The Korean journal of internal medicine

The Korean Association of Internal Medicine (대한내과학회)
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New therapeutic agents in diabetic nephropathy

  • Kim, Yaeni (Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea) ;
  • Park, Cheol Whee (Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea)
  • Received : 2016.05.19
  • Accepted : 2016.12.25
  • Published : 2017.01.01
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Abstract

Studies investigating diabetic nephropathy (DN) have mostly focused on interpreting the pathologic molecular mechanisms of DN, which may provide valuable tools for early diagnosis and prevention of disease onset and progression. Currently, there are few therapeutic drugs for DN, which mainly consist of antihypertensive and antiproteinuric measures that arise from strict renin-angiotensin-aldosterone system inactivation. However, these traditional therapies are suboptimal and there is a clear, unmet need for treatments that offer effective schemes beyond glucose control. The complexity and heterogeneity of the DN entity, along with ambiguous renal endpoints that may deter accurate appraisal of new drug potency, contribute to a worsening of the situation. To address these issues, current research into original therapies to treat DN is focusing on the intrinsic renal pathways that intervene with intracellular signaling of anti-inflammatory, antifibrotic, and metabolic pathways. Mounting evidence in support of the favorable metabolic effects of these novel agents with respect to the renal aspects of DN supports the likelihood of systemic beneficial effects as well. Thus, when translated into clinical use, these novel agents would also address the co-morbid factors associated with diabetes, such as obesity and risk of cardiovascular disease. This review will provide a discussion of the promising and effective therapeutic agents for the management of DN.

Keywords

Acknowledgement

Supported by : National Research Foundation of Korea (NRF), Catholic University of Korea

References

  1. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet 2013;382:260-272. https://doi.org/10.1016/S0140-6736(13)60687-X
  2. Foley RN, Murray AM, Li S, et al. Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999. J Am Soc Nephrol 2005;16:489-495. https://doi.org/10.1681/ASN.2004030203
  3. Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med 2004;164:659-663. https://doi.org/10.1001/archinte.164.6.659
  4. Kim S, Lim CS, Han DC, et al. The prevalence of chronic kidney disease (CKD) and the associated factors to CKD in urban Korea: a population-based cross-sectional epidemiologic study. J Korean Med Sci 2009;24 Suppl:S11-S21. https://doi.org/10.3346/jkms.2009.24.S1.S11
  5. Jin DC. Major changes and improvements of dialysis therapy in Korea: review of end-stage renal disease registry. Korean J Intern Med 2015;30:17-22. https://doi.org/10.3904/kjim.2015.30.1.17
  6. Park CW. Diabetic kidney disease: from epidemiology to clinical perspectives. Diabetes Metab J 2014;38:252-260. https://doi.org/10.4093/dmj.2014.38.4.252
  7. Ruggenenti P, Remuzzi G. Nephropathy of type 1 and type 2 diabetes: diverse pathophysiology, same treatment? Nephrol Dial Transplant 2000;15:1900-1902. https://doi.org/10.1093/ndt/15.12.1900
  8. Barnes DJ, Pinto JR, Viberti GC. The patient with diabetes mellitus. In: Davison AM, Cameron S, Gunfeld JP, Kerr DN, Ritz E, Winearls CG, eds. Oxford Textbook of Clinical Nephrology. 2nd ed. Oxford: Oxford University Press, 1998:723-775.
  9. Vallon V, Thomson SC. Renal function in diabetic disease models: the tubular system in the pathophysiology of the diabetic kidney. Annu Rev Physiol 2012;74:351-375. https://doi.org/10.1146/annurev-physiol-020911-153333
  10. Saad S, Stevens VA, Wassef L, et al. High glucose transactivates the EGF receptor and up-regulates serum glucocorticoid kinase in the proximal tubule. Kidney Int 2005;68:985-997. https://doi.org/10.1111/j.1523-1755.2005.00492.x
  11. Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000;404:787-790. https://doi.org/10.1038/35008121
  12. Navarro-Gonzalez JF, Mora-Fernandez C, Muros de Fuentes M, Garcia-Perez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol 2011;7:327-340. https://doi.org/10.1038/nrneph.2011.51
  13. Fioretto P, Mauer M. Histopathology of diabetic nephropathy. Semin Nephrol 2007;27:195-207. https://doi.org/10.1016/j.semnephrol.2007.01.012
  14. Rutledge JC, Ng KF, Aung HH, Wilson DW. Role of triglyceride-rich lipoproteins in diabetic nephropathy. Nat Rev Nephrol 2010;6:361-370.
  15. Cooper ME, Jandeleit-Dahm KA. Lipids and diabetic renal disease. Curr Diab Rep 2005;5:445-448. https://doi.org/10.1007/s11892-005-0053-9
  16. Bobulescu IA. Renal lipid metabolism and lipotoxicity. Curr Opin Nephrol Hypertens 2010;19:393-402. https://doi.org/10.1097/MNH.0b013e32833aa4ac
  17. Jiang T, Wang XX, Scherzer P, et al. Farnesoid X receptor modulates renal lipid metabolism, fibrosis, and diabetic nephropathy. Diabetes 2007;56:2485-2493. https://doi.org/10.2337/db06-1642
  18. Herman-Edelstein M, Scherzer P, Tobar A, Levi M, Gafter U. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J Lipid Res 2014;55:561-572. https://doi.org/10.1194/jlr.P040501
  19. Klag MJ, Whelton PK, Randall BL, et al. Blood pressure and end-stage renal disease in men. N Engl J Med 1996;334:13-18. https://doi.org/10.1056/NEJM199601043340103
  20. Iseki K, Ikemiya Y, Iseki C, Takishita S. Proteinuria and the risk of developing end-stage renal disease. Kidney Int 2003;63:1468-1474. https://doi.org/10.1046/j.1523-1755.2003.00868.x
  21. Locatelli F, Marcelli D, Comelli M, et al. Proteinuria and blood pressure as causal components of progression to end-stage renal failure: Northern Italian Cooperative Study Group. Nephrol Dial Transplant 1996;11:461-467. https://doi.org/10.1093/ndt/11.3.461
  22. Iseki K, Kinjo K, Iseki C, Takishita S. Relationship between predicted creatinine clearance and proteinuria and the risk of developing ESRD in Okinawa, Japan. Am J Kidney Dis 2004;44:806-814. https://doi.org/10.1016/S0272-6386(04)01080-7
  23. Abbate M, Zoja C, Remuzzi G. How does proteinuria cause progressive renal damage? J Am Soc Nephrol 2006;17:2974-2984. https://doi.org/10.1681/ASN.2006040377
  24. Basi S, Fesler P, Mimran A, Lewis JB. Microalbuminuria in type 2 diabetes and hypertension: a marker, treatment target, or innocent bystander? Diabetes Care 2008;31 Suppl 2:S194-S201. https://doi.org/10.2337/dc08-s249
  25. Perkins BA, Ficociello LH, Roshan B, Warram JH, Krolewski AS. In patients with type 1 diabetes and new-onset microalbuminuria the development of advanced chronic kidney disease may not require progression to proteinuria. Kidney Int 2010;77:57-64. https://doi.org/10.1038/ki.2009.399
  26. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-393. https://doi.org/10.1056/NEJMoa021778
  27. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-869. https://doi.org/10.1056/NEJMoa011161
  28. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-860. https://doi.org/10.1056/NEJMoa011303
  29. Azizi M, Menard J. Combined blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation 2004;109:2492-2499. https://doi.org/10.1161/01.CIR.0000131449.94713.AD
  30. Azizi M, Webb R, Nussberger J, Hollenberg NK. Renin inhibition with aliskiren: where are we now, and where are we going? J Hypertens 2006;24:243-256. https://doi.org/10.1097/01.hjh.0000202812.72341.99
  31. Muller DN, Luft FC. Direct renin inhibition with aliskiren in hypertension and target organ damage. Clin J Am Soc Nephrol 2006;1:221-228. https://doi.org/10.2215/CJN.01201005
  32. Persson F, Lewis JB, Lewis EJ, et al. Impact of baseline renal function on the efficacy and safety of aliskiren added to losartan in patients with type 2 diabetes and nephropathy. Diabetes Care 2010;33:2304-2309. https://doi.org/10.2337/dc10-0833
  33. Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2009;4:542-551. https://doi.org/10.2215/CJN.04750908
  34. 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;157:263-275. https://doi.org/10.7326/0003-4819-157-4-201208210-00007
  35. Rodrigues CJ. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Sao Paulo Med J 2015;133:541-542. https://doi.org/10.1590/1516-3180.20151336T2
  36. Mann JF, Green D, Jamerson K, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol 2010;21:527-535. https://doi.org/10.1681/ASN.2009060593
  37. Schievink B, de Zeeuw D, Smink PA, et al. Prediction of the effect of atrasentan on renal and heart failure outcomes based on short-term changes in multiple risk markers. Eur J Prev Cardiol 2016;23:758-768. https://doi.org/10.1177/2047487315598709
  38. de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med 2013;369:2492-2503. https://doi.org/10.1056/NEJMoa1306033
  39. Packham DK, Wolfe R, Reutens AT, et al. Sulodexide fails to demonstrate renoprotection in overt type 2 diabetic nephropathy. J Am Soc Nephrol 2012;23:123-130. https://doi.org/10.1681/ASN.2011040378
  40. Coyne DW, Andress DL, Amdahl MJ, Ritz E, de Zeeuw D. Effects of paricalcitol on calcium and phosphate metabolism and markers of bone health in patients with diabetic nephropathy: results of the VITAL study. Nephrol Dial Transplant 2013;28:2260-2268. https://doi.org/10.1093/ndt/gft227
  41. Lindhardt M, Persson F, Currie G, et al. Proteomic prediction and renin angiotensin aldosterone system Inhibition prevention of early diabetic nephropathy in type 2 diabetic patients with normoalbuminuria (PRIORITY): essential study design and rationale of a randomised clinical multicentre trial. BMJ Open 2016;6:e010310. https://doi.org/10.1136/bmjopen-2015-010310
  42. Sircar D, Chatterjee S, Waikhom R, et al. Efficacy of febuxostat for slowing the GFR decline in patients with CKD and asymptomatic hyperuricemia: a 6-month, double- blind, randomized, placebo-controlled trial. Am J Kidney Dis 2015;66:945-950. https://doi.org/10.1053/j.ajkd.2015.05.017
  43. Navarro-Gonzalez JF, Mora-Fernandez C, Muros de Fuentes M, et al. Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: the PREDIAN trial. J Am Soc Nephrol 2015;26:220-229. https://doi.org/10.1681/ASN.2014010012
  44. Abdel Aziz MT, Wassef MA, Ahmed HH, et al. The role of bone marrow derived-mesenchymal stem cells in attenuation of kidney function in rats with diabetic nephropathy. Diabetol Metab Syndr 2014;6:34. https://doi.org/10.1186/1758-5996-6-34
  45. Ezquer F, Giraud-Billoud M, Carpio D, Cabezas F, Conget P, Ezquer M. Proregenerative microenvironment triggered by donor mesenchymal stem cells preserves renal function and structure in mice with severe diabetes mellitus. Biomed Res Int 2015;2015:164703.
  46. Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 2001;50:609-613. https://doi.org/10.2337/diabetes.50.3.609
  47. Ahren B, Larsson H, Holst JJ. Reduced gastric inhibitory polypeptide but normal glucagon-like peptide 1 response to oral glucose in postmenopausal women with impaired glucose tolerance. Eur J Endocrinol 1997;137:127-131. https://doi.org/10.1530/eje.0.1370127
  48. Vilsboll T, Krarup T, Madsbad S, Holst JJ. Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients. Diabetologia 2002;45:1111-1119. https://doi.org/10.1007/s00125-002-0878-6
  49. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 2002;122:531-544. https://doi.org/10.1053/gast.2002.31068
  50. Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 1997;273(5 Pt 1):E981-E988.
  51. Verdich C, Flint A, Gutzwiller JP, et al. A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans. J Clin Endocrinol Metab 2001;86:4382-4389.
  52. Muskiet MH, Smits MM, Morsink LM, Diamant M. The gut-renal axis: do incretin-based agents confer renoprotection in diabetes? Nat Rev Nephrol 2014;10:88-103. https://doi.org/10.1038/nrneph.2013.272
  53. Hattori S. Sitagliptin reduces albuminuria in patients with type 2 diabetes. Endocr J 2011;58:69-73. https://doi.org/10.1507/endocrj.K10E-382
  54. Sakata K, Hayakawa M, Yano Y, et al. Efficacy of alogliptin, a dipeptidyl peptidase-4 inhibitor, on glucose parameters, the activity of the advanced glycation end product (AGE): receptor for AGE (RAGE) axis and albuminuria in Japanese type 2 diabetes. Diabetes Metab Res Rev 2013;29:624-630. https://doi.org/10.1002/dmrr.2437
  55. 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;36:3460-3468. https://doi.org/10.2337/dc13-0323
  56. Zhang H, Zhang X, Hu C, Lu W. Exenatide reduces urinary transforming growth factor-beta1 and type IV collagen excretion in patients with type 2 diabetes and microalbuminuria. Kidney Blood Press Res 2012;35:483-488. https://doi.org/10.1159/000337929
  57. Kanasaki K, Shi S, Kanasaki M, et al. Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen. Diabetes 2014;63:2120-2131. https://doi.org/10.2337/db13-1029
  58. Wong MG, Panchapakesan U, Qi W, Silva DG, Chen XM, Pollock CA. Cation-independent mannose 6-phosphate receptor inhibitor (PXS25) inhibits fibrosis in human proximal tubular cells by inhibiting conversion of latent to active TGF-beta1. Am J Physiol Renal Physiol 2011;301:F84-F93. https://doi.org/10.1152/ajprenal.00287.2010
  59. Panchapakesan U, Pollock CA. DPP-4 inhibitors-renoprotection in diabetic nephropathy? Diabetes 2014;63:1829-1830. https://doi.org/10.2337/db14-0366
  60. Ghosh RK, Ghosh SM, Chawla S, Jasdanwala SA. SGLT2 inhibitors: a new emerging therapeutic class in the treatment of type 2 diabetes mellitus. J Clin Pharmacol 2012;52:457-463. https://doi.org/10.1177/0091270011400604
  61. Thomson SC, Rieg T, Miracle C, et al. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol 2012;302:R75-R83. https://doi.org/10.1152/ajpregu.00357.2011
  62. Panchapakesan U, Pegg K, Gross S, et al. Effects of SGLT2 inhibition in human kidney proximal tubular cells: renoprotection in diabetic nephropathy? PLoS One 2013;8:e54442. https://doi.org/10.1371/journal.pone.0054442
  63. Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 2013;382:941-950. https://doi.org/10.1016/S0140-6736(13)60683-2
  64. Nicolle LE, Capuano G, Ways K, Usiskin K. Effect of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, on bacteriuria and urinary tract infection in subjects with type 2 diabetes enrolled in a 12-week, phase 2 study. Curr Med Res Opin 2012;28:1167-1171. https://doi.org/10.1185/03007995.2012.689956
  65. Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 2014;85:962-971. https://doi.org/10.1038/ki.2013.356
  66. Musso G, Gambino R, Cassader M, Pagano G. A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors: systematic review and meta-analysis of randomized trials. Ann Med 2012;44:375-393. https://doi.org/10.3109/07853890.2011.560181
  67. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2013;159:262-274. https://doi.org/10.7326/0003-4819-159-4-201308200-00007
  68. Viollet B, Lantier L, Devin-Leclerc J, et al. Targeting the AMPK pathway for the treatment of type 2 diabetes. Front Biosci (Landmark Ed) 2009;14:3380-3400.
  69. Dronavalli S, Duka I, Bakris GL. The pathogenesis of diabetic nephropathy. Nat Clin Pract Endocrinol Metab 2008;4:444-452. https://doi.org/10.1038/ncpendmet0894
  70. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 2012;13:251-262.
  71. Hallows KR, Mount PF, Pastor-Soler NM, Power DA. Role of the energy sensor AMP-activated protein kinase in renal physiology and disease. Am J Physiol Renal Physiol 2010;298:F1067-F1077. https://doi.org/10.1152/ajprenal.00005.2010
  72. Kim MY, Lim JH, Youn HH, et al. Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1alpha axis in db/db mice. Diabetologia 2013;56:204-217. https://doi.org/10.1007/s00125-012-2747-2
  73. Hawley SA, Selbert MA, Goldstein EG, Edelman AM, Carling D, Hardie DG. 5'-AMP activates the AMP-activated protein kinase cascade, and Ca2+/calmodulin activates the calmodulin-dependent protein kinase I cascade, via three independent mechanisms. J Biol Chem 1995;270:27186-27191. https://doi.org/10.1074/jbc.270.45.27186
  74. Momcilovic M, Hong SP, Carlson M. Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. J Biol Chem 2006;281:25336-25343. https://doi.org/10.1074/jbc.M604399200
  75. Hawley SA, Boudeau J, Reid JL, et al. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2003;2:28. https://doi.org/10.1186/1475-4924-2-28
  76. Sanders MJ, Ali ZS, Hegarty BD, Heath R, Snowden MA, Carling D. Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family. J Biol Chem 2007;282:32539-32548. https://doi.org/10.1074/jbc.M706543200
  77. Hong YA, Lim JH, Kim MY, et al. Fenofibrate improves renal lipotoxicity through activation of AMPK-PGC-1alpha in db/db mice. PLoS One 2014;9:e96147. https://doi.org/10.1371/journal.pone.0096147
  78. Koh ES, Lim JH, Kim MY, et al. Anthocyanin-rich Seoritae extract ameliorates renal lipotoxicity via activation of AMP-activated protein kinase in diabetic mice. J Transl Med 2015;13:203. https://doi.org/10.1186/s12967-015-0563-4
  79. Kim Y, Park CW. Adenosine monophosphate-activated protein kinase in diabetic nephropathy. Kidney Res Clin Pract 2016;35:69-77. https://doi.org/10.1016/j.krcp.2016.02.004

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