Existing treatment approaches for progressive diabetic nephropathy include anti-hypertensive agents such as angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs). Although recent studies demonstrate the utility of this approach in both type 1 and type 2 diabetic patients, the potency of these agents to arrest diabetic nephropathy in patients with declining renal function is not clear. Although, further modifications of the renin-Angll-aldosterone system may prove to be beneficial, high doses of these agents are difficult to use in patients with declining renal function due to hyperkalemia. low blood pressure, and drug-induced reduction of renal perfusion. The recognition that progressive diabetic nephropathy is largely due to progressive glomerulosclerosis and tubulointerstitial fibrosis has focused attention on mediators and blockers of this process. Our prior studies have helped to establish that a key factor in the mediation of progressive matrix depositrion in the diabetic kidney is transforming growth factor-beta (TGF-beta). However, direct inhibitors of the TGF-beta system are not yet available for clinical trials. We have recently identified that an orally administered drug, pirfenidone, is extremely potent to block progressive glomerulosclerosis when administered after the onset of disease in a mouse model of diabetic nephropathy. Pilot data in patients with type 1 diabetes and nephropathy indicate that this drug is well tolerated. In addition, preliminary data from a recent open-label study in patients with advanced focal sclerosis suggests that pirfenidone may lower the rate of decline of renal function. However, the mode of action of pirfenidone is unclear. Based on the encouraging data in animal models and small clinical studies, we have undertaken a trial to evaluate the role of pirfenidone in patients with type 1 and type 2 diabetes and renal insufficiency. The requested two year renewal of our ongoing randomized, double-blind, placebo study will allow us to assess whether pirfenidone will lower the rate of progression of diabetic nephropathy. In addition, the clinical study will determine whether serial measures of TGF-beta may be used as a biomarker to identify patients who may have a rapid decline in renal function and to determine if the therapeutic benefit of pirfenidone is indeed via inhibition of the TGF-beta system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK063017-05
Application #
7522837
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (O4))
Program Officer
Meyers, Catherine M
Project Start
2002-09-30
Project End
2008-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
5
Fiscal Year
2005
Total Cost
$58,058
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Sharma, Kumar; Ix, Joachim H; Mathew, Anna V et al. (2011) Pirfenidone for diabetic nephropathy. J Am Soc Nephrol 22:1144-51
Sanchez, Amber Paratore; Sharma, Kumar (2009) Transcription factors in the pathogenesis of diabetic nephropathy. Expert Rev Mol Med 11:e13
Deelman, Leo; Sharma, Kumar (2009) Mechanisms of kidney fibrosis and the role of antifibrotic therapies. Curr Opin Nephrol Hypertens 18:85-90
RamachandraRao, Satish P; Zhu, Yanqing; Ravasi, Timothy et al. (2009) Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol 20:1765-75
Kovesdy, Csaba P; Sharma, Kumar; Kalantar-Zadeh, Kamyar (2008) Glycemic control in diabetic CKD patients: where do we stand? Am J Kidney Dis 52:766-77
Zhu, Yanqing; Usui, Hitomi Kataoka; Sharma, Kumar (2007) Regulation of transforming growth factor beta in diabetic nephropathy: implications for treatment. Semin Nephrol 27:153-60
McGowan, Tracy A; Dunn, Stephen R; Falkner, Bonita et al. (2006) Stimulation of urinary TGF-beta and isoprostanes in response to hyperglycemia in humans. Clin J Am Soc Nephrol 1:263-8
Sharma, Kumar; Lee, SoHee; Han, Steven et al. (2005) Two-dimensional fluorescence difference gel electrophoresis analysis of the urine proteome in human diabetic nephropathy. Proteomics 5:2648-55
McGowan, Tracy A; Zhu, Yanqing; Sharma, Kumar (2004) Transforming growth factor-beta: a clinical target for the treatment of diabetic nephropathy. Curr Diab Rep 4:447-54