials. Given greater reduction of proteinuria with dual RAAS blockade compared to monotherapy alone, the potential benefit of dual therapy on progression of DN has been tested in three large randomized clinical trials. Unfortunately, results from these studies demonstrated lack of benefit of dual blockade on renal or cardiovascular outcomes in patients with diabetes. The overall objectives of this review are to provide both the rationale for dual blockade as potential therapy as well as review the literature of its use in patients with DN.

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References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010;87(1):4–14. doi:10.1016/j.diabres.2009.10.007.

    Article  CAS  PubMed  Google Scholar 

  2. Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010;8:29. doi:10.1186/1478-7954-8-29.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Collins AJ, Foley RN, Herzog C, Chavers B, Gilbertson D, Ishani A et al. US Renal Data System 2012 Annual Data Report. Am J Kidney Dis. 2013;61(1 Suppl 1):A7, e1-476. doi:10.1053/j.ajkd.2012.11.031.

  4. Andresdottir G, Jensen ML, Carstensen B, Parving HH, Hovind P, Hansen TW, et al. Improved prognosis of diabetic nephropathy in type 1 diabetes. Kidney Int. 2015;87(2):417–26. doi:10.1038/ki.2014.206.

    Article  CAS  PubMed  Google Scholar 

  5. Cooper WC, Wong O, Graebner R. Mortality of workers in two Minnesota taconite mining and milling operations. J Occup Med. 1988;30(6):506–11.

    Article  CAS  PubMed  Google Scholar 

  6. Bojestig M, Arnqvist HJ, Hermansson G, Karlberg BE, Ludvigsson J. Declining incidence of nephropathy in insulin-dependent diabetes mellitus. N Engl J Med. 1994;330(1):15–8. doi:10.1056/NEJM199401063300103.

    Article  CAS  PubMed  Google Scholar 

  7. Anderson S, Vora JP. Current concepts of renal hemodynamics in diabetes. J Diabetes Complications. 1995;9(4):304–7.

    Article  CAS  PubMed  Google Scholar 

  8. Wolf G. Renal injury due to renin-angiotensin-aldosterone system activation of the transforming growth factor-beta pathway. Kidney Int. 2006;70(11):1914–9. doi:10.1038/sj.ki.5001846.

    CAS  PubMed  Google Scholar 

  9. Hollenberg NK, Price DA, Fisher ND, Lansang MC, Perkins B, Gordon MS, et al. Glomerular hemodynamics and the renin-angiotensin system in patients with type 1 diabetes mellitus. Kidney Int. 2003;63(1):172–8. doi:10.1046/j.1523-1755.2003.00701.x.

    Article  CAS  PubMed  Google Scholar 

  10. Zimpelmann J, Kumar D, Levine DZ, Wehbi G, Imig JD, Navar LG, et al. Early diabetes mellitus stimulates proximal tubule renin mRNA expression in the rat. Kidney Int. 2000;58(6):2320–30. doi:10.1046/j.1523-1755.2000.00416.x.

    Article  CAS  PubMed  Google Scholar 

  11. Rahimi Z, Moradi M, Nasri H. A systematic review of the role of renin angiotensin aldosterone system genes in diabetes mellitus, diabetic retinopathy and diabetic neuropathy. J Res Med Sci. 2014;19(11):1090–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Vervoort G, Veldman B, Berden JH, Smits P, Wetzels JF. Glomerular hyperfiltration in type 1 diabetes mellitus results from primary changes in proximal tubular sodium handling without changes in volume expansion. Eur J Clin Invest. 2005;35(5):330–6. doi:10.1111/j.1365-2362.2005.01497.x.

    Article  CAS  PubMed  Google Scholar 

  13. Nicholas SB, Mauer M, Basgen JM, Aguiniga E, Chon Y. Effect of angiotensin II on glomerular structure in streptozotocin-induced diabetic rats. Am J Nephrol. 2004;24(5):549–56. doi:10.1159/000082001.

    Article  CAS  PubMed  Google Scholar 

  14. Ruiz-Ortega M, Lorenzo O, Egido J. Angiotensin III up-regulates genes involved in kidney damage in mesangial cells and renal interstitial fibroblasts. Kidney Int Suppl. 1998;68:S41–5.

    Article  CAS  PubMed  Google Scholar 

  15. Hoffmann S, Podlich D, Hahnel B, Kriz W, Gretz N. Angiotensin II type 1 receptor overexpression in podocytes induces glomerulosclerosis in transgenic rats. J Am Soc Nephrol. 2004;15(6):1475–87.

    Article  CAS  PubMed  Google Scholar 

  16. Durvasula RV, Shankland SJ. Activation of a local renin angiotensin system in podocytes by glucose. Am J Physiol Renal Physiol. 2008;294(4):F830–9. doi:10.1152/ajprenal.00266.2007.

    Article  CAS  PubMed  Google Scholar 

  17. Brinkkoetter PT, Holtgrefe S, van der Woude FJ, Yard BA. Angiotensin II type 1-receptor mediated changes in heparan sulfate proteoglycans in human SV40 transformed podocytes. J Am Soc Nephrol. 2004;15(1):33–40.

    Article  CAS  PubMed  Google Scholar 

  18. Wolf G, Ziyadeh FN. Renal tubular hypertrophy induced by angiotensin II. Semin Nephrol. 1997;17(5):448–54.

    CAS  PubMed  Google Scholar 

  19. Lan HY. Tubular epithelial-myofibroblast transdifferentiation mechanisms in proximal tubule cells. Curr Opin Nephrol Hypertens. 2003;12(1):25–9. doi:10.1097/01.mnh.0000049812.98789.97.

    Article  CAS  PubMed  Google Scholar 

  20. Luetscher JA, Kraemer FB, Wilson DM, Schwartz HC, Bryer-Ash M. Increased plasma inactive renin in diabetes mellitus. A marker of microvascular complications. N Engl J Med. 1985;312(22):1412–7. doi:10.1056/NEJM198505303122202.

    Article  CAS  PubMed  Google Scholar 

  21. Huang Y, Wongamorntham S, Kasting J, McQuillan D, Owens RT, Yu L, et al. Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int. 2006;69(1):105–13. doi:10.1038/sj.ki.5000011.

    Article  CAS  PubMed  Google Scholar 

  22. Hollenberg NK, Stevanovic R, Agarwal A, Lansang MC, Price DA, Laffel LM, et al. Plasma aldosterone concentration in the patient with diabetes mellitus. Kidney Int. 2004;65(4):1435–9. doi:10.1111/j.1523-1755.2004.00524.x.

    Article  CAS  PubMed  Google Scholar 

  23. Kang YS, Ko GJ, Lee MH, Song HK, Han SY, Han KH, et al. Effect of eplerenone, enalapril and their combination treatment on diabetic nephropathy in type II diabetic rats. Nephrol Dial Transplant. 2009;24(1):73–84. doi:10.1093/ndt/gfn448.

    Article  CAS  PubMed  Google Scholar 

  24. Blasi ER, Rocha R, Rudolph AE, Blomme EA, Polly ML, McMahon EG. Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats. Kidney Int. 2003;63(5):1791–800. doi:10.1046/j.1523-1755.2003.00929.x.

    Article  CAS  PubMed  Google Scholar 

  25. Miyata K, Rahman M, Shokoji T, Nagai Y, Zhang GX, Sun GP, et al. Aldosterone stimulates reactive oxygen species production through activation of NADPH oxidase in rat mesangial cells. J Am Soc Nephrol. 2005;16(10):2906–12. doi:10.1681/ASN.2005040390.

    Article  CAS  PubMed  Google Scholar 

  26. Han SY, Kim CH, Kim HS, Jee YH, Song HK, Lee MH, et al. Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J Am Soc Nephrol. 2006;17(5):1362–72. doi:10.1681/ASN.2005111196.

    Article  CAS  PubMed  Google Scholar 

  27. van den Meiracker AH, Man in ’t Veld AJ, Admiraal PJ, van Eck HJ R, Boomsma F, Derkx FH, et al. 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. 1992;10(8):803–12.

    PubMed  Google Scholar 

  28. 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(12):2116–23. doi:10.1038/sj.ki.5001854.

    CAS  PubMed  Google Scholar 

  29. Ménard J, Campbell DJ, Azizi M, Gonzales MF. Synergistic effects of ACE inhibition and Ang II antagonism on blood pressure, cardiac weight, and renin in spontaneously hypertensive rats. Circulation. 1997;96(9):3072–8.

    Article  PubMed  Google Scholar 

  30. Cao Z, Bonnet F, Davis B, Allen TJ, Cooper ME. Additive hypotensive and anti-albuminuric effects of angiotensin-converting enzyme inhibition and angiotensin receptor antagonism in diabetic spontaneously hypertensive rats. Clin Sci (Lond). 2001;100(6):591–9.

    Article  CAS  Google Scholar 

  31. Whaley-Connell A, Habibi J, Nistala R, Hayden MR, Pulakat L, Sinak C, et al. Combination of direct renin inhibition with angiotensin type 1 receptor blockade improves aldosterone but does not improve kidney injury in the transgenic Ren2 rat. Regul Pept. 2012;176(1–3):36–44. doi:10.1016/j.regpep.2012.03.002.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, 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(7274):1440–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. 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(5):1874–80. doi:10.1046/j.1523-1755.2003.00940.x.

    Article  CAS  PubMed  Google Scholar 

  34. Sengul AM, Altuntas Y, Kürklü A, Aydin L. Beneficial effect of lisinopril plus telmisartan in patients with type 2 diabetes, microalbuminuria and hypertension. Diabetes Res Clin Pract. 2006;71(2):210–9. doi:10.1016/j.diabres.2005.06.010.

    Article  CAS  PubMed  Google Scholar 

  35. Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol. 2009;20(12):2641–50. doi:10.1681/ASN.2009070737.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547–59. doi:10.1056/NEJMoa0801317.

    Article  CAS  PubMed  Google Scholar 

  37. Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, 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(9638):547–53. doi:10.1016/S0140-6736(08)61236-2.

    Article  CAS  PubMed  Google Scholar 

  38. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204–13. doi:10.1056/NEJMoa1208799. The ALTITUDE study evaluated the effect of aliskiren on cardiovascular and renal outcomes compared to placebo in type 2 diabetic patients. This study demonstrates that aliskiren may increase risk for cardiovascular events, does not affect renal outcomes, but does increase risk for hyperkalemia.

    Article  CAS  PubMed  Google Scholar 

  39. Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892–903. doi:10.1056/NEJMoa1303154. This study involving type 2 diabetic patients with significant albuminuria was stopped early due to increased risk for hyperkalemia and acute kidney injury in the dual blockade arm. Dual blockade did not reduce risk for renal outcomes compared to losartan alone.

    Article  CAS  PubMed  Google Scholar 

  40. Fried LF, Duckworth W, Zhang JH, O’Connor T, Brophy M, Emanuele N, et al. Design of combination angiotensin receptor blocker and angiotensin-converting enzyme inhibitor for treatment of diabetic nephropathy (VA NEPHRON-D). Clin J Am Soc Nephrol. 2009;4(2):361–8. doi:10.2215/CJN.03350708.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Packham DK, Rasmussen HS, Lavin PT, El-Shahawy MA, Roger SD, Block G, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med. 2015;372(3):222–31. doi:10.1056/NEJMoa1411487.

    Article  PubMed  Google Scholar 

  42. Tylicki L, Lizakowski S, Rutkowski B. Renin-angiotensin-aldosterone system blockade for nephroprotection: current evidence and future directions. J Nephrol. 2012;25(6):900–10.

    Article  CAS  PubMed  Google Scholar 

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Conflict of Interest

Boutros El-Haddad, Scott Reule, and Paul E. Drawz declare that they have no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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  1. Division of Renal Diseases and Hypertension, University of Minnesota, 717 Delaware St SE, Suite 353, Minneapolis, MN, 55414, USA

    Boutros El-Haddad, Scott Reule & Paul E. Drawz

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  1. Boutros El-Haddad
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Correspondence to Paul E. Drawz.

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This article is part of the Topical Collection on Microvascular Complications—Nephropathy

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El-Haddad, B., Reule, S. & Drawz, P.E. Dual Renin-Angiotensin-Aldosterone System Inhibition for the Treatment of Diabetic Kidney Disease: Adverse Effects and Unfulfilled Promise. Curr Diab Rep 15, 70 (2015). https://doi.org/10.1007/s11892-015-0640-3

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