DOI QR코드

DOI QR Code

Treatment of diabetic kidney disease: current and future targets

  • Kim, Mi-Kyung (Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine)
  • Received : 2016.07.03
  • Accepted : 2017.06.14
  • Published : 2017.07.01

Abstract

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease in Korea and worldwide, and is a risk factor for the development of cardiovascular complications. The conventional treatments for DKD are control of blood glucose and blood pressure levels by inhibiting the renin-angiotensin system. However, the prevalence of DKD continues to increase and additional therapies are required to prevent or ameliorate the condition. Many drugs have been, or are being, developed to target the molecular mechanisms in play in DKD. This review focuses on DVD treatment, considering current and emerging therapeutic targets and the clinical trial-based evidence.

Keywords

Acknowledgement

Supported by : National Research Foundation of Korea (NRF)

References

  1. 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
  2. Ahn JH, Yu JH, Ko SH, et al. Prevalence and determinants of diabetic nephropathy in Korea: Korea National Health and Nutrition Examination Survey. Diabetes Metab J 2014;38:109-119. https://doi.org/10.4093/dmj.2014.38.2.109
  3. Gregg EW, Li Y, Wang J, et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med 2014;370:1514-1523. https://doi.org/10.1056/NEJMoa1310799
  4. Rhee EJ. Diabetes in Asians. Endocrinol Metab (Seoul) 2015;30:263-269. https://doi.org/10.3803/EnM.2015.30.3.263
  5. Parving HH, Lewis JB, Ravid M, Remuzzi G, Hunsicker LG; DEMAND investigators. Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective. Kidney Int 2006;69:2057-2063. https://doi.org/10.1038/sj.ki.5000377
  6. Macisaac RJ, Ekinci EI, Jerums G. Markers of and risk factors for the development and progression of diabetic kidney disease. Am J Kidney Dis 2014;63(2 Suppl 2):S39-S62. https://doi.org/10.1053/j.ajkd.2013.10.048
  7. Kim Y, Park CW. New therapeutic agents in diabetic nephropathy. Korean J Intern Med 2017;32:11-25. https://doi.org/10.3904/kjim.2016.174
  8. 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
  9. Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-986. https://doi.org/10.1056/NEJM199309303291401
  10. 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). Lancet 1998;352:837-853. https://doi.org/10.1016/S0140-6736(98)07019-6
  11. ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-2572. https://doi.org/10.1056/NEJMoa0802987
  12. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-412. https://doi.org/10.1136/bmj.321.7258.405
  13. Zoungas S, Chalmers J, Ninomiya T, et al. Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds. Diabetologia 2012;55:636-643. https://doi.org/10.1007/s00125-011-2404-1
  14. Korean Diabetes Association. Treatment guideline for diabetes: 2015 [Internet]. Seoul: Korean Diabetes Association, c2011 [cited 2017 Jun 14]. Available from: http://www.diabetes.or.kr/pro/publish/guide.php?code=guide&-mode=view&number=625.
  15. American Diabetes Association. 5: Glycemic targets. Diabetes Care 2016;39 Suppl 1:S39-S46. https://doi.org/10.2337/dc16-S008
  16. National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis 2012;60:850-886. https://doi.org/10.1053/j.ajkd.2012.07.005
  17. Penno G, Garofolo M, Del Prato S. Dipeptidyl peptidase-4 inhibition in chronic kidney disease and potential for protection against diabetes-related renal injury. Nutr Metab Cardiovasc Dis 2016;26:361-373. https://doi.org/10.1016/j.numecd.2016.01.001
  18. Panchapakesan U, Pollock C. The role of dipeptidyl peptidase: 4 inhibitors in diabetic kidney disease. Front Immunol 2015;6:443.
  19. Solini A. Role of SGLT2 inhibitors in the treatment of type 2 diabetes mellitus. Acta Diabetol 2016;53:863-870. https://doi.org/10.1007/s00592-016-0856-y
  20. Gilbert RE. Sodium-glucose linked transporter-2 inhibitors: potential for renoprotection beyond blood glucose lowering? Kidney Int 2014;86:693-700. https://doi.org/10.1038/ki.2013.451
  21. Zhong J, Rao X, Rajagopalan S. An emerging role of dipeptidyl peptidase 4 (DPP4) beyond glucose control: potential implications in cardiovascular disease. Atherosclerosis 2013;226:305-314. https://doi.org/10.1016/j.atherosclerosis.2012.09.012
  22. Tiruppathi C, Miyamoto Y, Ganapathy V, Roesel RA, Whitford GM, Leibach FH. Hydrolysis and transport of proline-containing peptides in renal brush-border membrane vesicles from dipeptidyl peptidase IV-positive and dipeptidyl peptidase IV-negative rat strains. J Biol Chem 1990;265:1476-1483.
  23. Mentlein R. Dipeptidyl-peptidase IV (CD26): role in the inactivation of regulatory peptides. Regul Pept 1999;85:9-24. https://doi.org/10.1016/S0167-0115(99)00089-0
  24. Sharkovska Y, Reichetzeder C, Alter M, et al. Blood pressure and glucose independent renoprotective effects of dipeptidyl peptidase-4 inhibition in a mouse model of type-2 diabetic nephropathy. J Hypertens 2014;32:2211-2223. https://doi.org/10.1097/HJH.0000000000000328
  25. Yang J, Campitelli J, Hu G, Lin Y, Luo J, Xue C. Increase in DPP-IV in the intestine, liver and kidney of the rat treated with high fat diet and streptozotocin. Life Sci 2007;81:272-279. https://doi.org/10.1016/j.lfs.2007.04.040
  26. Pala L, Mannucci E, Pezzatini A, et al. Dipeptidyl peptidase-IV expression and activity in human glomerular endothelial cells. Biochem Biophys Res Commun 2003;310:28-31. https://doi.org/10.1016/j.bbrc.2003.08.111
  27. Mega C, de Lemos ET, Vala H, et al. Diabetic nephropathy amelioration by a low-dose sitagliptin in an animal model of type 2 diabetes (Zucker diabetic fatty rat). Exp Diabetes Res 2011;2011:162092.
  28. Marques C, Mega C, Goncalves A, et al. Sitagliptin prevents inflammation and apoptotic cell death in the kidney of type 2 diabetic animals. Mediators Inflamm 2014;2014:538737.
  29. Liu WJ, Xie SH, Liu YN, et al. Dipeptidyl peptidase IV inhibitor attenuates kidney injury in streptozotocin-induced diabetic rats. J Pharmacol Exp Ther 2012;340:248-255. https://doi.org/10.1124/jpet.111.186866
  30. Jung GS, Jeon JH, Choe MS, et al. Renoprotective effect of gemigliptin, a dipeptidyl peptidase-4 inhibitor, in streptozotocin-induced type 1 diabetic mice. Diabetes Metab J 2016;40:211-221. https://doi.org/10.4093/dmj.2016.40.3.211
  31. Kodera R, Shikata K, Takatsuka T, et al. Dipeptidyl peptidase-4 inhibitor ameliorates early renal injury through its anti-inflammatory action in a rat model of type 1 diabetes. Biochem Biophys Res Commun 2014;443:828-833. https://doi.org/10.1016/j.bbrc.2013.12.049
  32. 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
  33. Gangadharan Komala M, Gross S, Zaky A, Pollock C, Panchapakesan U. Saxagliptin reduces renal tubulointerstitial inflammation, hypertrophy and fibrosis in diabetes. Nephrology (Carlton) 2016;21:423-431. https://doi.org/10.1111/nep.12618
  34. 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
  35. Fujita H, Taniai H, Murayama H, et al. DPP-4 inhibition with alogliptin on top of angiotensin II type 1 receptor blockade ameliorates albuminuria via up-regulation of SDF-1alpha in type 2 diabetic patients with incipient nephropathy. Endocr J 2014;61:159-166. https://doi.org/10.1507/endocrj.EJ13-0305
  36. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-1335. https://doi.org/10.1056/NEJMoa1305889
  37. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-1326. https://doi.org/10.1056/NEJMoa1307684
  38. 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
  39. Katz PM, Leiter LA. The role of the kidney and SGLT2 inhibitors in type 2 diabetes. Can J Diabetes 2015;39 Suppl 5:S167-S175. https://doi.org/10.1016/j.jcjd.2015.09.001
  40. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323-334. https://doi.org/10.1056/NEJMoa1515920
  41. Vallon V, Gerasimova M, Rose MA, et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol 2014;306:F194-F204. https://doi.org/10.1152/ajprenal.00520.2013
  42. De Nicola L, Gabbai FB, Liberti ME, Sagliocca A, Conte G, Minutolo R. Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes. Am J Kidney Dis 2014;64:16-24. https://doi.org/10.1053/j.ajkd.2014.02.010
  43. Chilton R, Tikkanen I, Cannon CP, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab 2015;17:1180-1193. https://doi.org/10.1111/dom.12572
  44. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000;321:412-419. https://doi.org/10.1136/bmj.321.7258.412
  45. Patel A; ADVANCE Collaborative Group, MacMahon S, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007;370:829-840. https://doi.org/10.1016/S0140-6736(07)61303-8
  46. American Diabetes Association. 9: Microvascular complications and foot care. Diabetes Care 2016;39 Suppl 1:S72-S80. https://doi.org/10.2337/dc16-S012
  47. Taler SJ, Agarwal R, Bakris GL, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for management of blood pressure in CKD. Am J Kidney Dis 2013;62:201-213. https://doi.org/10.1053/j.ajkd.2013.03.018
  48. Kitada M, Kanasaki K, Koya D. Clinical therapeutic strategies for early stage of diabetic kidney disease. World J Diabetes 2014;5:342-356. https://doi.org/10.4239/wjd.v5.i3.342
  49. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-553. https://doi.org/10.1016/S0140-6736(08)61236-2
  50. Brem AS, Morris DJ, Gong R. Aldosterone-induced fibrosis in the kidney: questions and controversies. Am J Kidney Dis 2011;58:471-479. https://doi.org/10.1053/j.ajkd.2011.03.029
  51. Hou J, Xiong W, Cao L, Wen X, Li A. Spironolactone addon for preventing or slowing the progression of diabetic nephropathy: a meta-analysis. Clin Ther 2015;37:2086-2103.e10. https://doi.org/10.1016/j.clinthera.2015.05.508
  52. Pitt B, Kober L, Ponikowski P, et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J 2013;34:2453-2463. https://doi.org/10.1093/eurheartj/eht187
  53. Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA 2015;314:884-894. https://doi.org/10.1001/jama.2015.10081
  54. Gagliardini E, Zoja C, Benigni A. Et and diabetic nephropathy: preclinical and clinical studies. Semin Nephrol 2015;35:188-196. https://doi.org/10.1016/j.semnephrol.2015.03.003
  55. 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
  56. Perez-Gomez MV, Sanchez-Nino MD, Sanz AB, et al. Horizon 2020 in diabetic kidney disease: the clinical trial pipeline for add-on therapies on top of renin angiotensin system blockade. J Clin Med 2015;4:1325-1347. https://doi.org/10.3390/jcm4061325
  57. Shintani T, Klionsky DJ. Autophagy in health and disease: a double-edged sword. Science 2004;306:990-995. https://doi.org/10.1126/science.1099993
  58. White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 2012;12:401-410. https://doi.org/10.1038/nrc3262
  59. Masini M, Bugliani M, Lupi R, et al. Autophagy in human type 2 diabetes pancreatic beta cells. Diabetologia 2009;52:1083-1086. https://doi.org/10.1007/s00125-009-1347-2
  60. Kume S, Koya D. Autophagy: a novel therapeutic target for diabetic nephropathy. Diabetes Metab J 2015;39:451-460. https://doi.org/10.4093/dmj.2015.39.6.451
  61. Kim SI, Na HJ, Ding Y, Wang Z, Lee SJ, Choi ME. Autophagy promotes intracellular degradation of type I collagen induced by transforming growth factor (TGF)-${\beta}1$. J Biol Chem 2012;287:11677-11688. https://doi.org/10.1074/jbc.M111.308460
  62. Yamahara K, Kume S, Koya D, et al. Obesity-mediated autophagy insufficiency exacerbates proteinuria-induced tubulointerstitial lesions. J Am Soc Nephrol 2013;24:1769-1781. https://doi.org/10.1681/ASN.2012111080
  63. Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 2004;15:1101-1111. https://doi.org/10.1091/mbc.e03-09-0704
  64. Bromann PA, Korkaya H, Courtneidge SA. The interplay between Src family kinases and receptor tyrosine kinases. Oncogene 2004;23:7957-7968. https://doi.org/10.1038/sj.onc.1208079
  65. Thomas SM, Brugge JS. Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol 1997;13:513-609. https://doi.org/10.1146/annurev.cellbio.13.1.513
  66. Kopetz S, Shah AN, Gallick GE. Src continues aging: current and future clinical directions. Clin Cancer Res 2007;13:7232-7236. https://doi.org/10.1158/1078-0432.CCR-07-1902
  67. Mima A, Matsubara T, Arai H, et al. Angiotensin II-dependent Src and Smad1 signaling pathway is crucial for the development of diabetic nephropathy. Lab Invest 2006;86:927-939. https://doi.org/10.1038/labinvest.3700445
  68. Taniguchi K, Xia L, Goldberg HJ, 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 2013;62:3874-3886. https://doi.org/10.2337/db12-1010
  69. Yan Y, Ma L, Zhou X, et al. Src inhibition blocks renal interstitial fibroblast activation and ameliorates renal fibrosis. Kidney Int 2016;89:68-81. https://doi.org/10.1038/ki.2015.293
  70. Zhou D, Liu Y. Therapy for kidney fibrosis: is the Src kinase a potential target? Kidney Int 2016;89:12-14. https://doi.org/10.1016/j.kint.2015.10.007
  71. Seo HY, Jeon JH, Jung YA, et al. Fyn deficiency attenuates renal fibrosis by inhibition of phospho-STAT3. Kidney Int 2016;90:1285-1297. https://doi.org/10.1016/j.kint.2016.06.038

Cited by

  1. Changes in co-morbidity pattern in patients starting renal replacement therapy in Europe-data from the ERA-EDTA Registry vol.33, pp.10, 2018, https://doi.org/10.1093/ndt/gfx355
  2. Triptolide Attenuates Renal Tubular Epithelial-mesenchymal Transition Via the MiR-188-5p-mediated PI3K/AKT Pathway in Diabetic Kidney Disease vol.14, pp.11, 2017, https://doi.org/10.7150/ijbs.24032
  3. Adiponectin for the treatment of diabetic nephropathy vol.34, pp.3, 2019, https://doi.org/10.3904/kjim.2019.109
  4. Comparing the Effect of Dipeptidyl-Peptidase 4 Inhibitors and Sulfonylureas on Albuminuria in Patients with Newly Diagnosed Type 2 Diabetes Mellitus: A Prospective Open-Label Study vol.8, pp.10, 2019, https://doi.org/10.3390/jcm8101715
  5. Lipid mediators of insulin signaling in diabetic kidney disease vol.317, pp.5, 2019, https://doi.org/10.1152/ajprenal.00379.2019
  6. DACH1, a novel target of miR-218, participates in the regulation of cell viability, apoptosis, inflammatory response, and epithelial-mesenchymal transition process in renal tubule cells treated by hig vol.42, pp.1, 2020, https://doi.org/10.1080/0886022x.2020.1762647
  7. A Novel Indoline Derivative Ameliorates Diabesity-Induced Chronic Kidney Disease by Reducing Metabolic Abnormalities vol.11, pp.None, 2017, https://doi.org/10.3389/fendo.2020.00091
  8. Therapeutic application of nutraceuticals in diabetic nephropathy: Current evidence and future implications vol.36, pp.8, 2017, https://doi.org/10.1002/dmrr.3336
  9. RIPK3 blockade attenuates tubulointerstitial fibrosis in a mouse model of diabetic nephropathy vol.10, pp.None, 2017, https://doi.org/10.1038/s41598-020-67054-x
  10. Jowiseungki decoction affects diabetic nephropathy in mice through renal injury inhibition as evidenced by network pharmacology and gut microbiota analyses vol.15, pp.None, 2017, https://doi.org/10.1186/s13020-020-00306-0
  11. Changing the Concept: From the Traditional Glucose-centric to the New Cardiorenal-metabolic Approach for the Treatment of Type 2 Diabetes vol.17, pp.2, 2017, https://doi.org/10.17925/ee.2021.17.2.92
  12. Is there a relationship between the prevalence of autoimmune thyroid disease and diabetic kidney disease? vol.16, pp.1, 2017, https://doi.org/10.1515/biol-2021-0064
  13. Diabetic Nephropathy: Challenges in Pathogenesis, Diagnosis, and Treatment vol.2021, pp.None, 2017, https://doi.org/10.1155/2021/1497449
  14. The effect of isosorbide-mononitrate on proteinuria in patients with diabetic nephropathy vol.5, pp.6, 2017, https://doi.org/10.28982/josam.807627
  15. Severe hypoglycemia and the risk of end stage renal disease in type 2 diabetes vol.11, pp.1, 2017, https://doi.org/10.1038/s41598-021-82838-5