Diabetes mellitus is the leading cause of end stage renal disease and is responsible for more than 40% of all cases in the United States. Several therapeutic interventions for the treatment of diabetic nephropathy have been developed and implemented over the past few decades with some degree of success. However, the renal protection provided by these therapeutic modalities is incomplete. More effective approaches are therefore urgently needed. Recently, several novel therapeutic strategies have been explored in treating DN patients including Islet cell transplant, Aldose reductase inhibitors, Sulodexide (GAC), Protein Kinase C (PKC) inhibitors, Connective tissue growth factor (CTGF) inhibitors, Transforming growth factor-beta (TGF-β) inhibitors and bardoxolone. The benefits and risks of these agents are still under investigation. This review aims to summarize the utility of these novel therapeutic approaches.
KeywordsMarkersAlbuminuriaDiabetesTherapy
United States Renal Data System (USRDS), “The National Institutes of Diabetes and Digestive and Kidney Diseases,” Annual Data Report, Bethesda, 2005.
G. Eknoyan, T. Hostetter, G. L. Bakris, L. Hebert, A. S. Levey, H. H. Parving, M. W. Steffes and R. Toto, “Proteinuria and Other Markers of Chronic Kidney Disease: A Position Statement of the National Kidney Foundation (NKF) and the National Institute of Diabetes and Diges tive and Kidney Diseases (NIDDK),” Journal of Kidney Diseases, Vol. 42, No. 4, 2003, pp. 617622. doi:10.1016/S02726386(03)008266
C. E. Mogensen, “Microalbuminuria as a predictor of clinical diabetic nephropathy,” Kidney International, Vol. 31, 1987, pp. 673689. doi:10.1038/ki.1987.50
A. S. Krolewski, J. H. Warram, L. I. Rand and C. R. Kahn, “Epidemiologic Approach to the Etiology of Type I Diabetes Mellitus and Its Complications,” The New England Journal of Medicine, Vol. 317, No. 22, 1987, pp. 13901398. doi:10.1056/NEJM198711263172206
A. M. Berhane, E. J. Weil, W. C. Knowler, R. G. Nelson and R. L. Hanson, “Albuminuria and Estimated Glomerular Filtration Rate as Predictors of Diabetic EndStage Renal Disease and Death,” Clinical Journal of the Ame rican Society of Nephrology, Vol. 6, No. 10, 2011, pp. 24442451. doi:10.2215/CJN.00580111
H. C. Gerstein, J. F. Mann, Q. Yi, B. Zinman, S. F. Dinneen, B. Hoogwerf, J. P. Halle, J. Young, A. Rashkow, C. Joyce, S. Nawaz and S. Yusuf, “Albuminuria and Risk of Cardiovascular Events, Death, and Heart Failure in Diabetic and Nondiabetic Individuals,” The Journal of the American Medical Association, Vol. 286, No. 4, 2001, pp. 421426. doi:10.1001/jama.286.4.421
E. M. AbdelRahman, L. Saadulla, W. B. Reeves and A. S. Awad, “Therapeutic Modalities in Diabetic Nephropathy: Standard and Emerging Approaches,” Journal of General Internal Medicine, Vol. 27, No. 4, 2011, pp. 458 468.
D. W. Cockcroft and M. H. Gault, “Prediction of Cre atinine Clearance from Serum Creatinine,” Nephron, Vol. 16, No. 1, 1976, pp. 3141. doi:10.1159/000180580
A. S. Levey, J. Coresh, E. Balk, A. T. Kausz, A. Levin, M. W. Steffes, R. J. Hogg, R. D. Perrone, J. Lau and G. Eknoyan, “National Kidney Foundation Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification,” Annals of Internal Medicine, Vol. 139, No. 2, 2003, pp. 137147.
A. S. Levey, L. A. Stevens, C. H. Schmid, Y. L. Zhang, A. F. Castro, H. I. Feldman, J. W. Kusek, P. Eggers, F. Van Lente, T. Greene and J. Coresh, “A New Equation to Estimate Glomerular Filtration Rate,” Annals of Internal Medicine, Vol. 150, No. 9, 2009, pp. 604612.
B. A. Perkins, R. G. Nelson, B. E. Ostrander, K. L. Blouch, A. S. Krolewski, B. D. Myers and J. H. Warram, “Detection of Renal Function Decline in Patients with Diabetes and Normal or Elevated GFR by Serial Mea surements of Serum Cystatin C Concentration: Results of a 4Year Followup Study,” Journal of the American Society of Nephrology, Vol. 16, No. 5, 2005, pp. 14041412. doi:10.1681/ASN.2004100854
R. J. Macisaac, C. Tsalamandris, M. C. Thomas, E. Premaratne, S. Panagiotopoulos, T. J. Smith, A. Poon, M. A. Jenkins, S. I. Ratnaike, D. A. Power and G. Jerums, “The Accuracy of Cystatin C and Commonly Used Creatinine Based Methods for Detecting Moderate and Mild Chronic Kidney Disease in Diabetes,” Diabetic Medicine, Vol. 24, No. 4, 2007, pp. 443448. doi:10.1111/j.14645491.2007.02112.x
B. P. Tabaei, A. S. AlKassab, L. L. Ilag, C. M. Zawacki and W. H. Herman, “Does Microalbuminuria Predict Diabetic Nephropathy?” Diabetes Care, Vol. 24, No. 9, 2001, pp. 15601566. doi:10.2337/diacare.24.9.1560
B. A. Perkins, L. H. Ficociello, B. E. Ostrander, K. H. Silva, J. Weinberg, J. H. Warram and A. S. Krolewski, “Microalbuminuria and the Risk for Early Progressive Renal Function Decline in Type 1 Diabetes,” Journal of the American Society of Nephrology, Vol. 18, No. 4, 2007, pp. 13531361.
Y. Ito, J. Aten, R. J. Bende, B. S. Oemar, T. J. Rabelink, J. J. Weening and R. Goldschmeding, “Expression of Connective Tissue Growth Factor in Human Renal Fibrosis,” Kidney International, Vol. 53, 1998, pp. 853861. doi:10.1111/j.15231755.1998.00820.x
T. Q. Nguyen, L. Tarnow, S. Andersen, P. Hovind, H. H. Parving, R. Goldschmeding and F. A. van Nieuwenhoven, “Urinary Connective Tissue Growth Factor Excretion Correlates with Clinical Markers of Renal Disease in a Large Population of Type 1 Diabetic Patients with Diabetic Nephropathy,” Diabetes Care, Vol. 29, No. 1, 2006, pp. 8388. doi:10.2337/diacare.29.01.06.dc051670
A. A. Jaffa, W. R. Usinger, M. B. McHenry, M. A. Jaffa, S. R. Lipstiz, D. Lackland, M. LopesVirella, L. M. Luttrell and P. W. Wilson, “Connective Tissue Growth Factor and Susceptibility to Renal and Vascular Disease Risk in Type 1 Diabetes,” The Journal of Clinical Endocrinology & Metabolism, Vol. 93, No. 5, 2008, pp. 1893 1900. doi:10.1210/jc.20072544
R. G. Langham, D. J. Kelly, R. M. Gow, Y. Zhang, D. J. Cordonnier, N. Pinel, P. Zaoui and R. E. Gilbert, “Transforming Growth Factor? in Human Diabetic Nephropathy: Effects of ACE Inhibition,” Diabetes Care, Vol. 29, No. 12, 2006, pp. 26702675. doi:10.2337/dc060911
K. Kalantarinia, A. S. Awad and H. M. Siragy, “Urinary and Renal Interstitial Concentrations of TNFα Increase Prior to the Rise in Albuminuria in Diabetic Rats,” Kidney International, Vol. 64, 2003, pp. 12081213. doi:10.1046/j.15231755.2003.00237.x
T. Nakamura, C. Ushiyama, S. Suzuki, M. Hara, N. Shimada, I. Ebihara and H. Koide, “Urinary Excretion of Podocytes in Patients with Diabetic Nephropathy,” Nephrology Dialysis Transplantation, Vol. 15, No. 9, 2000, pp. 13791383. doi:10.1093/ndt/15.9.1379
T. Matsubara, H. Abe, H. Arai, K. Nagai, A. Mima, H. Kanamori, E. Sumi, T. Takahashi, M. Matsuura, N. Iehara, A. Fukatsu, T. Kita and T. Doi, “Expression of Smad1 is Directly Associated with Mesangial Matrix Expansion in Rat Diabetic Nephropathy,” Laboratory Investigation, Vol. 86, 2006, pp. 357368. doi:10.1038/labinvest.3700400
A. Mima, H. Arai, T. Matsubara, H. Abe, K. Nagai, Y. Tamura, K. Torikoshi, M. Araki, H. Kanamori, T. Takahashi, T. Tominaga, M. Matsuura, N. Iehara, A. Fukatsu, T. Kita and T. Doi, “Urinary Smad1 Is a Novel Marker to Predict Later Onset of Mesangial Matrix Expansion in Diabetic Nephropathy,” Diabetes, Vol. 57, No. 6, 2008, pp. 17121722. doi:10.2337/db071726
J. Mishra, C. Dent, R. Tarabishi, M. M. Mitsnefes, Q. Ma, C. Kelly, S. M. Ruff, K. Zahedi, M. Shao, J. Bean, K. Mori, J. Barasch and P. Devarajan, “Neutrophil GelatinaseAssociated Lipocalin (NGAL) as a Biomarker for Acute Renal Injury after Cardiac Surgery,” The Lancet, Vol. 365, No. 9466, 2005, pp. 12311238. doi:10.1016/S01406736(05)74811X
C. R. Parikh, J. Mishra, H. ThiessenPhilbrook, B. Dursun, Q. Ma, C. Kelly, C. Dent, P. Devarajan and C. L. Edelstein, “Urinary IL18 Is an Early Predictive Biomarker of Acute Kidney Injury after Cardiac Surgery,” Kidney International, Vol. 70, 2006, pp. 199203. doi:10.1038/sj.ki.5001527
M. Bennett, C. L. Dent, Q. Ma, S. Dastrala, F. Grenier, R. Workman, H. Syed, S. Ali, J. Barasch and P. Devarajan, “Urine NGAL Predicts Severity of Acute Kidney Injury after Cardiac Surgery: A Prospective Study,” Clinical Journal of the American Society of Nephrology, Vol. 3, No. 3, 2008, pp. 665673. doi:10.2215/CJN.04010907
W. Ling, N. Zhaohui, H. Ben, G. Leyi, L. Jianping, D. Huili and Q. Jiaqi, “Urinary IL18 and NGAL as Early Predictive Biomarkers in ContrastInduced Nephropathy after Coronary Angiography,” Nephron Clinical Practice, Vol. 108, No. 3, 2008, pp. 176181. doi:10.1159/000117814
T. L. Nickolas, M. J. O’Rourke, J. Yang, M. E. Sise, P. A. Canetta, N. Barasch, C. Buchen, F. Khan, K. Mori, J. Giglio, P. Devarajan and J. Barasch, “Sensitivity and Specificity of a Single Emergency Department Measure ment of Urinary Neutrophil GelatinaseAssociated Lipocalin for Diagnosing Acute Kidney Injury,” Annals of Internal Medicine, Vol. 148, No. 11, 2008, pp. 810819.
D. Bolignano, A. Lacquaniti, G. Coppolino, V. Donato, S. Campo, M. R. Fazio, G. Nicocia and M. Buemi, “Neutrophil GelatinaseAssociated Lipocalin (NGAL) and Progression of Chronic Kidney Disease,” Clinical Journal of the American Society of Nephrology, Vol. 4, No. 2, 2009, pp. 337344. doi:10.2215/CJN.03530708
W. K. Han, V. Bailly, R. Abichandani, R. Thadhani and J. V. Bonventre, “Kidney Injury Molecule1 (KIM1): A Novel Biomarker for Human Renal Proximal Tubule Injury,” Kidney International, Vol. 62, 2002, pp. 237244. doi:10.1046/j.15231755.2002.00433.x
M. M. van Timmeren, M. C. van den Heuvel, V. Bailly, S. J. Bakker, H. van Goor and C. A. Stegeman, “Tubular Kidney Injury Molecule1 (KIM1) in Human Renal Di sease,” The Journal of Pathology, Vol. 212, No. 2, 2007, pp. 209217. doi:10.1002/path.2175
S. E. Nielsen, K. J. Schjoedt, A. S. Astrup, L. Tarnow, M. Lajer, P. R. Hansen, H. H. Parving and P. Rossing, “Neutrophil GelatinaseAssociated Lipocalin (NGAL) and Kidney Injury Molecule 1 (KIM1) in Patients with Diabetic Nephropathy: A CrossSectional Study and the Effects of Lisinopril,” Diabetic Medicine, Vol. 27, No. 10, 2010, pp. 11441150. doi:10.1111/j.14645491.2010.03083.x
S. E. Nielsen, S. Andersen, D. Zdunek, G. Hess, H. H. Parving and P. Rossing, “Tubular Markers Do Not Predict the Decline in Glomerular Filtration Rate in Type 1 Diabetic Patients with Overt Nephropathy,” Kidney International, Vol. 79, No. 10, 2011, pp. 11131118. doi:10.1038/ki.2010.554
G. L. Warnock, D. M. Thompson, R. M. Meloche, R. J. Shapiro, Z. Ao, P. Keown, J. D. Johnson, C. B. Verchere, N. Partovi, I. S. Begg, M. Fung, S. E. Kozak, S. O. Tong, K. M. Alghofaili and C. Harris, “A MultiYear Analysis of Islet Transplantation Compared with Intensive Medical Therapy on Progression of Complications in Type 1 Diabetes,” Transplantation, Vol. 86, No. 12, 2008, pp. 1762 1766. doi:10.1097/TP.0b013e318190b052
M. A. Webb, S. C. Illouz, C. A. Pollard, R. Gregory, J. F. Mayberry, S. G. Tordoff, M. Bone, C. J. Cordle, D. P. Berry, M. L. Nicholson, P. P. Musto and A. R. Dennison, “Islet Auto Transplantation Following Total Pancreatectomy: A LongTerm Assessment of Graft Function,” Pancreas, Vol. 37, No. 3, 2008, pp. 282287. doi:10.1097/mpa.0b013e31816fd7b6
D. L. Vander Jagt, B. Robinson, K. K. Taylor and L. A. Hunsaker, “Aldose Reductase from Human Skeletal and Heart Muscle. Interconvertible Forms Related by Thiol Disulfide Exchange,” The Journal of Biological Chemistry, Vol. 265, No. 34, 1990, pp. 2098220987.
H. Kasajima, S. Yamagishi, S. Sugai, N. Yagihashi and S. Yagihashi, “Enhanced in Situ Expression of Aldose Reductase in Peripheral Nerve and Renal Glomeruli in Diabetic Patients,” Virchows Archiv, Vol. 439, No. 1, 2001, pp. 4654. doi:10.1007/s004280100444
R. G. Tilton, K. Chang, G. Pugliese, D. M. Eades, M. A. Province, W. R. Sherman, C. Kilo and J. R. Williamson, “Prevention of Hemodynamic and Vascular Albumin Filtration Changes in Diabetic Rats by Aldose Reductase Inhibitors,” Diabetes, Vol. 38, No. 10, 1989, pp. 12581270. doi:10.2337/diabetes.38.10.1258
W. G. Robison, Jr., T. N. Tillis, N. Laver and J. H. Kinoshita, “DiabetesRelated Histopathologies of the Rat Retina Prevented with an Aldose Reductase Inhibitor,” Experimental Eye Research, Vol. 50, No. 4, 1990, pp. 355 366. doi:10.1016/00144835(90)90136I
J. P. Kassab, R. Guillot, J. Andre, N. Claperon, G. Bellon, G. Feldmann, J. Peyroux and M. Sternberg, “Renal and Microvascular Effects of an Aldose Reductase Inhibitor in Experimental Diabetes. Biochemical, Functional and Ultrastructural Studies,” Biochemical Pharmacology, Vol. 48, No. 5, 1994, pp. 10031008. doi:10.1016/00062952(94)903719
N. Passariello, J. Sepe, G. Marrazzo, A. de Cicco, A. Peluso, M. C. Pisano, S. Sgambato, P. Tesauro and F. D’Onofrio, “Effect of Aldose Reductase Inhibitor (Tolrestat) on Urinary Albumin Excretion Rate and Glomerular Filtration Rate in Iddm Subjects with Nephropathy,” Diabetes Care, Vol. 16, No. 5, 1993, pp. 789795. doi:10.2337/diacare.16.5.789
K. Iso, H. Tada, K. Kuboki and T. Inokuchi, “LongTerm Effect of Epalrestat, an Aldose Reductase Inhibitor, on the Development of Incipient Diabetic Nephropathy in Type 2 Diabetic Patients,” Journal of Diabetes and Its Complications, Vol. 15, No. 5, 2001, pp. 241244. doi:10.1016/S10568727(01)00160X
A. V. McAuliffe, B. A. Brooks, E. J. Fisher, L. M. Molyneaux and D. K. Yue, “Administration of Ascorbic Acid and an Aldose Reductase Inhibitor (Tolrestat) in Diabetes: Effect on Urinary Albumin Excretion,” Nephron, Vol. 80, No. 3, 1998, pp. 277284. doi:10.1159/000045187
G. Andriuoli, R. Mastacchi and M. Barbanti, “Antithrombotic Activity of a Glycosaminoglycan (Sulodexide) in Rats,” Thrombosis Research, Vol. 34, No. 1, 1984, pp. 8186. doi:10.1016/00493848(84)901087
C. A. Solini A, Barzon I and Crepaldi G, “Therapy with Glycosaminoglycans Lowers Albumin Excretion Rate in NonInsulin Dependent Diabetic Patients with Microalbuminuria,” Diabetes, Nutrition & Metabolism, Vol. 7, 1994, pp. 304307.
J. Skrha, J. Perusicova, P. Pontuch and A. Oksa, “Glycosaminoglycan Sulodexide Decreases Albuminuria in Dia betic Patients,” Diabetes Research and Clinical Practice, Vol. 38, No. 1, 1997, pp. 2531. doi:10.1016/S01688227(97)000764
M. Velussi, et al., “Glycosaminoglycans Oral Therapy Reduces Microalbuminuria, Blood Fibrinogen Levels and Limb Arteriopathy Clinical Signs in Patients with Non Insulin Dependent Diabetes Mellitus,” Diabetes, Nutrition & Metabolism, Vol. 9, 1996, pp. 5358.
A. Solini, L. Vergnani, F. Ricci and G. Crepaldi, “Gly cosaminoglycans Delay the Progression of Nephropathy in NIDDM,” Diabetes Care, Vol. 20, No. 5, 1997, pp. 819823. doi:10.2337/diacare.20.5.819
X. Xu, et al., “Mechanism of Action of SulodexideMe diated Control of Diabetic Proteinuria: Inhibition of He paranase1 Activity,” Journal of the American Society of Nephrology, Vol. 16, 2005, p. 673.
J. B. Maxhimer, M. Somenek, G. Rao, C. E. Pesce, D. Baldwin, P. Gattuso, M. M. Schwartz, E. J. Lewis, R. A. Prinz and X. Xu, “Heparanase1 Gene Expression and Regulation by High Glucose in Renal Epithelial Cells: A Potential Role in the Pathogenesis of Proteinuria in Diabetic Patients,” Diabetes, Vol. 54, No. 7, 2005, pp. 2172 2178. doi:10.2337/diabetes.54.7.2172
G. Gambaro, A. O. Cavazzana, P. Luzi, A. Piccoli, A. Borsatti, G. Crepaldi, E. Marchi, A. P. Venturini and B. Baggio, “Glycosaminoglycans Prevent Morphological Re nal Alterations and Albuminuria in Diabetic Rats,” Kidney International, Vol. 42, 1992, pp. 285291. doi:10.1038/ki.1992.288
M. Rossini, T. Naito, H. Yang, M. Freeman, E. Donnert, L. J. Ma, S. R. Dunn, K. Sharma and A. B. Fogo, “Sulodexide Ameliorates Early But Not Late Kidney Disease in Models of Radiation Nephropathy and Diabetic Nephropathy,” Nephrology Dialysis Transplantation, Vol. 25, No. 6, 2010, pp. 18031810. doi:10.1093/ndt/gfp724
G. Gambaro, I. Kinalska, A. Oksa, P. Pontuch, M. Hertlova, J. Olsovsky, J. Manitius, D. Fedele, S. Czekalski, J. Perusicova, J. Skrha, J. Taton, W. Grzeszczak and G. Crepaldi, “Oral Sulodexide Reduces Albuminuria in Microalbuminuric and Macroalbuminuric Type 1 and Type 2 Diabetic Patients: The Di.N.A.S. Randomized Trial,” Journal of the American Society of Nephrology, Vol. 13, No. 6, 2002, pp. 16151625. doi:10.1097/01.ASN.0000014254.87188.E5
A. Achour, M. Kacem, K. Dibej, H. Skhiri, S. Bouraoui and M. El May, “One Year Course of Oral Sulodexide in the Management of Diabetic Nephropathy,” Journal of Nephrology, Vol. 18, No. 5, 2005, pp. 568574.
H. L. Heerspink, T. Greene, J. B. Lewis, I. Raz, R. D. Rohde, L. G. Hunsicker, S. L. Schwartz, S. Aronoff, M. A. Katz, G. M. Eisner, J. H. Mersey and T. B. Wiegmann, “Effects of Sulodexide in Patients with Type 2 Diabetes and Persistent Albuminuria,” Nephrology Dialysis Transplantation, Vol. 23, No. 6, 2008, pp. 19461954. doi:10.1093/ndt/gfm893
H. J. Lambers Heerspink, et al., “Rationale for and Study Design of the Sulodexide Trials in Type 2 Diabetic, Hypertensive Patients with Microalbuminuria or Overt Ne phropathy,” Diabetic Medicine, Vol. 24, No. 11, 2007, 12901295. doi:10.1111/j.14645491.2007.02249.x
P. G. Goekjian and M. R. Jirousek, “Protein Kinase C in the Treatment of Disease: Signal Transduction Pathways, Inhibitors and Agents in Development,” Current Medicinal Chemistry, Vol. 6, No. 9, 1999, pp. 877903.
K. R. Tuttle, “Protein Kinase C? Inhibition for Diabetic Kidney Disease,” Diabetes Research and Clinical Practice, Vol. 82, Suppl. 1, 2008, pp. 7074. doi:10.1016/j.diabres.2008.09.041
S. Yamagishi, K. Fukami, S. Ueda and S. Okuda, “Molecular Mechanisms of Diabetic Nephropathy and Its Therapeutic Intervention,” Current Drug Targets, Vol. 8, No. 8, 2007, pp. 952959. doi:10.2174/138945007781386884
M. Kunisaki, S. E. Bursell, F. Umeda, H. Nawata and G. L. King, “Normalization of DiacylglycerolProtein Ki nase C Activation by Vitamin E in Aorta of Diabetic Rats and Cultured Rat Smooth Muscle Cells Exposed to Elevated Glucose Levels,” Diabetes, Vol. 43, No. 11, 1994, pp. 13721377. doi:10.2337/diabetes.43.11.1372
M. R. Jirousek, J. R. Gillig, C. M. Gonzalez, W. F. Heath, J. H. McDonald, D. A. Neel, C. J. Rito, U. Singh, L. E. Stramm, A. MelikianBadalian, M. Baevsky, L. M. Ballas, S. E. Hall, L. L. Winneroski and M. M. Faul, “(S)13 [(Dimethylamino)methyl]10,11,14,15tetrahydro4,9:16, 21dimetheno1H, 13Hdibenzo[e,k]pyrrolo[3,4h][1,4,13] oxadiazacyclohexadecene1,3(2H)dione (LY333531) and Related Analogues: Isozyme Selective Inhibitors of Pro tein Kinase C?,” Journal of Medicinal Chemistry, Vol. 39, No. 14, 1996, pp. 2664
H. Ishii, M. R. Jirousek, D. Koya, C. Takagi, P. Xia, A. Clermont, S. E. Bursell, T. S. Kern, L. M. Ballas, W. F. Heath, L. E. Stramm, E. P. Feener and G. L. King, “Amelioration of Vascular Dysfunctions in Diabetic Rats by an Oral PKC ? Inhibitor,” Science, Vol. 272, No. 5262, 1996, pp. 728731. doi:10.1126/science.272.5262.728
D. Koya, M. Haneda, H. Nakagawa, K. Isshiki, H. Sato, S. Maeda, T. Sugimoto, H. Yasuda, A. Kashiwagi, D. K. Ways, G. L. King and R. Kikkawa, “Amelioration of Accelerated Diabetic Mesangial Expansion by Treatment with a PKC ? Inhibitor in Diabetic db/db Mice, a Rodent Model for Type 2 Diabetes,” The FASEB Journal, Vol. 14, No. 3, 2000, pp. 439447.
D. J. Kelly, Y. Zhang, C. Hepper, R. M. Gow, K. Jaworski, B. E. Kemp, J. L. WilkinsonBerka and R. E. Gilbert, “Protein Kinase C? Inhibition Attenuates the Progression of Experimental Diabetic Nephropathy in the Pre sence of Continued Hypertension,” Diabetes, Vol. 52, No. 2, 2003, pp. 512518. doi:10.2337/diabetes.52.2.512
K. R. Tuttle, G. L. Bakris, R. D. Toto, J. B. McGill, K. Hu and P. W. Anderson, “The Effect of Ruboxistaurin on Nephropathy in Type 2 Diabetes,” Diabetes Care, Vol. 28, No. 11, 2005, pp. 26862690. doi:10.2337/diacare.28.11.2686
L. P. Aiello, M. D. Davis, A. Girach, K. A. Kles, R. C. Milton, M. J. Sheetz, L. Vignati and X. E. Zhi, “Effect of Ruboxistaurin on Visual Loss in Patients with Diabetic Retinopathy,” Ophthalmology, Vol. 113, No. 12, 2006, pp. 22212230. doi:10.1016/j.ophtha.2006.07.032
K. R. Tuttle, J. B. McGill, D. J. Haney, T. E. Lin and P. W. Anderson, “Kidney Outcomes in LongTerm Studies of Ruboxistaurin for Diabetic Eye Disease,” Clinical Journal of the American Society of Nephrology, Vol. 2, No. 4, 2007, pp. 631636. doi:10.2215/CJN.00840207
F. A. van Nieuwenhoven, L. J. Jensen, A. Flyvbjerg and R. Goldschmeding, “Imbalance of Growth Factor Signalling in Diabetic Kidney Disease: Is Connective Tissue Growth Factor (CTGF, CCN2) the Perfect Intervention Point?” Nephrology Dialysis Transplantation, Vol. 20, No. 1, 2005, pp. 610. doi:10.1093/ndt/gfh570
N. A. Wahab, N. Yevdokimova, B. S. Weston, T. Roberts, X. J. Li, H. Brinkman and R. M. Mason, “Role of Connective Tissue Growth Factor in the Pathogenesis of Diabetic Nephropathy,” Biochemical Journal, Vol. 359, Pt. 1, 2001, pp. 7787. doi:10.1042/02646021:3590077
L. F. Lau and S. C. Lam, “The CCN Family of Angiogenic Regulators: The Integrin Connection,” Experimental Cell Research, Vol. 248, No. 1, 1999, pp. 4457. doi:10.1006/excr.1999.4456
B. L. Riser, M. Denichilo, P. Cortes, C. Baker, J. M. Grondin, J. Yee and R. G. Narins, “Regulation of Connective Tissue Growth Factor Activity in Cultured Rat Mesangial Cells and Its Expression in Experimental Diabetic Glomerulosclerosis,” Journal of the American So ciety of Nephrology, Vol. 11, No. 1, 2000, pp. 2538.
S. M. Twigg, A. H. Joly, M. M. Chen, J. Tsubaki, H. S. Kim, V. Hwa, Y. Oh and R. G. Rosenfeld, “Connective tissue Growth Factor/IGFBinding ProteinRelated Protein2 Is a Mediator in the Induction of Fibronectin by Advanced Glycosylation EndProducts in Human Dermal Fibroblasts,” Endocrinology, Vol. 143, No. 4, 2002, pp. 12601269. doi:10.1210/en.143.4.1260
G. Zhou, C. Li and L. Cai, “Advanced Glycation End Products Induce Connective Tissue Growth FactorMe diated Renal Fibrosis Predominantly through Transforming Growth Factor ?Independent Pathway,” American Jour nal of Pathology, Vol. 165, No. 6, 2004, pp. 20332043. doi:10.1016/S00029440(10)632543
N. A. Wahab, B. S. Weston and R. M. Mason, “Connective Tissue Growth Factor CCN2 Interacts with and Activates the Tyrosine Kinase Receptor TrkA,” Journal of the American Society of Nephrology, Vol. 16, No. 2, 2005, pp. 340351. doi:10.1681/ASN.2003100905
P. Roestenberg, F. A. van Nieuwenhoven, J. A. Joles, C. Trischberger, P. P. Martens, N. Oliver, J. Aten, J. W. Hoppener and R. Goldschmeding, “Temporal Expression Profile and Distribution Pattern Indicate a Role of Connective Tissue Growth Factor (CTGF/CCN2) in Diabetic Nephropathy in Mice,” American Journal of Physiology, Vol. 290, No. 6, 2006, pp. 13441354. doi:10.1152/ajprenal.00174.2005
H. Yokoi, M. Mukoyama, T. Nagae, K. Mori, T. Suganami, K. Sawai, T. Yoshioka, M. Koshikawa, T. Nishida, M. Takigawa, A. Sugawara and K. Nakao, “Reduction in Connective Tissue Growth Factor by Antisense Treatment Ameliorates Renal Tubulointerstitial Fibrosis,” Journal of the American Society of Nephrology, Vol. 15, No. 6, 2004, pp. 14301440. doi:10.1097/01.ASN.0000130565.69170.85
H. Okada, T. Kikuta, T. Inoue, Y. Kanno, S. Ban, T. Sugaya, M. Takigawa and H. Suzuki, “Dexamethasone Induces Connective Tissue Growth Factor Expression in Renal Tubular Epithelial Cells in a Mouse StrainSpecific Manner,” American Journal of Pathology, Vol. 168, No. 3, 2006, pp. 737747. doi:10.2353/ajpath.2006.050656
A. Flyvbjerg, et al., “LongTerm Renal Effects of a Neutralizing Connective Tissue Growth Factor (Ctgf)Anti body in Obese Type 2 Diabetic Mice,” Journal of the American Society of Nephrology, Vol. 15, 2004, p. 261.
Q. Wang, et al., “Amelioration of Diabetic Nephropathy (DN) Incused by Renal IschemiaReperfusion (IR) in Rats with Diabetes Mellitus (DM) by Treatment with FG3019, a Monoclonal Antibody Against Connective Tissue Growth Factor (CTGF),” Journal of the American Society of Nephrology, 2004, p. 731.
S. G. Adler, S. Schwartz, M. E. Williams, C. Arauz Pacheco, W. K. Bolton, T. Lee, D. Li, T. B. Neff, P. R. Urquilla and K. L. Sewell, “Phase 1 Study of AntiCTGF Monoclonal Antibody in Patients with Diabetes and Microalbuminuria,” Clinical Journal of the American Society of Nephrology, Vol. 5, No. 8, 2010, pp. 14201428. doi:10.2215/CJN.09321209
S. Schwartz, “Phase 1 Study of FG3019, an AntiCTGF Monoclonal Antibody, in Type 1/2 Diabetes Mellitus with Microalbuminuria,” Diabetes, Vol. 56, 2007, p. 151.
W. Qi, X. Chen, P. Poronnik and C. A. Pollock, “Transforming Growth Factor?/Connective Tissue Growth Factor Axis in the Kidney,” The International Journal of Biochemistry & Cell Biology, Vol. 40, No. 1, 2008, pp. 913. doi:10.1016/j.biocel.2007.01.006
T. A. McGowan, Y. Zhu and K. Sharma, “Transforming Growth Factor?: A Clinical Target for the Treatment of Diabetic Nephropathy,” Current Diabetes Reports, Vol. 4, No. 6, 2004, pp. 447454. doi:10.1007/s118920040055z
K. Sharma, Y. Jin, J. Guo and F. N. Ziyadeh, “Neutralization of TGF? by AntiTGF? Antibody Attenuates Kidney Hypertrophy and the Enhanced Extracellular Matrix Gene Expression in STZInduced Diabetic Mice,” Diabetes, Vol. 45, 1996, pp. 522530. doi:10.2337/diabetes.45.4.522
F. N. Ziyadeh, B. B. Hoffman, D. C. Han, M. C. Iglesiasde la Cruz, S. W. Hong, M. Isono, S. Chen, T. A. McGowan and K. Sharma, “LongTerm Prevention of Renal Insufficiency, Excess Matrix Gene Expression and Glomerular Mesangial Matrix Expansion by Treatment with Monoclonal Antitransforming Growth Factor? Antibody in db/db Diabetic Mice,” Proceedings of the National Academy of Sciences, Vol. 97, No. 14, 2000, pp. 80158020. doi:10.1073/pnas.120055097
K. Sharma, F. N. Ziyadeh, B. Alzahabi, T. A. McGowan, S. Kapoor, B. R. Kurnik, P. B. Kurnik and L. S. Weisberg, “Increased Renal Production of Transforming Growth Factor?1 in Patients with Type II Diabetes,” Diabetes, Vol. 46, No. 5, 1997, pp. 854859. doi:10.2337/diabetes.46.5.854
T. Yamamoto, T. Nakamura, N. A. Noble, E. Ruoslahti and W. A. Border, “Expression of Transforming Growth Factor ? Is Elevated in Human and Experimental Diabetic Nephropathy,” Proceedings of the National Aca demy of Sciences, Vol. 90, No. 5, 1993, pp. 18141818. doi:10.1073/pnas.90.5.1814
S. P. RamachandraRao, Y. Zhu, T. Ravasi, T. A. Mc Gowan, I. Toh, S. R. Dunn, S. Okada, M. A. Shaw and K. Sharma, “Pirfenidone Is Renoprotective in Diabetic Kidney Disease,” Journal of the American Society of Nephrology, Vol. 20, No. 8, 2009, pp. 17651775.
M. Iwano, A. Kubo, T. Nishino, H. Sato, H. Nishioka, Y. Akai, H. Kurioka, Y. Fujii, M. Kanauchi, H. Shiiki and K. Dohi, “Quantification of Glomerular TGF?1 mRNA in Patients with Diabetes Mellitus,” Kidney International, Vol. 49, 1996, pp. 11201126. doi:10.1038/ki.1996.162
T. Yamamoto, N. A. Noble, A. H. Cohen, C. C. Nast, A. Hishida, L. I. Gold and W. A. Border, “Expression of Transforming Growth Factor? Isoforms in Human Glo merular Diseases,” Kidney International, Vol. 49, 1996, pp. 461469. doi:10.1038/ki.1996.65
K. Sharma, J. H. Ix, A. V. Mathew, M. Cho, A. Pflueger, S. R. Dunn, B. Francos, S. Sharma, B. Falkner, T. A. McGowan, M. Donohue, S. Ramachandrarao, R. Xu, F. C. Fervenza and J. B. Kopp, “Pirfenidone for Diabetic Nephropathy,” Journal of the American Society of Nephrology, Vol. 22, No. 6, 2011, pp. 11441151. doi:10.1681/ASN.2010101049
P. E. Pergola, M. Krauth, J. W. Huff, D. A. Ferguson, S. Ruiz, C. J. Meyer and D. G. Warnock, “Effect of Bardoxolone Methyl on Kidney Function in Patients with T2D and Stage 3b4 CKD,” American Journal of Nephrology, Vol. 33, No. 5, 2011, pp. 469476. doi:10.1159/000327599
P. E. Pergola, P. Raskin, R. D. Toto, C. J. Meyer, J. W. Huff, E. B. Grossman, M. Krauth, S. Ruiz, P. Audhya, H. ChristSchmidt, J. Wittes and D. G. Warnock, “Bardoxo lone Methyl and Kidney Function in CKD with Type 2 Diabetes,” The New England Journal of Medicine, Vol. 365, 2011, pp. 327336. doi:10.1056/NEJMoa1105351
“Retinopathy and Nephropathy in Patients with Type 1 Diabetes Four Years after a Trial of Intensive Therapy. The Diabetes Control and Complications Trial/Epidemi ology of Diabetes Interventions and Complications Research Group,” The New England Journal of Medicine, Vol. 342, 2000, pp. 381389. doi:10.1056/NEJM200002103420603
“Sustained Effect of Intensive Treatment of Type 1 Diabetes Mellitus on Development and Progression of Diabetic Nephropathy: The Epidemiology of Diabetes Interventions and Complications (EDIC) Study,” The Journal of the American Medical Association, Vol. 290, No. 16, 2003, pp. 21592167. doi:10.1001/jama.290.16.2159
D. M. Nathan, P. A. Cleary, J. Y. Backlund, S. M. Genuth, J. M. Lachin, T. J. Orchard, P. Raskin and B. Zinman, “Intensive Diabetes Treatment and Cardiovascular Di sease in Patients with Type 1 Diabetes,” The New England Journal of Medicine, Vol. 353, 2005, pp. 26432653. doi:10.1056/NEJMoa052187
I. M. Stratton, A. I. Adler, H. A. Neil, D. R. Matthews, S. E. Manley, C. A. Cull, D. Hadden, R. C. Turner and R. R. Holman, “Association of Glycaemia with Macrovascular and Microvascular Complications of Type 2 Diabetes (UKPDS 35): Prospective Observational Study,” British Medical Journal, Vol. 321, 2000, pp. 405412. doi:10.1136/bmj.321.7258.405
R. R. Holman, S. K. Paul, M. A. Bethel, D. R. Matthews and H. A. Neil, “10Year Followup of Intensive Glucose Control in Type 2 Diabetes,” The New England Journal of Medicine, Vol. 359, 2008, pp. 15771589. doi:10.1056/NEJMoa0806470
UK Prospective Diabetes Study (UKPDS) Group, “Intensive BloodGlucose Control with Sulphonylureas or In sulin Compared with Conventional Treatment and Risk of Complications in Patients with Type 2 Diabetes (UKPDS 33),” The Lancet, Vol. 352, No. 9131, 1998, pp. 837853. doi:10.1016/S01406736(98)070196
A. Patel, S. MacMahon, J. Chalmers, B. Neal, L. Billot, M. Woodward, M. Marre, M. Cooper, P. Glasziou, D. Grobbee, P. Hamet, S. Harrap, S. Heller, L. Liu, G. Mancia, C. E. Mogensen, C. Pan, N. Poulter, A. Rodgers, B. Williams, S. Bompoint, B. E. de Galan, R. Joshi and F. Travert, “Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes,” The New England Journal of Medicine, Vol. 358, 2008, pp. 2560 2572. doi:10.1056/NEJMoa0802987
C. E. Mogensen, “LongTerm Antihypertensive Treatment Inhibiting Progression of Diabetic Nephropathy,” British Medical Journal, Vol. 285, 1982, pp. 685688. doi:10.1136/bmj.285.6343.685
R. W. Schrier, R. O. Estacio, A. Esler and P. Mehler, “Effects of Aggressive Blood Pressure Control in Normotensive Type 2 Diabetic Patients on Albuminuria, Re tinopathy and Strokes,” Kidney International, Vol. 61, 2002, pp. 10861097. doi:10.1046/j.15231755.2002.00213.x
UK Prospective Diabetes Study Group, “Tight Blood Pressure Control and Risk of Macrovascular and Microvascular Complications in Type 2 Diabetes: UKPDS 38,” British Medical Journal, Vol. 317, 1998, pp. 703 713. doi:10.1136/bmj.317.7160.703
UK Prospective Diabetes Study Group, “Cost Effectiveness Analysis of Improved Blood Pressure Control in Hypertensive Patients with Type 2 Diabetes: UKPDS 40,” British Medical Journal, Vol. 317, 1998, pp. 720 726. doi:10.1136/bmj.317.7160.720
A. Patel, S. MacMahon, J. Chalmers, B. Neal, M. Woodward, L. Billot, S. Harrap, N. Poulter, M. Marre, M. Cooper, P. Glasziou, D. E. Grobbee, P. Hamet, S. Heller, L. S. Liu, G. Mancia, C. E. Mogensen, C. Y. Pan, A. Rodgers and B. Williams, “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,” The Lancet, Vol. 370, No. 9590, 2007, pp. 829840. doi:10.1016/S01406736(
B. E. de Galan, V. Perkovic, T. Ninomiya, A. Pillai, A. Patel, A. Cass, B. Neal, N. Poulter, S. Harrap, C. E. Mogensen, M. Cooper, M. Marre, B. Williams, P. Hamet, G. Mancia, M. Woodward, P. Glasziou, D. E. Grobbee, S. MacMahon and J. Chalmers, “Lowering Blood Pressure Reduces Renal Events in Type 2 Diabetes,” Journal of the American Society of Nephrology, Vol. 20, No. 4, 2009, pp. 883892. doi:10.1681/ASN.2008070667
A. V. Chobanian, G. L. Bakris, H. R. Black, W. C. Cushman, L. A. Green, J. L. Izzo, D. W. Jones, B. J. Materson, S. Oparil, J. T. Wright and E. J. Roccella, “Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure,” Hypertension, Vol. 42, 2003, pp. 12061252. doi:10.1161/01.HYP.0000107251.49515.c2
American Diabetes Association, “Standards of Medical Care in Diabetes,” Diabetes Care, Vol. 28, Suppl. 1, 2005, pp. 436. doi:10.2337/diacare.28.suppl_1.S4
Kidney Disease Outcomes Quality Initiative (K/DOQI), “K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease,” American Journal of Kidney Disease, Vol. 43, No. 5, 2004, pp. 1290. doi:10.1053/j.ajkd.2003.11.027
The ACCORD Study Group, “Effects of Intensive Blood Pressure Control in Type 2 Diabetes Mellitus,” The New England Journal of Medicine, 2010, Vol. 362, pp. 1575 1585. doi:10.1056/NEJMoa1001286
The EUCLID Study Group, “Randomised PlaceboCon trolled Trial of Lisinopril in Normotensive Patients with InsulinDependent Diabetes and Normoalbuminuria or Microalbuminuria,” Lancet, Vol. 349, No. 9068, 1997, pp. 17871792. doi:10.1016/S01406736(96)102440
M. Ravid, D. Brosh, Z. Levi, Y. BarDayan, D. Ravid and R. Rachmani, “Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus,” Annals of Internal Medicine, Vol. 128, No. 12, 1998, pp. 982988.
R. O. Estacio, B. W. Jeffers, N. Gifford and R. W. Schrier, “Effect of Blood Pressure Control on Diabetic Microvascular Complications in Patients with Hypertension and Type 2 Diabetes,” Diabetes Care, Vol. 23, Suppl. 2, 2000, pp. 5464.
M. Ravid, H. Savin, I. Jutrin, T. Bental, B. Katz and M. Lishner, “LongTerm Stabilization of AngiotensinCon verting Enzyme Inhibition on Plasma Creatinine and on Proteinuria in Normotensive Type II Diabetic Patients,” Annals of Internal Medicine, Vol. 118, 1993, pp. 577 581.
S. Andersen, L. Tarnow, P. Rossing, B. V. Hansen and H. H. Parving, “Renoprotective Effects of Angiotensin II Receptor Blockade in Type 1 Diabetic Patients with Diabetic Nephropathy,” Kidney International, Vol. 57, 2000, pp. 601606. doi:10.1046/j.15231755.2000.00880.x
B. M. Brenner, M. E. Cooper, D. de Zeeuw, W. F. Keane, W. E. Mitch, H. H. Parving, G. Remuzzi, S. M. Snapinn, Z. Zhang and S. Shahinfar, “Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy,” The New England Journal of Medicine, Vol. 345, 2001, pp. 861869. doi:10.1056/NEJMoa011161
E. J. Lewis, L. G. Hunsicker, W. R. Clarke, T. Berl, M. A. Pohl, J. B. Lewis, E. Ritz, R. C. Atkins, R. Rohde and I. Raz, “Renoprotective Effect of the AngiotensinReceptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes,” The New England Journal of Medicine, Vol. 345, 2001, pp. 851860. doi:10.1056/NEJMoa011303
H. H. Parving, H. Lehnert, J. BrochnerMortensen, R. Gomis, S. Andersen and P. Arner, “The Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes,” The New England Journal of Medicine, Vol. 345, 2001, pp. 870878. doi:10.1056/NEJMoa011489
Y. Uresin, A. A. Taylor, C. Kilo, D. Tschope, M. Santonastaso, G. Ibram, H. Fang and A. Satlin, “Efficacy and Safety of the Direct Renin Inhibitor Aliskiren and Ramipril Alone or in Combination in Patients with Diabetes and Hypertension,” Journal of the ReninAngiotensin Aldosterone System, Vol. 8, No. 4, 2007, pp. 190198. doi:10.3317/jraas.2007.028
H. H. Parving, F. Persson, J. B. Lewis, E. J. Lewis and N. K. Hollenberg, “Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy,” The New England Journal of Medicine, Vol. 358, 2008, pp. 24332446. doi:10.1056/NEJMoa0708379
M. J. Dunn, “Prostaglandins, Angiotension II, and Proteinuria,” Nephron, Vol. 55, Suppl. 1, 1990, pp. 3037. doi:10.1159/000186032
W. R. Melchior, V. Bindlish and L. A. Jaber, “AngiotensinConverting Enzyme Inhibitors in Diabetic Nephropathy,” The Annals of Pharmacotherapy, Vol. 27, 1993, pp. 344350.
G. L. Bakris, M. R. Weir, M. Secic, B. Campbell and A. WeisMcNulty, “Differential Effects of Calcium Antagonist Subclasses on Markers of Nephropathy Progression,” Kidney International, Vol. 65, 2004, pp. 19912002. doi:10.1111/j.15231755.2004.00620.x
G. Remuzzi, P. Ruggenenti and A. Benigni, “Understanding the Nature of Renal Disease Progression,” Kidney International, Vol. 51, 1997, pp. 215. doi:10.1038/ki.1997.2
H. J. Kloke, A. J. Branten, F. T. Huysmans and J. F. Wetzels, “Antihypertensive Treatment of Patients with Proteinuric Renal Diseases: Risks or Benefits of Calcium Channel Blockers?” Kidney International, Vol. 53, 1998, pp. 15591573. doi:10.1046/j.15231755.1998.00912.x
R. T. Gansevoort, W. J. Sluiter, M. H. Hemmelder, D. de Zeeuw and P. E. de Jong, “Antiproteinuric Effect of BloodPressureLowering Agents: A MetaAnalysis of Comparative Trials,” Nephrology Dialysis Transplantation, Vol. 10, 1995, pp. 19631974.
G. L. Bakris, “Effects of Diltiazem or Lisinopril on Massive Proteinuria Associated with Diabetes Mellitus,” Annals of Internal Medicine, Vol. 112, No. 9, 1990, pp. 707708.
G. L. Bakris, J. B. Copley, N. Vicknair, R. Sadler and S. Leurgans, “Calcium Channel Blockers Versus Other Antihypertensive Therapies on Progression of NIDDM Associated Nephropathy,” Kidney International, Vol. 50, 1996, pp. 16411650. doi:10.1038/ki.1996.480
G. Tonolo, M. Velussi, E. Brocco, C. Abaterusso, A. Carraro, G. Morgia, A. Satta, R. Faedda, A. Abhyankar, H. Luthman and R. Nosadini, “Simvastatin Maintains Steady Patterns of GFR and Improves AER and Expression of Slit Diaphragm Proteins in Type II Diabetes,” Kidney International, Vol. 70, 2006, pp. 177186. doi:10.1038/sj.ki.5001515
R. W. Bilous, S. M. Mauer, D. E. Sutherland, J. S. Najarian, F. C. Goetz and M. W. Steffes, “The Effects of Pancreas Transplantation on the Glomerular Structure of Renal Allografts in Patients with InsulinDependent Diabetes,” The New England Journal of Medicine, Vol. 321, No. 2, 1989, pp. 8085. doi:10.1056/NEJM198907133210204