Concepts in Diabetic Nephropathy: From Pathophysiology to Treatment

Main Article Content

Mustafa Kinaan
Hanford Yau
Suzanne Quinn Martinez
Pran Kar

Keywords

Chronic kidney disease, Diabetes, Diabetic complications, Diabetic nephropathy, Microalbuminuria.

Abstract

Since the 1930s when Kimmelstiel and Wilson first described the classic nodular glomerulosclerosis lesions in diabetic kidneys, nephropathy has been recognized as a major and common complication of diabetes. Nearly 40% of diabetics around the world have microalbuminuria, a marker of progression to chronic kidney disease (CKD). Diabetic kidney disease (DKD) is also considered a leading cause of CKD worldwide. Given the significant morbidity, mortality, and health-care burden, several clinical and scientific societies continue to seek a better understanding of this disease. Screening for microalbuminuria and controlling hyperglycemia remain the pillars for the prevention of diabetic nephropathy. However, evidence from multiple studies suggests that controlling DKD is more challenging. Some studies suggest that there is variability in the incidence of renal complications among patients despite comparable hyperglycemic control. Therefore, there has been great interest in studying the inherent, renal protective role of the different antihyperglycemic agents. This review will shed light on the pathophysiology, screening, and diagnosis of DKD. It will also discuss the treatment and prevention of diabetic nephropathy, with a specific focus on comparing the mechanisms, safety profiles, and efficacy of the different antihyperglycemic medications.

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References

1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care. 2004 May;27(5):1047–53. http://dx.doi.org/10.2337/diacare.27.5.1047
2. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract. 2014 Feb;103(2):137–49. http://dx.doi.org/10.1016/j.diabres.2013.11.002
3. Boyle JP, Honeycutt AA, Narayan KM, Hoerger TJ, Geiss LS, Chen H, et al. Projection of diabetes burden through 2050: Impact of changing demography and disease prevalence in the U.S. Diabetes Care. 2001 Nov;24(11):1936–40. http://dx.doi.org/10.2337/diacare.24.11.1936
4. Bethesda M. US renal data system: USRDS 2015 annual data report [Internet]. The National Institute of Diabetes and Digestive and Kidney Diseases. 2015 [cited 2016 Nov 17]. Available from: https://www.usrds.org/2015/view/Default.aspx
5. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. The Diabetes Control and Complications (DCCT) Research Group. Kidney Int. 1995 Jun;47(6):1703–20. http://dx.doi.org/10.1038/ki.1995.236
6. Freedman BI, Spray BJ, Tuttle AB, Buckalew VM Jr. The familial risk of end-stage renal disease in African Americans. Am J Kidney Dis. 1993 Apr;21(4):387–93. http://dx.doi.org/10.1016/S0272-6386(12)80266-6
7. Stanton RC. Clinical challenges in diagnosis and management of diabetic kidney disease. Am J Kidney Dis. 2014 Feb;63(2 Suppl 2):S3–21. http://dx.doi.org/10.1053/j.ajkd.2013.10.050
8. 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 Nov;70(10):1840–6. http://dx.doi.org/10.1038/sj.ki.5001882
9. Wu AY, Kong NC, de Leon FA, Pan CY, Tai TY, Yeung VT, et al. An alarmingly high prevalence of diabetic nephropathy in Asian type 2 diabetic patients: The MicroAlbuminuria Prevalence (MAP) Study. Diabetologia. 2005 Jan;48(1):17–26. http://dx.doi.org/10.1007/s00125-004-1599-9
10. Freedman BI, Volkova NV, Satko SG, Krisher J, Jurkovitz C, Soucie JM, et al. Population-based screening for family history of end-stage renal disease among incident dialysis patients. Am J Nephrol. 2005 Nov–Dec;25(6):529–35. http://dx.doi.org/10.1159/000088491
11. McClellan W, Speckman R, McClure L, Howard V, Campbell RC, Cushman M, et al. Prevalence and characteristics of a family history of end-stage renal disease among adults in the United States population: Reasons for Geographic and Racial Differences in Stroke (REGARDS) renal cohort study. J Am Soc Nephrol. 2007 Apr;18(4):1344–52. http://dx.doi.org/10.1681/ASN.2006090952
12. Bohlender JM, Franke S, Stein G, Wolf G. Advanced glycation end products and the kidney. Am J Physiol Renal Physiol. 2005 Oct;289(4):F645–59. http://dx.doi.org/10.1152/ajprenal.00398.2004
13. Wautier JL, Zoukourian C, Chappey O, Wautier MP, Guillausseau PJ, Cao R, et al. Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats. J Clin Invest. 1996 Jan 1;97(1):238–43. http://dx.doi.org/10.1172/JCI118397
14. Tan AL, Forbes JM, Cooper ME. AGE, RAGE, and ROS in diabetic nephropathy. Semin Nephrol. 2007 Mar;27(2):130–43. http://dx.doi.org/10.1016/j.semnephrol.2007.01.006
15. Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy. J Am Soc Nephrol. 2005 Mar;16 Suppl 1:S30–3. http://dx.doi.org/10.1681/ASN.2004110970
16. Miura J, Yamagishi Si, Uchigata Y, Takeuchi M, Yamamoto H, Makita Z, et al. Serum levels of non-carboxymethyllysine advanced glycation endproducts are correlated to severity of microvascular complications in patients with type 1 diabetes. J Diabetes Complications. 2003 Jan–Feb;17(1):16–21. http://dx.doi.org/10.1016/S1056-8727(02)00183-6
17. Wautier MP, Massin P, Guillausseau PJ, Huijberts M, Levy B, Boulanger E, et al. N(carboxymethyl)lysine as a biomarker for microvascular complications in type 2 diabetic patients. Diabetes Metab. 2003 Feb;29(1):44–52. http://dx.doi.org/10.1016/S1262-3636(07)70006-X
18. Suzuki D, Miyata T, Saotome N, Horie K, Inagi R, Yasuda Y, et al. Immunohistochemical evidence for an increased oxidative stress and carbonyl modification of proteins in diabetic glomerular lesions. J Am Soc Nephrol. 1999 Apr;10(4):822–32.
19. Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes. 2005 Dec;54(12):3427–34. http://dx.doi.org/10.2337/diabetes.54.12.3427
20. Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu Rev Med. 2015;66:255–70. http://dx.doi.org/10.1146/annurev-med-051013-110046
21. Gnudi L, Coward RJ, Long DA. Diabetic nephropathy: Perspective on novel molecular mechanisms. Trends Endocrinol Metab. 2016 Nov;27(11):820–30. http://dx.doi.org/10.1016/j.tem.2016.07.002
22. Fujita H, Morii T, Fujishima H, Sato T, Shimizu T, Hosoba M, et al. The protective roles of GLP-1R signaling in diabetic nephropathy: Possible mechanism and therapeutic potential. Kidney Int. 2014 Mar;85(3):579–89. http://dx.doi.org/10.1038/ki.2013.427
23. Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: Diagnosis, prevention, and treatment. Diabetes Care. 2005 Jan;28(1):164–76. http://dx.doi.org/10.2337/diacare.28.1.164
24. Bakker AJ. Detection of microalbuminuria. Receiver operating characteristic curve analysis favors albumin-to-creatinine ratio over albumin concentration. Diabetes Care. 1999 Feb;22(2):307–13. http://dx.doi.org/10.2337/diacare.22.2.307
25. Zelmanovitz T, Gross JL, Oliveira JR, Paggi A, Tatsch M, Azevedo MJ. The receiver operating characteristics curve in the evaluation of a random urine specimen as a screening test for diabetic nephropathy. Diabetes Care. 1997 Apr;20(4):516–9. http://dx.doi.org/10.2337/diacare.20.4.516
26. Mathiesen ER, Rønn B, Storm B, Foght H, Deckert T. The natural course of microalbuminuria in insulin-dependent diabetes: A 10-year prospective study. Diabet Med. 1995 Jun;12(6):482–7. http://dx.doi.org/10.1111/j.1464-5491.1995.tb00528.x
27. Mogensen CE, Vestbo E, Poulsen PL, Christiansen C, Damsgaard EM, Eiskjaer H, et al. Microalbuminuria and potential confounders. A review and some observations on variability of urinary albumin excretion. Diabetes Care. 1995 Apr;18(4):572–81. http://dx.doi.org/10.2337/diacare.18.4.572
28. Kramer HJ, Nguyen QD, Curhan G, Hsu CY. Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA. 2003 Jun 25;289(24):3273–7. http://dx.doi.org/10.1001/jama.289.24.3273
29. Caramori ML, Fioretto P, Mauer M. The need for early predictors of diabetic nephropathy risk: Is albumin excretion rate sufficient? Diabetes. 2000 Sep;49(9):1399–408. http://dx.doi.org/10.2337/diabetes.49.9.1399
30. Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, et al. National Kidney Foundation. National Kidney Foundation practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Ann Intern Med. 2003 Jul 15;139(2):137–47. Erratum in: Ann Intern Med. 2003 Oct 7;139(7):605. http://dx.doi.org/10.7326/0003-4819-139-2-200307150-00013
31. Orchard TJ, Dorman JS, Maser RE, Becker DJ, Drash AL, Ellis D, et al. Prevalence of complications in IDDM by sex and duration. Pittsburgh Epidemiology of Diabetes Complications Study II. Diabetes. 1990 Sep;39(9):1116–24. http://dx.doi.org/10.2337/diab.39.9.1116
32. National Kidney Foundation, Kidney Disease Outcomes Quality Initiative (KDOQI). KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease [Internet]. 2007 [cited 2016 Nov 17]. Available from: http://www2.kidney.org/professionals/KDOQI/guideline_diabetes
33. Tervaert TW, Mooyaart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB, et al. Renal Pathology Society. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol. 2010 Apr;21(4):556–63. http://dx.doi.org/10.1681/ASN.2010010010
34. 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. JAMA. 2003 Oct 22;290(16):2159–67. http://dx.doi.org/10.1001/jama.290.16.2159
35. DCCT/EDIC Research Group, de Boer IH, Sun W, Cleary PA, Lachin JM, Molitch ME, et al. Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes. N Engl J Med. 2011 Dec 22;365(25):2366–76. http://dx.doi.org/10.1056/NEJMoa1111732
36. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: A randomized prospective 6-year study. Diabetes Res Clin Pract. 1995 May;28(2):103–17. http://dx.doi.org/10.1016/0168-8227(95)01064-K
37. 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 Sep 12;352(9131):837–53. http://dx.doi.org/10.1016/S0140-6736(98)07019-6
38. Levin SR, Coburn JW, Abraira C, Henderson WG, Colwell JA, Emanuele NV, et al. Effect of intensive glycemic control on microalbuminuria in type 2 diabetes. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes Feasibility Trial Investigators. Diabetes Care. 2000 Oct;23(10):1478–85. http://dx.doi.org/10.2337/diacare.23.10.1478
39. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009 Jan 8;360(2):129–39. http://dx.doi.org/10.1056/NEJMoa0808431
40. ADVANCE Collaborative Group., Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2560–72. http://dx.doi.org/10.1056/NEJMoa0802987
41. Zoungas S, Chalmers J, Neal B, Billot L, Li Q, Hirakawa Y, et al. ADVANCE-ON Collaborative Group. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014 Oct 9;371(15):1392–406. http://dx.doi.org/10.1056/NEJMoa1407963
42. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, et al. ACCORD trial group. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: An analysis of the ACCORD randomised trial. Lancet. 2010 Aug 7;376(9739):419–30. http://dx.doi.org/10.1016/S0140-6736(10)60576-4
43. 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 Oct;37(10):2864–83. http://dx.doi.org/10.2337/dc14-1296
44. Kinaan M, Ding H, Triggle CR. Metformin: An old drug for the treatment of diabetes but a new drug for the protection of the endothelium. Med Princ Pract. 2015;24(5):401–15. http://dx.doi.org/10.1159/000381643
45. Lalau JD, Arnouts P, Sharif A, De Broe ME. Metformin and other antidiabetic agents in renal failure patients. Kidney Int. 2015 Feb;87(2):308–22. http://dx.doi.org/10.1038/ki.2014.19
46. Heaf J. Metformin in chronic kidney disease: Time for a rethink. Perit Dial Int. 2014 Jun;34(4):353–7. http://dx.doi.org/10.3747/pdi.2013.00344
47. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: Systematic review and meta-analysis. Arch Intern Med. 2003 Nov 24;163(21):2594–602. http://dx.doi.org/10.1001/archinte.163.21.2594
48. Ashcroft FM. Mechanisms of the glycaemic effects of sulfonylureas. Horm Metab Res. 1996 Sep;28(9):456–63. http://dx.doi.org/10.1055/s-2007-979837
49. Roussel R, Lorraine J, Rodriguez A, Salaun-Martin C. Overview of data concerning the safe use of antihyperglycemic medications in type 2 diabetes mellitus and chronic kidney disease. Adv Ther. 2015 Nov;32(11):1029–64. http://dx.doi.org/10.1007/s12325-015-0261-x
50. Yki-Järvinen H. Thiazolidinediones. N Engl J Med. 2004 Sep 9;351(11):1106–18. http://dx.doi.org/10.1056/NEJMra041001
51. Bakris G, Viberti G, Weston WM, Heise M, Porter LE, Freed MI. Rosiglitazone reduces urinary albumin excretion in type II diabetes. J Hum Hypertens. 2003 Jan;17(1):7–12. http://dx.doi.org/10.1038/sj.jhh.1001444
52. Yale JF. Oral antihyperglycemic agents and renal disease: New agents, new concepts. J Am Soc Nephrol. 2005 Mar;16 Suppl 1:S7–10. http://dx.doi.org/10.1681/ASN.2004110974
53. Haluzík M, Frolík J, Rychlík I. Renal effects of DPP-4 inhibitors: A focus on microalbuminuria. Int J Endocrinol. 2013;2013:895102. http://dx.doi.org/10.1155/2013/895102
54. Morrison ME, Vijayasaradhi S, Engelstein D, Albino AP, Houghton AN. A marker for neoplastic progression of human melanocytes is a cell surface ectopeptidase. J Exp Med. 1993 Apr 1;177(4):1135–43. http://dx.doi.org/10.1084/jem.177.4.1135
55. Tofovic DS, Bilan VP, Jackson EK. Sitagliptin augments angiotensin II-induced renal vasoconstriction in kidneys from rats with metabolic syndrome. Clin Exp Pharmacol Physiol. 2010 Jul;37(7):689–91. http://dx.doi.org/10.1111/j.1440-1681.2010.05389.x
56. Mega C, de Lemos ET, Vala H, Fernandes R, Oliveira J, Mascarenhas-Melo F, et al. Diabetic nephropathy amelioration by a low-dose sitagliptin in an animal model of type 2 diabetes (Zucker diabetic fatty rat). Exp Diabetes Res. 2011;2011:162092. http://dx.doi.org/10.1155/2011/162092
57. Mori H, Okada Y, Arao T, Tanaka Y. Sitagliptin improves albuminuria in patients with type 2 diabetes mellitus. J Diabetes Investig. 2014 May 4;5(3):313–9. http://dx.doi.org/10.1111/jdi.12142
58. Groop PH, Cooper ME, Perkovic V, Emser A, Woerle HJ, von Eynatten M. Linagliptin lowers albuminuria on top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction. Diabetes Care. 2013 Nov;36(11):3460–8. http://dx.doi.org/10.2337/dc13-0323
59. Groop PH, Cooper ME, Perkovic V, Sharma K, Schernthaner G, Haneda M, et al. Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: Rationale and design of the MARLINA-T2D™ trial. Diab Vasc Dis Res. 2015 Nov;12(6):455–62. http://dx.doi.org/10.1177/1479164115579002
60. Boehringer Ingelheim and Eli Lilly and Company. New study results show Tradjenta® (linagliptin) reduces blood sugar in adults with type 2 diabetes at risk for kidney impairment. 2016 [cited 2016 Nov 17]. Available from: http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2016/6-11-2016-new-study-results-show-tradjenta-linagliptin-reduces-blood-sugar-adults-type-2-diabetes-risk-kidney-impairment.html
61. Avogaro A, Fadini GP. The effects of dipeptidyl peptidase-4 inhibition on microvascular diabetes complications. Diabetes Care. 2014 Oct;37(10):2884–94. http://dx.doi.org/10.2337/dc14-0865
62. Mosenzon O, Leibowitz G, Bhatt DL, Cahn A, Hirshberg B, Wei C, et al. Effect of saxagliptin on renal outcomes in the SAVOR-TIMI 53 Trial. Diabetes Care. 2017 Jan;40(1):69–76. http://dx.doi.org/10.2337/dc16-0621
63. Zhao X, Liu G, Shen H, Gao B, Li X, Fu J, et al. Liraglutide inhibits autophagy and apoptosis induced by high glucose through GLP-1R in renal tubular epithelial cells. Int J Mol Med. 2015 Mar;35(3):684–92.
64. Zobel EH, von Scholten BJ, Lindhardt M, Persson F, Hansen TW, Rossing P. Pleiotropic effects of liraglutide treatment on renal risk factors in type 2 diabetes: Individual effects of treatment. J Diabetes Complications. 2017 Jan;31(1):162–168. http://dx.doi.org/10.1016/j.jdiacomp.2016.09.016
65. Shiraki A, Oyama J, Komoda H, Asaka M, Komatsu A, Sakuma M, et al. The glucagon-like peptide 1 analog liraglutide reduces TNF-?-induced oxidative stress and inflammation in endothelial cells. Atherosclerosis. 2012 Apr;221(2):375–82. http://dx.doi.org/10.1016/j.atherosclerosis.2011.12.039
66. Hendarto H, Inoguchi T, Maeda Y, Ikeda N, Zheng J, Takei R, et al. GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases. Metabolism. 2012 Oct;61(10):1422–34. http://dx.doi.org/10.1016/j.metabol.2012.03.002
67. Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjøth TV, et al. NN8022-1922 Study Group. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: The SCALE Diabetes Randomized Clinical Trial. JAMA. 2015 Aug 18;314(7):687–99. http://dx.doi.org/10.1001/jama.2015.9676
68. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016 Jul 28;375(4):311–22. http://dx.doi.org/10.1056/NEJMoa1603827
69. Zhang H, Zhang X, Hu C, Lu W. Exenatide reduces urinary transforming growth factor-?1 and type IV collagen excretion in patients with type 2 diabetes and microalbuminuria. Kidney Blood Press Res. 2012;35(6):483–8. http://dx.doi.org/10.1159/000337929
70. Weise WJ, Sivanandy MS, Block CA, Comi RJ. Exenatide-associated ischemic renal failure. Diabetes Care. 2009 Feb;32(2):e22–3. http://dx.doi.org/10.2337/dc08-1309
71. Johansen OE, Whitfield R. Exenatide may aggravate moderate diabetic renal impairment: A case report. Br J Clin Pharmacol. 2008 Oct;66(4):568–9. http://dx.doi.org/10.1111/j.1365-2125.2008.03221.x
72. Betônico CC, Titan SM, Correa-Giannella ML, Nery M, Queiroz M. Management of diabetes mellitus in individuals with chronic kidney disease: Therapeutic perspectives and glycemic control. Clinics (Sao Paulo). 2016 Jan;71(1):47–53. http://dx.doi.org/10.6061/clinics/2016(01)08
73. Sampanis C. Management of hyperglycemia in patients with diabetes mellitus and chronic renal failure. Hippokratia. 2008 Jan;12(1):22–7.
74. Ingelfinger JR, Rosen CJ. Cardiac and renovascular complications in type 2 diabetes—Is there hope? N Engl J Med. 2016 Jul 28;375(4):380–2. http://dx.doi.org/10.1056/NEJMe1607413
75. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016 Jul 28;375(4):323–34. http://dx.doi.org/10.1056/NEJMoa1515920
76. Hattersley AT, Thorens B. Type 2 diabetes, SGLT2 inhibitors, and glucose secretion. N Engl J Med. 2015 Sep 3;373(10):974–6. http://dx.doi.org/10.1056/NEJMcibr1506573
77. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015 Nov 26;373(22):2117–28. http://dx.doi.org/10.1056/NEJMoa1504720
78. Parving HH, Hommel E, Mathiesen E, Skøtt P, Edsberg B, Bahnsen M, et al. Prevalence of microalbuminuria, arterial hypertension, retinopathy and neuropathy in patients with insulin dependent diabetes. Br Med J (Clin Res Ed). 1988 Jan 16;296(6616):156–60. http://dx.doi.org/10.1136/bmj.296.6616.156
79. Van Buren PN, Toto R. Hypertension in diabetic nephropathy: Epidemiology, mechanisms, and management. Adv Chronic Kidney Dis. 2011 Jan;18(1):28–41. http://dx.doi.org/10.1053/j.ackd.2010.10.003
80. 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 Aug;62(2):201–13. http://dx.doi.org/10.1053/j.ajkd.2013.03.018
81. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, 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 Sep 20;345(12):851–60. http://dx.doi.org/10.1056/NEJMoa011303
82. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, 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 Sep 20;345(12):861–9. http://dx.doi.org/10.1056/NEJMoa011161
83. Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P. Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001 Sep 20;345(12):870–8. http://dx.doi.org/10.1056/NEJMoa011489
84. Haller H, Ito S, Izzo JL Jr, Januszewicz A, Katayama S, Menne J, et al. ROADMAP Trial Investigators. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med. 2011 Mar 10;364(10):907–17. http://dx.doi.org/10.1056/NEJMoa1007994
85. Barnett A. Preventing renal complications in type 2 diabetes: Results of the diabetics exposed to telmisartan and enalapril trial. J Am Soc Nephrol. 2006 Apr;17(4 Suppl 2):S132–5. http://dx.doi.org/10.1681/ASN.2005121326
86. Makani H, Bangalore S, Desouza KA, Shah A, Messerli FH. Efficacy and safety of dual blockade of the renin-angiotensin system: Meta-analysis of randomized trials. BMJ. 2013 Jan 28;346:f360. http://dx.doi.org/10.1136/bmj.f360
87. ONTARGET Investigators., Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008 Apr 10;358(15):1547–59. http://dx.doi.org/10.1056/NEJMoa0801317
88. Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, et al. VA NEPHRON-D Investigators. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013 Nov 14;369(20):1892–903. http://dx.doi.org/10.1056/NEJMoa1303154
89. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, et al. ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012 Dec 6;367(23):2204–13. http://dx.doi.org/10.1056/NEJMoa1208799
90. Bakris GL, Barnhill BW, Sadler R. Treatment of arterial hypertension in diabetic humans: Importance of therapeutic selection. Kidney Int. 1992 Apr;41(4):912–9. http://dx.doi.org/10.1038/ki.1992.139
91. Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, et al. BEAM Study Investigators. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med. 2011 Jul 28;365(4):327–36. http://dx.doi.org/10.1056/NEJMoa1105351
92. de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, et al. BEACON Trial Investigators. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013 Dec 26;369(26):2492–503. http://dx.doi.org/10.1056/NEJMoa1306033
93. Krolewski AS, Warram JH, Christlieb AR. Hypercholesterolemia—A determinant of renal function loss and deaths in IDDM patients with nephropathy. Kidney Int Suppl. 1994 Feb;45:S125–31.
94. Palmer SC, Craig JC, Navaneethan SD, Tonelli M, Pellegrini F, Strippoli GF. Benefits and harms of statin therapy for persons with chronic kidney disease: A systematic review and meta-analysis. Ann Intern Med. 2012 Aug 21;157(4):263–75. http://dx.doi.org/10.7326/0003-4819-157-4-201208210-00007
95. Haynes R, Lewis D, Emberson J, Reith C, Agodoa L, Cass A, et al. SHARP Collaborative Group; SHARP Collaborative Group. Effects of lowering LDL cholesterol on progression of kidney disease. J Am Soc Nephrol. 2014 Aug;25(8):1825–33. http://dx.doi.org/10.1681/ASN.2013090965
96. Ansquer JC, Foucher C, Rattier S, Taskinen MR, Steiner G; DAIS Investigators. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: Results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis. 2005 Mar;45(3):485–93. http://dx.doi.org/10.1053/j.ajkd.2004.11.004
97. Park CW, Zhang Y, Zhang X, Wu J, Chen L, Cha DR, et al. PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice. Kidney Int. 2006 May;69(9):1511–7. http://dx.doi.org/10.1038/sj.ki.5000209
98. Okopie? B, Krysiak R, Herman ZS. Effects of short-term fenofibrate treatment on circulating markers of inflammation and hemostasis in patients with impaired glucose tolerance. J Clin Endocrinol Metab. 2006 May;91(5):1770–8. http://dx.doi.org/10.1210/jc.2005-1615