Journal of General Internal Medicine

, Volume 27, Issue 4, pp 458–468 | Cite as

Therapeutic Modalities in Diabetic Nephropathy: Standard and Emerging Approaches

  • Emaad M. Abdel-Rahman
  • Lawand Saadulla
  • W. Brian Reeves
  • Alaa S. AwadEmail author


Diabetes mellitus is the leading cause of end stage renal disease and is responsible for more than 40% of all cases in the United States. Current therapy directed at delaying the progression of diabetic nephropathy includes intensive glycemic and optimal blood pressure control, proteinuria/albuminuria reduction, interruption of the renin-angiotensin-aldosterone system through the use of angiotensin converting enzyme inhibitors and angiotensin type-1 receptor blockers, along with dietary modification and cholesterol lowering agents. However, the renal protection provided by these therapeutic modalities is incomplete. More effective approaches are urgently needed. This review highlights the available standard therapeutic approaches to manage progressive diabetic nephropathy, including markers for early diagnosis of diabetic nephropathy. Furthermore, we will discuss emerging strategies such as PPAR-gamma agonists, Endothelin blockers, vitamin D activation and inflammation modulation. Finally, we will summarize the recommendations of these interventions for the primary care practitioner.


diabetes mellitus nephropathy disease management measurement therapeutic strategies 



This work was supported by NIH Grant DK077444.

Conflict of Interest

None disclosed.


  1. 1.
    USRDS TUSRDS. Annual Data Report. Bethesda: The National Institutes of Diabetes and Digestive and Kidney Diseases; 2005.Google Scholar
  2. 2.
    Eknoyan G, Hostetter T, Bakris GL, et al. Proteinuria and other markers of chronic kidney disease: a position statement of the national kidney foundation (NKF) and the national institute of diabetes and digestive and kidney diseases (NIDDK). Am J Kidney Dis. 2003;42:617–22.PubMedCrossRefGoogle Scholar
  3. 3.
    Adler S. Diabetic nephropathy: linking histology, cell biology, and genetics. Kidney Int. 2004;66:2095–106.PubMedCrossRefGoogle Scholar
  4. 4.
    Mogensen CE, Christensen CK. Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med. 1984;311:89–93.PubMedCrossRefGoogle Scholar
  5. 5.
    Caramori ML, Fioretto P, Mauer M. The need for early predictors of diabetic nephropathy risk: is albumin excretion rate sufficient? Diabetes. 2000;49:1399–408.PubMedCrossRefGoogle Scholar
  6. 6.
    Caramori ML, Fioretto P, Mauer M. Enhancing the predictive value of urinary albumin for diabetic nephropathy. J Am Soc Nephrol. 2006;17:339–52.PubMedCrossRefGoogle Scholar
  7. 7.
    Caramori ML, Fioretto P, Mauer M. Low glomerular filtration rate in normoalbuminuric type 1 diabetic patients: an indicator of more advanced glomerular lesions. Diabetes. 2003;52:1036–40.PubMedCrossRefGoogle Scholar
  8. 8.
    Zerbini G, Bonfanti R, Meschi F, et al. Persistent renal hypertrophy and faster decline of glomerular filtration rate precede the development of microalbuminuria in type 1 diabetes. Diabetes. 2006;55:2620–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Ito Y, Aten J, Bende RJ, et al. Expression of connective tissue growth factor in human renal fibrosis. Kidney Int. 1998;53:853–61.PubMedCrossRefGoogle Scholar
  10. 10.
    Nguyen TQ, Tarnow L, Andersen S, et al. Urinary connective tissue growth factor excretion correlates with clinical markers of renal disease in a large population of type 1 diabetic patients with diabetic nephropathy. Diabetes Care. 2006;29:83–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Langham RG, Kelly DJ, Gow RM, et al. Transforming growth factor-beta in human diabetic nephropathy: effects of ACE inhibition. Diabetes Care. 2006;29:2670–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Kalantarinia K, Awad AS, Siragy HM. Urinary and renal interstitial concentrations of TNF-alpha increase prior to the rise in albuminuria in diabetic rats. Kidney Int. 2003;64:1208–13.PubMedCrossRefGoogle Scholar
  13. 13.
    Nakamura T, Ushiyama C, Suzuki S, et al. Urinary excretion of podocytes in patients with diabetic nephropathy. Nephrol Dial Transplant. 2000;15:1379–83.PubMedCrossRefGoogle Scholar
  14. 14.
    Bolignano D, Lacquaniti A, Coppolino G, et al. Neutrophil Gelatinase-Associated Lipocalin (NGAL) and progression of chronic kidney disease. Clin J Am Soc Nephrol. 2009;4:337–44.PubMedCrossRefGoogle Scholar
  15. 15.
    Vaidya VS, Niewczas MA, Ficociello LH, et al. Regression of microalbuminuria in type 1 diabetes is associated with lower levels of urinary tubular injury biomarkers, kidney injury molecule-1, and N-acetyl-beta-D-glucosaminidase. Kidney Int. 2011;79:464–70.PubMedCrossRefGoogle Scholar
  16. 16.
    The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977986.Google Scholar
  17. 17.
    Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med. 2000;342:381389.Google Scholar
  18. 18.
    Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA. 2003;290:21592167.Google Scholar
  19. 19.
    Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643–53.PubMedCrossRefGoogle Scholar
  20. 20.
    Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405–12.PubMedCrossRefGoogle Scholar
  21. 21.
    Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.PubMedCrossRefGoogle Scholar
  22. 22.
    Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837853.Google Scholar
  23. 23.
    Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.PubMedCrossRefGoogle Scholar
  24. 24.
    Ismail-Beigi F, Craven T, Banerji MA, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010;376:419–30.PubMedCrossRefGoogle Scholar
  25. 25.
    Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39.PubMedCrossRefGoogle Scholar
  26. 26.
    Kelly WD, Lillehei RC, Merkel FK, et al. Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy. Surgery. 1967;61:827–37.PubMedGoogle Scholar
  27. 27.
    Gruessner AC, Sutherland DE. Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of October 2002. Clin Transplant. 2002;2002:41–77.Google Scholar
  28. 28.
    Coppelli A, Giannarelli R, Vistoli F, et al. The beneficial effects of pancreas transplant alone on diabetic nephropathy. Diabetes Care. 2005;28:1366–70.PubMedCrossRefGoogle Scholar
  29. 29.
    Bilous RW, Mauer SM, Sutherland DE, et al. The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes. N Engl J Med. 1989;321:80–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Fioretto P, Mauer SM, Bilous RW, et al. Effects of pancreas transplantation on glomerular structure in insulin-dependent diabetic patients with their own kidneys. Lancet. 1993;342:1193–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Fioretto P, Steffes MW, Sutherland DE, et al. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med. 1998;339:69–75.PubMedCrossRefGoogle Scholar
  32. 32.
    Huang ES, Zhang Q, Gandra N, et al. The effect of comorbid illness and functional status on the expected benefits of intensive glucose control in older patients with type 2 diabetes: a decision analysis. Ann Intern Med. 2008;149:11–9.PubMedGoogle Scholar
  33. 33.
    Mogensen CE. Long-term antihypertensive treatment inhibiting progression of diabetic nephropathy. Br Med J (Clin Res Ed). 1982;285:685–8.CrossRefGoogle Scholar
  34. 34.
    Schrier RW, Estacio RO, Esler A, et al. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int. 2002;61:1086–97.PubMedCrossRefGoogle Scholar
  35. 35.
    Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317:703713.Google Scholar
  36. 36.
    Cost effectiveness analysis of improved blood pressure control in hypertensive patients with type 2 diabetes: UKPDS 40. UK Prospective Diabetes Study Group. BMJ. 1998;317:720726.Google Scholar
  37. 37.
    Patel A, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829–40.PubMedCrossRefGoogle Scholar
  38. 38.
    de Galan BE, Perkovic V, Ninomiya T, et al. Lowering blood pressure reduces renal events in type 2 diabetes. J Am Soc Nephrol. 2009;20:883–92.PubMedCrossRefGoogle Scholar
  39. 39.
    Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206–52.PubMedCrossRefGoogle Scholar
  40. 40.
    Standards of medical care in diabetes. Diabetes Care. 2005;28(Suppl 1):S4-S36.Google Scholar
  41. 41.
    K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;43:S1-290.Google Scholar
  42. 42.
    Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010.Google Scholar
  43. 43.
    Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med. 2001;344:3–10.PubMedCrossRefGoogle Scholar
  44. 44.
    Mogensen CE, Keane WF, Bennett PH, et al. Prevention of diabetic renal disease with special reference to microalbuminuria. Lancet. 1995;346:1080–4.PubMedCrossRefGoogle Scholar
  45. 45.
    Kasiske BL, Kalil RS, Ma JZ, et al. Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med. 1993;118:129–38.PubMedGoogle Scholar
  46. 46.
    Schrier RW, Estacio RO, Jeffers B. Appropriate Blood Pressure Control in NIDDM (ABCD) trial. Diabetologia. 1996;39:1646–54.PubMedCrossRefGoogle Scholar
  47. 47.
    Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351:1755–62.PubMedCrossRefGoogle Scholar
  48. 48.
    Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control and the progression of chronic renal disease. N Engl J Med. 1994;330:877–84.PubMedCrossRefGoogle Scholar
  49. 49.
    Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288:2421–31.PubMedCrossRefGoogle Scholar
  50. 50.
    Nilsson PM, Cederholm J. Diabetes, hypertension, and outcome studies: overview 2010. Diabetes Care. 2011;34(Suppl 2):S109–13.PubMedCrossRefGoogle Scholar
  51. 51.
    Arauz-Pacheco C, Parrott MA, Raskin P. Treatment of hypertension in adults with diabetes. Diabetes Care. 2003;26(Suppl 1):S80–2.PubMedGoogle Scholar
  52. 52.
    Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560–72.PubMedCrossRefGoogle Scholar
  53. 53.
    Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575–85.PubMedCrossRefGoogle Scholar
  54. 54.
    Cooper-DeHoff RM, Gong Y, Handberg EM, et al. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA. 2010;304:61–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Cederholm J, Gudbjornsdottir S, Eliasson B, et al. Systolic blood pressure and risk of cardiovascular diseases in type 2 diabetes: an observational study from the Swedish national diabetes register. J Hypertens. 2010;28:2026–35.PubMedGoogle Scholar
  56. 56.
    Dunn MJ. Prostaglandins, angiotension II, and proteinuria. Nephron. 1990;55(Suppl 1):30–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Melchior WR, Bindlish V, Jaber LA. Angiotensin-converting enzyme inhibitors in diabetic nephropathy. Ann Pharmacother. 1993;27:344–50.PubMedGoogle Scholar
  58. 58.
    Barnett AH, Bain SC, Bouter P, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med. 2004;351:1952–61.PubMedCrossRefGoogle Scholar
  59. 59.
    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.PubMedCrossRefGoogle Scholar
  60. 60.
    Burgess E, Muirhead N, Rene de Cotret P, et al. Supramaximal dose of candesartan in proteinuric renal disease. J Am Soc Nephrol. 2009;20:893–900.PubMedCrossRefGoogle Scholar
  61. 61.
    Kunz R, Friedrich C, Wolbers M, et al. 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.PubMedGoogle Scholar
  62. 62.
    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.PubMedCrossRefGoogle Scholar
  63. 63.
    Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. The EUCLID Study Group. Lancet. 1997;349:17871792.Google Scholar
  64. 64.
    Ravid M, Brosh D, Levi Z, et al. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med. 1998;128:982–8.PubMedGoogle Scholar
  65. 65.
    Estacio RO, Jeffers BW, Gifford N, et al. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care. 2000;23(Suppl 2):B54–64.PubMedGoogle Scholar
  66. 66.
    Ravid M, Savin H, Jutrin I, et al. Long-term stabilization of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med. 1993;118:577–81.PubMedGoogle Scholar
  67. 67.
    Andersen S, Tarnow L, Rossing P, et al. Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. Kidney Int. 2000;57:601–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–60.PubMedCrossRefGoogle Scholar
  70. 70.
    Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870–8.PubMedCrossRefGoogle Scholar
  71. 71.
    Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993;329:1456–62.PubMedCrossRefGoogle Scholar
  72. 72.
    van den Meiracker AH, AJ Man in 't Veld, Admiraal PJ, 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;10:803–12.PubMedGoogle Scholar
  73. 73.
    Bomback AS, Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol. 2007;3:486–92.PubMedCrossRefGoogle Scholar
  74. 74.
    Ingelfinger JR. Aliskiren and dual therapy in type 2 diabetes mellitus. N Engl J Med. 2008;358:2503–5.PubMedCrossRefGoogle Scholar
  75. 75.
    Nussberger J, Wuerzner G, Jensen C, et al. Angiotensin II suppression in humans by the orally active renin inhibitor Aliskiren (SPP100): comparison with enalapril. Hypertension. 2002;39:E1–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Azizi M, Menard J, Bissery A, et al. Pharmacologic demonstration of the synergistic effects of a combination of the renin inhibitor aliskiren and the AT1 receptor antagonist valsartan on the angiotensin II-renin feedback interruption. J Am Soc Nephrol. 2004;15:3126–33.PubMedCrossRefGoogle Scholar
  77. 77.
    Azizi M, Menard J, Bissery A, et al. Hormonal and hemodynamic effects of aliskiren and valsartan and their combination in sodium-replete normotensive individuals. Clin J Am Soc Nephrol. 2007;2:947–55.PubMedCrossRefGoogle Scholar
  78. 78.
    Oparil S, Yarows SA, Patel S, et al. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet. 2007;370:221–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Pool JL, Schmieder RE, Azizi M, et al. Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Am J Hypertens. 2007;20:11–20.PubMedCrossRefGoogle Scholar
  80. 80.
    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.PubMedCrossRefGoogle Scholar
  81. 81.
    Parving HH, Persson F, Lewis JB, et al. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358:2433–46.PubMedCrossRefGoogle Scholar
  82. 82.
    Ustundag A, Tugrul A, Ustundag S, et al. The effects of spironolactone on nephron function in patients with diabetic nephropathy. Ren Fail. 2008;30:982–91.PubMedCrossRefGoogle Scholar
  83. 83.
    Saklayen MG, Gyebi LK, Tasosa J, et al. 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. 2008;56:714–9.PubMedGoogle Scholar
  84. 84.
    Kang YS, Ko GJ, Lee MH, et al. Effect of eplerenone, enalapril and their combination treatment on diabetic nephropathy in type II diabetic rats. Nephrol Dial Transplant. 2009;24:73–84.PubMedCrossRefGoogle Scholar
  85. 85.
    Epstein M, Buckalew VJ, Martinez F, Altamirano J, Roniker B, Kleiman J, Krause S, Eplerenone 021 Investigators. Antiproteinuric efficacy of eplerenone, enalapril, and eplerenone/enalapril combination therapy in diabetic hypertensives with microalbuminuria. Am J Hypertens. 2002;15:24A.CrossRefGoogle Scholar
  86. 86.
    Rachmani R, Slavachevsky I, Amit M, et al. The effect of spironolactone, cilazapril and their combination on albuminuria in patients with hypertension and diabetic nephropathy is independent of blood pressure reduction: a randomized controlled study. Diabet Med. 2004;21:471–5.PubMedCrossRefGoogle Scholar
  87. 87.
    Sato A, Hayashi K, Naruse M, et al. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension. 2003;41:64–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Rossing K, Schjoedt KJ, Smidt UM, et al. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study. Diabetes Care. 2005;28:2106–12.PubMedCrossRefGoogle Scholar
  89. 89.
    Schjoedt KJ, Rossing K, Juhl TR, et al. Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney Int. 2006;70:536–42.PubMedGoogle Scholar
  90. 90.
    Ogawa S, Takeuchi K, Mori T, et al. Spironolactone further reduces urinary albumin excretion and plasma B-type natriuretic peptide levels in hypertensive type II diabetes treated with angiotensin-converting enzyme inhibitor. Clin Exp Pharmacol Physiol. 2006;33:477–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Schjoedt KJ, Rossing K, Juhl TR, et al. Beneficial impact of spironolactone in diabetic nephropathy. Kidney Int. 2005;68:2829–36.PubMedCrossRefGoogle Scholar
  92. 92.
    Bianchi S, Bigazzi R, Campese VM. Antagonists of aldosterone and proteinuria in patients with CKD: an uncontrolled pilot study. Am J Kidney Dis. 2005;46:45–51.PubMedCrossRefGoogle Scholar
  93. 93.
    Mehdi UF, Adams-Huet B, Raskin P, et al. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol. 2009;20:2641–50.PubMedCrossRefGoogle Scholar
  94. 94.
    Parving HH, Tarnow L, Rossing P. Renal protection in diabetes: an emerging role for calcium antagonists. J Hypertens Suppl. 1996;14:S21–5.PubMedCrossRefGoogle Scholar
  95. 95.
    Mimran A, Insua A, Ribstein J, et al. Comparative effect of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy. Diabetes Care. 1988;11:850–3.PubMedCrossRefGoogle Scholar
  96. 96.
    Baba T, Murabayashi S, Takebe K. Comparison of the renal effects of angiotensin converting enzyme inhibitor and calcium antagonist in hypertensive type 2 (non-insulin-dependent) diabetic patients with microalbuminuria: a randomised controlled trial. Diabetologia. 1989;32:40–4.PubMedGoogle Scholar
  97. 97.
    Comparison between perindopril and nifedipine in hypertensive and normotensive diabetic patients with microalbuminuria. Melbourne Diabetic Nephropathy Study Group. BMJ. 1991;302:210216.Google Scholar
  98. 98.
    Mosconi L, Ruggenenti P, Perna A, et al. Nitrendipine and enalapril improve albuminuria and glomerular filtration rate in non-insulin dependent diabetes. Kidney Int Suppl. 1996;55:S91–3.PubMedGoogle Scholar
  99. 99.
    Crepaldi G, Carraro A, Brocco E, et al. Hypertension and non-insulin-dependent diabetes. A comparison between an angiotensin-converting enzyme inhibitor and a calcium antagonist. Acta Diabetol. 1995;32:203–8.PubMedCrossRefGoogle Scholar
  100. 100.
    Velussi M, Brocco E, Frigato F, et al. Effects of cilazapril and amlodipine on kidney function in hypertensive NIDDM patients. Diabetes. 1996;45:216–22.PubMedCrossRefGoogle Scholar
  101. 101.
    Corradi LLP, Pasotti C, Zoppi A, Preti P, Lazzari P, et al. Effect of amlopidine vs. fosinopril on microalbuminuria in elderly hypertensive patients with type II diabetes. Am J Hypertens. 1996;9:152A.CrossRefGoogle Scholar
  102. 102.
    Jungmann EHT, Malanyn M, Mortasawi N, Schererich J, Usadel KH. Comparative study on renal effects of nitrendipine vs. enalapril in microalbuminuric patients with type 1 diabetes mellitus. Diabetologia. 1992;35:A149.Google Scholar
  103. 103.
    Stornello M, Valvo EV, Scapellato L. Hemodynamic, renal, and humoral effects of the calcium entry blocker nicardipine and converting enzyme inhibitor captopril in hypertensive type II diabetic patients with nephropathy. J Cardiovasc Pharmacol. 1989;14:851–5.PubMedCrossRefGoogle Scholar
  104. 104.
    Bakris GL. Effects of diltiazem or lisinopril on massive proteinuria associated with diabetes mellitus. Ann Intern Med. 1990;112:707–8.PubMedGoogle Scholar
  105. 105.
    Romero R, Salinas I, Lucas A, et al. Comparative effects of captopril versus nifedipine on proteinuria and renal function of type 2 diabetic patients. Diabetes Res Clin Pract. 1992;17:191–8.PubMedCrossRefGoogle Scholar
  106. 106.
    Ferder L, Daccordi H, Martello M, et al. Angiotensin converting enzyme inhibitors versus calcium antagonists in the treatment of diabetic hypertensive patients. Hypertension. 1992;19:II237–42.PubMedGoogle Scholar
  107. 107.
    Bakris GL, Barnhill BW, Sadler R. Treatment of arterial hypertension in diabetic humans: importance of therapeutic selection. Kidney Int. 1992;41:912–9.PubMedCrossRefGoogle Scholar
  108. 108.
    Norgaard K, Jensen T, Christensen P, et al. A comparison of spirapril and isradipine in patients with diabetic nephropathy and hypertension. Blood Press. 1993;2:301–8.PubMedCrossRefGoogle Scholar
  109. 109.
    Rossing P, Tarnow L, Boelskifte S, et al. Differences between nisoldipine and lisinopril on glomerular filtration rates and albuminuria in hypertensive IDDM patients with diabetic nephropathy during the first year of treatment. Diabetes. 1997;46:481–7.PubMedCrossRefGoogle Scholar
  110. 110.
    Corradi LFR, Zoppi A, Lusardi P, Preti P, Lazzari P, et al. Long term effects of ramipril and nitrendipine on albuminuria in diabetic hypertensive patients with impaired renal function. Am J Hypertens. 1996;9:151A.CrossRefGoogle Scholar
  111. 111.
    Bakris GL CJ, Vicknair N, Leurgans S. Effect of nondihydropyridine calcium antagonists (NDCAs) on progression of nephropathy from noninsulin dependent diabetes (NIDDM). J Am Soc Nephrol. 1995;6:446.Google Scholar
  112. 112.
    O'Donnell MJ, Rowe B, Lawson N, Horton A, Gide OHV, Barnett AH. Comparative study of lisinopril and nifedipine in treatment of diabetic patients with hypertension and macroproteinuria. Diabetes. 1991;40:505A.Google Scholar
  113. 113.
    Holdaas H, Hartmann A, Lien MG, Nielsen L, Fauchald T, Jervell J, et al. Lisinopril but not nifedipine reduces urinary albumin excretion in diabetic nephropathy. Kidney Int. 1990;37:239.Google Scholar
  114. 114.
    Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359:2417–28.PubMedCrossRefGoogle Scholar
  115. 115.
    Bakris GL, Sarafidis PA, Weir MR, et al. Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial. Lancet. 2010;375:1173–81.PubMedCrossRefGoogle Scholar
  116. 116.
    Bakris GL, Weir MR, Secic M, et al. Differential effects of calcium antagonist subclasses on markers of nephropathy progression. Kidney Int. 2004;65:1991–2002.PubMedCrossRefGoogle Scholar
  117. 117.
    Remuzzi G, Ruggenenti P, Benigni A. Understanding the nature of renal disease progression. Kidney Int. 1997;51:2–15.PubMedCrossRefGoogle Scholar
  118. 118.
    Kloke HJ, Branten AJ, Huysmans FT, et al. Antihypertensive treatment of patients with proteinuric renal diseases: risks or benefits of calcium channel blockers? Kidney Int. 1998;53:1559–73.PubMedCrossRefGoogle Scholar
  119. 119.
    Gansevoort RT, Sluiter WJ, Hemmelder MH, et al. Antiproteinuric effect of blood-pressure-lowering agents: a meta-analysis of comparative trials. Nephrol Dial Transplant. 1995;10:1963–74.PubMedGoogle Scholar
  120. 120.
    Bakris GL, Copley JB, Vicknair N, et al. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int. 1996;50:1641–50.PubMedCrossRefGoogle Scholar
  121. 121.
    Bakris GL, Mangrum A, Copley JB, et al. Effect of calcium channel or beta-blockade on the progression of diabetic nephropathy in African Americans. Hypertension. 1997;29:744–50.PubMedGoogle Scholar
  122. 122.
    Nakao N, Yoshimura A, Morita H, et al. 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.PubMedCrossRefGoogle Scholar
  123. 123.
    Keane WF, Eknoyan G. Proteinuria, albuminuria, risk, assessment, detection, elimination (PARADE): a position paper of the National Kidney Foundation. Am J Kidney Dis. 1999;33:1004–10.PubMedCrossRefGoogle Scholar
  124. 124.
    Nielsen FS, Rossing P, Gall MA, et al. Long-term effect of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy. Diabetes. 1997;46:1182–8.PubMedCrossRefGoogle Scholar
  125. 125.
    Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ. 1998;317:713720.Google Scholar
  126. 126.
    Marre M, Puig JG, Kokot F, et al. Equivalence of indapamide SR and enalapril on microalbuminuria reduction in hypertensive patients with type 2 diabetes: the NESTOR Study. J Hypertens. 2004;22:1613–22.PubMedCrossRefGoogle Scholar
  127. 127.
    Bakris GL, Toto RD, McCullough PA, et al. Effects of different ACE inhibitor combinations on albuminuria: results of the GUARD study. Kidney Int. 2008;73:1303–9.PubMedCrossRefGoogle Scholar
  128. 128.
    National Kidney Foundation. K/DOQI clinical practice guidelines for managing dyslipidemias in chronic kidney disease. Am J Kidney Dis. 2003;41:S1–92.Google Scholar
  129. 129.
    O'Brien T, Nguyen TT, Zimmerman BR. Hyperlipidemia and diabetes mellitus. Mayo Clin Proc. 1998;73:969–76.PubMedCrossRefGoogle Scholar
  130. 130.
    Ginsberg HN. REVIEW: efficacy and mechanisms of action of statins in the treatment of diabetic dyslipidemia. J Clin Endocrinol Metab. 2006;91:383–92.PubMedCrossRefGoogle Scholar
  131. 131.
    Koskinen P, Manttari M, Manninen V, et al. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diabetes Care. 1992;15:820–5.PubMedCrossRefGoogle Scholar
  132. 132.
    Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615–22.PubMedCrossRefGoogle Scholar
  133. 133.
    Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs. usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002;288:29983007.Google Scholar
  134. 134.
    MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:722.Google Scholar
  135. 135.
    Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361:2005–16.PubMedCrossRefGoogle Scholar
  136. 136.
    Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623–30.PubMedCrossRefGoogle Scholar
  137. 137.
    Sever PS, Poulter NR, Dahlof B, et al. Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial–lipid-lowering arm (ASCOT-LLA). Diabetes Care. 2005;28:1151–7.PubMedCrossRefGoogle Scholar
  138. 138.
    Vijan S, Hayward RA. Pharmacologic lipid-lowering therapy in type 2 diabetes mellitus: background paper for the American College of Physicians. Ann Intern Med. 2004;140:650–8.PubMedGoogle Scholar
  139. 139.
    Tonelli M, Moye L, Sacks FM, et al. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Ann Intern Med. 2003;138:98–104.PubMedGoogle Scholar
  140. 140.
    Gaede P, Lund-Andersen H, Parving HH, et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580–91.PubMedCrossRefGoogle Scholar
  141. 141.
    Jones C, Roderick P, Harris S, et al. Decline in kidney function before and after nephrology referral and the effect on survival in moderate to advanced chronic kidney disease. Nephrol Dial Transplant. 2006;21:2133–43.PubMedCrossRefGoogle Scholar
  142. 142.
    Chan MR, Dall AT, Fletcher KE, et al. Outcomes in patients with chronic kidney disease referred late to nephrologists: a meta-analysis. Am J Med. 2007;120:1063–70.PubMedCrossRefGoogle Scholar
  143. 143.
    Avorn J, Bohn RL, Levy E, et al. Nephrologist care and mortality in patients with chronic renal insufficiency. Arch Intern Med. 2002;162:2002–6.PubMedCrossRefGoogle Scholar
  144. 144.
    Kinchen KS, Sadler J, Fink N, et al. The timing of specialist evaluation in chronic kidney disease and mortality. Ann Intern Med. 2002;137:479–86.PubMedGoogle Scholar
  145. 145.
    Ghossein C, Serrano A, Rammohan M, et al. The role of comprehensive renal clinic in chronic kidney disease stabilization and management: the Northwestern experience. Semin Nephrol. 2002;22:526–32.PubMedGoogle Scholar
  146. 146.
    Lebovitz HE, Banerji MA. Insulin resistance and its treatment by thiazolidinediones. Recent Prog Horm Res. 2001;56:265–94.PubMedCrossRefGoogle Scholar
  147. 147.
    Natali A, Baldeweg S, Toschi E, et al. Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes. Diabetes Care. 2004;27:1349–57.PubMedCrossRefGoogle Scholar
  148. 148.
    Pistrosch F, Passauer J, Fischer S, et al. In type 2 diabetes, rosiglitazone therapy for insulin resistance ameliorates endothelial dysfunction independent of glucose control. Diabetes Care. 2004;27:484–90.PubMedCrossRefGoogle Scholar
  149. 149.
    Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998;391:82–6.PubMedCrossRefGoogle Scholar
  150. 150.
    Harte A, McTernan P, Chetty R, et al. Insulin-mediated upregulation of the renin angiotensin system in human subcutaneous adipocytes is reduced by rosiglitazone. Circulation. 2005;111:1954–61.PubMedCrossRefGoogle Scholar
  151. 151.
    Takeda K, Ichiki T, Tokunou T, et al. Peroxisome proliferator-activated receptor gamma activators downregulate angiotensin II type 1 receptor in vascular smooth muscle cells. Circulation. 2000;102:1834–9.PubMedGoogle Scholar
  152. 152.
    Sugawara A, Takeuchi K, Uruno A, et al. Differential effects among thiazolidinediones on the transcription of thromboxane receptor and angiotensin II type 1 receptor genes. Hypertens Res. 2001;24:229–33.PubMedCrossRefGoogle Scholar
  153. 153.
    Nakamura T, Ushiyama C, Shimada N, et al. Comparative effects of pioglitazone, glibenclamide, and voglibose on urinary endothelin-1 and albumin excretion in diabetes patients. J Diabetes Complications. 2000;14:250–4.PubMedCrossRefGoogle Scholar
  154. 154.
    Ruan XZ, Moorhead JF, Fernando R, et al. PPAR agonists protect mesangial cells from interleukin 1beta-induced intracellular lipid accumulation by activating the ABCA1 cholesterol efflux pathway. J Am Soc Nephrol. 2003;14:593–600.PubMedCrossRefGoogle Scholar
  155. 155.
    Wu J, Zhang Y, Wang N, et al. Liver X receptor-alpha mediates cholesterol efflux in glomerular mesangial cells. Am J Physiol Renal Physiol. 2004;287:F886–95.PubMedCrossRefGoogle Scholar
  156. 156.
    Chana RS, Lewington AJ, Brunskill NJ. Differential effects of peroxisome proliferator activated receptor-gamma (PPAR gamma) ligands in proximal tubular cells: thiazolidinediones are partial PPAR gamma agonists. Kidney Int. 2004;65:2081–90.PubMedCrossRefGoogle Scholar
  157. 157.
    Panchapakesan U, Pollock CA, Chen XM. The effect of high glucose and PPAR-gamma agonists on PPAR-gamma expression and function in HK-2 cells. Am J Physiol Renal Physiol. 2004;287:F528–34.PubMedCrossRefGoogle Scholar
  158. 158.
    Yoshimoto T, Naruse M, Nishikawa M, et al. Antihypertensive and vasculo- and renoprotective effects of pioglitazone in genetically obese diabetic rats. Am J Physiol. 1997;272:E989–96.PubMedGoogle Scholar
  159. 159.
    Buckingham RE, Al-Barazanji KA, Toseland CD, et al. Peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats. Diabetes. 1998;47:1326–34.PubMedCrossRefGoogle Scholar
  160. 160.
    Yamashita H, Nagai Y, Takamura T, et al. Thiazolidinedione derivatives ameliorate albuminuria in streptozotocin-induced diabetic spontaneous hypertensive rat. Metabolism. 2002;51:403–8.PubMedCrossRefGoogle Scholar
  161. 161.
    Isshiki K, Haneda M, Koya D, et al. Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats. Diabetes. 2000;49:1022–32.PubMedCrossRefGoogle Scholar
  162. 162.
    Baylis C, Atzpodien EA, Freshour G, et al. Peroxisome proliferator-activated receptor [gamma] agonist provides superior renal protection versus angiotensin-converting enzyme inhibition in a rat model of type 2 diabetes with obesity. J Pharmacol Exp Ther. 2003;307:854–60.PubMedCrossRefGoogle Scholar
  163. 163.
    Yoshida K, Kohzuki M, Xu HL, et al. Effects of troglitazone and temocapril in spontaneously hypertensive rats with chronic renal failure. J Hypertens. 2001;19:503–10.PubMedCrossRefGoogle Scholar
  164. 164.
    Imano E, Kanda T, Nakatani Y, et al. Effect of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy. Diabetes Care. 1998;21:2135–9.PubMedCrossRefGoogle Scholar
  165. 165.
    Nakamura T, Ushiyama C, Suzuki S, et al. Effect of troglitazone on urinary albumin excretion and serum type IV collagen concentrations in Type 2 diabetic patients with microalbuminuria or macroalbuminuria. Diabet Med. 2001;18:308–13.PubMedCrossRefGoogle Scholar
  166. 166.
    Nakamura T, Ushiyama C, Osada S, et al. Pioglitazone reduces urinary podocyte excretion in type 2 diabetes patients with microalbuminuria. Metabolism. 2001;50:1193–6.PubMedCrossRefGoogle Scholar
  167. 167.
    Aljabri K, Kozak SE, Thompson DM. Addition of pioglitazone or bedtime insulin to maximal doses of sulfonylurea and metformin in type 2 diabetes patients with poor glucose control: a prospective, randomized trial. Am J Med. 2004;116:230–5.PubMedCrossRefGoogle Scholar
  168. 168.
    Yanagawa T, Araki A, Sasamoto K, et al. Effect of antidiabetic medications on microalbuminuria in patients with type 2 diabetes. Metabolism. 2004;53:353–7.PubMedCrossRefGoogle Scholar
  169. 169.
    Hanefeld M, Brunetti P, Schernthaner GH, et al. One-year glycemic control with a sulfonylurea plus pioglitazone versus a sulfonylurea plus metformin in patients with type 2 diabetes. Diabetes Care. 2004;27:141–7.PubMedCrossRefGoogle Scholar
  170. 170.
    Schernthaner G, Matthews DR, Charbonnel B, et al. Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double-blind, randomized trial. J Clin Endocrinol Metab. 2004;89:6068–76.PubMedCrossRefGoogle Scholar
  171. 171.
    Agarwal R, Saha C, Battiwala M, et al. A pilot randomized controlled trial of renal protection with pioglitazone in diabetic nephropathy. Kidney Int. 2005;68:285–92.PubMedCrossRefGoogle Scholar
  172. 172.
    Lebovitz HE, Dole JF, Patwardhan R, et al. Rosiglitazone monotherapy is effective in patients with type 2 diabetes. J Clin Endocrinol Metab. 2001;86:280–8.PubMedCrossRefGoogle Scholar
  173. 173.
    Sarafidis PA, Lasaridis AN, Nilsson PM, et al. The effect of rosiglitazone on urine albumin excretion in patients with type 2 diabetes mellitus and hypertension. Am J Hypertens. 2005;18:227–34.PubMedCrossRefGoogle Scholar
  174. 174.
    Pistrosch F, Herbrig K, Kindel B, et al. Rosiglitazone improves glomerular hyperfiltration, renal endothelial dysfunction, and microalbuminuria of incipient diabetic nephropathy in patients. Diabetes. 2005;54:2206–11.PubMedCrossRefGoogle Scholar
  175. 175.
    Bakris GL, Ruilope LM, McMorn SO, et al. Rosiglitazone reduces microalbuminuria and blood pressure independently of glycemia in type 2 diabetes patients with microalbuminuria. J Hypertens. 2006;24:2047–55.PubMedCrossRefGoogle Scholar
  176. 176.
    Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly medicare patients treated with rosiglitazone or pioglitazone. JAMA. 2010;304:411–8.PubMedCrossRefGoogle Scholar
  177. 177.
    Burns KD. The emerging role of angiotensin-converting enzyme-2 in the kidney. Curr Opin Nephrol Hypertens. 2007;16:116–21.PubMedCrossRefGoogle Scholar
  178. 178.
    Rice GI, Thomas DA, Grant PJ, et al. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 2004;383:45–51.PubMedCrossRefGoogle Scholar
  179. 179.
    Ren Y, Garvin JL, Carretero OA. Vasodilator action of angiotensin-(1–7) on isolated rabbit afferent arterioles. Hypertension. 2002;39:799–802.PubMedCrossRefGoogle Scholar
  180. 180.
    Ye M, Wysocki J, William J, et al. Glomerular localization and expression of Angiotensin-converting enzyme 2 and Angiotensin-converting enzyme: implications for albuminuria in diabetes. J Am Soc Nephrol. 2006;17:3067–75.PubMedCrossRefGoogle Scholar
  181. 181.
    Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411–5.PubMedCrossRefGoogle Scholar
  182. 182.
    Minchenko AG, Stevens MJ, White L, et al. Diabetes-induced overexpression of endothelin-1 and endothelin receptors in the rat renal cortex is mediated via poly(ADP-ribose) polymerase activation. FASEB J. 2003;17:1514–6.PubMedGoogle Scholar
  183. 183.
    Hocher B, Lun A, Priem F, et al. Renal endothelin system in diabetes: comparison of angiotensin-converting enzyme inhibition and endothelin-A antagonism. J Cardiovasc Pharmacol. 1998;31(Suppl 1):S492–5.PubMedCrossRefGoogle Scholar
  184. 184.
    Klahr S, Morrissey J. Progression of chronic renal disease. Am J Kidney Dis. 2003;41:S3–7.PubMedCrossRefGoogle Scholar
  185. 185.
    Benigni A. Defining the role of endothelins in renal pathophysiology on the basis of selective and unselective endothelin receptor antagonist studies. Curr Opin Nephrol Hypertens. 1995;4:349–53.PubMedCrossRefGoogle Scholar
  186. 186.
    Kohan DE. Autocrine role of endothelin in rat inner medullary collecting duct: inhibition of AVP-induced cAMP accumulation. J Cardiovasc Pharmacol. 1993;22(Suppl 8):S174–9.PubMedCrossRefGoogle Scholar
  187. 187.
    Ahn D, Ge Y, Stricklett PK, et al. Collecting duct-specific knockout of endothelin-1 causes hypertension and sodium retention. J Clin Invest. 2004;114:504–11.PubMedGoogle Scholar
  188. 188.
    Lee YJ, Shin SJ, Tsai JH. Increased urinary endothelin-1-like immunoreactivity excretion in NIDDM patients with albuminuria. Diabetes Care. 1994;17:263–6.PubMedCrossRefGoogle Scholar
  189. 189.
    De Mattia G, Cassone-Faldetta M, Bellini C, et al. Role of plasma and urinary endothelin-1 in early diabetic and hypertensive nephropathy. Am J Hypertens. 1998;11:983–8.PubMedCrossRefGoogle Scholar
  190. 190.
    Ak G, Buyukberber S, Sevinc A, et al. The relation between plasma endothelin-1 levels and metabolic control, risk factors, treatment modalities, and diabetic microangiopathy in patients with Type 2 diabetes mellitus. J Diabetes Complications. 2001;15:150–7.PubMedCrossRefGoogle Scholar
  191. 191.
    Candido R, Allen TJ. Haemodynamics in microvascular complications in type 1 diabetes. Diabetes Metab Res Rev. 2002;18:286–304.PubMedCrossRefGoogle Scholar
  192. 192.
    Zanatta CM, Gerchman F, Burttet L, et al. Endothelin-1 levels and albuminuria in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2008;80:299–304.PubMedCrossRefGoogle Scholar
  193. 193.
    Chade AR, Krier JD, Textor SC, et al. Endothelin-a receptor blockade improves renal microvascular architecture and function in experimental hypercholesterolemia. J Am Soc Nephrol. 2006;17:3394–403.PubMedCrossRefGoogle Scholar
  194. 194.
    Sasser JM, Sullivan JC, Hobbs JL, et al. Endothelin A receptor blockade reduces diabetic renal injury via an anti-inflammatory mechanism. J Am Soc Nephrol. 2007;18:143–54.PubMedCrossRefGoogle Scholar
  195. 195.
    Thone-Reinke C, Simon K, Richter CM, et al. Inhibition of both neutral endopeptidase and endothelin-converting enzyme by SLV306 reduces proteinuria and urinary albumin excretion in diabetic rats. J Cardiovasc Pharmacol. 2004;44(Suppl 1):S76–9.PubMedCrossRefGoogle Scholar
  196. 196.
    Sugimoto K, Fujimori A, Yuyama H, et al. Renal protective effect of YM598, a selective endothelin type A receptor antagonist. J Cardiovasc Pharmacol. 2004;44(Suppl 1):S451–4.PubMedCrossRefGoogle Scholar
  197. 197.
    Gross ML, Ritz E, Schoof A, et al. Renal damage in the SHR/N-cp type 2 diabetes model: comparison of an angiotensin-converting enzyme inhibitor and endothelin receptor blocker. Lab Investig. 2003;83:1267–77.PubMedCrossRefGoogle Scholar
  198. 198.
    Cosenzi A, Bernobich E, Trevisan R, et al. Nephroprotective effect of bosentan in diabetic rats. J Cardiovasc Pharmacol. 2003;42:752–6.PubMedCrossRefGoogle Scholar
  199. 199.
    Honing ML, Hijmering ML, Ballard DE, et al. ABT-627, a selective eta-receptor antagonist, reduces proteinuria in patients with diabetes mellitus. In: Regulation of Vascular Tone in Humans by Endothelium-Derived Mediators. Utrecht, Netherlands: Elinkwijk BV; 2000;89–102Google Scholar
  200. 200.
    Wenzel RR et al. The ETA-selective antagonist SPP301 on top of standard treatment reduces urinary albumin excretion rate in patients with diabetic nephropathy. ASN Renal Week 2005.Google Scholar
  201. 201.
    Mann JF, Green D, Jamerson K, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol. 2010;21:527–35.PubMedCrossRefGoogle Scholar
  202. 202.
    Glomb MA, Pfahler C. Amides are novel protein modifications formed by physiological sugars. J Biol Chem. 2001;276:41638–47.PubMedCrossRefGoogle Scholar
  203. 203.
    Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med. 1988;318:1315–21.PubMedCrossRefGoogle Scholar
  204. 204.
    Abdel-Rahman E, Bolton WK. Pimagedine: a novel therapy for diabetic nephropathy. Expert Opin Investig Drugs. 2002;11:565–74.PubMedCrossRefGoogle Scholar
  205. 205.
    Freedman BI, Wuerth JP, Cartwright K, et al. Design and baseline characteristics for the aminoguanidine Clinical Trial in Overt Type 2 Diabetic Nephropathy (ACTION II). Control Clin Trials. 1999;20:493–510.PubMedCrossRefGoogle Scholar
  206. 206.
    Williams ME. Clinical studies of advanced glycation end product inhibitors and diabetic kidney disease. Curr Diab Rep. 2004;4:441–6.PubMedCrossRefGoogle Scholar
  207. 207.
    Williams ME. A phase 2 clinical trial of pyridoxamine (Pyridorin) in type 1 and type 2 diabetic patients with overt nephropathy (PYR-206). J Am Soc Nephrol. 2003;2003:7A.Google Scholar
  208. 208.
    Kass DA, Shapiro EP, Kawaguchi M, et al. Improved arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation. 2001;104:1464–70.PubMedCrossRefGoogle Scholar
  209. 209.
    Vasan S, Foiles P, Founds H. Therapeutic potential of breakers of advanced glycation end product-protein crosslinks. Arch Biochem Biophys. 2003;419:89–96.PubMedCrossRefGoogle Scholar
  210. 210.
    de Zeeuw D, Agarwal R, Amdahl M, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet. 2010;376:1543–51.PubMedCrossRefGoogle Scholar
  211. 211.
    Pergola PE, Krauth M, Huff JW, et al. Effect of bardoxolone methyl on kidney function in patients with T2D and Stage 3b-4 CKD. Am J Nephrol. 2011;33:469–76.PubMedCrossRefGoogle Scholar
  212. 212.
    Pergola PE, Raskin P, Toto RD, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med. 2011.Google Scholar
  213. 213.
    Standards of medical care in diabetes--2007. Diabetes Care. 2007;30(Suppl 1):S4-S41.Google Scholar

Copyright information

© Society of General Internal Medicine 2011

Authors and Affiliations

  • Emaad M. Abdel-Rahman
    • 1
  • Lawand Saadulla
    • 2
  • W. Brian Reeves
    • 2
  • Alaa S. Awad
    • 2
    Email author
  1. 1.Department of Medicine, Division of NephrologyUniversity of VirginiaCharlottesvilleUSA
  2. 2.Department of Medicine, Division of NephrologyPenn State Hershey Medical Center, College of MedicineHersheyUSA

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