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Pathophysiology of Diabetic Nephropathy

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Proteinuria: Basic Mechanisms, Pathophysiology and Clinical Relevance

Abstract

Diabetic nephropathy is the leading cause of end stage kidney disease, accounting for approximately 50 % of cases of end stage renal disease. Microalbuminuria is the earliest clinical manifestation of diabetic nephropathy. Microalbuminuria may progress to overt albuminuria, which is a hallmark of irreversible nephropathy and predicts progression of kidney disease. Many of the pathophysiological changes seen in the kidney in diabetic nephropathy result from prolonged hyperglycemia. The podocyte is one of the key targets in diabetic kidney disease and podocyte damage leads to foot process effacement and the development of proteinuria. While angiotensin converting enzyme inhibitors and angiotensin receptor blockers have long been used as the mainstay of treatment for diabetic nephropathy, targeted, effective new therapies are urgently needed.

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Abbreviations

ACE:

Angiotensin-converting enzyme

ACTH:

Adrenocorticotropic hormone

AGEs:

Advanced glycation end products

AKI:

Acute kidney injury

ARBs:

Angiotensin II receptor blockers

ATF6:

Activating transcription factor 6

CKD:

Chronic kidney diseases

CVD:

Cardiovascular disease

DAMPs:

Damage-associated molecular patterns

DKD:

Diabetic kidney disease

DN:

Diabetic nephropathy

eGFR:

Estimated glomerular filtration rate

EMT:

Epithelial-to-mesenchymal transition

ER:

Endoplasmic reticulum

ESRD:

End-stage renal disease

ET-1:

Endothelin Receptor Antagonists

GBM:

Glomerular basement membrane

IRE1:

Inositol requiring enzyme 1

MCR:

Melanocortin receptors

MMPs:

Matrix metalloproteinases

NF-kB:

Nuclear factor Kappa B

PERK:

Protein-kinase-RNA-like ER kinase

RAGE:

Receptors for AGE

RAS:

Renin-angiotensin system

ROS:

Reactive oxygen species

T2DM:

Type 2 diabetes

UAE:

Urinary albumin excretion

α-SMA:

α-Smooth muscle actin

References

  1. Collins AJ, Foley RN, Gilbertson DT, Chen SC. United States Renal Data System public health surveillance of chronic kidney disease and end-stage renal disease. Kidney Int Suppl. 2015;5(1):2–7.

    Article  Google Scholar 

  2. Saran R, Li Y, Robinson B, Ayanian J, Balkrishnan R, Bragg-Gresham J, et al. US Renal Data System 2014 Annual Data Report: epidemiology of kidney disease in the United States. Am J Kidney Dis. 2015;65(6 Suppl 1):A7.

    Article  Google Scholar 

  3. Papale M, Di Paolo S, Magistroni R, Lamacchia O, Di Palma AM, De Mattia A, et al. Urine proteome analysis may allow noninvasive differential diagnosis of diabetic nephropathy. Diabetes Care. 2010;33(11):2409–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tuttle KR, Bakris GL, Bilous RW, Chiang JL, de Boer IH, Goldstein-Fuchs J, et al. Diabetic kidney disease: a report from an ADA Consensus Conference. Am J Kidney Dis. 2014;64(4):510–33.

    Article  PubMed  Google Scholar 

  5. de Boer IH, Rue TC, Hall YN, Heagerty PJ, Weiss NS, Himmelfarb J. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA. 2011;305(24):2532–9.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ninomiya T, Perkovic V, de Galan BE, Zoungas S, Pillai A, Jardine M, et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol. 2009;20(8):1813–21.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Toyama T, Furuichi K, Ninomiya T, Shimizu M, Hara A, Iwata Y, et al. The impacts of albuminuria and low eGFR on the risk of cardiovascular death, all-cause mortality, and renal events in diabetic patients: meta-analysis. PLoS One. 2013;8(8), e71810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Schmieder RE, Schutte R, Schumacher H, Bohm M, Mancia G, Weber MA, et al. Mortality and morbidity in relation to changes in albuminuria, glucose status and systolic blood pressure: an analysis of the ONTARGET and TRANSCEND studies. Diabetologia. 2014;57(10):2019–29.

    Article  CAS  PubMed  Google Scholar 

  9. Tuttle KR, Bakris GL, Bilous RW, Chiang JL, de Boer IH, Goldstein-Fuchs J, et al. Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care. 2014;37(10):2864–83.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Perkins BA, Ficociello LH, Ostrander BE, Silva KH, Weinberg J, Warram JH, et al. Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes. J Am Soc Nephrol. 2007;18(4):1353–61.

    Article  CAS  PubMed  Google Scholar 

  11. Salinero-Fort MA, San Andres-Rebollo FJ, de Burgos-Lunar C, Gomez-Campelo P, Chico-Moraleja RM, Lopez de Andres A, et al. Five-year incidence of chronic kidney disease (stage 3-5) and associated risk factors in a Spanish cohort: the MADIABETES Study. PLoS One. 2015;10(4):e0122030.

    Google Scholar 

  12. National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 update. Am J Kidney Dis. 2012;60(5):850–86.

    Article  Google Scholar 

  13. Berhane AM, Weil EJ, Knowler WC, Nelson RG, Hanson RL. Albuminuria and estimated glomerular filtration rate as predictors of diabetic end-stage renal disease and death. Clin J Am Soc Nephrol. 2011;6(10):2444–51.

    Article  PubMed  PubMed Central  Google Scholar 

  14. de Boer IH, Afkarian M, Rue TC, Cleary PA, Lachin JM, Molitch ME, et al. Renal outcomes in patients with type 1 diabetes and macroalbuminuria. J Am Soc Nephrol. 2014;25(10):2342–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Stanton RC. Clinical challenges in diagnosis and management of diabetic kidney disease. Am J Kidney Dis. 2014;63(2 Suppl 2):S3–21.

    Article  PubMed  Google Scholar 

  16. Gosmanov AR, Gosmanova EO. Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria: an analysis of the DCCT/EDIC cohort. Arch Intern Med. 2011;171(17):1596. author reply 7.

    Article  PubMed  Google Scholar 

  17. Gregg EW, Cheng YJ, Saydah S, Cowie C, Garfield S, Geiss L, et al. Trends in death rates among U.S. adults with and without diabetes between 1997 and 2006: findings from the National Health Interview Survey. Diabetes Care. 2012;35(6):1252–7.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329(20):1456–62.

    Article  CAS  PubMed  Google Scholar 

  19. Ficociello LH, Perkins BA, Roshan B, Weinberg JM, Aschengrau A, Warram JH, et al. Renal hyperfiltration and the development of microalbuminuria in type 1 diabetes. Diabetes Care. 2009;32(5):889–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nelson RG, Knowler WC, Pettitt DJ, Saad MF, Bennett PH. Diabetic kidney disease in Pima Indians. Diabetes Care. 1993;16(1):335–41.

    Article  CAS  PubMed  Google Scholar 

  21. Pavkov ME, Knowler WC, Bennett PH, Looker HC, Krakoff J, Nelson RG. Increasing incidence of proteinuria and declining incidence of end-stage renal disease in diabetic Pima Indians. Kidney Int. 2006;70(10):1840–6.

    Article  CAS  PubMed  Google Scholar 

  22. Robles NR, Villa J, Gallego RH. Non-proteinuric diabetic nephropathy. J Clin Med. 2015;4(9):1761–73.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Chawla V, Roshan B. Non-proteinuric diabetic nephropathy. Curr Diab Rep. 2014;14(10):529.

    Article  PubMed  Google Scholar 

  24. Porrini E, Ruggenenti P, Mogensen CE, Barlovic DP, Praga M, Cruzado JM, et al. Non-proteinuric pathways in loss of renal function in patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2015;3(5):382–91.

    Article  CAS  PubMed  Google Scholar 

  25. MacIsaac RJ, Panagiotopoulos S, McNeil KJ, Smith TJ, Tsalamandris C, Hao H, et al. Is nonalbuminuric renal insufficiency in type 2 diabetes related to an increase in intrarenal vascular disease? Diabetes Care. 2006;29(7):1560–6.

    Article  PubMed  Google Scholar 

  26. MacIsaac RJ, Tsalamandris C, Panagiotopoulos S, Smith TJ, McNeil KJ, Jerums G. Nonalbuminuric renal insufficiency in type 2 diabetes. Diabetes Care. 2004;27(1):195–200.

    Article  PubMed  Google Scholar 

  27. Retnakaran R, Cull CA, Thorne KI, Adler AI, Holman RR, Group US. Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes. 2006;55(6):1832–9.

    Article  CAS  PubMed  Google Scholar 

  28. McClelland AD, Herman-Edelstein M, Komers R, Jha JC, Winbanks CE, Hagiwara S, et al. miR-21 promotes renal fibrosis in diabetic nephropathy by targeting PTEN and SMAD7. Clin Sci (Lond). 2015;129(12):1237–49.

    Article  CAS  Google Scholar 

  29. Herman-Edelstein M, Scherzer P, Tobar A, Levi M, Gafter U. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J Lipid Res. 2014;55(3):561–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang XX, Edelstein MH, Gafter U, Qiu L, Luo Y, Dobrinskikh E, et al. G protein-coupled bile acid receptor TGR5 activation inhibits kidney disease in obesity and diabetes. J Am Soc Nephrol. 2016;27(5):1362–78.

    Article  PubMed  Google Scholar 

  31. Bilous R. Microvascular disease: what does the UKPDS tell us about diabetic nephropathy? Diabet Med. 2008;25 Suppl 2:25–9.

    Article  PubMed  Google Scholar 

  32. 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(4):1036–40.

    Article  CAS  PubMed  Google Scholar 

  33. Katavetin P, Katavetin P. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med. 2009;361(14):1410–1. author reply 1.

    Article  CAS  PubMed  Google Scholar 

  34. Nosadini R, Velussi M, Brocco E, Bruseghin M, Abaterusso C, Saller A, et al. Course of renal function in type 2 diabetic patients with abnormalities of albumin excretion rate. Diabetes. 2000;49(3):476–84.

    Article  CAS  PubMed  Google Scholar 

  35. Perkins BA, Ficociello LH, Roshan B, Warram JH, Krolewski AS. In patients with type 1 diabetes and new-onset microalbuminuria the development of advanced chronic kidney disease may not require progression to proteinuria. Kidney Int. 2010;77(1):57–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, 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(9739):419–30.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Bjornstad P, Cherney DZ, Snell-Bergeon JK, Pyle L, Rewers M, Johnson RJ, et al. Rapid GFR decline is associated with renal hyperfiltration and impaired GFR in adults with Type 1 diabetes. Nephrol Dial Transplant. 2015;30(10):1706–11.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Yang GK, Har RLH, Lytvyn Y, Yip P, Cherney DZI. Renal hyperfiltration is associated with glucose-dependent changes in fractional excretion of sodium in patients with uncomplicated type 1 diabetes. Diabetes Care. 2014;37(10):2774–81.

    Article  CAS  PubMed  Google Scholar 

  39. Thomas MC, Moran JL, Harjutsalo V, Thorn L, Waden J, Saraheimo M, et al. Hyperfiltration in type 1 diabetes: does it exist and does it matter for nephropathy? Diabetologia. 2012;55(5):1505–13.

    Article  CAS  PubMed  Google Scholar 

  40. KDOQI. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis. 2007;49(2 Suppl 2):S12–154.

    Google Scholar 

  41. Tone A, Shikata K, Matsuda M, Usui H, Okada S, Ogawa D, et al. Clinical features of non-diabetic renal diseases in patients with type 2 diabetes. Diabetes Res Clin Pract. 2005;69(3):237–42.

    Article  CAS  PubMed  Google Scholar 

  42. Pham TT, Sim JJ, Kujubu DA, Liu IL, Kumar VA. Prevalence of nondiabetic renal disease in diabetic patients. Am J Nephrol. 2007;27(3):322–8.

    Article  PubMed  Google Scholar 

  43. He F, Xia X, Wu XF, Yu XQ, Huang FX. Diabetic retinopathy in predicting diabetic nephropathy in patients with type 2 diabetes and renal disease: a meta-analysis. Diabetologia. 2013;56(3):457–66.

    Article  CAS  PubMed  Google Scholar 

  44. Chen JLT, Francis J. Pyridoxamine, advanced glycation inhibition, and diabetic nephropathy. J Am Soc Nephrol. 2012;23(1):6–8.

    Article  CAS  PubMed  Google Scholar 

  45. Jha JC, Jandeleit-Dahm KAM, Cooper ME. New insights into the use of biomarkers of diabetic nephropathy. Adv Chronic Kidney Dis. 2014;21(3):318–26.

    Article  PubMed  Google Scholar 

  46. Ben Ameur R, Molina L, Bolvin C, Kifagi C, Jarraya F, Ayadi H, et al. Proteomic approaches for discovering biomarkers of diabetic nephropathy. Nephrol Dial Transplant. 2010;25(9):2866–75.

    Article  CAS  PubMed  Google Scholar 

  47. Hellemons ME, Kerschbaum J, Bakker SJL, Neuwirt H, Mayer B, Mayer G, et al. Validity of biomarkers predicting onset or progression of nephropathy in patients with Type 2 diabetes: a systematic review. Diabet Med. 2012;29(5):567–77.

    Article  CAS  PubMed  Google Scholar 

  48. Mann JF, Rossing P, Wiecek A, Rosivall L, Mark P, Mayer G. Diagnosis and treatment of early renal disease in patients with type 2 diabetes mellitus: what are the clinical needs? Nephrol Dial Transplant. 2015;30 Suppl 4:iv1–5.

    Article  PubMed  Google Scholar 

  49. Badal SS, Danesh FR. New insights into molecular mechanisms of diabetic kidney disease. Am J Kidney Dis. 2014;63(2 Suppl 2):S63–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Brenner BM, Lawler EV, Mackenzie HS. The hyperfiltration theory: a paradigm shift in nephrology. Kidney Int. 1996;49(6):1774–7.

    Article  CAS  PubMed  Google Scholar 

  51. Hostetter TH, Rennke HG, Brenner BM. The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am J Med. 1982;72(3):375–80.

    Article  CAS  PubMed  Google Scholar 

  52. Zatz R, Meyer TW, Rennke HG, Brenner BM. Predominance of hemodynamic rather than metabolic factors in the pathogenesis of diabetic glomerulopathy. Proc Natl Acad Sci U S A. 1985;82(17):5963–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Reubi FC. Glomerular filtration rate, renal blood flow and blood viscosity during and after diabetic coma. Circ Res. 1953;1(5):410–3.

    Article  CAS  PubMed  Google Scholar 

  54. Stalder G, Schmid R. Severe functional disorders of glomerular capillaries and renal hemodynamics in treated diabetes mellitus during childhood. Ann Paediatr. 1959;193:129–38.

    CAS  PubMed  Google Scholar 

  55. Mogensen CE, Andersen MJ. Increased kidney size and glomerular filtration rate in untreated juvenile diabetes: normalization by insulin-treatment. Diabetologia. 1975;11(3):221–4.

    Article  CAS  PubMed  Google Scholar 

  56. Hostetter TH, Troy JL, Brenner BM. Glomerular hemodynamics in experimental diabetes mellitus. Kidney Int. 1981;19(3):410–5.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  58. Premaratne E, Verma S, Ekinci EI, Theverkalam G, Jerums G, MacIsaac RJ. The impact of hyperfiltration on the diabetic kidney. Diabetes Metab. 2015;41(1):5–17.

    Article  CAS  PubMed  Google Scholar 

  59. Harris RC, Haralson MA, Badr KF. Continuous stretch-relaxation in culture alters rat mesangial cell morphology, growth characteristics, and metabolic activity. Lab Invest. 1992;66(5):548–54.

    CAS  PubMed  Google Scholar 

  60. Endlich N, Kress KR, Reiser J, Uttenweiler D, Kriz W, Mundel P, et al. Podocytes respond to mechanical stress in vitro. J Am Soc Nephrol. 2001;12(3):413–22.

    CAS  PubMed  Google Scholar 

  61. Duffield JS. Cellular and molecular mechanisms in kidney fibrosis. J Clin Invest. 2014;124(6):2299–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Essawy M, Soylemezoglu O, Muchaneta-Kubara EC, Shortland J, Brown CB, el Nahas AM. Myofibroblasts and the progression of diabetic nephropathy. Nephrol Dial Transplant. 1997;12(1):43–50.

    Article  CAS  PubMed  Google Scholar 

  63. Barnes JL, Gorin Y. Myofibroblast differentiation during fibrosis: role of NAD(P)H oxidases. Kidney Int. 2011;79(9):944–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Gabbiani G. The biology of the myofibroblast. Kidney Int. 1992;41(3):530–2.

    Article  CAS  PubMed  Google Scholar 

  65. Abrass CK, Spicer D, Raugi GJ. Insulin induces a change in extracellular matrix glycoproteins synthesized by rat mesangial cells in culture. Kidney Int. 1994;46(3):613–20.

    Article  CAS  PubMed  Google Scholar 

  66. Herbach N, Schairer I, Blutke A, Kautz S, Siebert A, Goke B, et al. Diabetic kidney lesions of GIPRdn transgenic mice: podocyte hypertrophy and thickening of the GBM precede glomerular hypertrophy and glomerulosclerosis. Am J Physiol Renal Physiol. 2009;296(4):F819–29.

    Article  CAS  PubMed  Google Scholar 

  67. Holderied A, Romoli S, Eberhard J, Konrad LA, Devarapu SK, Marschner JA, et al. Glomerular parietal epithelial cell activation induces collagen secretion and thickening of Bowman's capsule in diabetes. Lab Invest. 2015;95(3):273–82.

    Article  CAS  PubMed  Google Scholar 

  68. Simonson MS. Phenotypic transitions and fibrosis in diabetic nephropathy. Kidney Int. 2007;71(9):846–54.

    Article  CAS  PubMed  Google Scholar 

  69. Loeffler I, Wolf G. Epithelial-to-mesenchymal transition in diabetic nephropathy: fact or fiction? Cells. 2015;4(4):631–52.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Xu X, Xiao L, Xiao P, Yang S, Chen G, Liu F, et al. A glimpse of matrix metalloproteinases in diabetic nephropathy. Curr Med Chem. 2014;21(28):3244–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Del Prete D, Anglani F, Forino M, Ceol M, Fioretto P, Nosadini R, et al. Down-regulation of glomerular matrix metalloproteinase-2 gene in human NIDDM. Diabetologia. 1997;40(12):1449–54.

    Article  PubMed  Google Scholar 

  72. Romanic AM, Burns-Kurtis CL, Ao Z, Arleth AJ, Ohlstein EH. Upregulated expression of human membrane type-5 matrix metalloproteinase in kidneys from diabetic patients. Am J Physiol Renal Physiol. 2001;281(2):F309–17.

    CAS  PubMed  Google Scholar 

  73. Catania JM, Chen G, Parrish AR. Role of matrix metalloproteinases in renal pathophysiologies. Am J Physiol Renal Physiol. 2007;292(3):F905–11.

    Article  CAS  PubMed  Google Scholar 

  74. 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(20):1315–21.

    Article  CAS  PubMed  Google Scholar 

  75. Cerami A, Vlassara H, Brownlee M. Role of advanced glycosylation products in complications of diabetes. Diabetes Care. 1988;11 Suppl 1:73–9.

    PubMed  Google Scholar 

  76. Yang CW, Vlassara H, Peten EP, He CJ, Striker GE, Striker LJ. Advanced glycation end products up-regulate gene expression found in diabetic glomerular disease. Proc Natl Acad Sci U S A. 1994;91(20):9436–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kirstein M, Aston C, Hintz R, Vlassara H. Receptor-specific induction of insulin-like growth factor I in human monocytes by advanced glycosylation end product-modified proteins. J Clin Invest. 1992;90(2):439–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Vlassara H. The AGE-receptor in the pathogenesis of diabetic complications. Diabetes Metab Res Rev. 2001;17(6):436–43.

    Article  CAS  PubMed  Google Scholar 

  79. Nowotny K, Jung T, Hohn A, Weber D, Grune T. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules. 2015;5(1):194–222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Abel M, Ritthaler U, Zhang Y, Deng Y, Schmidt AM, Greten J, et al. Expression of receptors for advanced glycosylated end-products in renal disease. Nephrol Dial Transplant. 1995;10(9):1662–7.

    CAS  PubMed  Google Scholar 

  81. Tanji N, Markowitz GS, Fu C, Kislinger T, Taguchi A, Pischetsrieder M, et al. Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. J Am Soc Nephrol. 2000;11(9):1656–66.

    CAS  PubMed  Google Scholar 

  82. Wendt TM, Tanji N, Guo J, Kislinger TR, Qu W, Lu Y, et al. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol. 2003;162(4):1123–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bierhaus A, Nawroth PP. Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications. Diabetologia. 2009;52(11):2251–63.

    Article  CAS  PubMed  Google Scholar 

  84. Kierdorf K, Fritz G. RAGE regulation and signaling in inflammation and beyond. J Leukoc Biol. 2013;94(1):55–68.

    Article  CAS  PubMed  Google Scholar 

  85. Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res. 2004;63(4):582–92.

    Article  CAS  PubMed  Google Scholar 

  86. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404(6779):787–90.

    Article  CAS  PubMed  Google Scholar 

  87. Ha H, Hwang IA, Park JH, Lee HB. Role of reactive oxygen species in the pathogenesis of diabetic nephropathy. Diabetes Res Clin Pract. 2008;82 Suppl 1:S42–5.

    Article  CAS  PubMed  Google Scholar 

  88. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54(6):1615–25.

    Article  CAS  PubMed  Google Scholar 

  89. Sharma K. Mitochondrial hormesis and diabetic complications. Diabetes. 2015;64(3):663–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kumar A, Yerra VG, Malik RA. Comment on Sharma. Mitochondrial hormesis and diabetic complications. Diabetes. 2015;64:663–72; Diabetes. 2015;64(9):e32–3; discussion e4.

    Google Scholar 

  91. Hasegawa G, Nakano K, Sawada M, Uno K, Shibayama Y, Ienaga K, et al. Possible role of tumor necrosis factor and interleukin-1 in the development of diabetic nephropathy. Kidney Int. 1991;40(6):1007–12.

    Article  CAS  PubMed  Google Scholar 

  92. Elmarakby AA, Sullivan JC. Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. Cardiovasc Ther. 2012;30(1):49–59.

    Article  CAS  PubMed  Google Scholar 

  93. Garcia-Garcia PM, Getino-Melian MA, Dominguez-Pimentel V, Navarro-Gonzalez JF. Inflammation in diabetic kidney disease. World J Diabetes. 2014;5(4):431–43.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Donate-Correa J, Martin-Nunez E, Muros-de-Fuentes M, Mora-Fernandez C, Navarro-Gonzalez JF. Inflammatory cytokines in diabetic nephropathy. J Diabetes Res. 2015;2015:948417.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Navarro JF, Mora-Fernandez C. The role of TNF-alpha in diabetic nephropathy: pathogenic and therapeutic implications. Cytokine Growth Factor Rev. 2006;17(6):441–50.

    Article  CAS  PubMed  Google Scholar 

  96. Dadras F, Khoshjou F. Endoplasmic reticulum and its role in diabetic nephropathy. Iran J Kidney Dis. 2015;9(4):267–72.

    PubMed  Google Scholar 

  97. Zhuang A, Forbes JM. Stress in the kidney is the road to pERdition: is endoplasmic reticulum stress a pathogenic mediator of diabetic nephropathy? J Endocrinol. 2014;222(3):R97–111.

    Article  CAS  PubMed  Google Scholar 

  98. Chung AC, Yu X, Lan HY. MicroRNA and nephropathy: emerging concepts. Int J Nephrol Renovasc Dis. 2013;6:169–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Hou J, Zhao D. MicroRNA regulation in renal pathophysiology. Int J Mol Sci. 2013;14(7):13078–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Wei Q, Mi QS, Dong Z. The regulation and function of microRNAs in kidney diseases. IUBMB Life. 2013;65(7):602–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kato M, Zhang J, Wang M, Lanting L, Yuan H, Rossi JJ, et al. MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci U S A. 2007;104(9):3432–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wang Q, Wang Y, Minto AW, Wang J, Shi Q, Li X, et al. MicroRNA-377 is up-regulated and can lead to increased fibronectin production in diabetic nephropathy. FASEB J. 2008;22(12):4126–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Bijkerk R, Duijs JM, Khairoun M, Ter Horst CJ, van der Pol P, Mallat MJ, et al. Circulating microRNAs associate with diabetic nephropathy and systemic microvascular damage and normalize after simultaneous pancreas-kidney transplantation. Am J Transplant. 2015;15(4):1081–90.

    Article  CAS  PubMed  Google Scholar 

  104. Patrakka J, Tryggvason K. New insights into the role of podocytes in proteinuria. Nat Rev Nephrol. 2009;5(8):463–8.

    Article  CAS  PubMed  Google Scholar 

  105. Huber TB, Benzing T. The slit diaphragm: a signaling platform to regulate podocyte function. Curr Opin Nephrol Hypertens. 2005;14(3):211–6.

    Article  PubMed  Google Scholar 

  106. Benzing T. Signaling at the slit diaphragm. J Am Soc Nephrol. 2004;15(6):1382–91.

    Article  PubMed  Google Scholar 

  107. Maezawa Y, Takemoto M, Yokote K. Cell biology of diabetic nephropathy: roles of endothelial cells, tubulointerstitial cells and podocytes. J Diabetes Investig. 2015;6(1):3–15.

    Article  PubMed  Google Scholar 

  108. Anil Kumar P, Welsh GI, Saleem MA, Menon RK. Molecular and cellular events mediating glomerular podocyte dysfunction and depletion in diabetes mellitus. Front Endocrinol (Lausanne). 2014;5:151.

    Google Scholar 

  109. Jefferson JA, Alpers CE, Shankland SJ. Podocyte biology for the bedside. Am J Kidney Dis. 2011;58(5):835–45.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Teng B, Duong M, Tossidou I, Yu X, Schiffer M. Role of protein kinase C in podocytes and development of glomerular damage in diabetic nephropathy. Front Endocrinol (Lausanne). 2014;5:179.

    Google Scholar 

  111. Diez-Sampedro A, Lenz O, Fornoni A. Podocytopathy in diabetes: a metabolic and endocrine disorder. Am J Kidney Dis. 2011;58(4):637–46.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Fu J, Lee K, Chuang PY, Liu Z, He JC. Glomerular endothelial cell injury and cross talk in diabetic kidney disease. Am J Physiol Renal Physiol. 2015;308(4):F287–97.

    Article  CAS  PubMed  Google Scholar 

  113. Haraldsson B, Nystrom J, Deen WM. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev. 2008;88(2):451–87.

    Article  CAS  PubMed  Google Scholar 

  114. de Boer IH, Group DER. Kidney disease and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care. 2014;37(1):24–30.

    Article  PubMed  CAS  Google Scholar 

  115. Thompson A. Proteinuria as a surrogate end point--more data are needed. Nat Rev Nephrol. 2012;8(5):306–9.

    Article  CAS  PubMed  Google Scholar 

  116. Tonna S, El-Osta A, Cooper ME, Tikellis C. Metabolic memory and diabetic nephropathy: potential role for epigenetic mechanisms. Nat Rev Nephrol. 2010;6(6):332–41.

    Article  CAS  PubMed  Google Scholar 

  117. Group AC, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560–72.

    Article  Google Scholar 

  118. Gerstein HC, Miller ME, Ismail-Beigi F, Largay J, McDonald C, Lochnan HA, et al. Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trial. Lancet. 2014;384(9958):1936–41.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129–39.

    Article  CAS  PubMed  Google Scholar 

  120. Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010;340:b4909.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Wheeler DC, Becker GJ. Summary of KDIGO guideline. What do we really know about management of blood pressure in patients with chronic kidney disease? Kidney Int. 2013;83(3):377–83.

    Article  CAS  PubMed  Google Scholar 

  122. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, 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(5):507–20.

    Article  CAS  PubMed  Google Scholar 

  123. Taler SJ, Agarwal R, Bakris GL, Flynn JT, Nilsson PM, Rahman M, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for management of blood pressure in CKD. Am J Kidney Dis. 2013;62(2):201–13.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Patil MR, Mishra A, Jain N, Gutch M, Tewari R. Weight loss for reduction of proteinuria in diabetic nephropathy: comparison with angiotensin-converting enzyme inhibitor therapy. Indian J Nephrol. 2013;23(2):108–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Friedman AN, Wolfe B. Is bariatric surgery an effective treatment for type II diabetic kidney disease? Clin J Am Soc Nephrol. 2016;11(3):528–35.

    Article  PubMed  Google Scholar 

  126. Otoda T, Kanasaki K, Koya D. Low-protein diet for diabetic nephropathy. Curr Diab Rep. 2014;14(9):523.

    Article  PubMed  CAS  Google Scholar 

  127. Nezu U, Kamiyama H, Kondo Y, Sakuma M, Morimoto T, Ueda S. Effect of low-protein diet on kidney function in diabetic nephropathy: meta-analysis of randomised controlled trials. BMJ Open. 2013;3(5).

    Google Scholar 

  128. Pan Y, Guo LL, Jin HM. Low-protein diet for diabetic nephropathy: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2008;88(3):660–6.

    CAS  PubMed  Google Scholar 

  129. Viberti GC, Walker J, Dodds R. Low-protein diet and progression of renal disease in diabetic nephropathy. Lancet. 1990;335(8688):550–1.

    Article  CAS  PubMed  Google Scholar 

  130. Slinin Y, Ishani A, Rector T, Fitzgerald P, MacDonald R, Tacklind J, et al. Management of hyperglycemia, dyslipidemia, and albuminuria in patients with diabetes and CKD: a systematic review for a KDOQI clinical practice guideline. Am J Kidney Dis. 2012;60(5):747–69.

    Article  PubMed  Google Scholar 

  131. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377(9784):2181–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Tolonen N, Forsblom C, Makinen V-P, Harjutsalo V, Gordin D, Feodoroff M, et al. Different lipid variables predict incident coronary artery disease in patients with type 1 diabetes with or without diabetic nephropathy: the FinnDiane study. Diabetes Care. 2014;37(8):2374–82.

    Article  CAS  PubMed  Google Scholar 

  133. Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int. 2001;59(1):260–9.

    Article  CAS  PubMed  Google Scholar 

  134. Allison SJ. Acute kidney injury: mechanism of AKI sensitivity in diabetic nephropathy. Nat Rev Nephrol. 2014;10(9):484.

    Google Scholar 

  135. Bedford M, Farmer CK, Irving J, Stevens PE. Acute kidney injury: an acceptable risk of treatment with renin-angiotensin system blockade in primary care? Can J Kidney Health Dis. 2015;2:14.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Onuigbo MAC. Can ACE, inhibitors and angiotensin receptor blockers be detrimental in CKD patients? Nephron Clin Pract. 2011;118(4):c407–19.

    Article  CAS  PubMed  Google Scholar 

  137. Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med. 1996;334(15):939–45.

    Article  CAS  PubMed  Google Scholar 

  138. Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R, Remuzzi G. Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). Ramipril Efficacy in Nephropathy. Lancet. 1998;352(9136):1252–6.

    Article  CAS  PubMed  Google Scholar 

  139. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861–9.

    Article  CAS  PubMed  Google Scholar 

  140. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, 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(12):851–60.

    Article  CAS  PubMed  Google Scholar 

  141. Kalaitzidis RG, Bakris GL. The current state of RAAS blockade in the treatment of hypertension and proteinuria. Curr Cardiol Rep. 2009;11(6):436–42.

    Article  PubMed  Google Scholar 

  142. Johnson SA, Spurney RF. Twenty years after ACEIs and ARBs: emerging treatment strategies for diabetic nephropathy. Am J Physiol Renal Physiol. 2015;309(10):F807–20.

    CAS  PubMed  Google Scholar 

  143. Mann JFE, Anderson C, Gao P, Gerstein HC, Boehm M, Ryden L, et al. Dual inhibition of the renin-angiotensin system in high-risk diabetes and risk for stroke and other outcomes: results of the ONTARGET trial. J Hypertens. 2013;31(2):414–21.

    Article  CAS  PubMed  Google Scholar 

  144. Tobe SW, Clase CM, Gao P, McQueen M, Grosshennig A, Wang X, et al. Cardiovascular and renal outcomes with telmisartan, ramipril, or both in people at high renal risk: results from the ONTARGET and TRANSCEND studies. Circulation. 2011;123(10):1098–107.

    Article  CAS  PubMed  Google Scholar 

  145. Mann JFE, 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.

    Article  CAS  PubMed  Google Scholar 

  146. El-Haddad B, Reule S, Drawz PE. Dual renin-angiotensin-aldosterone system inhibition for the treatment of diabetic kidney disease: adverse effects and unfulfilled promise. Curr Diab Rep. 2015;15(10):640.

    Article  CAS  Google Scholar 

  147. Chen SS, Seliger SL, Fried LF. Complete inhibition of the renin-angiotensin-aldosterone system; where do we stand? Curr Opin Nephrol Hypertens. 2014;23(5):449–55.

    Article  CAS  PubMed  Google Scholar 

  148. Rutkowski B, Tylicki L. Nephroprotective action of renin-angiotensin-aldosterone system blockade in chronic kidney disease patients: the landscape after ALTITUDE and VA NEPHRON-D trails. J Ren Nutr. 2015;25(2):194–200.

    Article  CAS  PubMed  Google Scholar 

  149. 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.

    Article  CAS  PubMed  Google Scholar 

  150. Mavrakanas TA, Gariani K, Martin PY. 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(2):173–6.

    Article  CAS  PubMed  Google Scholar 

  151. Esteghamati A, Noshad S, Jarrah S, Mousavizadeh M, Khoee SH, Nakhjavani M. Long-term effects of addition of mineralocorticoid receptor antagonist to angiotensin II receptor blocker in patients with diabetic nephropathy: a randomized clinical trial. Nephrol Dial Transplant. 2013;28(11):2823–33.

    Article  CAS  PubMed  Google Scholar 

  152. Bakris GL, Agarwal R, Chan JC, Cooper ME, Gansevoort RT, Haller H, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA. 2015;314(9):884–94.

    Article  CAS  PubMed  Google Scholar 

  153. Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med. 2011;365(4):327–36.

    Article  CAS  PubMed  Google Scholar 

  154. Chin MP, Reisman SA, Bakris GL, O'Grady M, Linde PG, McCullough PA, et al. Mechanisms contributing to adverse cardiovascular events in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl. Am J Nephrol. 2014;39(6):499–508.

    Article  CAS  PubMed  Google Scholar 

  155. de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013;369(26):2492–503.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Harcourt BE, Sourris KC, Coughlan MT, Walker KZ, Dougherty SL, Andrikopoulos S, et al. Targeted reduction of advanced glycation improves renal function in obesity. Kidney Int. 2011;80(2):190–8.

    Article  CAS  PubMed  Google Scholar 

  157. He C, Sabol J, Mitsuhashi T, Vlassara H. Dietary glycotoxins: inhibition of reactive products by aminoguanidine facilitates renal clearance and reduces tissue sequestration. Diabetes. 1999;48(6):1308–15.

    Article  CAS  PubMed  Google Scholar 

  158. Freedman BI, Wuerth JP, Cartwright K, Bain RP, Dippe S, Hershon 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(5):493–510.

    Article  CAS  PubMed  Google Scholar 

  159. Unoki-Kubota H, Yamagishi S-i, Takeuchi M, Bujo H, Saito Y. Pyridoxamine, an inhibitor of advanced glycation end product (AGE) formation ameliorates insulin resistance in obese, type 2 diabetic mice. Protein Pept Lett. 2010;17(9):1177–81.

    Article  CAS  PubMed  Google Scholar 

  160. Proceedings of a conference on insulin pump therapy in diabetes. Multicenter study of effect on microvascular disease. Introduction. The Kroc Collaborative Study Group. Diabetes. 1985;34(Suppl 3):1–4.

    Google Scholar 

  161. Lewis EJ, Greene T, Spitalewiz S, Blumenthal S, Berl T, Hunsicker LG, et al. Pyridorin in type 2 diabetic nephropathy. J Am Soc Nephrol. 2012;23(1):131–6.

    Article  CAS  PubMed  Google Scholar 

  162. Klaus G. Renoprotection with vitamin D: specific for diabetic nephropathy? Kidney Int. 2008;73(2):141–3.

    Article  CAS  PubMed  Google Scholar 

  163. Chokhandre MK, Mahmoud MI, Hakami T, Jafer M, Inamdar AS. Vitamin D & its analogues in type 2 diabetic nephropathy: a systematic review. J Diabetes Metab Disord. 2015;14:58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Derakhshanian H, Shab-Bidar S, Speakman JR, Nadimi H, Djafarian K. Vitamin D and diabetic nephropathy: a systematic review and meta-analysis. Nutrition. 2015;31(10):1189–94.

    Article  CAS  PubMed  Google Scholar 

  165. Tumlin JA, Galphin CM, Rovin BH. Advanced diabetic nephropathy with nephrotic range proteinuria: a pilot study of the long-term efficacy of subcutaneous ACTH gel on proteinuria, progression of CKD, and urinary levels of VEGF and MCP-1. J Diabetes Res. 2013;2013:489869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Sharma K, Ix JH, Mathew AV, Cho M, Pflueger A, Dunn SR, et al. Pirfenidone for diabetic nephropathy. J Am Soc Nephrol. 2011;22(6):1144–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Mann JF, Green D, Jamerson K, Ruilope LM, Kuranoff SJ, Littke T, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol. 2010;21(3):527–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Parvanova A, van der Meer IM, Iliev I, Perna A, Gaspari F, Trevisan R, et al. Effect on blood pressure of combined inhibition of endothelin-converting enzyme and neutral endopeptidase with daglutril in patients with type 2 diabetes who have albuminuria: a randomised, crossover, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2013;1(1):19–27.

    Article  CAS  PubMed  Google Scholar 

  169. Navarro JF, Mora C, Muros M, Garcia J. Additive antiproteinuric effect of pentoxifylline in patients with type 2 diabetes under angiotensin II receptor blockade: a short-term, randomized, controlled trial. J Am Soc Nephrol. 2005;16(7):2119–26.

    Article  CAS  PubMed  Google Scholar 

  170. Navarro-Gonzalez JF, Mora-Fernandez C, Muros de Fuentes M, Chahin J, Mendez ML, Gallego E, et al. Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: the PREDIAN trial. J Am Soc Nephrol. 2015;26(1):220–9.

    Google Scholar 

  171. Zhu H, Chen X, Cai G, Zheng Y, Liu M, Liu W, et al. Telmisartan combined with probucol effectively reduces urinary protein in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, multi-center clinical study. J Diabetes. 2015.

    Google Scholar 

  172. Maahs DM, Caramori L, Cherney DZ, Galecki AT, Gao C, Jalal D, et al. Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study. Curr Diab Rep. 2013;13(4):550–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Doria A, Krolewski AS. Diabetes: lowering serum uric acid levels to prevent kidney failure. Nat Rev Nephrol. 2011;7(9):495–6.

    Article  CAS  PubMed  Google Scholar 

  174. Liu P, Chen Y, Wang B, Zhang F, Wang D, Wang Y. Allopurinol treatment improves renal function in patients with type 2 diabetes and asymptomatic hyperuricemia: 3-year randomized parallel-controlled study. Clin Endocrinol (Oxf). 2015;83(4):475–82.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Felsenstein Medical Research Center and Department of Nephrology and Hypertension, Rabin Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Michal Herman-Edelstein

  2. Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    Sonia Q. Doi

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Correspondence to Michal Herman-Edelstein .

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  1. Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA

    Judith Blaine

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Herman-Edelstein, M., Doi, S.Q. (2016). Pathophysiology of Diabetic Nephropathy. In: Blaine, J. (eds) Proteinuria: Basic Mechanisms, Pathophysiology and Clinical Relevance. Springer, Cham. https://doi.org/10.1007/978-3-319-43359-2_4

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