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Diabetic nephropathy: diagnosis and treatment

Key Points

  • Diabetes mellitus remains the major cause of end-stage renal disease in the Western world

  • Increasingly, individuals with diabetes mellitus have reduced glomerular filtration rate in the absence of albuminuria; this heterogenous group includes some individuals with classic morphological changes of diabetic nephropathy on renal biopsy

  • Clinical research activity is increasing to identify new biomarkers to predict and monitor diabetic nephropathy

  • Studies focusing on drugs that inhibit the renin–angiotensin system suggest that early administration of such agents in normalbuminuric individuals is not particularly effective at preventing the development of diabetic nephropathy

  • Whether the newer glucose lowering agents, such as glucagon-like peptide 1 analogues and dipeptidyl peptidase-4 inhibitors, will confer renoprotection, independent of their hypoglycaemic effect remains to be determined

Abstract

Nephropathy remains a major cause of morbidity and a key determinant of mortality in patients with type 1 or type 2 diabetes mellitus. Research is ongoing to identify biomarkers that in addition to albuminuria and glomerular filtration rate assist in the prediction and monitoring of renal disease in diabetes mellitus. Current strategies to treat this condition focus on intensification of glycaemic control and excellent control of blood pressure using regimens based on blockade of the renin–angiotensin system. Other approaches to control blood pressure and afford renoprotection are under active clinical investigation, including renal denervation and endothelin receptor antagonism. With increasing understanding of the underlying pathophysiological processes implicated in diabetic nephropathy, new specific renoprotective treatment strategies are anticipated to become available over the next few years.

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Figure 1: Putative pathways implicated in the pathogenesis of diabetic nephropathy, including established and potential new treatment strategies.

References

  1. Ritz, E. & Orth, S. R. Nephropathy in patients with type 2 diabetes mellitus. N. Engl. J. Med. 341, 1127–1133 (1999).

    CAS  Article  PubMed  Google Scholar 

  2. Adler, A. I. et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 321, 412–419 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Stratton, I. M. et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321, 405–412 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Reutens, A. T. & Atkins, R. C. Epidemiology of diabetic nephropathy. Contrib. Nephrol. 170, 1–7 (2011).

    Article  PubMed  Google Scholar 

  5. KDOQI. KDOQI Clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am. J. Kidney Dis. 49, S12–S154 (2007).

  6. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. Suppl. 3, 1–150 (2013).

  7. American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care 35 (Suppl 1), S11–S63 (2012).

  8. National Kidney, Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am. J. Kidney Dis. 39, S1–S266 (2002).

  9. Sampson, M. J. & Drury, P. L. Accurate estimation of glomerular filtration rate in diabetic nephropathy from age, body weight, and serum creatinine. Diabetes Care 15, 609–612 (1992).

    CAS  Article  PubMed  Google Scholar 

  10. Krolewski, A. S. et al. Serum concentration of cystatin C and risk of end-stage renal disease in diabetes. Diabetes Care 35, 2311–2316 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Perkins, B. A. et al. Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes. J. Am. Soc. Nephrol. 18, 1353–1361 (2007).

    CAS  Article  PubMed  Google Scholar 

  12. Andersen, A. R., Christiansen, J. S., Andersen, J. K., Kreiner, S. & Deckert, T. Diabetic nephropathy in Type 1 (insulin-dependent) diabetes: an epidemiological study. Diabetologia 25, 496–501 (1983).

    CAS  Article  PubMed  Google Scholar 

  13. Krolewski, A. S., Laffel, L. M., Krolewski, M., Quinn, M. & Warram, J. H. Glycosylated hemoglobin and the risk of microalbuminuria in patients with insulin-dependent diabetes mellitus. N. Engl. J. Med. 332, 1251–1255 (1995).

    CAS  Article  PubMed  Google Scholar 

  14. Cooper, M. E. Is diabetic nephropathy disappearing from clinical practice? Pediatr. Diabetes 7, 237–238 (2006).

    Article  PubMed  Google Scholar 

  15. Groop, P. H. et al. The presence and severity of chronic kidney disease predicts all-cause mortality in type 1 diabetes. Diabetes 58, 1651–1658 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Orchard, T. J., Secrest, A. M., Miller, R. G. & Costacou, T. In the absence of renal disease, 20 year mortality risk in type 1 diabetes is comparable to that of the general population: a report from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia 53, 2312–2319 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Adler, A. I. et al. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 63, 225–232 (2003).

    Article  PubMed  Google Scholar 

  18. Mogensen, C. E. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N. Engl. J. Med. 310, 356–360 (1984).

    CAS  Article  PubMed  Google Scholar 

  19. Lane, P. H., Steffes, M. W. & Mauer, S. M. Glomerular structure in IDDM women with low glomerular filtration rate and normal urinary albumin excretion. Diabetes 41, 581–586 (1992).

    CAS  Article  PubMed  Google Scholar 

  20. Macisaac, R. J. & Jerums, G. Diabetic kidney disease with and without albuminuria. Curr. Opin. Nephrol. Hypertens. 20, 246–257 (2011).

    CAS  Article  PubMed  Google Scholar 

  21. Ekinci, E. I. et al. Renal structure in normoalbuminuric and albuminuric patients with type 2 diabetes and impaired renal function. Diabetes Care http://dx.doi.org/10.2337/dc12-2572.

  22. Mottl, A. K. et al. Normoalbuminuric diabetic kidney disease in the U. S. population. J. Diabetes Complications 27, 123–127 (2013).

    Article  PubMed  Google Scholar 

  23. Calcutt, N. A., Cooper, M. E., Kern, T. S. & Schmidt, A. M. Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials. Nat. Rev. Drug Discov. 8, 417–429 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Wong, M. G. et al. Circulating bone morphogenetic protein-7 and transforming growth factor-β1 are better predictors of renal end points in patients with type 2 diabetes mellitus. Kidney Int. 83, 278–284 (2013).

    CAS  Article  PubMed  Google Scholar 

  25. Papale, M. et al. Urine proteome analysis may allow noninvasive differential diagnosis of diabetic nephropathy. Diabetes Care 33, 2409–2415 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Hansen, T. K. et al. Association between mannose-binding lectin, high-sensitivity C-reactive protein and the progression of diabetic nephropathy in type 1 diabetes. Diabetologia 53, 1517–1524 (2010).

    CAS  Article  PubMed  Google Scholar 

  27. Hovind, P. et al. Mannose-binding lectin as a predictor of microalbuminuria in type 1 diabetes: an inception cohort study. Diabetes 54, 1523–1527 (2005).

    CAS  Article  PubMed  Google Scholar 

  28. Gohda, T. et al. Circulating TNF receptors 1 and 2 predict stage 3 CKD in type 1 diabetes. J. Am. Soc. Nephrol. 23, 516–524 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Niewczas, M. A. et al. Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes. J. Am. Soc. Nephrol. 23, 507–515 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Makinen, V. P. et al. Sphingomyelin is associated with kidney disease in type 1 diabetes (The FinnDiane Study). Metabolomics 8, 369–375 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Currie, D., McKnight, A. J., Patterson, C. C., Sadlier, D. M. & Maxwell, A. P. Investigation of ACE, ACE2 and AGTR1 genes for association with nephropathy in Type 1 diabetes mellitus. Diabet. Med. 27, 1188–1194 (2010).

    CAS  Article  PubMed  Google Scholar 

  32. Hadjadj, S. et al. Prognostic value of the insertion/deletion polymorphism of the ACE gene in type 2 diabetic subjects: results from the Non-insulin-dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR), Diabete de type 2, Nephropathie et Genetique (DIAB2NEPHROGENE), and Survie, Diabete de type 2 et Genetique (SURDIAGENE) studies. Diabetes Care 31, 1847–1852 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Ng, D. P., Tai, B. C., Koh, D., Tan, K. W. & Chia, K. S. Angiotensin-I converting enzyme insertion/deletion polymorphism and its association with diabetic nephropathy: a meta-analysis of studies reported between 1994 and 2004 and comprising 14,727 subjects. Diabetologia 48, 1008–1016 (2005).

    CAS  Article  PubMed  Google Scholar 

  34. Pezzolesi, M. G. et al. Confirmation of genetic associations at ELMO1 in the GoKinD collection supports its role as a susceptibility gene in diabetic nephropathy. Diabetes 58, 2698–2702 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Shimazaki, A. et al. Genetic variations in the gene encoding ELMO1 are associated with susceptibility to diabetic nephropathy. Diabetes 54, 1171–1178 (2005).

    CAS  Article  PubMed  Google Scholar 

  36. Boger, C. A. & Sedor, J. R. GWAS of diabetic nephropathy: is the GENIE out of the bottle? PLoS Genet. 8, e1002989 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sandholm, N. et al. New susceptibility loci associated with kidney disease in type 1 diabetes. PLoS Genet. 8, e1002921 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Kantharidis, P., Wang, B., Carew, R. M. & Lan, H. Y. Diabetes complications: the microRNA perspective. Diabetes 60, 1832–1837 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Argyropoulos, C. et al. Urinary microRNA profiling in the nephropathy of type 1 diabetes. PLoS ONE 8, e0054662 (2013).

    Article  Google Scholar 

  40. Forbes, J. M. & Cooper, M. E. Mechanisms of diabetic complications. Physiol. Rev. 93, 137–188 (2013).

    CAS  Article  PubMed  Google Scholar 

  41. Tervaert, T. W. et al. Pathologic classification of diabetic nephropathy. J. Am. Soc. Nephrol. 21, 556–563 (2010).

    Article  PubMed  Google Scholar 

  42. Gaede, P., Lund-Andersen, H., Parving, H. H. & Pedersen, O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N. Engl. J. Med. 358, 580–591 (2008).

    CAS  Article  PubMed  Google Scholar 

  43. Zoungas, S. et al. Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes: new results from the ADVANCE trial. Diabetes Care 32, 2068–2074 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Borch-Johnsen, K., Andersen, P. K. & Deckert, T. The effect of proteinuria on relative mortality in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 28, 590–596 (1985).

    CAS  Article  PubMed  Google Scholar 

  45. Gaede, P. et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N. Engl. J. Med. 348, 383–393 (2003).

    Article  PubMed  Google Scholar 

  46. Gaede, P., Vedel, P., Parving, H. H. & Pedersen, O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet 353, 617–622 (1999).

    CAS  Article  PubMed  Google Scholar 

  47. Araki, S. et al. Factors associated with frequent remission of microalbuminuria in patients with type 2 diabetes. Diabetes 54, 2983–2987 (2005).

    CAS  Article  PubMed  Google Scholar 

  48. Fioretto, P., Steffes, M. W., Sutherland, D. E., Goetz, F. C. & Mauer, M. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N. Engl. J. Med. 339, 69–75 (1998).

    CAS  Article  PubMed  Google Scholar 

  49. Fioretto, P. et al. Effects of pancreas transplantation on glomerular structure in insulin-dependent diabetic patients with their own kidneys. Lancet 342, 1193–1196 (1993).

    CAS  Article  PubMed  Google Scholar 

  50. Wang, P. H., Lau, J. & Chalmers, T. C. Meta-analysis of effects of intensive blood-glucose control on late complications of type I diabetes. Lancet 341, 1306–1309 (1993).

    CAS  Article  PubMed  Google Scholar 

  51. The Diabetes Control and Complications (DCCT) Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int. 47, 1703–1720 (1995).

  52. Writing Team for the Diabetes Control Complications Trial/Epidemiology of Diabetes Interventions Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 287, 2563–2569 (2002).

  53. 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). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 837–853 (1998).

  54. Shichiri, M., Kishikawa, H., Ohkubo, Y. & Wake, N. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 23 (Suppl. 2), B21–B29 (2000).

    PubMed  Google Scholar 

  55. Ohkubo, Y. 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. 28, 103–117 (1995).

    CAS  Article  PubMed  Google Scholar 

  56. CONTROL Group. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 52, 2288–2298 (2009).

  57. Perkovic, V. et al. Intensive glucose control improves kidney outcomes in patients with type 2 diabetes. Kidney Int. 83, 517–523 (2013).

    CAS  Article  PubMed  Google Scholar 

  58. Yang, J. et al. Role of PPARγ in renoprotection in type 2 diabetes: molecular mechanisms and therapeutic potential. Clin. Sci. (Lond.) 116, 17–26 (2009).

    CAS  Article  Google Scholar 

  59. Thomas, M. C., Jandeleit-Dahm, K. A. & Tikellis, C. The renoprotective actions of peroxisome proliferator-activated receptors agonists in diabetes. PPAR Res. 2012, 456529 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Graham, D. J. et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA 304, 411–418 (2010).

    CAS  Article  PubMed  Google Scholar 

  61. Kermode-Scott, B. Meta-analysis confirms raised risk of bladder cancer from pioglitazone. BMJ 345, e4541 (2012).

    Article  PubMed  Google Scholar 

  62. Hocher, B., Reichetzeder, C. & Alter, M. L. Renal and cardiac effects of DPP4 inhibitors--from preclinical development to clinical research. Kidney Blood Press. Res. 36, 65–84 (2012).

    CAS  Article  PubMed  Google Scholar 

  63. Alter, M. L. et al. DPP-4 inhibition on top of angiotensin receptor blockade offers a new therapeutic approach for diabetic nephropathy. Kidney Blood Press. Res. 36, 119–130 (2012).

    CAS  Article  PubMed  Google Scholar 

  64. Groop, P.-H. et al. Linagliptin lowers albuminuria on top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction. Diabetes Care http://dx.doi.org/10.2337/dc13-0323.

  65. Monami, M., Ahren, B., Dicembrini, I. & Mannucci, E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes. Metab. 15, 112–120 (2013).

    CAS  Article  PubMed  Google Scholar 

  66. Chao, E. C. & Henry, R. R. SGLT2 inhibition–a novel strategy for diabetes treatment. Nat. Rev. Drug Discov. 9, 551–559 (2010).

    CAS  Article  PubMed  Google Scholar 

  67. Ferrannini, E., Veltkamp, S. A., Smulders, R. A. & Kadokura, T. Renal glucose handling: Impact of chronic kidney disease and sodium-glucose cotransporter 2 inhibition in patients with type 2 diabetes. Diabetes Care 36, 1260–1265 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Vallon, V. & Thomson, S. C. Renal function in diabetic disease models: the tubular system in the pathophysiology of the diabetic kidney. Annu. Rev. Physiol. 74, 351–375 (2012).

    CAS  Article  PubMed  Google Scholar 

  69. Bailey, C. J., Gross, J. L., Pieters, A., Bastien, A. & List, J. F. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 375, 2223–2233 (2010).

    CAS  Article  PubMed  Google Scholar 

  70. ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann. Intern. Med. 134, 370–379 (2001).

  71. Parving, H. H. et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N. Engl. J. Med. 345, 870–878 (2001).

    CAS  Article  PubMed  Google Scholar 

  72. Andersen, S., Brochner-Mortensen, J. & Parving, H. H. Kidney function during and after withdrawal of long-term irbesartan treatment in patients with type 2 diabetes and microalbuminuria. Diabetes Care 26, 3296–3302 (2003).

    Article  PubMed  Google Scholar 

  73. Viberti, G., Wheeldon, N. M. & MicroAlbuminuria Reduction With VALsartan Study Investigators. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation 106, 672–678 (2002).

    CAS  Article  PubMed  Google Scholar 

  74. Lewis, E. J., Hunsicker, L. G., Bain, R. P. & Rohde, R. D. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N. Engl. J. Med. 329, 1456–1462 (1993).

    CAS  Article  PubMed  Google Scholar 

  75. Brenner, B. M. et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med. 345, 861–869 (2001).

    CAS  Article  PubMed  Google Scholar 

  76. Lewis, E. J. et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N. Engl. J. Med. 345, 851–860 (2001).

    CAS  Article  PubMed  Google Scholar 

  77. Mogensen, C. E. et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 321, 1440–1444 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. Yusuf, S. et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N. Engl. J. Med. 358, 1547–1559 (2008).

    CAS  Article  PubMed  Google Scholar 

  79. Mann, J. F. 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 372, 547–553 (2008).

    CAS  Article  PubMed  Google Scholar 

  80. Weber, M. A. et al. Cardiovascular events during differing hypertension therapies in patients with diabetes. J. Am. Coll. Cardiol. 56, 77–85 (2010).

    CAS  Article  PubMed  Google Scholar 

  81. Jamerson, K. et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N. Engl. J. Med. 359, 2417–2428 (2008).

    CAS  Article  PubMed  Google Scholar 

  82. Dahlöf, B. et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 366, 895–906 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Ostergren, J. et al. The Anglo-Scandinavian Cardiac Outcomes Trial: blood pressure-lowering limb: effects in patients with type II diabetes. J. Hypertens. 26, 2103–2111 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Parving, H. H., Persson, F., Lewis, J. B., Lewis, E. J. & Hollenberg, N. K. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N. Engl. J. Med. 358, 2433–2446 (2008).

    CAS  Article  PubMed  Google Scholar 

  85. Parving, H. H. et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N. Engl. J. Med. 367, 2204–2213 (2012).

    CAS  Article  PubMed  Google Scholar 

  86. Imai, E. et al. Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study. Diabetologia 54, 2978–2986 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. Navaneethan, S. D., Nigwekar, S. U., Sehgal, A. R. & Strippoli, G. F. Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin. J. Am. Soc. Nephrol. 4, 542–551 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. Epstein, M. et al. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin. J. Am. Soc. Nephrol. 1, 940–951 (2006).

    CAS  Article  PubMed  Google Scholar 

  89. Mann, J. F. et al. Avosentan for overt diabetic nephropathy. J. Am. Soc. Nephrol. 21, 527–535 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. Kohan, D. E. et al. Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy. J. Am. Soc. Nephrol. 22, 763–772 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. Krum, H. et al. Device-based antihypertensive therapy: therapeutic modulation of the autonomic nervous system. Circulation 123, 209–215 (2011).

    Article  PubMed  Google Scholar 

  92. Luippold, G., Beilharz, M. & Muhlbauer, B. Chronic renal denervation prevents glomerular hyperfiltration in diabetic rats. Nephrol. Dial. Transplant. 19, 342–347 (2004).

    Article  PubMed  Google Scholar 

  93. Mahfoud, F. et al. Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation 123, 1940–1946 (2011).

    CAS  Article  PubMed  Google Scholar 

  94. Heusser, K. et al. Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients. Hypertension 55, 619–626 (2010).

    CAS  Article  PubMed  Google Scholar 

  95. Morton, J. et al. Low HDL cholesterol and the risk of diabetic nephropathy and retinopathy: results of the ADVANCE study. Diabetes Care 35, 2201–2206 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. Jenkins, A. J. et al. Serum lipoproteins in the diabetes control and complications trial/epidemiology of diabetes intervention and complications cohort: associations with gender and glycemia. Diabetes Care 26, 810–818 (2003).

    CAS  Article  PubMed  Google Scholar 

  97. Tolonen, N. et al. Lipid abnormalities predict progression of renal disease in patients with type 1 diabetes. Diabetologia 52, 2522–2530 (2009).

    CAS  Article  PubMed  Google Scholar 

  98. Bonnet, F. & Cooper, M. E. Potential influence of lipids in diabetic nephropathy: insights from experimental data and clinical studies. Diabetes Metab. 26, 254–264 (2000).

    CAS  PubMed  Google Scholar 

  99. Koya, D. & Campese, V. M. Statin use in patients with diabetes and kidney disease: the Japanese experience. J. Atheroscler. Thromb. 20, 407–424 (2013).

    Article  PubMed  Google Scholar 

  100. Colhoun, H. M. et al. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am. J. Kidney Dis. 54, 810–819 (2009).

    CAS  Article  PubMed  Google Scholar 

  101. Jun, M. et al. Effects of fibrates in kidney disease: a systematic review and meta-analysis. J. Am. Coll. Cardiol. 60, 2061–2071 (2012).

    CAS  Article  PubMed  Google Scholar 

  102. Davis, T. M. et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia 54, 280–290 (2011).

    CAS  Article  PubMed  Google Scholar 

  103. Mychaleckyj, J. C. et al. Reversibility of fenofibrate therapy-induced renal function impairment in ACCORD type 2 diabetic participants. Diabetes Care 35, 1008–1014 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. Thomas, M. C. Emerging drugs for managing kidney disease in patients with diabetes. Expert Opin. Emerg. Drugs 18, 55–70 (2013).

    CAS  Article  PubMed  Google Scholar 

  105. Lassila, M. et al. Accelerated nephropathy in diabetic apolipoprotein e-knockout mouse: role of advanced glycation end products. J. Am. Soc. Nephrol. 15, 2125–2138 (2004).

    CAS  Article  PubMed  Google Scholar 

  106. Forbes, J. M. et al. The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes. FASEB J. 17, 1762–1764 (2003).

    CAS  Article  PubMed  Google Scholar 

  107. Soulis-Liparota, T., Cooper, M., Papazoglou, D., Clarke, B. & Jerums, G. Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat. Diabetes 40, 1328–1334 (1991).

    CAS  Article  PubMed  Google Scholar 

  108. Degenhardt, T. P. et al. Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat. Kidney Int. 61, 939–950 (2002).

    CAS  Article  PubMed  Google Scholar 

  109. Thomas, M. C. et al. Interactions between renin angiotensin system and advanced glycation in the kidney. J. Am. Soc. Nephrol. 16, 2976–2984 (2005).

    CAS  Article  PubMed  Google Scholar 

  110. Forbes, J. M. et al. Reduction of the accumulation of advanced glycation end products by ACE inhibition in experimental diabetic nephropathy. Diabetes 51, 3274–3282 (2002).

    CAS  Article  PubMed  Google Scholar 

  111. Bolton, W. K. et al. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am. J. Nephrol. 24, 32–40 (2004).

    CAS  Article  PubMed  Google Scholar 

  112. Williams, M. E. et al. Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy. Am. J. Nephrol. 27, 605–614 (2007).

    CAS  Article  PubMed  Google Scholar 

  113. Hovind, P., Rossing, P., Tarnow, L., Johnson, R. J. & Parving, H. H. Serum uric acid as a predictor for development of diabetic nephropathy in type 1 diabetes: an inception cohort study. Diabetes 58, 1668–1671 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. Rosolowsky, E. T. et al. High-normal serum uric acid is associated with impaired glomerular filtration rate in nonproteinuric patients with type 1 diabetes. Clin. J. Am. Soc. Nephrol. 3, 706–713 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. Sanchez-Lozada, L. G. et al. Treatment with the xanthine oxidase inhibitor febuxostat lowers uric acid and alleviates systemic and glomerular hypertension in experimental hyperuricaemia. Nephrol. Dial. Transplant. 23, 1179–1185 (2008).

    CAS  Article  PubMed  Google Scholar 

  116. Achour, A. et al. One year course of oral sulodexide in the management of diabetic nephropathy. J. Nephrol. 18, 568–574 (2005).

    CAS  PubMed  Google Scholar 

  117. Packham, D. K. et al. Sulodexide fails to demonstrate renoprotection in overt type 2 diabetic nephropathy. J. Am. Soc. Nephrol. 23, 123–130 (2012).

    CAS  Article  PubMed  Google Scholar 

  118. Thomas, M. C. & Cooper, M. E. Into the light? Diabetic nephropathy and vitamin D. Lancet 376, 1521–1522 (2010).

    Article  PubMed  Google Scholar 

  119. de Zeeuw, D. et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet 376, 1543–1551 (2010).

    CAS  Article  PubMed  Google Scholar 

  120. Kim, M. J. et al. Oral cholecalciferol decreases albuminuria and urinary TGF-beta1 in patients with type 2 diabetic nephropathy on established renin-angiotensin-aldosterone system inhibition. Kidney Int. 80, 851–860 (2011).

    CAS  Article  PubMed  Google Scholar 

  121. Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813–820 (2001).

    CAS  Article  PubMed  Google Scholar 

  122. Koya, D. et al. Characterization of protein kinase C β isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats. J. Clin. Invest. 100, 115–126 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. Kelly, D. J. et al. Protein kinase C β inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension. Diabetes 52, 512–518 (2003).

    CAS  Article  PubMed  Google Scholar 

  124. Tuttle, K. R. et al. The effect of ruboxistaurin on nephropathy in type 2 diabetes. Diabetes Care 28, 2686–2690 (2005).

    CAS  Article  PubMed  Google Scholar 

  125. Menne, J. et al. Diminished loss of proteoglycans and lack of albuminuria in protein kinase C-α-deficient diabetic mice. Diabetes 53, 2101–2109 (2004).

    CAS  Article  PubMed  Google Scholar 

  126. Thallas-Bonke, V. & Cooper, M. E. Tandem inhibition of PKC in diαβetic nephropathy: it takes two to tango? Diabetes 62, 1010–1011 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. Menne, J. et al. Dual inhibition of classical protein kinase C-α and protein kinase C-β isoforms protects against experimental murine diabetic nephropathy. Diabetes 62, 1167–1174 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. Sharma, K. et al. Pirfenidone for diabetic nephropathy. J. Am. Soc. Nephrol. 22, 1144–1151 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. Adler, S. G. et al. Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria. Clin. J. Am. Soc. Nephrol. 5, 1420–1428 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  130. Gilbert, R. E. et al. A purpose-synthesised anti-fibrotic agent attenuates experimental kidney diseases in the rat. PLoS ONE 7, e47160 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. Thomas, M. C. & Cooper, M. E. Diabetes: bardoxolone improves kidney function in type 2 diabetes. Nat. Rev. Nephrol. 7, 552–553 (2011).

    CAS  Article  PubMed  Google Scholar 

  132. Motohashi, H. & Yamamoto, M. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol. Med. 10, 549–557 (2004).

    CAS  Article  PubMed  Google Scholar 

  133. Pergola, P. E. et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N. Engl. J. Med. 365, 327–336 (2011).

    CAS  Article  PubMed  Google Scholar 

  134. de Zeeuw, D. 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. 37, 212–222 (2013).

    CAS  Article  PubMed  Google Scholar 

  135. Tayek, J. A. & Kalantar-Zadeh, K. The extinguished BEACON of bardoxolone: not a Monday morning quarterback story. Am. J. Nephrol. 37, 208–211 (2013).

    Article  PubMed  Google Scholar 

  136. Zoja, C. et al. Analogs of bardoxolone methyl worsen diabetic nephropathy in rats with additional adverse effects. Am. J. Physiol. Renal Physiol. 304, F808–F819 (2013).

    CAS  Article  PubMed  Google Scholar 

  137. Mauer, M. et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N. Engl. J. Med. 361, 40–51 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  138. Bilous, R. et al. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Ann. Intern. Med. 151, 11–20, W3–W4 (2009).

    Article  PubMed  Google Scholar 

  139. Haller, H. et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N. Engl. J. Med. 364, 907–917 (2011).

    CAS  Article  PubMed  Google Scholar 

  140. Remuzzi, G., Macia, M. & Ruggenenti, P. Prevention and treatment of diabetic renal disease in type 2 diabetes: the BENEDICT study. J. Am. Soc. Nephrol. 17 (4 Suppl. 2), S90–S97 (2006).

    Article  PubMed  Google Scholar 

  141. de Galan, B. E. et al. Lowering blood pressure reduces renal events in type 2 diabetes. J. Am. Soc. Nephrol. 20, 883–892 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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D. Fineberg researched data for the article, contributed to discussion of the content, wrote the article and reviewed and edited the manuscript before submission. K. A. M. Jandeleit-Dahm researched data for the article, contributed to discussion of the content and reviewed and edited the manuscript before submission. M. E. Cooper contributed to discussion of the content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Daniel Fineberg.

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M. E. Cooper declares associations with the following companies: AstraZeneca (advisory board), Boehringer Ingelheim (speakers fees), Lilly (speakers fees), MSD (advisory board), Novo Nordisk (advisory board), Servier (speakers fees), Takeda (advisory board). The other authors declare no competing interests.

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Fineberg, D., Jandeleit-Dahm, K. & Cooper, M. Diabetic nephropathy: diagnosis and treatment. Nat Rev Endocrinol 9, 713–723 (2013). https://doi.org/10.1038/nrendo.2013.184

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