Skip to main content
SpringerLink
Log in

Diabetic Nephropathy

  • Reference work entry
  • First Online:
Principles of Diabetes Mellitus

Abstract

Diabetes is the most common cause of end-stage kidney disease in the world. Diabetic nephropathy is due to cellular and subcellular mechanisms and involves induction of signaling pathways in the kidney which perpetuate the destruction of glomeruli, the intrarenal vasculature, and the interstitium. Diagnosis and prevention center on the detection of albuminuria, tight plasma glucose control, as well as primary interruption of the renin–angiotensin–aldosterone system, which reduces the transglomerular hydrostatic pressure. Some of the newer glucose control therapeutic agents have shown benefit in diabetic nephropathy, and the future holds promise for specific inhibitors of inflammation, as well as inhibitors of microRNA species. Comorbid conditions such as large vessel disease are also commonly associated and require vigilance on the part of the physician and those supervising the predialysis and dialysis patients.

Donald Feinfeld: deceased.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 699.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 899.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Saran R, Li Y, Robinson B, et al. US Renal Data System 2014 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis. 2015;66 Suppl 1:S1–306.

    Google Scholar 

  2. Lameire N, Jager K, Van Biesen W, et al. Chronic kidney disease: a European perspective Kidney Int Suppl. 2005; 99:S30–8.

    Google Scholar 

  3. Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world – a growing challenge. N Engl J Med. 2007;356:213–5.

    Article  CAS  PubMed  Google Scholar 

  4. Ramezani M, Ghoddousi K, Hashemi M, et al. Diabetes as the cause of end-stage renal disease affects the pattern of post kidney transplant rehospitalizations. Transplant Proc. 2007;39:966–9.

    Article  CAS  PubMed  Google Scholar 

  5. Burroughs TE, Swindle J, Takemoto S, et al. Diabetic complications associated with new-onset diabetes mellitus in renal transplant recipients. Transplantation. 2007;83:1027–34.

    Article  PubMed  Google Scholar 

  6. Centers for Disease Control and Prevention (CDC). Prevalence of chronic kidney disease and associated risk factors – United States, 1999–2004. MMWR Morb Mortal Wkly Rep. 2007;56:161–5.

    Google Scholar 

  7. Osterby R, Parving HH, Hommel E, et al. Glomerular structure and function in diabetic nephropathy. Early to advanced stages. Diabetes. 1990;39:1057–63.

    Article  CAS  PubMed  Google Scholar 

  8. Gilbert RE, Cooper ME. The tubulointerstitium in progressive diabetic kidney disease: more than an aftermath of glomerular injury? Kidney Int. 1999;56:1627–37.

    Article  CAS  PubMed  Google Scholar 

  9. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813–20.

    Article  CAS  PubMed  Google Scholar 

  10. Boyle PJ. Diabetes mellitus and macrovascular disease: mechanisms and mediators. Am J Med. 2007;120(9 Suppl 2):S12–7.

    Article  CAS  PubMed  Google Scholar 

  11. Cavusoglu AC, Bilgili S, Alaluf A, et al. Vascular endothelial growth factor level in the serum of diabetic patients with retinopathy. Ann Ophthalmol (Skokie). 2007;39:205–8.

    Article  CAS  Google Scholar 

  12. Ryan GJ. New pharmacologic approaches to treating diabetic retinopathy. Am J Health Syst Pharm. 2007;64(17 Suppl 12):S15–21.

    Article  CAS  PubMed  Google Scholar 

  13. Zatz R, Dunn BR, Meyer TW, et al. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest. 1986;77:1925–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gruden G, Zonca S, Hayward A, et al. Mechanical stretch-induced fibronectin and transforming growth factor-beta1 production in human mesangial cells is p38 mitogen-activated protein kinase-dependent. Diabetes. 2000;49:655–61.

    Article  CAS  PubMed  Google Scholar 

  15. Lassila M, Jandeleit-Dahm K, Seah KK, et al. Imatinib attenuates diabetic nephropathy in apolipoprotein E-knockout mice. J Am Soc Nephrol. 2004;15:2125–38.

    Article  CAS  PubMed  Google Scholar 

  16. Goldberg R, Rubinstein AM, Gil N, et al. Role of heparanase-driven inflammatory cascade in pathogenesis of diabetic nephropathy. Diabetes. 2014;63:4302–13.

    Article  CAS  PubMed  Google Scholar 

  17. Kato M, Natarajan R. Diabetic nephropathy – emerging epigenetic mechanisms. Nat Rev Nephrol. 2014;10:517–30.

    Article  CAS  PubMed  Google Scholar 

  18. Deshpande SD, Putta S, Wang M, et al. Transforming growth factor- β induces cross talk between P53 and a microRNA in the pathogenesis of diabetic nephropathy. Diabetes. 2013;62:3151–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kato M, Natarajan R. MicroRNA circuits in transforming growth factor-β actions and diabetic nephropathy. Semin Nephrol. 2012;32:253–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jenkins RH, Davies LC, Taylor PR, et al. miR-192 induces G2/M growth arrest in aristolochic acid nephropathy. Am J Pathol. 2014;184:996–1009.

    Article  CAS  PubMed  Google Scholar 

  21. Trionfini P, Begnini A, Remuzzi G. MicroRNAs in kidney physiology and disease. Nat Rev Nephrol. 2015;11:23–33.

    Article  CAS  PubMed  Google Scholar 

  22. Tomuleasa C, Fuji S, Cucuianu A, et al. MicroRNAs as biomarkers for graft-versus-host disease following allogeneic stem cell transplantation. Ann Hematol. 2015;94:1081–92.

    Article  CAS  PubMed  Google Scholar 

  23. Izquierdo A, Lopez-Luna P, Ortega A, et al. The parathyroid hormone-related protein system and diabetic nephropathy outcome in streptozotocin-induced diabetes. Kidney Int. 2006;69:2171–7.

    Article  CAS  PubMed  Google Scholar 

  24. Wang Y, Zhou J, Minto AW, et al. Altered vitamin D metabolism in type II diabetic mouse glomeruli may provide protection from diabetic nephropathy. Kidney Int. 2006;70:882–91.

    Article  PubMed  CAS  Google Scholar 

  25. Zhang Z, Yuan W, Sun L, et al. 1,25 dihydroxy vitamin D3 targeting of NFκB suppresses high glucose-induced MCP-1 expression in mesangial cells. Kidney Int. 2007;72:193–201.

    Article  CAS  PubMed  Google Scholar 

  26. Zhang Z, Sun L, Wang Y, et al. Renoprotective role of the vitamin D receptor in diabetic nephropathy. Kidney Int. 2008;73:163–7.

    Article  CAS  PubMed  Google Scholar 

  27. Earle KS, Walker J, Hill C, et al. Familial clustering of cardiovascular disease in patients with insulin-dependent diabetes and nephropathy. N Engl J Med. 1992;325:673–7.

    Article  Google Scholar 

  28. Krolewski A, Fogarty D, Warram J. Hypertension and nephropathy in diabetes mellitus: what is inherited and what is acquired? Diabetes Res Clin Pract. 1998;39(Suppl):S1–14.

    Article  PubMed  Google Scholar 

  29. Fioretto P, Steffes M, Barbosa J, et al. Is diabetic nephropathy inherited? Studies of glomerular structure in type 1 diabetic sibling pairs. Diabetes. 1999;48:865–9.

    Article  CAS  PubMed  Google Scholar 

  30. Canani L, Gerchman F, Gross J. Familial clustering of diabetic nephropathy in Brazilian type 2 diabetic patients. Diabetes. 1999;48:909–13.

    Article  CAS  PubMed  Google Scholar 

  31. Marshall SM. Recent advances in diabetic nephropathy. Postgrad Med J. 2004;80:624–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Krolewski A, Canessa M, Warram J, et al. Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus. N Engl J Med. 1998;318:140–5.

    Article  Google Scholar 

  33. Fujita J, Tsuda K, Seno M, et al. Erythrocyte sodium-lithium countertransport activity as a marker of predisposition to hypertension and diabetic nephropathy in NIDDM. Diabetes Care. 1994;17:977–82.

    Article  CAS  PubMed  Google Scholar 

  34. Lindsay R, Little J, Jaap A, et al. Diabetic nephropathy is associated with an increased familial risk of stroke. Diabetes Care. 1999;22:422–5.

    Article  CAS  PubMed  Google Scholar 

  35. Freire MB, van Dijk DJ, Erman A, et al. DNA polymorphisms in the ACE gene, serum ACE activity and the risk of nephropathy in insulin-dependent diabetes mellitus. Nephrol Dial Transplant. 1998;13:2553–8.

    Article  CAS  PubMed  Google Scholar 

  36. Vleming LJ, van der Pijl JW, Lemkes HH, et al. The DD genotype of the ACE gene polymorphism is associated with progression of diabetic nephropathy to end stage renal failure in IDDM. Clin Nephrol. 1999;51:133–40.

    CAS  PubMed  Google Scholar 

  37. Miller JA, Scholey JW. The impact of renin-angiotensin system polymorphisms on physiological and pathophysiological processes in humans. Curr Opin Nephrol Hypertens. 2004;13:101–6.

    Article  CAS  PubMed  Google Scholar 

  38. Tervaert TW, Mooyaart AL, Amann K, et al. Pathologic classification of diabetic nephropathy. J Clin Am Soc Nephrol. 2010;21:556–63.

    Article  Google Scholar 

  39. Levey AS, Stevens LA, Schmid CH, et al. CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–12.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Mogensen CE. Glomerular filtration rate and renal plasma flow in short-term and long-term juvenile diabetes mellitus. Scand J Clin Lab Invest. 1971;28:91–100.

    Article  CAS  PubMed  Google Scholar 

  41. Nowack R, Raum E, Blum W, et al. Renal hemodynamics in recent-onset type II diabetes. Am J Kidney Dis. 1992;20:342–7.

    Article  CAS  PubMed  Google Scholar 

  42. Parving HH, Chaturvedi N, Viberti GC, et al. Does microalbuminuria predict diabetic nephropathy? Diabetes Care. 2002;25:406–7.

    Article  PubMed  Google Scholar 

  43. Stephenson JM, Kenny S, Stevens LK, et al. Proteinuria and mortality in diabetes: the WHO multinational study of vascular disease in diabetes. Diabet Med. 1995;12:149–55.

    Article  CAS  PubMed  Google Scholar 

  44. Sowers JR, Epstein M. Diabetes mellitus and associated hypertension, vascular disease, and nephropathy. Hypertension. 1995;26:869–79.

    Article  CAS  PubMed  Google Scholar 

  45. Amin AP, Whaley-Connell AT, Li S, et al. The synergistic relationship between estimated GFR and microalbuminuria in predicting long-term progression to ESRD or death in patients with diabetes: results from the Kidney Early Evaluation Program (KEEP). Am J Kidney Dis. 2013;61(4 Suppl 2):S12–23.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Herlitz H, Aurell M, Holm G, et al. Renal degradation of insulin in patients with renal hypertension. Scand J Urol Nephrol. 1983;17:109–13.

    Article  CAS  PubMed  Google Scholar 

  47. Feneberg R, Sparber M, Veldhuis JD, et al. Altered temporal organization of plasma insulin oscillations in chronic renal failure. J Clin Endocrinol Metab. 2002;87:1965–73.

    Article  CAS  PubMed  Google Scholar 

  48. Chimori K, Miyazaki S, Kosaka J, et al. The significance of autonomic neuropathy in the elevation of inactive renin in diabetes mellitus. Clin Exp Hypertens. 1987;9:1–18.

    CAS  Google Scholar 

  49. Oh MS, Carroll HJ, Clemmons JE, et al. A mechanism for hyporeninemic hypoaldosteronism in chronic renal disease. Metabolism. 1974;23:1157–66.

    Article  CAS  PubMed  Google Scholar 

  50. Vander AJ. Direct effects of potassium on renin secretion and renal function. Am J Physiol. 1970;219:455–9.

    CAS  PubMed  Google Scholar 

  51. Sebastian A, Schambelan M, Lindenfeld S, et al. Amelioration of metabolic acidosis with fludrocortisone therapy in hyporeninemic hypoaldosteronism. N Engl J Med. 1977;297:576–83.

    Article  CAS  PubMed  Google Scholar 

  52. Eurich DT, McAlister FA, Blackburn DF, et al. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. Br Med J. 2007;335:497.

    Article  CAS  Google Scholar 

  53. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. J Am Med Assoc. 2007;298:1180–8.

    Article  CAS  Google Scholar 

  54. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. J Am Med Assoc. 2007;298:1189–95.

    Article  CAS  Google Scholar 

  55. DCCT Research Group. Effect of intensive therapy on the development and progression on diabetic nephropathy in the Diabetic Control and Complications Trial. Kidney Int. 1995;47:1703–20.

    Article  Google Scholar 

  56. Reichard P, Nilsson BY, Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med. 1993;329:304–9.

    Article  CAS  PubMed  Google Scholar 

  57. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. 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. J Am Med Assoc. 2003;290:2159–67.

    Article  Google Scholar 

  58. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–53.

    Article  Google Scholar 

  59. 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. Br Med J. 2000;321:405–12.

    Article  CAS  Google Scholar 

  60. Perkovic V, Heerspink HL, Chalmer J, et al. Intensive glucose control improves kidney outcomes in patients with type 2 diabetes. Kidney Int. 2013;83:517–23.

    Article  CAS  PubMed  Google Scholar 

  61. ADVANCE Study Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.

    Article  Google Scholar 

  62. Executive summary: standards of medical care in diabetes – 2013. Diabetes Care. 2013;36(Suppl 1):S4–10.

    Google Scholar 

  63. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. Br Med J. 2000;321:412–9.

    Article  CAS  Google Scholar 

  64. James P, Oparil S, Carter B, et al. 2014 evidence-based guideline for the management of high blood pressure in adults report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507–20.

    Article  CAS  PubMed  Google Scholar 

  65. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 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.

    Article  CAS  PubMed  Google Scholar 

  67. American Diabetes Association. Position Statement. Hypertension management in adults with diabetes. Diabetes Care. 2004;27(S1):S65–7.

    Google Scholar 

  68. 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.

    Article  CAS  PubMed  Google Scholar 

  69. Gerstein H C, Yusuf S, Mann JFE et al for the HOPE investigators Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253–9.

    Google Scholar 

  70. Parving HH, Brenner BM, Cooper ME, 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.

    Article  CAS  PubMed  Google Scholar 

  71. Brenner BM, Cooper ME, de Zeeuw D, et al. RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9.

    Article  CAS  PubMed  Google Scholar 

  72. Lewis EJ, Hunsicker LG, Clarke WR, et al. Collaborative Study Group. 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.

    Article  CAS  PubMed  Google Scholar 

  73. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. Br Med J. 1998;317:713–20.

    Article  Google Scholar 

  74. 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.

    Article  PubMed  Google Scholar 

  75. Casas JP, Chua W, Loukogeorgakis S, et al. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet. 2005;366:2026–33.

    Article  CAS  PubMed  Google Scholar 

  76. Green EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model. J Clin Invest. 1996;98:1063–8.

    Article  Google Scholar 

  77. Sato A, Hayashi K, Naruse M, et al. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension. 2003;41:64–8.

    Article  CAS  PubMed  Google Scholar 

  78. Schjoedt KJ, Anderen S, Rossing P, et al. Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate. Diabetologia. 2004;47:1936–9.

    Article  CAS  PubMed  Google Scholar 

  79. van den Meiracker AH, Man in’t Veld AJ, 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.

    PubMed  Google Scholar 

  80. Hollenberg NK, Osei SY, Lansang MC, et al. Salt intake and non-ACE pathways for intrarenal angiotensin II generation in man. J Renin Angiotensin Aldosterone Syst. 2001;2:14–8.

    Article  CAS  PubMed  Google Scholar 

  81. Weinberg AJ, Zappe DH, Ashton M, et al. Safety and tolerability of high-dose angiotensin receptor blocker therapy in patients with chronic kidney disease: a pilot study. Am J Nephrol. 2004;24:340–5.

    Article  CAS  PubMed  Google Scholar 

  82. Mogensen CE, Neldam S, Tikkanen I, 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. Br Med J. 2000;321:1440–4.

    Article  CAS  Google Scholar 

  83. van den Meiracker AH, Baggen RG, Pauli S, et al. Spironolactone in type 2 diabetic nephropathy: effects on proteinuria, blood pressure and renal function. J Hypertens. 2006;24:2285–92.

    Article  PubMed  CAS  Google Scholar 

  84. Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369:1892–903.

    Article  CAS  PubMed  Google Scholar 

  85. Brem AS, Morris DJ, Gong R. Aldosterone-induced fibrosis in the kidney: questions and controversies. Am J Kidney Dis. 2011;58:471–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mavrakanas T, Gariani K, Martin P, et al. Mineralocorticoid receptor blockade in addition to angiotensin converting enzyme inhibitor or angiotensin II receptor blocker treatment: an emerging paradigm in diabetic nephropathy a systematic review. Eur J Intern Med. 2014;25:173–6.

    Article  CAS  PubMed  Google Scholar 

  87. Hollenberg NK. Aldosterone in the development and progression of renal injury. Kidney Int. 2004;66:1–9.

    Article  CAS  PubMed  Google Scholar 

  88. Schersten B, Thulin T, Kuylenstierna J, et al. Clinical and biochemical effects of spironolactone administered once daily in primary hypertension. Multicenter Sweden study. Hypertension. 1980;2:672–9.

    Article  CAS  PubMed  Google Scholar 

  89. Sato A. The necessity and effectiveness of mineralocorticoid receptor antagonist in the treatment of diabetic nephropathy. Hypertens Res. 2015;38:367–74.

    Article  CAS  PubMed  Google Scholar 

  90. Yano Y, Hoshida Y, Tamaki N, et al. Efficacy of eplerenone added to renin-angiotensin blockade in elderly hypertensive patients: the Jichi-Eplerenone Treatment (JET) study. J Renin Angiotensin Aldosterone Syst. 2011;12:340–7.

    Article  CAS  PubMed  Google Scholar 

  91. Saklayen M, Gyebi L, Tasosa J, Yap J. Effects of additive therapy with spironolactone with on proteinuria in diabetic patients already on ACEI or ARB therapy. J Investig Med. 2008;56:714–9.

    Article  CAS  PubMed  Google Scholar 

  92. Chrysostomou A, Becker G. Spironolactone in addition to ACE inhibition to reduce proteinuria in patients with chronic renal disease. N Engl J Med. 2001;345:925–6.

    Article  CAS  PubMed  Google Scholar 

  93. Epstein M, Williams GH, Weinberger M, et al. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol. 2006;1:940–51.

    Article  CAS  PubMed  Google Scholar 

  94. Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the Randomized Aldactone Evaluation Study (RALES). Circulation. 2000;102:2700–6.

    Article  CAS  PubMed  Google Scholar 

  95. Iraqi W, Rossignol P, Angioi M, et al. Extracellular cardiac matrix biomarkers in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study. Circulation. 2009;119:2471–9.

    Article  CAS  PubMed  Google Scholar 

  96. Parving HH, Persson F, Lewis JB, et al. Aliskerin combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358:2433–46.

    Article  CAS  PubMed  Google Scholar 

  97. Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367:2204–13.

    Article  CAS  PubMed  Google Scholar 

  98. Schrijvers BF, De Vriese AS, Flyvbjerg A. From hyperglycemia to diabetic kidney disease: the role of metabolic, hemodynamic, intracellular factors and growth factors/cytokines. Endocr Rev. 2004;25:971–1010.

    Article  CAS  PubMed  Google Scholar 

  99. Ha H, Yu MR, Choi YJ, Kitamura M, Lee HB. Role of high glucose induced nuclear factor-kappaB activation in monocyte chemoattractant protein-1 expression by mesangial cells. J Am Soc Nephrol. 2002;13:894–902.

    CAS  PubMed  Google Scholar 

  100. Brosius III FC. New insights into the mechanisms of fibrosis and sclerosis in diabetic nephropathy. Rev Endocr Metab Disord. 2008;9:245–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Huang JS, Chuang LY, Guh JY, et al. Antioxidants attenuates high glucose-induced hypertrophic growth renal tubular epithelial cells. Am J Physiol. 2007;293:F1072–82.

    Article  CAS  Google Scholar 

  102. Amiri F, Shaw S, Wang X, Tang J, et al. Angiotensin II activation of the JAK/STAT pathway in mesangial cells is altered by high glucose. Kidney Int. 2002;61:1605–16.

    Article  CAS  PubMed  Google Scholar 

  103. Wang X, Shaw S, Amiri F, et al. Inhibition of the JAK/STAT signaling pathway prevents the high-glucose induced increase in TGF-beta and fibronectin synthesis in mesangial cells. Diabetes. 2002;51:3505–9.

    Article  CAS  PubMed  Google Scholar 

  104. US National Library of Medicine. Clinicaltrials.gov (online). 2014. http://www.clinicaltrials.gov/ct2/show/NCT01683409

  105. Schneider CA, Ferrannini E, Defronzo R, et al. Effect of pioglitazone on cardiovascular outcome in diabetes and chronic kidney disease. J Am Soc Nephrol. 2008;19:182–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Sarafidis PA, Stafylas PC, Georgianos PI, et al. Effect of thiazolidinediones on albuminuria and proteinuria in diabetes: a meta-analysis. Am J Kidney Dis. 2010;55:835–47.

    Article  CAS  PubMed  Google Scholar 

  107. Alter ML, Ott IM, von Websky K, et al. DPP-4 inhibition on top of angiotensin receptor blockade offers a new therapeutic approach for diabetic nephropathy. Kidney Blood Press Res. 2012;36:119–30.

    Article  CAS  PubMed  Google Scholar 

  108. Sakata K, Hayakawa M, Yano Y, et al. Efficacy of alogliptin, a dipeptidyl peptidase-4 inhibitor, on glucose parameters, the activity of the advanced glycation end product (AGE) – receptor for AGE (RAGE) axis and albuminuria in Japanese type 2 diabetes. Diabetes Metab Res Rev. 2013;29:624–30.

    Article  CAS  PubMed  Google Scholar 

  109. Groop PH, Cooper ME, Perkovic V, et al. Linagliptin lowers albuminuria on top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction. Diabetes Care. 2013;36:3460–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Mori H, Okada Y, Arao T, Tanaka Y. Sitagliptin improved albuminuria in patients with type 2 diabetes. J Diabetes Invest. 2014;5:313–9.

    Article  CAS  Google Scholar 

  111. RamachandraRao SP, Zhu Y, Ravasi T, et al. Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol. 2009;20:1765–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Sharma K, Ix JH, Mathew A, Cho M, et al. Pirfenidone for diabetic nephropathy. J Am Soc Nephrol. 2011;22:1144–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Gambaro G, Venturini AP, Noonan DM, et al. Treatment with a glycosaminoglycan formulation amleiorates diabetic nephropathy. Kidney Int. 1994;46:797–806.

    Article  CAS  PubMed  Google Scholar 

  114. Dedov I, Shestakova M, Vorontzov A, Palazzini E. A randomized, controlled study of sulodexide therapy for the treatment of diabetic nephropathy. Nephrol Dial Transplant. 1997;12:2295–300.

    Article  CAS  PubMed  Google Scholar 

  115. Szelanowska M, Poplawska A, Jopdska J, et al. A pilot study of the effect of the glycosaminoglycan sulodexide on microalbuminuria in type I diabetic patients. Curr Med Res Opin. 1997;13(9):539–45.

    Article  CAS  PubMed  Google Scholar 

  116. Solini A, Vergnani L, Ricci F, Crepaldi G. Glycosaminoglycans delay the progression of nephropathy in NIDDM. Diabetes Care. 1997;20(5):819–23.

    Article  CAS  PubMed  Google Scholar 

  117. Gambaro G, Kinalska I, Oksa A, et al. Oral sulodexide reduces albuminuria in microalbuminuric and macroalbuminuric type 1 and type 2 diabetic patients: the Di.N.A.S. randomized trial. J Am Soc Nephrol. 2002;13:615–1625.

    Article  CAS  Google Scholar 

  118. Packham D, Wolfe R, Reutens AT, et al and for the Collaborative Study Group. Sulodexide fails to demonstrate renoprotection in overt type 2 diabetic nephropathy. J Am Soc Nephrol. 2012;23:123–30.

    Google Scholar 

  119. Tuttle KB, Bakris GL, Toto RD, McGill JB, Hu K, Anderson PW. The effect of ruboxistaurin on nephopathy in type 2 diabetes. Diabetes Care. 2005;28:2686–90.

    Article  CAS  PubMed  Google Scholar 

  120. Tuttle KR, McGill JB, Haney DJ, Lin TE, Anderson PW. Kidney outcomes in long-term studies of ruoxistaurin for diabetic eye disease. Clin J Am Soc Nephrol. 2007;2:31–636.

    Article  CAS  Google Scholar 

  121. Gembardt F, Bartuan C, Jarzebka N, et al. The SGLT-2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob/ type 2 diabetic mice with and without hypertension. Am J Physiol Renal Physiol. 2014;307:F317–25.

    Article  CAS  PubMed  Google Scholar 

  122. Terami N, Ogawa D, Tachibana H, et al. Long term treatment with the sodium glucose cotransporter 2 inhibitor, dapagliflozin, ameliorates glucose homeostasis and diabetic nephropathy in db/db mice. PLoS One. 2014;9:e100777.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Cefalu W, Leiter LA, Yoon KH, Niskanen L, Xie J, Balis DA, Canovatchel W, Meininger G. Efficacy and safety of canagliflozin versus glimepiride in patient with type 2 diabetes inadequately controlled with metformin (CATATA-SU): 52 week results from a randomized, double blind, phase 3 non-inferiority trial. Lancet. 2013;382:941–50.

    Article  CAS  PubMed  Google Scholar 

  124. Vlassara H, Striker GE. Dietary restriction of advanced glycation end products in diabetes and diabetic complications. Endocrinol Metab Clin North Am. 2013;42:697–719.

    Article  PubMed  Google Scholar 

  125. Yubero-Serrano EM, Woodward M, Poretsky L, et al. AGE-less Study Group. Effects of sevelamer carbonate on advanced glycation end products and antioxidant/pro-oxidant status in patients with diabetic kidney disease. Clin J Am Soc Nephrol. 2015;10:759–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Fernandez-Fernandez B, Ortiz A, Gomez-Guerrero C, et al. The therapeutic approaches to diabetic nephropathy – beyond RAS. Nat Rev Nephrol. 2014;10:325–46.

    Article  CAS  PubMed  Google Scholar 

  127. Pergola P, Raskin P, Toto R, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med. 2011;365:327–36.

    Article  CAS  PubMed  Google Scholar 

  128. de Zeeuw D, Akizawa T, Agarwal R, et al. Rationale and trial design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON). Am J Nephrol. 2013;37:212–22.

    Article  PubMed  CAS  Google Scholar 

  129. Gonzalez-Parra E, Rojas-Rivera J, Tuñón J, et al. Vitamin D receptor activation and cardiovascular disease. Nephrol Dial Transplant. 2012;27 Suppl 4:iv17–21.

    Article  CAS  PubMed  Google Scholar 

  130. Rojas-Rivera J, De La Piedra C, Ramos A, et al. The expanding spectrum of biological actions of vitamin D. Nephrol Dial Transplant. 2010;25:2850–65.

    Article  CAS  PubMed  Google Scholar 

  131. Sanchez-Nino MD, Bozic M, Córdoba-Lanús E, et al. Beyond proteinuria: VDR activation reduces renal inflammation in experimental diabetic nephropathy. Am J Physiol Renal Physiol. 2012;302:F647–57.

    Article  CAS  PubMed  Google Scholar 

  132. de Zeeuw D, Agarawal R, Amdahl M, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes: a randomized controlled trial. Lancet. 2010;376:1543–51.

    Article  PubMed  CAS  Google Scholar 

  133. Pérez-Gòmez M, Ortiz-Arduan A. Vitamin D and proteinuria: a critical review of molecular bases and clinical experience. Nefrologia. 2013;33:716–26.

    PubMed  Google Scholar 

  134. Kohan DE, Pollock DM. Endothelin antagonists for diabetic and non-diabetic chronic kidney disease. Br J Clin Pharmacol. 2013;76:573–9.

    CAS  PubMed  Google Scholar 

  135. Mann J, Green D, Jamerson K, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol. 2010;21:527–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Coll B. A randomized, multicountry, multicenter, double-blind, parallel, placebo-controlled study of the effects of atrasentan on renal outcomes in subjects with type 2 diabetes and nephropathy. SONAR: Study of Diabetic Nephropathy with Atrasentan. https://clinicaltrials.gov/ct2/show/NCT01858532

Internet Sites Pertaining to Diabetic Nephropathy

Download references

Author information

Authors and Affiliations

  1. Division of Nephrology and Hypertension, Department of Medicine, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Nikolas B. Harbord, James F. Winchester, Elliot Charen, Chiarra Ornillo, Naitik Sheth, Donald Feinfeld & Alan Dubrow

Authors
  1. Nikolas B. Harbord
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James F. Winchester
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elliot Charen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chiarra Ornillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Naitik Sheth
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Donald Feinfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alan Dubrow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James F. Winchester .

Editor information

Editors and Affiliations

  1. Division of Endocrinology, Gerald J. Friedman Diabetes Institute, Lenox Hill Hospital, Hofstra Northwell School of Medicine, Northwell Health, New York, New York, USA

    Leonid Poretsky

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this entry

Cite this entry

Harbord, N.B. et al. (2017). Diabetic Nephropathy. In: Poretsky, L. (eds) Principles of Diabetes Mellitus. Springer, Cham. https://doi.org/10.1007/978-3-319-18741-9_22

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-18741-9_22

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-18740-2

  • Online ISBN: 978-3-319-18741-9

  • eBook Packages: MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation