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  • Review Article
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Therapeutic approaches to diabetic nephropathy—beyond the RAS

Nature Reviews Nephrology volume 10, pages 325–346 (2014)Cite this article

Subjects

Key Points

  • Current therapy for diabetic kidney disease is based on blood pressure control and the antialbuminuric and antihypertensive effects of renin–angiotensin system (RAS) blockers

  • Diabetic kidney disease remains the most common cause of end-stage renal disease, indicating the need for additional therapeutic approaches beyond the RAS

  • In the past few years, several major trials have failed to show a favourable risk to benefit ratio of promising novel therapeutic approaches to diabetic kidney disease

  • Insufficient understanding of drug mechanisms and the pathogenesis of diabetic kidney disease, lack of a gold standard for diagnosis, heterogeneity of trial populations and a paucity of hard outcomes might underlie these failures

  • Ongoing clinical trials are testing novel approaches that target signalling pathways, inflammation and fibrosis in diabetic kidney disease

  • Unfortunately, the primary outcome of most of these trials is albuminuria (which might be dissociated from loss of renal function) or estimated glomerular filtration rate (GFR), which might not adequately represent actual GFR

Abstract

Despite improvements in glycaemic and blood pressure control, and the efficacy of renin–angiotensin system (RAS) blockade for proteinuria reduction, diabetic nephropathy is the most frequent cause of end-stage renal disease in developed countries. This finding is consistent with the hypothesis that key pathogenetic mechanisms leading to progression of renal disease are not modified or inactivated by current therapeutic approaches. Although extensive research has elucidated molecular signalling mechanisms that are involved in progression of diabetic kidney disease, a number of high-profile clinical trials of potentially nephroprotective agents have failed, highlighting an insufficient understanding of pathogenic pathways. These include trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced-stage disease. Various strategies based on encouraging data from preclinical studies that showed renoprotective effects of receptor antagonists, neutralizing antibodies, kinase inhibitors, small compounds and peptide-based technologies are currently been tested in randomized controlled trials. Phase II clinical trials are investigating approaches targeting inflammation, fibrosis and signalling pathways. However, only one trial that aims to provide evidence for marketing approval of a potentially renoprotective drug (atrasentan) is underway—further research into the potential nephroprotective effects of novel glucose-lowering agents is required.

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Figure 1: Pathogenesis of diabetic kidney disease and targets for therapy.

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References

  1. WHO. Diabetes fact sheet N°312. WHO Media Centre [online], (2013).

  2. 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 27, 1047–1053 (2004).

    Article  PubMed  Google Scholar 

  3. Afkarian, M. et al. Kidney disease and increased mortality risk in type 2 diabetes. J. Am. Soc. Nephrol. 24, 302–308 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Haffner, S. M., Lehto, S., Ronnemaa, T., Pyorala, K. & Laakso, M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N. Engl. J. Med. 339, 229–234 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. KDIGO BP Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int. 2, 337–414 (2012).

  6. American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care 37 (Suppl. 1), S14–S80 (2014).

  7. Fernandez-Fernandez. B. et al. 2012 update on diabetic kidney disease: the expanding spectrum, novel pathogenic insights and recent clinical trials. Minerva Med. 103, 219–234 (2012).

    CAS  PubMed  Google Scholar 

  8. Collins, A. J. et al. US renal data system 2013 annual data report. Am. J. Kidney Dis. 63, A7 (2014).

    Article  PubMed  Google Scholar 

  9. Kussman, M. J., Goldstein, H. & Gleason, R. E. The clinical course of diabetic nephropathy. JAMA 236, 1861–1863 (1976).

    Article  CAS  PubMed  Google Scholar 

  10. 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 

  11. de Boer, I. H. et al. Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria: an analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort. Arch. Intern. Med. 171, 412–420 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Molitch, M. E. et al. Development and progression of renal insufficiency with and without albuminuria in adults with type 1 diabetes in the diabetes control and complications trial and the epidemiology of diabetes interventions and complications study. Diabetes Care 33, 1536–1543 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Kramer, H. J., Nguyen, Q. D., Curhan, G. & Hsu, C. Y. Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA 289, 3273–3277 (2003).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Retnakaran, R., Cull, C. A., Thorne, K. I., Adler, A. I. & Holman, R. R. Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes 55, 1832–1839 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Garg, A. X., Kiberd, B. A., Clark, W. F., Haynes, R. B. & Clase, C. M. Albuminuria and renal insufficiency prevalence guides population screening: results from the NHANES III. Kidney Int. 61, 2165–2175 (2002).

    Article  PubMed  Google Scholar 

  17. Dwyer, J. P. et al. Renal dysfunction in the presence of normoalbuminuria in type 2 diabetes: results from the DEMAND Study. Cardiorenal. Med. 2, 1–10 (2012).

    Article  CAS  PubMed  Google Scholar 

  18. Dwyer, J. P. & Lewis, J. B. Nonproteinuric diabetic nephropathy: when diabetics don't read the textbook. Med. Clin. North Am. 97, 53–58 (2013).

    Article  PubMed  Google Scholar 

  19. MacIsaac, R. J. et al. Is nonalbuminuric renal insufficiency in type 2 diabetes related to an increase in intrarenal vascular disease? Diabetes Care 29, 1560–1566 (2006).

    Article  PubMed  Google Scholar 

  20. Caramori, M. L., Fioretto, P. & Mauer, M. Low glomerular filtration rate in normoalbuminuric type 1 diabetic patients: an indicator of more advanced glomerular lesions. Diabetes 52, 1036–1040 (2003).

    Article  CAS  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 36, 3620–3626 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Wolkow, P. P. et al. Association of urinary inflammatory markers and renal decline in microalbuminuric type 1 diabetics. J. Am. Soc. Nephrol. 19, 789–797 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Ficociello, L. H. et al. High-normal serum uric acid increases risk of early progressive renal function loss in type 1 diabetes: results of a 6-year follow-up. Diabetes Care 33, 1337–1343 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Perlstein, T. S. et al. Uric acid and the state of the intrarenal renin-angiotensin system in humans. Kidney Int. 66, 1465–1470 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Justo, P., Sanz, A. B., Egido, J. & Ortiz, A. 3,4-Dideoxyglucosone-3-ene induces apoptosis in renal tubular epithelial cells. Diabetes 54, 2424–2429 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Sanchez-Nino, M. D. et al. BASP1 promotes apoptosis in diabetic nephropathy. J. Am. Soc. Nephrol. 21, 610–621 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. 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).

    Article  CAS  PubMed  Google Scholar 

  29. 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).

    Article  CAS  PubMed  Google Scholar 

  30. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Lewis, E. J. et al. Sulodexide for kidney protection in type 2 diabetes patients with microalbuminuria: a randomized controlled trial. Am. J. Kidney Dis. 58, 729–736 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  33. Tumlin, J. A., Galphin, C. M. & Rovin, B. H. 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, 489869 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am. J. Kidney Dis. 60, 850–886 (2012).

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. Fried, L. F. et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N. Engl. J. Med. 369, 1892–1903 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. KDOQI. KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am. J. Kidney Dis. 49 (Suppl. 2), S12–S154 (2007).

  40. ACCORD Study Group et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N. Engl. J. Med. 362, 1575–1585 (2010).

  41. Onuigbo, M. A. Can ACE inhibitors and angiotensin receptor blockers be detrimental in CKD patients? Nephron Clin. Pract. 118, c407–c419 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Goncalves, A. R., Khwaja, A., Ahmed, A. K., El Kossi, M. & El Nahas, M. Stopping renin-angiotensin system inhibitors in chronic kidney disease: predictors of response. Nephron Clin. Pract. 119, c348–c354 (2011).

    Article  PubMed  Google Scholar 

  43. KIDGO. KDIGO clinical practice guideline for lipid management in chronic kidney disease. Kidney Int. 3, 259–305 (2013).

  44. 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).

  45. DCCT/EDIC Research Group et al. Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes. N. Engl. J. Med. 365, 2366–2376 (2011).

  46. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N. Engl. J. Med. 342, 381–389 (2000).

  47. de Boer, I. H. Kidney disease and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care 37, 24–30 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Patel, A. et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 358, 2560–2572 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  50. Daniels, M. et al. Factors associated with microalbuminuria in 7,549 children and adolescents with type 1 diabetes in the T1D Exchange clinic registry. Diabetes Care 36, 2639–2645 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Martin, J. H., Deacon, C. F., Gorrell, M. D. & Prins, J. B. Incretin-based therapies—review of the physiology, pharmacology and emerging clinical experience. Intern. Med. J. 41, 299–307 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Gerich, J. DPP-4 inhibitors: what may be the clinical differentiators? Diabetes Res. Clin. Pract. 90, 131–140 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Finan, B. et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci. Transl. Med. 5, 209ra151 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Muskiet, M. H., Smits, M. M., Morsink, L. M. & Diamant, M. The gut–renal axis: do incretin-based agents confer renoprotection in diabetes? Nat. Rev. Nephrol. 10, 88–103 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. 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).

    Article  CAS  PubMed  Google Scholar 

  56. Schernthaner, G. et al. Safety and tolerability of linagliptin: a pooled analysis of data from randomized controlled trials in 3572 patients with type 2 diabetes mellitus. Diabetes Obes. Metab. 14, 470–478 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. 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 36, 3460–3468 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Fujita, H. et al. DPP-4 inhibition with alogliptin on top of angiotensin II type 1 receptor blockade ameliorates albuminuria via up-regulation of SDF-1α in type 2 diabetic patients with incipient nephropathy. Endocr. J. 61, 159–166 (2014).

    Article  CAS  PubMed  Google Scholar 

  59. Ayaori, M. et al. Dipeptidyl peptidase-4 inhibitors attenuate endothelial function as evaluated by flow-mediated vasodilatation in type 2 diabetic patients. J. Am. Heart Assoc. 2, e003277 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Rossi, M. C. et al. Obesity and changes in urine albumin/creatinine ratio in patients with type 2 diabetes: the DEMAND study. Nutr. Metab. Cardiovasc. Dis. 20, 110–116 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Friedman, A. N., Chambers, M., Kamendulis, L. M. & Temmerman, J. Short-term changes after a weight reduction intervention in advanced diabetic nephropathy. Clin. J. Am. Soc. Nephrol. 8, 1892–1898 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Morales, E., Valero, M. A., Leon, M., Hernandez, E. & Praga, M. Beneficial effects of weight loss in overweight patients with chronic proteinuric nephropathies. Am. J. Kidney Dis. 41, 319–327 (2003).

    Article  PubMed  Google Scholar 

  63. Neff, K. J. et al. The effect of bariatric surgery on renal function and disease: a focus on outcomes and inflammation. Nephrol. Dial. Transplant. 28 (Suppl. 4), iv73–iv82 (2013).

    PubMed  Google Scholar 

  64. Solano, M. P. & Goldberg, R. B. Management of dyslipidemia in diabetes. Cardiol. Rev. 14, 125–135 (2006).

    Article  PubMed  Google Scholar 

  65. Stone, N. J. et al. 2013 ACC/AHA Guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation http://dx.doi.org/10.1161/01.cir.0000437738.63853.7a.

  66. Tonkin, A. M. & Chen, L. Effects of combination lipid therapy in the management of patients with type 2 diabetes mellitus in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Circulation 122, 850–852 (2010).

    Article  PubMed  Google Scholar 

  67. Abe, M. et al. Effects of lipid-lowering therapy with rosuvastatin on kidney function and oxidative stress in patients with diabetic nephropathy. J. Atheroscler. Thromb. 18, 1018–1028 (2011).

    Article  CAS  PubMed  Google Scholar 

  68. Kimura, S. et al. Randomized comparison of pitavastatin and pravastatin treatment on the reduction of urinary albumin in patients with type 2 diabetic nephropathy. Diabetes Obes. Metab. 14, 666–669 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Baigent, 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 377, 2181–2192 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Ting, R. D. et al. Benefits and safety of long-term fenofibrate therapy in people with type 2 diabetes and renal impairment: the FIELD Study. Diabetes Care 35, 218–225 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. ACCORD Study Group et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N. Engl. J. Med. 362, 1563–1574 (2010).

  72. Bonds, D. E. et al. Fenofibrate-associated changes in renal function and relationship to clinical outcomes among individuals with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) experience. Diabetologia 55, 1641–1650 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Ruiz, S., Pergola, P. E., Zager, R. A. & Vaziri, N. D. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int. 83, 1029–1041 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Hong, D. S. et al. A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas. Clin. Cancer Res. 18, 3396–3406 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Yoh, K. et al. Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient mice. Genes Cells 13, 1159–1170 (2008).

    CAS  PubMed  Google Scholar 

  76. Jiang, T. et al. The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy. Diabetes 59, 850–860 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Zheng, H. et al. Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. Diabetes 60, 3055–3066 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. 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).

    Article  CAS  PubMed  Google Scholar 

  79. Chin, M. et al. Bardoxolone methyl analogs RTA 405 and dh404 are well tolerated and exhibit efficacy in rodent models of Type 2 diabetes and obesity. Am. J. Physiol. Renal Physiol. 304, F1438–F1446 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Zoja, C., Benigni, A. & Remuzzi, G. The Nrf2 pathway in the progression of renal disease. Nephrol. Dial. Transplant. 29 (Suppl. 1), i19–i24 (2013).

    PubMed  Google Scholar 

  81. de Zeeuw, D. et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N. Engl. J. Med. 369, 2492–2503 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Gold, R. et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N. Engl. J. Med. 367, 1098–1107 (2012).

    Article  CAS  PubMed  Google Scholar 

  83. Rojas-Rivera, J., De La Piedra, C., Ramos, A., Ortiz, A. & Egido, J. The expanding spectrum of biological actions of vitamin D. Nephrol. Dial. Transplant. 25, 2850–2865 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Gonzalez-Parra, E. et al. Vitamin D receptor activation and cardiovascular disease. Nephrol. Dial. Transplant. 27 (Suppl. 4), iv17–iv21 (2012).

    CAS  PubMed  Google Scholar 

  85. Sanchez-Nino, M. D. et al. Beyond proteinuria: VDR activation reduces renal inflammation in experimental diabetic nephropathy. Am. J. Physiol. Renal Physiol. 302, F647–F657 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Perez-Gomez, M. V., Ortiz-Arduan, A. & Lorenzo-Sellares, V. Vitamin D and proteinuria: a critical review of molecular bases and clinical experience. Nefrologia 33, 716–726 (2013).

    PubMed  Google Scholar 

  87. Alborzi, P. et al. Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial. Hypertension 52, 249–255 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Fishbane, S. et al. Oral paricalcitol in the treatment of patients with CKD and proteinuria: a randomized trial. Am. J. Kidney Dis. 54, 647–652 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Gonzalez, E. et al. Effects of oral paricalcitol on secondary hyperparathyroidism and proteinuria of kidney transplant patients. Transplantation 95, e49–e52 (2013).

    Article  PubMed  Google Scholar 

  90. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  91. Perez, A., Raab, R., Chen, T. C., Turner, A. & Holick, M. F. Safety and efficacy of oral calcitriol (1,25-dihydroxyvitamin D3) for the treatment of psoriasis. Br. J. Dermatol. 134, 1070–1078 (1996).

    Article  CAS  PubMed  Google Scholar 

  92. Fernandez-Fernandez, B. et al. Juxtaglomerular apparatus hyperplasia under dual angiotensin blockade. A footprint of adequate RAS inhibition or a concern for renal fibrosis? BMC. Nephrol. 13, 21 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Ortiz, A., Sanchez Nino, M. D., Rojas, J. & Egido, J. Paricalcitol for reduction of albuminuria in diabetes. Lancet 377, 635–636 (2011).

    Article  PubMed  Google Scholar 

  94. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  95. US Department of Health and Human Services. Orange Book: approved drug products with therapeutic equivalence evaluations. US Food and Drug Administration [online], (2014).

  96. Ramasamy, R., Yan, S. F. & Schmidt, A. M. The diverse ligand repertoire of the receptor for advanced glycation endproducts and pathways to the complications of diabetes. Vascul. Pharmacol. 57, 160–167 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Kim, J. H., Hong, C. O., Koo, Y. C., Kim, S. J. & Lee, K. W. Oral administration of ethyl acetate-soluble portion of Terminalia chebula conferring protection from streptozotocin-induced diabetic mellitus and its complications. Biol. Pharm. Bull. 34, 1702–1709 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. 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).

    Article  CAS  PubMed  Google Scholar 

  99. [No authors listed] Alteon may drop pimagedine in NIDDM. thepharmaletter [online], (1998).

  100. Lewis, E. J. et al. Pyridorin in type 2 diabetic nephropathy. J. Am. Soc. Nephrol. 23, 131–136 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. 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).

    Article  CAS  PubMed  Google Scholar 

  102. Ceol, M. et al. Glycosaminoglycan therapy prevents TGF-β1 overexpression and pathologic changes in renal tissue of long-term diabetic rats. J. Am. Soc. Nephrol. 11, 2324–2336 (2000).

    CAS  PubMed  Google Scholar 

  103. Gambaro, G. et al. Oral sulodexide reduces albuminuria in microalbuminuric and macroalbuminuric type 1 and type 2 diabetic patients: the Di.N.A.S. randomized trial. J. Am. Soc. Nephrol. 13, 1615–1625 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  105. Bhattacharya, S., Manna, P., Gachhui, R. & Sil, P. C. D-saccharic acid 1,4-lactone protects diabetic rat kidney by ameliorating hyperglycemia-mediated oxidative stress and renal inflammatory cytokines via NF-κB and PKC signaling. Toxicol. Appl. Pharmacol. 267, 16–29 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Sharma, S., Kulkarni, S. K. & Chopra, K. Curcumin, the active principle of turmeric (Curcuma longa), ameliorates diabetic nephropathy in rats. Clin. Exp. Pharmacol. Physiol. 33, 940–945 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Ndisang, J. F. & Jadhav, A. Hemin therapy improves kidney function in male streptozotocin-induced diabetic rats: role of the heme oxygenase/atrial natriuretic peptide/adiponectin axis. Endocrinology 155, 215–229 (2014).

    Article  CAS  PubMed  Google Scholar 

  108. Wang, G. G., Lu, X. H., Li, W., Zhao, X. & Zhang, C. Protective effects of luteolin on diabetic nephropathy in STZ-induced diabetic rats. Evid . Based Complement. Alternat. Med. 2011, 323171 (2011).

    PubMed  PubMed Central  Google Scholar 

  109. Khazim, K., Gorin, Y., Cavaglieri, R. C., Abboud, H. E. & Fanti, P. The antioxidant silybin prevents high glucose-induced oxidative stress and podocyte injury in vitro and in vivo. Am. J. Physiol. Renal Physiol. 305, F691–F700 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Sedeek, M. et al. Renoprotective effects of a novel Nox1/4 inhibitor in a mouse model of type 2 diabetes. Clin. Sci. (Lond.) 124, 191–202 (2013).

    Article  CAS  Google Scholar 

  111. Thallas-Bonke, V. et al. Inhibition of NADPH oxidase prevents advanced glycation end product-mediated damage in diabetic nephropathy through a protein kinase C-α-dependent pathway. Diabetes 57, 460–469 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. Winiarska, K., Szymanski, K., Gorniak, P., Dudziak, M. & Bryla, J. Hypoglycaemic, antioxidative and nephroprotective effects of taurine in alloxan diabetic rabbits. Biochimie 91, 261–270 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  114. Tepel, M. et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N. Engl. J. Med. 343, 180–184 (2000).

    Article  CAS  PubMed  Google Scholar 

  115. Rasi, H. S. et al. Angiotensin receptor blocker and N-acetyl cysteine for reduction of proteinuria in patients with type 2 diabetes mellitus. Iran. J. Kidney Dis. 6, 39–43 (2012).

    Google Scholar 

  116. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  117. Fallahzadeh, M. K. et al. Effect of addition of silymarin to renin-angiotensin system inhibitors on proteinuria in type 2 diabetic patients with overt nephropathy: a randomized, double-blind, placebo-controlled trial. Am. J. Kidney Dis. 60, 896–903 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  119. Budhiraja, S. & Singh, J. Protein kinase C β inhibitors: a new therapeutic target for diabetic nephropathy and vascular complications. Fundam. Clin. Pharmacol. 22, 231–240 (2008).

    Article  CAS  PubMed  Google Scholar 

  120. Gilbert, R. E. et al. Effect of ruboxistaurin on urinary transforming growth factor-β in patients with diabetic nephropathy and type 2 diabetes. Diabetes Care 30, 995–996 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. [No authors listed] Ruboxistaurin: LY 333531. Drugs R. D. 8, 193–199 (2007).

  122. European Medicines Agency. Withdrawal assessment report for ARXXANT (Ruboxistaurin (as mesilate monohydrate) EMEA/H/C/753. European Medicines Agency [online], (2007).

  123. Tuttle, K. R. et al. Kidney outcomes in long-term studies of ruboxistaurin for diabetic eye disease. Clin. J. Am. Soc. Nephrol. 2, 631–636 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  127. Kohan, D. E. & Pollock, D. M. Endothelin antagonists for diabetic and non-diabetic chronic kidney disease. Br. J. Clin. Pharmacol. 76, 573–579 (2013).

    CAS  PubMed  Google Scholar 

  128. Gómez-Garre, D. et al. An orally active ETA/ETB receptor antagonist ameliorates proteinuria and glomerular lesions in rats with proliferative nephritis. Kidney Int. 50, 962–972 (1996).

    Article  PubMed  Google Scholar 

  129. Gómez-Garre, D. et al. Activation of NF-κB in tubular epithelial cells of rats with intense proteinuria: role of angiotensin II and endothelin-1. Hypertension 37, 1171–1178 (2001).

    Article  PubMed  Google Scholar 

  130. Rodriguez-Vita, J. et al. Endothelin-1, via ETA receptor and independently of transforming growth factor-β, increases the connective tissue growth factor in vascular smooth muscle cells. Circ. Res. 97, 125–134 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Kohan, D. E., Cleland, J. G., Rubin, L. J., Theodorescu, D. & Barton, M. Clinical trials with endothelin receptor antagonists: what went wrong and where can we improve? Life Sci. 91, 528–539 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Safdar, Z. Effect of transition from sitaxsentan to ambrisentan in pulmonary arterial hypertension. Vasc. Health Risk Manag. 7, 119–124 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Wenzel, R. R. et al. Avosentan reduces albumin excretion in diabetics with macroalbuminuria. J. Am. Soc. Nephrol. 20, 655–664 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  135. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  136. Andress, D. L. et al. Clinical efficacy of the selective endothelin A receptor antagonist, atrasentan, in patients with diabetes and chronic kidney disease (CKD). Life Sci. 91, 739–742 (2012).

    Article  CAS  PubMed  Google Scholar 

  137. Brem, A. S., Morris, D. J. & Gong, R. Aldosterone-induced fibrosis in the kidney: questions and controversies. Am. J. Kidney Dis. 58, 471–479 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Morales, E. et al. Renoprotective effects of mineralocorticoid receptor blockers in patients with proteinuric kidney diseases. Nephrol. Dial. Transplant. 28, 405–412 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  140. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  141. PRIORITY Consortium. EU Priority [online], (2014).

  142. Goicoechea, M. et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin. J. Am. Soc. Nephrol. 5, 1388–1393 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Maahs, D. M. et al. Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study. Curr. Diab. Rep. 13, 550–559 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Becker, M. A., MacDonald, P. A., Hunt, B. J. & Jackson, R. L. Diabetes and gout: efficacy and safety of febuxostat and allopurinol. Diabetes Obes. Metab. 15, 1049–1055 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Hosoya, T. et al. The effect of febuxostat to prevent a further reduction in renal function of patients with hyperuricemia who have never had gout and are complicated by chronic kidney disease stage 3: study protocol for a multicenter randomized controlled study. Trials 15, 26 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Ziyadeh, F. N. Different roles for TGF-β and VEGF in the pathogenesis of the cardinal features of diabetic nephropathy. Diabetes Res. Clin. Pract. 82 (Suppl. 1), S38–S41 (2008).

    Article  CAS  PubMed  Google Scholar 

  147. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  148. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  149. Castoldi, G. et al. Renal antifibrotic effect of N-acetyl-seryl-aspartyl-lysyl-proline in diabetic rats. Am. J. Nephrol. 37, 65–73 (2013).

    Article  CAS  PubMed  Google Scholar 

  150. Russo, L. M., del Re, E., Brown, D. & Lin, H. Y. Evidence for a role of transforming growth factor (TGF)-β1 in the induction of postglomerular albuminuria in diabetic nephropathy: amelioration by soluble TGF-β type II receptor. Diabetes 56, 380–388 (2007).

    Article  CAS  PubMed  Google Scholar 

  151. Han, D. C., Hoffman, B. B., Hong, S. W., Guo, J. & Ziyadeh, F. N. Therapy with antisense TGF-β1 oligodeoxynucleotides reduces kidney weight and matrix mRNAs in diabetic mice. Am. J. Physiol Renal Physiol. 278, F628–F634 (2000).

    Article  CAS  PubMed  Google Scholar 

  152. Navarro-González, J. F., Mora-Fernández, C., Muros de, F. M. & García-Pérez, J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat. Rev. Nephrol. 7, 327–340 (2011).

    Article  CAS  PubMed  Google Scholar 

  153. Shan, D. et al. Pentoxifylline for diabetic kidney disease. Cochra ne Database of Systematic Reviews, Issue 2. Art. No.: CD006800. http://dx.doi.org/10.1002/14651858.CD006800.pub2.

  154. Ghorbani, A., Omidvar, B., Beladi-Mousavi, S. S., Lak, E. & Vaziri, S. The effect of pentoxifylline on reduction of proteinuria among patients with type 2 diabetes under blockade of angiotensin system: a double blind and randomized clinical trial. Nefrologia 32, 790–796 (2012).

    PubMed  Google Scholar 

  155. Navarro-Gonzalez, J. F. et al. Pentoxifylline for renoprotection in diabetic nephropathy: the PREDIAN study. Rationale and basal results. J. Diabetes Complications 25, 314–319 (2011).

    Article  PubMed  Google Scholar 

  156. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  157. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  158. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  159. Moreno, J. A. et al. Targeting chemokines in proteinuria-induced renal disease. Expert. Opin. Ther. Targets 16, 833–845 (2012).

    Article  CAS  PubMed  Google Scholar 

  160. Sayyed, S. G. et al. An orally active chemokine receptor CCR2 antagonist prevents glomerulosclerosis and renal failure in type 2 diabetes. Kidney Int. 80, 68–78 (2011).

    Article  CAS  PubMed  Google Scholar 

  161. Sullivan, T. et al. CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice. Am. J. Physiol. Renal Physiol. 305, F1288–F1297 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  163. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  164. Tan, R. J. & Liu, Y. Matrix metalloproteinases in kidney homeostasis and diseases. Am. J. Physiol. Renal Physiol. 302, F1351–F1361 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Gooz, M. ADAM-17: the enzyme that does it all. Crit Rev. Biochem. Mol. Biol. 45, 146–169 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Williams, J. M. et al. Evaluation of metalloprotease inhibitors on hypertension and diabetic nephropathy. Am. J. Physiol. Renal Physiol. 300, F983–F998 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Abboud, H. et al. Effect of protease inhibition by XL784 in patients (Pts) with diabetic nephropathy (DN) [abstract F-PO1030]. Presented at ASN Kidney Week 2007, San Francisco.

  168. Aggarwal, H. K. et al. Evaluation of role of doxycycline (a matrix metalloproteinase inhibitor) on renal functions in patients of diabetic nephropathy. Ren. Fail. 32, 941–946 (2010).

    Article  CAS  PubMed  Google Scholar 

  169. Sanz, A. B. et al. NF-κB in renal inflammation. J. Am. Soc. Nephrol. 21, 1254–1262 (2010).

    Article  CAS  PubMed  Google Scholar 

  170. Kim, J. E. et al. Celastrol, an NF-κB inhibitor, improves insulin resistance and attenuates renal injury in db/db mice. PLoS ONE 8, e62068 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Gui, D. et al. Astragaloside IV ameliorates renal injury in streptozotocin-induced diabetic rats through inhibiting NF-κB-mediated inflammatory genes expression. Cytokine 61, 970–977 (2013).

    Article  CAS  PubMed  Google Scholar 

  172. Mora, E., Guglielmotti, A., Biondi, G. & Sassone-Corsi, P. Bindarit: an anti-inflammatory small molecule that modulates the NFκB pathway. Cell Cycle 11, 159–169 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Ble, A. et al. Antiproteinuric effect of chemokine C-C motif ligand 2 inhibition in subjects with acute proliferative lupus nephritis. Am. J. Nephrol. 34, 367–372 (2011).

    Article  CAS  PubMed  Google Scholar 

  174. Ruggenenti, P. Effects of MCP-1 inhibition by bindarit therapy in type 2 diabetes subjects with micro- or macro-albuminuria. J. Am. Soc. Nephrol. 21, F–FC194 (2010).

    Google Scholar 

  175. Berthier, C. C. et al. Enhanced expression of Janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy. Diabetes 58, 469–477 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Fernández-Sánchez, R. et al. AG490 promotes HIF-1α accumulation by inhibiting its hydroxylation. Curr. Med. Chem. 19, 4014–4023 (2012).

    Article  PubMed  Google Scholar 

  177. Miyata, T., Suzuki, N. & van Ypersele de Strihou, C. Diabetic nephropathy: are there new and potentially promising therapies targeting oxygen biology? Kidney Int. 84, 693–702 (2013).

    Article  CAS  PubMed  Google Scholar 

  178. Banes, A. K. et al. Angiotensin II blockade prevents hyperglycemia-induced activation of JAK and STAT proteins in diabetic rat kidney glomeruli. Am. J. Physiol. Renal Physiol. 286, F653–F659 (2004).

    Article  CAS  PubMed  Google Scholar 

  179. Taira, M. et al. Treatment of streptozotocin-induced diabetes mellitus in rats by transplantation of islet cells from two major histocompatibility complex disparate rats in combination with intra bone marrow injection of allogeneic bone marrow cells. Transplantation 79, 680–687 (2005).

    Article  CAS  PubMed  Google Scholar 

  180. Ortiz-Muñoz, G. et al. Suppressors of cytokine signaling abrogate diabetic nephropathy. J. Am. Soc. Nephrol. 21, 763–772 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Taylor, P. et al. A1.72 Baricitinib, an oral janus kinase inhibitor, in the treatment of rheumatoid arthritis: safety and efficacy in an open-label, long-term extension study. Ann. Rheum. Dis. 73 (Suppl. 1), A31 (2014).

    Google Scholar 

  182. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  183. Burstein, A. H. et al. Effect of TTP488 in patients with mild to moderate Alzheimer's disease. BMC. Neurol. 14, 12 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. US National Library of Medicine. ClinicalTrials.gov[online], (2009).

  185. Gross, M. L. et al. Renoprotective effect of a dopamine D3 receptor antagonist in experimental type II diabetes. Lab Invest. 86, 262–274 (2006).

    Article  CAS  PubMed  Google Scholar 

  186. Park, S. Y. et al. Evaluation of the effectiveness of sarpogrelate on the surrogate markers for macrovascular complications in patients with type 2 diabetes. Endocr. J. 59, 709–716 (2012).

    Article  CAS  PubMed  Google Scholar 

  187. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  188. Hodgetts, S. I., Simmons, P. J. & Plant, G. W. Human mesenchymal precursor cells (Stro-1+) from spinal cord injury patients improve functional recovery and tissue sparing in an acute spinal cord injury rat model. Cell Transplant. 22, 393–412 (2013).

    Article  PubMed  Google Scholar 

  189. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  190. Houtgraaf, J. H. et al. Intracoronary infusion of allogeneic mesenchymal precursor cells directly after experimental acute myocardial infarction reduces infarct size, abrogates adverse remodeling, and improves cardiac function. Circ. Res. 113, 153–166 (2013).

    Article  CAS  PubMed  Google Scholar 

  191. Eller, K. et al. Potential role of regulatory T cells in reversing obesity-linked insulin resistance and diabetic nephropathy. Diabetes 60, 2954–2962 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Zheng, D. et al. Transfused macrophages ameliorate pancreatic and renal injury in murine diabetes mellitus. Nephron Exp. Nephrol. 118, e87–e99 (2011).

    Article  PubMed  Google Scholar 

  193. Lin, M. et al. The TLR4 antagonist CRX-526 protects against advanced diabetic nephropathy. Kidney Int. 83, 887–900 (2013).

    Article  CAS  PubMed  Google Scholar 

  194. Lopez-Parra, V. et al. Fcγ receptor deficiency attenuates diabetic nephropathy. J. Am. Soc. Nephrol. 23, 1518–1527 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Sugimoto, H. et al. Increased expression of intercellular adhesion molecule-1 (ICAM-1) in diabetic rat glomeruli: glomerular hyperfiltration is a potential mechanism of ICAM-1 upregulation. Diabetes 46, 2075–2081 (1997).

    Article  CAS  PubMed  Google Scholar 

  196. Moriwaki, Y. et al. Effect of TNF-α inhibition on urinary albumin excretion in experimental diabetic rats. Acta Diabetol. 44, 215–218 (2007).

    Article  CAS  PubMed  Google Scholar 

  197. Gupta-Ganguli, M., Cox, K., Means, B., Gerling, I. & Solomon, S. S. Does therapy with anti-TNF-α improve glucose tolerance and control in patients with type 2 diabetes? Diabetes Care 34, e121 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Petersen, M. et al. Oral administration of GW788388, an inhibitor of TGF-β type I and II receptor kinases, decreases renal fibrosis. Kidney Int. 73, 705–715 (2008).

    Article  CAS  PubMed  Google Scholar 

  199. Sugimoto, H. et al. Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis. Nat. Med. 18, 396–404 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  200. Ka, S. M. et al. Kidney-targeting Smad7 gene transfer inhibits renal TGF-β/MAD homologue (SMAD) and nuclear factor κB (NF-κB) signalling pathways, and improves diabetic nephropathy in mice. Diabetologia 55, 509–519 (2012).

    Article  CAS  PubMed  Google Scholar 

  201. Putta, S. et al. Inhibiting microRNA-192 ameliorates renal fibrosis in diabetic nephropathy. J. Am. Soc. Nephrol. 23, 458–469 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Long, J., Wang, Y., Wang, W., Chang, B. H. & Danesh, F. R. MicroRNA-29c is a signature microRNA under high glucose conditions that targets Sprouty homolog 1, and its in vivo knockdown prevents progression of diabetic nephropathy. J. Biol. Chem. 286, 11837–11848 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  203. Taniguchi, K. et al. Inhibition of Src kinase blocks high glucose-induced EGFR transactivation and collagen synthesis in mesangial cells and prevents diabetic nephropathy in mice. Diabetes 62, 3874–3886 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Elmarakby, A. A. et al. Tyrosine kinase inhibitor, genistein, reduces renal inflammation and injury in streptozotocin-induced diabetic mice. Vascul. Pharmacol. 55, 149–156 (2011).

    Article  CAS  PubMed  Google Scholar 

  205. Lassila, M. et al. Imatinib attenuates diabetic nephropathy in apolipoprotein E-knockout mice. J. Am. Soc. Nephrol. 16, 363–373 (2005).

    Article  CAS  PubMed  Google Scholar 

  206. Kolavennu, V., Zeng, L., Peng, H., Wang, Y. & Danesh, F. R. Targeting of RhoA/ROCK signaling ameliorates progression of diabetic nephropathy independent of glucose control. Diabetes 57, 714–723 (2008).

    Article  CAS  PubMed  Google Scholar 

  207. Xie, X. et al. Activation of RhoA/ROCK regulates NF-κB signaling pathway in experimental diabetic nephropathy. Mol. Cell Endocrinol. 369, 86–97 (2013).

    Article  CAS  PubMed  Google Scholar 

  208. Jung, D. S. et al. FR167653 inhibits fibronectin expression and apoptosis in diabetic glomeruli and in high-glucose-stimulated mesangial cells. Am. J. Physiol. Renal Physiol. 295, F595–F604 (2008).

    Article  CAS  PubMed  Google Scholar 

  209. Ijaz, A. et al. Inhibition of C-jun N-terminal kinase improves insulin sensitivity but worsens albuminuria in experimental diabetes. Kidney Int. 75, 381–388 (2009).

    Article  CAS  PubMed  Google Scholar 

  210. Lim, A. K. et al. Evaluation of JNK blockade as an early intervention treatment for type 1 diabetic nephropathy in hypertensive rats. Am. J. Nephrol. 34, 337–346 (2011).

    Article  CAS  PubMed  Google Scholar 

  211. Kim, S. H. et al. The reno-protective effect of a phosphoinositide 3-kinase inhibitor wortmannin on streptozotocin-induced proteinuric renal disease rats. Exp. Mol. Med. 44, 45–51 (2012).

    Article  CAS  PubMed  Google Scholar 

  212. Durand, C. A. et al. Selective pharmacological inhibition of phosphoinositide 3-kinase p110δ opposes the progression of autoimmune diabetes in non-obese diabetic (NOD) mice. Autoimmunity 46, 62–73 (2013).

    Article  CAS  PubMed  Google Scholar 

  213. Day, R. T., Cavaglieri, R. C. & Feliers, D. Apelin retards the progression of diabetic nephropathy. Am. J. Physiol. Renal Physiol. 304, F788–F800 (2013).

    Article  CAS  PubMed  Google Scholar 

  214. Gil-Bernabe, P. et al. Exogenous activated protein C inhibits the progression of diabetic nephropathy. J. Thromb. Haemost. 10, 337–346 (2012).

    Article  CAS  PubMed  Google Scholar 

  215. Bock, F. et al. Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc. Proc. Natl Acad. Sci. USA 110, 648–653 (2013).

    Article  PubMed  Google Scholar 

  216. Tak, E. et al. CD73-Dependent generation of adenosine and endothelial Adora2b signaling attenuate diabetic nephropathy. J. Am. Soc. Nephrol. 25, 547–563 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  217. Cárdenas, A. et al. Adenosine A(2B) receptor-mediated VEGF induction promotes diabetic glomerulopathy. Lab Invest. 93, 135–144 (2013).

    Article  CAS  PubMed  Google Scholar 

  218. Nam, D. H. et al. Blockade of cannabinoid receptor 1 improves insulin resistance, lipid metabolism, and diabetic nephropathy in db/db mice. Endocrinology 153, 1387–1396 (2012).

    Article  CAS  PubMed  Google Scholar 

  219. Barutta, F. et al. Protective role of cannabinoid receptor type 2 in a mouse model of diabetic nephropathy. Diabetes 60, 2386–2396 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  220. Tanaka, Y. et al. Autophagy as a therapeutic target in diabetic nephropathy. Exp. Diabetes Res. 2012, 628978 (2012).

    Article  CAS  PubMed  Google Scholar 

  221. Fang, L. et al. Autophagy attenuates diabetic glomerular damage through protection of hyperglycemia-induced podocyte injury. PLoS ONE 8, e60546 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  222. Himmelfarb, J. & Tuttle, K. R. New therapies for diabetic kidney disease. N. Engl. J. Med. 369, 2549–2550 (2013).

    Article  CAS  PubMed  Google Scholar 

  223. Collins, F. S. Reengineering translational science: the time is right. Sci. Transl. Med. 3, 90cm17 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  224. Thompson, A. Proteinuria as a surrogate end point—more data are needed. Nat. Rev. Nephrol. 8, 306–309 (2012).

    Article  CAS  PubMed  Google Scholar 

  225. Mischak, H. et al. Implementation of proteomic biomarkers: making it work. Eur. J. Clin. Invest 42, 1027–1036 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  226. Gaspari, F. et al. The GFR and GFR decline cannot be accurately estimated in type 2 diabetics. Kidney Int. 84, 164–173 (2013).

    Article  CAS  PubMed  Google Scholar 

  227. de Zeeuw, D. The selective type A endothelin antagonist atrasentan reduces residual albuminuria in patients with type 2 diabetes and nephropathy. Presented at the 50th ERA–EDTA Congress (2013).

  228. US National Library of Medicine. ClinicalTrials.gov[online], (2007).

  229. Endo, K. et al. Probucol suppresses initiation of chronic hemodialysis therapy and renal dysfunction-related death in diabetic nephropathy patients: Sakura study. J. Atheroscler. Thromb. 20, 494–502 (2013).

    Article  CAS  PubMed  Google Scholar 

  230. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  231. Schjoedt, K. J. et al. Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney Int. 70, 536–542 (2006).

    Article  CAS  PubMed  Google Scholar 

  232. Japanese Pharmaceutical Information Center. ClinicalTrials.jp[online], (2008).

  233. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  234. US National Library of Medicine. ClinicalTrials.gov[online], (2010).

  235. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  236. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  237. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  238. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  239. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  240. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  241. Alkhalaf, A. et al. A double-blind, randomized, placebo-controlled clinical trial on benfotiamine treatment in patients with diabetic nephropathy. Diabetes Care 33, 1598–1601 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  242. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  243. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  244. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  245. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  246. Bell, J. et al. Results of a randomized trial to evaluate a novel rage inhibitor in patients with diabetic nephropathy [abstract 957-P], in 71st American Diabetes Association Scientific Sessions (2011).

  247. Darisipudi, M. N. et al. Dual blockade of the homeostatic chemokine CXCL12 and the proinflammatory chemokine CCL2 has additive protective effects on diabetic kidney disease. Am. J. Pathol. 179, 116–124 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  248. Kitada, M., Kume, S., Imaizumi, N. & Koya, D. Resveratrol improves oxidative stress and protects against diabetic nephropathy through normalization of Mn-SOD dysfunction in AMPK/SIRT1-independent pathway. Diabetes 60, 634–643 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  249. Cetkovic-Cvrlje, M., Dragt, A. L., Vassilev, A., Liu, X. P. & Uckun, F. M. Targeting JAK3 with JANEX-1 for prevention of autoimmune type 1 diabetes in NOD mice. Clin. Immunol. 106, 213–225 (2003).

    Article  CAS  PubMed  Google Scholar 

  250. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  251. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

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Acknowledgements

This work was supported by grants from the Spanish Ministry of Science (SAF 2012-38830 to C.G.-G.), Fondo de Investigaciones Sanitarias (FIS PS09/00447, FIS 10/0072, PI13/00047, FIS/PIE13/00051, ISCIII-RETIC REDinREN/RD06/0016 and 12/0021), Spanish Society of Nephrology, Comunidad de Madrid S2010/BMD-2378 and PRIORITY as well as ISCIII Rio Hortega to B.F.-F., Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to A.O., Fundacion Lilly and Diabetes kidney connect (Health-F2-2013-602422) to J.E.

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  1. Division of Nephrology and Hypertension, Renal, Diabetes and Vascular Research Laboratory, IIS-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Avenida Reyes Catolicos 2, Madrid, 28040, Spain

    Beatriz Fernandez-Fernandez & Carmen Gomez-Guerrero

  2. Fundacion Renal Iñigo Alvarez de Toledo/Instituto Reina Sofia de Investigacion Nefrologica, Universidad Autonoma de Madrid, Avenida Reyes Catolicos 2, Madrid, 28040, Spain

    Alberto Ortiz

  3. Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders [CIBERDEM], Universidad Autonoma de Madrid, Avenida Reyes Catolicos 2, Madrid, 28040, Spain

    Jesus Egido

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Fernandez-Fernandez, B., Ortiz, A., Gomez-Guerrero, C. et al. Therapeutic approaches to diabetic nephropathy—beyond the RAS. Nat Rev Nephrol 10, 325–346 (2014). https://doi.org/10.1038/nrneph.2014.74

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  • DOI: https://doi.org/10.1038/nrneph.2014.74

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