Emerging drugs for managing kidney disease in patients with diabetes

Expert Opinion on Emerging Drugs

Volumn 18, Issue 1, 2013, Pages 55-70

  Thomas, Merlin C ^a  

^a BAKER IDI HEART AND DIABETES INSTITUTE   (Australia)

Author keywords

Albuminuria; Chronic kidney disease; Diabetes; Diabetic nephropathy

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; 4 (1 AMINOETHYL) N (4 PYRIDYL)CYCLOHEXANECARBOXAMIDE; ADVANCED GLYCATION END PRODUCT; ALISKIREN; ANGIOTENSIN RECEPTOR ANTAGONIST; ANTIDIABETIC AGENT; AST 120; BARDOXOLONE METHYL; COLECALCIFEROL; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; ENDOTHELIN RECEPTOR ANTAGONIST; FASUDIL; FENOFIBRATE; FIBRIC ACID DERIVATIVE; LOSARTAN; PARICALCITOL; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONIST; PF 4494700; PIRFENIDONE; PROTEIN KINASE C INHIBITOR; PYRIDOXAMINE; RENIN INHIBITOR; ROSIGLITAZONE; SIMVASTATIN; UNINDEXED DRUG; UROTENSIN RECEPTOR ANTAGONIST; VALSARTAN; VITAMIN D;

ADD ON THERAPY; BLOOD GLUCOSE MONITORING; BLOOD PRESSURE REGULATION; BLOOD VESSEL COMPLIANCE; CHRONIC KIDNEY DISEASE; COGNITION; DIABETES MELLITUS; DIET THERAPY; DRUG DOSE TITRATION; DRUG SAFETY; FIBROSING ALVEOLITIS; GLOMERULUS FILTRATION RATE; GLYCEMIC CONTROL; HUMAN; HYPERGLYCEMIA; HYPERLIPIDEMIA; HYPERTENSION; INNATE IMMUNITY; INSULIN DEPENDENT DIABETES MELLITUS; KIDNEY DISEASE; KIDNEY FUNCTION; KINESIOTHERAPY; LIPID METABOLISM; MINERAL METABOLISM; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PATHOGENESIS; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; RENAL PROTECTION; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; SMOKING CESSATION; SYSTOLIC BLOOD PRESSURE;

ANIMALS; CLINICAL TRIALS AS TOPIC; DIABETIC NEPHROPATHIES; DRUGS, INVESTIGATIONAL; ENDOTHELINS; HUMANS; HYPOGLYCEMIC AGENTS; KIDNEY; PROTECTIVE AGENTS; RENAL INSUFFICIENCY, CHRONIC; RENIN;

EID: 84874630767     PISSN: 14728214     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728214.2013.762356     Document Type: Review

References (177)

1. Federation ID. IDF diabetes atlas. 4th edition. International Diabetes Federation, Brussels, Belgium; 2009
2. Hogan P, Dall T, Nikolov P. Economic costs of diabetes in the US in 2002. Diabetes Care 2003;26(3):917-32
3. Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med 1999;341(15):1127-33 (Pubitemid 29466226)
4. U. S. Renal Data System. USRDS 2004 annual data report: atlas of end-stage renal disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda, MD, USA; 2004
5. Groop PH, Thomas MC, Moran JL, et al. The presence and severity of chronic kidney disease predicts all-cause mortality in type 1 diabetes. Diabetes 2009;58(7):1651-8
6. Orchard TJ, Secrest AM, Miller RG, Costacou T. In the absence of renal disease, 20 year mortality risk in type 1 diabetes is comparable to that of the general population: a report from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia 2010;53(11):2312-19
7. Stephenson JM, Kenny S, Stevens LK, et al. Proteinuria and mortality in diabetes: the WHO Multinational Study of Vascular disease in diabetes. Diabet Med 1995;12(2):149-55
8. Adler AI, Stevens RJ, Manley SE, et al. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003;63(1):225-32 (Pubitemid 35463925)
9. Dwyer JP, Parving HH, Hunsicker LG, et al. Renal dysfunction in the presence of normoalbuminuria in type 2 diabetes: results from the DEMAND study. Cardiorenal Med 2012;2(1):1-10
10. Zoungas S, de Galan BE, Ninomiya T, et al. Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes: new results from the ADVANCE trial. Diabetes Care 2009;32(11):2068-74
11. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348(5):383-93 (Pubitemid 36159355)
12. Horita Y, Taura K, Taguchi T, et al. Aldosterone breakthrough during therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in proteinuric patients with immunoglobulin A nephropathy. Nephrology (Carlton) 2006;11(5):462-6 (Pubitemid 44470097)
13. Bomback AS, Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol 2007;3(9):486-92 (Pubitemid 47313030)
14. Schjoedt KJ, Andersen S, Rossing P, et al. Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate. Diabetologia 2004;47(11):1936-9 (Pubitemid 40110201)
15. Parving HH, Persson F, Lewis JB, et al. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008;358(23):2433-46 (Pubitemid 351793017)
16. Persson F, Rossing P, Reinhard H, et al. Renal effects of aliskiren compared with and in combination with irbesartan in patients with type 2 diabetes, hypertension, and albuminuria. Diabetes Care 2009;32(10):1873-9
17. Parving HH, Brenner BM, McMurray JJ, et al. Aliskiren trial in type 2 diabetes using cardio-renal endpoints (ALTITUDE): rationale and study design. Nephrol Dial Transplant 2009;24(5):1663-71
18. Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367(23):2204-13
19. Smulders YM, van Eeden AE, Stehouwer CD, et al. Can reduction in hypertriglyceridaemia slow progression of microalbuminuria in patients with non-insulin-dependent diabetes mellitus? Eur J Clin Invest 1997;27(12):997-1002 (Pubitemid 28012621)
20. Nagai T, Tomizawa T, Nakajima K, Mori M. Effect of bezafibrate or pravastatin on serum lipid levels and albuminuria in NIDDM patients. J Atheroscler Thromb 2000;7(2):91-6
21. Park CW, Zhang Y, Zhang X, et al. PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice. Kidney Int 2006;69(9):1511-17
22. Ren S, Xin C, Beck KF, et al. PPARalpha activation upregulates nephrin expression in human embryonic kidney epithelial cells and podocytes by a dual mechanism. Biochem Biophys Res Commun 2005;338(4):1818-24 (Pubitemid 41643096)
23. Zhao X, Li LY. PPAR-alpha agonist fenofibrate induces renal CYP enzymes and reduces blood pressure and glomerular hypertrophy in Zucker diabetic fatty rats. Am J Nephrol 2008;28(4):598-606 (Pubitemid 351832447)
24. Ansquer JC, Foucher C, Rattier S, et al. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis 2005;45(3):485-93 (Pubitemid 40341327)
25. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362(17):1563-74
26. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010;375(9729):1875-84
27. Sarafidis PA, Stafylas PC, Georgianos PI, et al. Effect of thiazolidinediones on albuminuria and proteinuria in diabetes: a meta-analysis. Am J Kidney Dis 2010;55(5):835-47
28. Nissen SE, Wolski K. Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. Arch Intern Med 2010;170(14):1191-201
29. Colhoun HM, Livingstone SJ, Looker HC, et al. Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs. Diabetologia 2012;55(11):2929-37
30. Li YC, Kong J, Wei M, et al. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 2002;110(2):229-38 (Pubitemid 34787360)
31. Porsti IH. Expanding targets of vitamin D receptor activation: downregulation of several RAS components in the kidney. Kidney Int 2008;74(11):1371-3
32. Rojas-Rivera J, De La Piedra C, Ramos A, et al. The expanding spectrum of biological actions of vitamin D. Nephrol Dial Transplant 2010;25(9):2850-65
33. Freundlich M, Quiroz Y, Zhang Z, et al. Suppression of renin-angiotensin gene expression in the kidney by paricalcitol. Kidney Int 2008;74(11):1394-402
34. Wu-Wong JR. Potential for vitamin D receptor agonists in the treatment of cardiovascular disease. Br J Pharmacol 2009;158(2):395-412
35. Zhang Z, Sun L, Wang Y, et al. Renoprotective role of the vitamin D receptor in diabetic nephropathy. Kidney Int 2008;73(2):163-71
36. Tanaka H, Hamano T, Fujii N, et al. The impact of diabetes mellitus on vitamin D metabolism in predialysis patients. Bone 2009;45(5):949-55
37. Kim MJ, Frankel AH, Donaldson M, et al. Oral cholecalciferol decreases albuminuria and urinary TGF-beta1 in patients with type 2 diabetic nephropathy on established renin-angiotensin-aldosterone system inhibition. Kidney Int 2011;80(8):851-60
38. Alborzi P, Patel NA, Peterson C, et al. Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial. Hypertension 2008;52(2):249-55
39. Agarwal R, Acharya M, Tian J, et al. Antiproteinuric effect of oral paricalcitol in chronic kidney disease. Kidney Int 2005;68(6):2823-8 (Pubitemid 43251029)
40. Fishbane S, Chittineni H, Packman M, et al. Oral paricalcitol in the treatment of patients with CKD and proteinuria: a randomized trial. Am J Kidney Dis 2009;54(4):647-52
41. de Zeeuw D, Agarwal R, Amdahl M, 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 2010;376(9752):1543-51
42. Witham MD, Dove FJ, Dryburgh M, et al. The effect of different doses of vitamin D(3) on markers of vascular health in patients with type 2 diabetes: a randomised controlled trial. Diabetologia 2010;53(10):2112-19
43. Burns WC, Thomas MC. The molecular mediators of type 2 epithelial to mesenchymal transition (EMT) and their role in renal pathophysiology. Expert Rev Mol Med 2010;12:e17
44. Rodrigues-Diez R, Carvajal-Gonzalez G, Sanchez-Lopez E, et al. Pharmacological modulation of epithelial mesenchymal transition caused by angiotensin II. Role of ROCK and MAPK pathways. Pharm Res 2008;25(10):2447-61
45. Bhowmick NA, Ghiassi M, Aakre M, et al. TGF-beta-induced RhoA and p160ROCK activation is involved in the inhibition of Cdc25A with resultant cell-cycle arrest. Proc Natl Acad Sci USA 2003;100(26):15548-53 (Pubitemid 38021027)
46. Guo X, Wang L, Chen B, et al. ERM protein moesin is phosphorylated by advanced glycation end products and modulates endothelial permeability. Am J Physiol Heart Circ Physiol 2009;297(1):H238-46
47. Zimering MB, Pan Z. Autoantibodies in type 2 diabetes induce stress fiber formation and apoptosis in endothelial cells. J Clin Endocrinol Metab 2009;94(6):2171-7
48. Laufs U, Marra D, Node K, Liao JK. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing rho GTPase-induced down-regulation of p27(Kip1). J Biol Chem 1999;274(31):21926-31
49. Colhoun HM, Betteridge DJ, Durrington PN, et al. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis 2009;54(5):810-19
50. Douglas K, O'Malley PG, Jackson JL. Meta-analysis: the effect of statins on albuminuria. Ann Intern Med 2006;145(2):117-24 (Pubitemid 46780585)
51. Noma K, Oyama N, Liao JK. Physiological role of ROCKs in the cardiovascular system. Am J Physiol Cell Physiol 2006;290(3):C661-8
52. Loirand G, Guerin P, Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circ Res 2006;98(3):322-34
53. Patel RA, Forinash KD, Pireddu R, et al. RKI-1447 is a potent inhibitor of the rho-associated ROCK kinases with anti-invasive and antitumor activities in breast cancer. Cancer Res 2012;72(19):5025-34
54. L1ohn M, Plettenburg O, Ivashchenko Y, et al. Pharmacological characterization of SAR407899, a novel rho-kinase inhibitor. Hypertension 2009;54(3):676-83
55. Soulis-Liparota T, Cooper ME, Dunlop M, Jerums G. The relative roles of advanced glycation, oxidation and aldose reductase inhibition in the development of experimental diabetic nephropathy in the Sprague-Dawley rat. Diabetologia 1995;38(4):387-94
56. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414(6865):813-20 (Pubitemid 34000785)
57. Soulis-Liparota T, Cooper M, Papazoglou D, et al. Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat. Diabetes 1991;40(10):1328-34
58. Bolton WK, Cattran DC, Williams ME, et al. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am J Nephrol 2004;24(1):32-40 (Pubitemid 38250484)
59. Wendt TM, Tanji N, Guo J, et al. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol 2003;162(4):1123-37 (Pubitemid 36350658)
60. La Selva M, Beltramo E, Pagnozzi F, et al. Thiamine corrects delayed replication and decreases production of lactate and advanced glycation end-products in bovine retinal and human umbilical vein endothelial cells cultured under high glucose conditions. Diabetologia 1996;39(11):1263-8 (Pubitemid 26356052)
61. Thornalley PJ. The potential role of thiamine (vitamin B1) in diabetic complications. Curr Diabetes Rev 2005;1(3):287-98
62. Riaz S, Skinner V, Srai SK. Effect of high dose thiamine on the levels of urinary protein biomarkers in diabetes mellitus type2. J Pharm Biomed Anal 2011; 54(4): 817-25
63. Rabbani N, Alam SS, Riaz S, et al. High-dose thiamine therapy for patients with type 2 diabetes and microalbuminuria: a randomised, double-blind placebo-controlled pilot study. Diabetologia 2009;52(2):208-12
64. Alkhalaf A, Klooster A, van Oeveren W, et al. A double-blind, randomized, placebo-controlled clinical trial on benfotiamine treatment in patients with diabetic nephropathy. Diabetes Care 2010;33(7):1598-601
65. House AA, Eliasziw M, Cattran DC, et al. Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial. JAMA 2010;303(16):1603-9
66. Degenhardt TP, Alderson NL, Arrington DD, et al. Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat. Kidney Int 2002;61(3):939-50 (Pubitemid 34175462)
67. Alderson NL, Chachich ME, Youssef NN, et al. The AGE inhibitor pyridoxamine inhibits lipemia and development of renal and vascular disease in Zucker obese rats. Kidney Int 2003;63(6):2123-33 (Pubitemid 36605823)
68. Williams ME, Bolton WK, Khalifah RG, 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 2007;27(6):605-14 (Pubitemid 350014947)
69. Lewis EJ, Greene T, Spitalewiz S, et al. Pyridorin in type 2 diabetic nephropathy. J Am Soc Nephrol 2012;23(1):131-6
70. Cai W, He JC, Zhu L, et al. High levels of dietary advanced glycation end products transform low-density lipoprotein into a potent redox-sensitive mitogen-activated protein kinase stimulant in diabetic patients. Circulation 2004;110(3):285-91 (Pubitemid 38955497)
71. Sanaka T, Akizawa T, Koide K, Koshikawa S. Protective effect of an oral adsorbent on renal function in chronic renal failure: determinants of its efficacy in diabetic nephropathy. Ther Apher Dial 2004;8(3):232-40 (Pubitemid 38900430)
72. Hayashino Y, Fukuhara S, Akizawa T, et al. Cost-effectiveness of administering oral adsorbent AST-120 to patients with diabetes and advance-stage chronic kidney disease. Diabetes Res Clin Pract 2010;90(2):154-9
73. Konishi K, Nakano S, Tsuda S, et al. AST-120 (Kremezin) initiated in early stage chronic kidney disease stunts the progression of renal dysfunction in type 2 diabetic subjects. Diabetes Res Clin Pract 2008;81(3):310-15
74. Hatakeyama S, Yamamoto H, Okamoto A, et al. Effect of an oral adsorbent, AST-120, on dialysis initiation and survival in patients with Chronic Kidney disease. Int J Nephrol 2012;2012:376128
75. Morcos M, Sayed AA, Bierhaus A, et al. Activation of tubular epithelial cells in diabetic nephropathy. Diabetes 2002;51(12):3532-44 (Pubitemid 35403461)
76. Reiniger N, Lau K, McCalla D, et al. Deletion of the receptor for advanced glycation end products reduces glomerulosclerosis and preserves renal function in the diabetic OVE26 mouse. Diabetes 2010;59(8):2043-54
77. Kanwar YS, Sun L, Xie P, et al. A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annu Rev Pathol 2011;6:395-423
78. Phillips AO, Steadman R. Diabetic nephropathy: the central role of renal proximal tubular cells in tubulointerstitial injury. Histol Histopathol 2002;17(1):247-52 (Pubitemid 34116428)
79. Okada H, Kikuta T, Kobayashi T, et al. Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis. J Am Soc Nephrol 2005;16(1):133-43 (Pubitemid 43073165)
80. Baelde HJ, Eikmans M, Lappin D, et al. Reduction of VEGF-A and CTGF expression in diabetic nephropathy is associated with podocyte loss. Kidney Int 2007;71(7):637-45 (Pubitemid 46494557)
81. Nishida T, Kondo S, Maeda A, et al. CCN family 2/connective tissue growth factor (CCN2/CTGF) regulates the expression of Vegf through Hif-1alpha expression in a chondrocytic cell line, HCS-2/8, under hypoxic condition. Bone 2009;44(1):24-31
82. Zhang M, Lv XY, Li J, et al. The characterization of high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model. Exp Diabetes Res 2008;2008:704045
83. Furumatsu T, Kanazawa T, Miyake Y, et al. Mechanical stretch increases Smad3-dependent CCN2 expression in inner meniscus cells. J Orthop Res 2012;30(11):1738-45
84. Nishida T, Maeda A, Kubota S, Takigawa M. Role of mechanical-stress inducible protein Hcs24/CTGF/CCN2 in cartilage growth and regeneration: mechanical stress induces expression of Hcs24/CTGF/CCN2 in a human chondrocytic cell line HCS-2/8, rabbit costal chondrocytes and meniscus tissue cells. Biorheology 2008;45(3-4):289-99
85. Burns WC, Kantharidis P, Thomas MC. The role of tubular epithelial-mesenchymal transition in progressive kidney disease. Cells Tissues Organs 2007;185(1-3):222-31 (Pubitemid 46956862)
86. Burns WC, Twigg SM, Forbes JM, et al. Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease. J Am Soc Nephrol 2006;17(9):2484-94 (Pubitemid 44300964)
87. Ito Y, Aten J, Bende RJ, et al. Expression of connective tissue growth factor in human renal fibrosis. Kidney Int 1998;53(4):853-61 (Pubitemid 28155657)
88. Ito Y, Aten J, Nguyen TQ, et al. Involvement of connective tissue growth factor in human and experimental hypertensive nephrosclerosis. Nephron Exp Nephrol 2011;117(1):e9-20
89. Roestenberg P, van Nieuwenhoven FA, Joles JA, et al. Temporal expression profile and distribution pattern indicate a role of connective tissue growth factor (CTGF/CCN-2) in diabetic nephropathy in mice. Am J Physiol Renal Physiol 2006;290(6):1344-54
90. Denton CP, Abraham DJ. Transforming growth factor-[beta] and connective tissue growth factor: key cytokines in scleroderma pathogenesis. Curr Opin Rheumatol 2001;13(6):505
91. Dendooven A, Gerritsen KG, Nguyen TQ, et al. Connective tissue growth factor (CTGF/CCN2) ELISA: a novel tool for monitoring fibrosis. Biomarkers 2011;16(4):289-301
92. Goldschmeding R, Aten J, Ito Y, et al. Connective tissue growth factor: just another factor in renal fibrosis? Nephrol Dial Transplant 2000;15(3):296-9 (Pubitemid 30116458)
93. Sanchez-Lopez E, Rayego S, Rodrigues-Diez R, et al. CTGF promotes inflammatory cell infiltration of the renal interstitium by activating NF-kappaB. J Am Soc Nephrol 2009;20(7):1513-26
94. Twigg SM, Cooper ME. The time has come to target connective tissue growth factor in diabetic complications. Diabetologia 2004;47(6):965-8 (Pubitemid 38918153)
95. Adler SG, Schwartz S, Williams ME, et al. Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria. CJASN 2010;5(8):1420-8
96. Lassila M, Jandeleit-Dahm K, Seah KK, et al. Imatinib attenuates diabetic nephropathy in apolipoprotein E-knockout mice. J Am Soc Nephrol 2005;16(2):363-73 (Pubitemid 41725131)
97. Mogyorosi A, Ziyadeh FN. What is the role of decorin in diabetic kidney disease? Nephrol Dial Transplant 1999;14(5):1078-81 (Pubitemid 29209286)
98. Hawthorne T, Giot L, Blake L, et al. A phase I study of CR002, a fully-human monoclonal antibody against platelet-derived growth factor-D. Int J Clin Pharmacol Ther 2008;46(5):236-44 (Pubitemid 351663160)
99. Cho ME, Smith DC, Branton MH, et al. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 2007;2(5):906-13
100. Soma J, Sato K, Saito H, Tsuchiya Y. Effect of tranilast in early-stage diabetic nephropathy. Nephrol Dial Transplant 2006;21(10):2795-9 (Pubitemid 44542233)
101. Soma J, Sugawara T, Huang YD, et al. Tranilast slows the progression of advanced diabetic nephropathy. Nephron 2002;92(3):693-8
102. Williams JM, Zhang J, North P, et al. Evaluation of metalloprotease inhibitors on hypertension and diabetic nephropathy. Am J Physiol Renal Physiol 2011;300(4):F983-98
103. Aggarwal HK, Jain D, Talapatra P, et al. Evaluation of role of doxycycline (a matrix metalloproteinase inhibitor) on renal functions in patients of diabetic nephropathy. Ren Fail 2010;32(8):941-6
104. Watanabe T, Pakala R, Katagiri T, Benedict CR. Synergistic effect of urotensin II with mildly oxidized LDL on DNA synthesis in vascular smooth muscle cells. Circulation 2001;104(1):16-18 (Pubitemid 32623283)
105. Watanabe T, Pakala R, Katagiri T, Benedict CR. Synergistic effect of urotensin II with serotonin on vascular smooth muscle cell proliferation. J Hypertens 2001;19(12):2191-6 (Pubitemid 33135241)
106. Langham RG, Kelly DJ, Gow RM, et al. Increased expression of urotensin II and urotensin II receptor in human diabetic nephropathy. Am J Kidney Dis 2004;44(5):826-31 (Pubitemid 39445914)
107. Totsune K, Takahashi K, Arihara Z, et al. Elevated plasma levels of immunoreactive urotensin II and its increased urinary excretion in patients with type 2 diabetes mellitus: association with progress of diabetic nephropathy. Peptides 2004;25(10):1809-14 (Pubitemid 39346225)
108. Clozel M, Binkert C, Birker-Robaczewska M, et al. Pharmacology of the urotensin-II receptor antagonist palosuran (ACT- 058362; 1-[2-(4-benzyl-4- hydroxypiperidin- 1-yl)-ethyl]-3-(2-methylquinolin- 4-yl)-urea sulfate salt): first demonstration of a pathophysiological role of the urotensin System. J Pharmacol Exp Ther 2004;311(1):204-12 (Pubitemid 39302621)
109. Sidharta PN, Wagner FD, Bohnemeier H, et al. Pharmacodynamics and pharmacokinetics of the urotensin II receptor antagonist palosuran in macroalbuminuric, diabetic patients. Clin Pharmacol Ther 2006;80(3):246-56 (Pubitemid 44313907)
110. Vogt L, Chiurchiu C, Chadha-Boreham H, et al. Effect of the urotensin receptor antagonist palosuran in hypertensive patients with type 2 diabetic nephropathy. Hypertension 2010;55(5):1206-9
111. Behm DJ, Aiyar NV, Olzinski AR, et al. GSK1562590, a slowly dissociating urotensin-II receptor antagonist, exhibits prolonged pharmacodynamic activity ex vivo. Br J Pharmacol 2010;161(1):207-28
112. Meier M, Park JK, Overheu D, et al. Deletion of protein kinase C-beta isoform in vivo reduces renal hypertrophy but not albuminuria in the streptozotocin-induced diabetic mouse model. Diabetes 2007;56(2):346-54
113. Koya D, Haneda M, Nakagawa H, et al. Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J 2000;14(3):439-47 (Pubitemid 30143162)
114. Ishii H, Jirousek MR, Koya D, et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 1996;272(5262):728-31 (Pubitemid 26000279)
115. Tuttle KR, Bakris GL, Toto RD, et al. The effect of ruboxistaurin on nephropathy in type 2 diabetes. Diabetes Care 2005;28(11):2686-90 (Pubitemid 43951160)
116. Tuttle KR, McGill JB, Haney DJ, et al. Kidney outcomes in long-term studies of ruboxistaurin for diabetic eye disease. Clin J Am Soc Nephrol 2007;2(4):631-6
117. Forbes JM, Coughlan MT, Cooper ME. Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes 2008;57(6):1446-54
118. Asaba K, Tojo A, Onozato ML, et al. Effects of NADPH oxidase inhibitor in diabetic nephropathy. Kidney Int 2005;67(5):1890-8 (Pubitemid 40577724)
119. Sedeek M, Gutsol A, Montezano AC, et al. Renoprotective effects of a novel Nox1/4 inhibitor in a mouse model of Type 2 diabetes. Clin Sci (Lond) 2013;124(3):191-202
120. Goicoechea M, de Vinuesa SG, Verdalles U, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol 2010;5(8):1388-93
121. Momeni A, Shahidi S, Seirafian S, et al. Effect of allopurinol in decreasing proteinuria in type 2 diabetic patients. Iran J Kidney Dis 2010;4(2):128-32
122. Abdellatif AA, Elkhalili N. Management of gouty arthritis in patients with Chronic Kidney disease. Am J Ther 2012; [Epub ahead of print]
123. Morcos M, Borcea V, Isermann B, et al. Effect of alpha-lipoic acid on the progression of endothelial cell damage and albuminuria in patients with diabetes mellitus: an exploratory study. Diabetes Res Clin Pract 2001;52(3):175-83 (Pubitemid 32385330)
124. Zibadi S, Rohdewald PJ, Park D, Watson RR. Reduction of cardiovascular risk factors in subjects with type 2 diabetes by pycnogenol supplementation. Nutr Res 2008;28(5):315-20 (Pubitemid 351609206)
125. Kar P, Laight D, Rooprai HK, et al. Effects of grape seed extract in type 2 diabetic subjects at high cardiovascular risk: a double blind randomized placebo controlled trial examining metabolic markers, vascular tone, inflammation, oxidative stress and insulin sensitivity. Diabet Med 2009;26(5):526-31
126. Kadhim HM, Ismail SH, Hussein KI, et al. Effects of melatonin and zinc on lipid profile and renal function in type 2 diabetic patients poorly controlled with metformin. J Pineal Res 2006;41(2):189-93 (Pubitemid 44141755)
127. Farvid MS, Jalali M, Siassi F, Hosseini M. Comparison of the effects of vitamins and/or mineral supplementation on glomerular and tubular dysfunction in type 2 diabetes. Diabetes Care 2005;28(10):2458-64 (Pubitemid 41384294)
128. Lonn E, Yusuf S, Hoogwerf B, et al. Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy. Diabetes Care 2002;25(11):1919-27 (Pubitemid 41071045)
129. Mann JF, Lonn EM, Yi Q, et al. Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficiency: results of the HOPE study. Kidney Int 2004;65(4):1375-80 (Pubitemid 38406976)
130. Yokoyama M, Torita M, Yoshizawa M, Usuda R. Indication of vitamin E on microalbuminuria in patients with incipient diabetic nephropathy. Diabetes Metab 2001;27(5 Pt 1):611-12 (Pubitemid 33051712)
131. Gaede P, Poulsen HE, Parving HH, Pedersen O. Double-blind, randomised study of the effect of combined treatment with vitamin C and E on albuminuria in Type 2 diabetic patients. Diabet Med 2001;18(9):756-60 (Pubitemid 32955529)
132. DeRubertis FR, Craven PA, Melhem MF. Acceleration of diabetic renal injury in the superoxide dismutase knockout mouse: effects of tempol. Metabolism 2007;56(9):1256-64 (Pubitemid 47223266)
133. Xue M, Qian Q, Adaikalakoteswari A, et al. Activation of NF-E2-related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease. Diabetes 2008;57(10):2809-17
134. Zheng H, Whitman SA, Wu W, et al. Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. Diabetes 2011;60(11):3055-66
135. Pergola PE, Raskin P, Toto RD, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med 2011;365(4):327-36
136. Pergola PE, Krauth M, Huff JW, et al. Effect of bardoxolone methyl on kidney function in patients with T2D and Stage 3b-4 CKD. Am J Nephrol 2010;33(5):469-76
137. Johnstone MT, Creager SJ, Scales KM, et al. Impaired endothelium- dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993;88(6):2510-16 (Pubitemid 23360174)
138. Williams SB, Cusco JA, Roddy M-A, et al. Impaired nitric oxide-mediated vasodilatation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1996;27:567-74 (Pubitemid 26081917)
139. Turnbull CM, Marcarino P, Sheldrake TA, et al. A novel hybrid aspirin-NO-releasing compound inhibits TNFalpha release from LPS-activated human monocytes and macrophages. J Inflamm (Lond) 2008;5:12
140. Schuhmacher S, Oelze M, Bollmann F, et al. Vascular dysfunction in experimental diabetes is improved by pentaerithrityl tetranitrate but not isosorbide-5-mononitrate therapy. Diabetes 2011;60(10):2608-16
141. Kuno Y, Iyoda M, Shibata T, et al. Sildenafil, a phosphodiesterase type 5 inhibitor, attenuates diabetic nephropathy in non-insulin-dependent Otsuka Long-Evans Tokushima Fatty rats. Br J Pharmacol 2011;162(6):1389-400
142. Grover-Paez F, Villegas Rivera G, Guillen Ortiz R. Sildenafil citrate diminishes microalbuminuria and the percentage of A1c in male patients with type 2 diabetes. Diabetes Res Clin Pract 2007;78(1):136-40 (Pubitemid 47351245)
143. Onozato ML, Tojo A, Goto A, Fujita T. Effect of combination therapy with dipyridamole and quinapril in diabetic nephropathy. Diabetes Res Clin Pract 2003;59(2):83-92 (Pubitemid 36135826)
144. Aizawa T, Suzuki S, Asawa T, et al. Dipyridamole reduces urinary albumin excretion in diabetic patients with normo- or microalbuminuria. Clin Nephrol 1990;33(3):130-5 (Pubitemid 20104001)
145. Navarro JF, Mora C, Muros M, Garcia J. Additive antiproteinuric effect of pentoxifylline in patients with type 2 diabetes under angiotensin II receptor blockade: a short-term, randomized, controlled trial. J Am Soc Nephrol 2005;16(7):2119-26 (Pubitemid 41716443)
146. Aminorroaya A, Janghorbani M, Rezvanian H, et al. Comparison of the effect of pentoxifylline and captopril on proteinuria in patients with type 2 diabetes mellitus. Nephron Clin Pract 2005;99(3):c73-7
147. Shan D, Wu HM, Yuan QY, et al. Pentoxifylline for diabetic kidney disease. Cochrane Database Syst Rev 2012;2:CD006800
148. Navarro-Gonzalez JF, Muros M, Mora-Fernandez C, et al. Pentoxifylline for renoprotection in diabetic nephropathy: the PREDIAN study. Rationale and basal results. J Diabetes Complications 2011;25(5):314-19
149. Salmon AH, Ferguson JK, Burford JL, et al. Loss of the endothelial glycocalyx links albuminuria and vascular dysfunction. J Am Soc Nephrol 2012;23(8):1339-50
150. Salmon AH, Satchell SC. Endothelial glycocalyx dysfunction in disease: albuminuria and increased microvascular permeability. J Pathol 2012;226(4):562-74
151. Gambaro G, Cavazzana AO, Luzi P, et al. Glycosaminoglycans prevent morphological renal alterations and albuminuria in diabetic rats. Kidney Int 1992;42(2):285-91
152. Achour A, Kacem M, Dibej K, et al. One year course of oral sulodexide in the management of diabetic nephropathy. J Nephrol 2005;18(5):568-74 (Pubitemid 41824477)
153. van der Pijl JW, van der Woude FJ, Geelhoed-Duijvestijn PH, et al. Danaparoid sodium lowers proteinuria in diabetic nephropathy. J Am Soc Nephrol 1997;8(3):456-62 (Pubitemid 127454181)
154. Gambaro G, Kinalska I, Oksa A, et al. Oral sulodexide reduces albuminuria
155. Sulikowska B, Olejniczak H, Muszynska M, et al. Effect of sulodexide on albuminuria, NAG excretion and glomerular filtration response to dopamine in diabetic patients. Am J Nephrol 2006;26(6):621-8 (Pubitemid 46143884)
156. Blouza S, Dakhli S, Abid H, et al. Efficacy of low-dose oral sulodexide in the management of diabetic nephropathy. J Nephrol 2010;23(4):415-24
157. Lewis EJ, Lewis JB, Greene T, et al. Sulodexide for kidney protection in type 2 diabetes patients with microalbuminuria: a randomized controlled trial. Am J Kidney Dis 2011;58(5):729-36
158. 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(1):123-30
159. Gambaro G. Discounting the efficacy of sulodexide in diabetic nephropathy is premature. Am J Kidney Dis 2012;60(1):169-70
160. Neuhofer W, Pittrow D. Role of endothelin and endothelin receptor antagonists in renal disease. Eur J Clin Invest 2006;36(Suppl 3):78-88 (Pubitemid 44179788)
161. Hocher B, Thone-Reineke C, Rohmeiss P, et al. Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension. J Clin Invest 1997;99(6):1380-9 (Pubitemid 27142776)
162. De Mattia G, Cassone-Faldetta M, Bellini C, et al. Role of plasma and urinary endothelin-1 in early diabetic and hypertensive nephropathy. Am J Hypertens 1998;11(8 Pt 1):983-8 (Pubitemid 28378413)
163. Nakamura T, Ebihara I, Fukui M, et al. Effect of a specific endothelin receptor A antagonist on mRNA levels for extracellular matrix components and growth factors in diabetic glomeruli. Diabetes 1995;44(8):895-9
164. Dhein S, Hochreuther S, Aus Dem Spring C, et al. Long-term effects of the endothelin(A) receptor antagonist LU 135252 and the angiotensin-converting enzyme inhibitor trandolapril on diabetic angiopathy and nephropathy in a chronic type I diabetes mellitus rat model. J Pharmacol Exp Ther 2000;293(2):351-9 (Pubitemid 30244081)
165. Hocher B, Schwarz A, Reinbacher D, et al. Effects of endothelin receptor antagonists on the progression of diabetic nephropathy. Nephron 2001;87(2):161-9 (Pubitemid 32215829)
166. Sasser JM, Sullivan JC, Hobbs JL, et al. Endothelin A receptor blockade reduces diabetic renal injury via an anti-inflammatory mechanism. J Am Soc Nephrol 2007;18(1):143-54 (Pubitemid 46053429)
167. Honing ML, Hijmering ML, Ballard DE, et al. Selective ET(A) receptor antagonism with ABT-627 attenuates all renal effects of endothelin in humans. J Am Soc Nephrol 2000;11(8):1498-504 (Pubitemid 30483466)
168. Kohan DE, Pritchett Y, Molitch M, et al. Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy. J Am Soc Nephrol 2011;22(4):763-72
169. Mann JF, Green D, Jamerson K, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol 2010;21(3):527-35
170. Wenzel RR, Littke T, Kuranoff S, et al. Avosentan reduces albumin excretion in diabetics with macroalbuminuria. J Am Soc Nephrol 2009;20(3):655-64
171. Baltatu OC, Iliescu R, Zaugg CE, et al. Antidiuretic effects of the endothelin receptor antagonist avosentan. Front Physiol 2012;3:103
172. Navarro JF, Milena FJ, Mora C, et al. Tumor necrosis factor-alpha gene expression in diabetic nephropathy: relationship with urinary albumin excretion and effect of angiotensin-converting enzyme inhibition. Kidney Int Suppl 2005(99):S98-102
173. Navarro JF, Mora C, Muros M, Garcia J. Urinary tumour necrosis factor-alpha excretion independently correlates with clinical markers of glomerular and tubulointerstitial injury in type 2 diabetic patients. Nephrol Dial Transplant 2006;21(12):3428-34 (Pubitemid 44817091)
174. Sfikakis PP, Grigoropoulos V, Emfietzoglou I, et al. Infliximab for diabetic macular edema refractory to laser photocoagulation: a randomized, double-blind, placebo-controlled, crossover, 32-week study. Diabetes Care 2010;33(7):1523-8
175. Dominguez H, Storgaard H, Rask-Madsen C, et al. Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes. J Vasc Res 2005;42(6):517-25 (Pubitemid 41527607)
176. Gupta-Ganguli M, Cox K, Means B, et al. Does therapy with anti-TNF-alpha improve glucose tolerance and control in patients with type 2 diabetes? Diabetes Care 2011;34(7):e121
177. Tesch GH. MCP-1/CCL2: a new diagnostic marker and therapeutic target for progressive renal injury in diabetic nephropathy. Am J Physiol Renal Physiol 2008;294(4):F697-701