TGF-β

Accumulation of matrix molecules in the glomerulus is a characteristic of established and progressive diabetic nephropathy. Several growth factors and cytokines produced in the kidney appear to contribute to the matrix accumulation and scarring in progressive diabetic nephropathy. Foremost among these is transforming growth factor-β (TGF-β) Our investigative group and many others have found that the TGF-b system is activated and plays a pathogenic role in diabetic kidney disease in both animal and human diabetes models. Approaches that block TGF-βaction and do not rely on glycemic control, BP control, or blocking the RAS axis will provide important additional therapies to prevent progressive diabetic nephropathy and renal failure.


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The significant role of TGF-β in mediating mesangial matrix accumulation has now been established in cell culture and animal models of diabetic kidney disease. The use of neutralizing anti-TGF-β have demonstrated that patients with diabetes have increased renal production of TGF-b. This is evidenced not only by increased renal vein blood levels of TGF-b but also increased urinary levels of TGF-β. Urine TGF-β levels may provide insight into the activity of the renal TGF-β system and reflect disease activity.

 

Methods to inhibit TGF-β production or activity may be divided into indirect and direct approaches. Indirect means of inhibiting TGF-β include blocking known stimulators of the TGF-β system, such as ele-vated glucose, RAS, advanced glycated proteins, PKC, hemodynamic stress, and reactive oxygen species generation. There are multiple pathways by which TGF-β may be stimulated, thus complicating the treatment approach to block TGF-β. Direct blockade with antibodies to TGF-β remains a possibility and awaits further clinical developments.

 

Pirfenidone

Another anti-fibrotic strategy involves pirfenidone, a low molecular weight synthetic molecule that exerts dramatic anti-fibrotic as well as anti-inflammatory and anti-oxidant activity. Although, the mechanism of action of pirfenidone as an anti-fibrotic agent is not fully understood, data from cell culture and various animal models suggest that pirfenidone is a selective regulator of gene expressions triggered by signals from a variety of cytokine factors, including TGF-β, PDGF, and TNF-α.

 

In addition, pirfenidone reduces the production of other fibrogenic factors such as connective tissue growth factor that are induced by TGF-β. As similar pathologic pathways contribute to the eventual scarring of ESRD from diabetes, it is likely that the combined inhibitory actions of pirfenidone on inflam-mation, growth factor production, fibroblast proliferation and matrix accumulation would be very effective in progressive fibrotic disorders. The combined experience with pirfenidone in limited patient studies and in animal models of progressive kidney disease suggests that the compound is safe and may provide stabilization of renal function, even when administered for a relatively short period.

 

We are conducting an NIH-sponsored study to determine if pirfenidone is beneficial in patients

with progressive diabetic nephropathy. This is the first randomized double-blind study to evaluate the role of this novel anti-fibrotic agent in diabetic nephropathy. Other anti-fibrotic approaches will likely be coming to the clinic in the near future, thus heralding a new wave of therapies aimed at arresting progressive kidney disease.

 

Conclusions

The prevalence of CKD, and its associated risk to the cardiovascular system, presents an opportune time for identifying innovative approaches to the treatment of diabetic nephropathy. Disease management approaches similar to the multidisciplinary clinical teams used to treat patients with cancer and heart failure should become the standard of care. Patients with diabetic nephropathy can benefit from early intervention by nephrologists, endocrinologists, and cardiologists. Efficient, cost-effective models that meet target goals should be strongly supported by insurers.

 

Novel therapies are clearly needed for this growing population before complications of CKD and

the need for dialysis overwhelm the health-care system. With recent insights gained from translational studies in diabetic kidney disease, it is likely that within the next 5-10 years, several innovative therapies based on PKC inhibition and anti-fibrotic strategies will become available. Consequently, for a large segment of the at-risk population, there is renewed optimism that diabetic nephropathy may be stopped in its early stages. Such strategies will have major repercussions for our patients and the health-care system.

 

Dr. Sharma is an endowed professor of medicine at JeffersonMedicalCollege and director of

the Center for Novel Therapies for Kidney Disease at ThomasJeffersonUniversityHospital in Philadelphia. Dr. Sharma is also a translational researcher and clinician focused on diabetic kidney disease. His work is funded by grants from the NIH, ADA, and JDRF.