April 22, 2011

New Drug for Kidney Disease in Diabetes

(Ivanhoe Newswire) -- Researchers have recently published some promising results of a clinical study using an experimental anti-fibrotic and anti-inflammatory drug called pirfenidone to treat patients with diabetic nephropathy.

Diabetes has become the most common single cause of end-stage renal disease (ESRD) in the U.S. and Europe due to the facts that 1) diabetes, particularly type 2, is increasing in prevalence; 2) diabetes patients now live longer; and 3) patients with diabetic ESRD are now being accepted for treatment in ESRD programs where formerly they had been excluded. In the U.S., diabetic nephropathy accounts for about 40 percent of new cases of ESRD, and in 1997, the cost for treatment of diabetic patients with ESRD was in excess of $15.6 billion. About 20 percent to 30 percent of patients with type 1 or type 2 diabetes develop evidence of nephropathy.

"The dramatic finding of this exploratory study is that an appropriate dose of pirfenidone not only halted decline but actually improved kidney function in these patients," Kumar Sharma, MD, FAHA, professor of medicine in the UCSD division of nephrology and director of the Center for Renal Translational Medicine, who headed the study, was quoted as saying.

The principal process underlying the progression of chronic kidney disease to ESRD -- where dialysis is required to keep a patient alive -- is called renal (kidney) fibrosis. The fibrosis, or scarring, damages tiny blood vessels in the glomerulus, structures that filter and remove waste from the blood, and in between tubular cells.

Transforming growth factor beta (TGF-ß) is a protein that controls many cellular functions, including extracellular matrix accumulation. TGF-ß is stimulated in the diabetic kidney due to uncontrolled blood sugar and elevated blood pressure and can promote renal fibrosis.

"To date, therapies for diabetic nephropathy have been limited to drugs that improve blood pressure or control blood sugar levels," added Sharma. Instead, pirfenidone seems to work by blocking TGF-ß; in effect, shutting down the growth factors that cause renal fibrosis.

The group of researchers formerly observed an exceptionally remarkable benefit in a mouse model of diabetic kidney disease in a study published nearly two years ago. The animal studies demonstrated improvement in matrix accumulation at gene and protein levels with just four weeks of treatment.

The novel randomized, double-blind study of 77 patients with diabetic nephropathy was carried out at Thomas Jefferson Hospital in Philadelphia, the Mayo Clinic in Rochester and the NIH, and comprised three study groups: one group received a high dose of pirfenidone (2400 mg); one group received a low dose of pirfenidone (1200 mg); and a control group.
The researchers investigated the rate of decline in kidney function in all three groups by measuring the predicted glomerular filtration rate, or eGFR. They discovered an improvement in the low-dose group over the course of the one-year study.

There was no clear advantage to those patients who in due course received the high dose, which is suggestive of higher doses not being tolerable in the diabetic population with average to advanced chronic kidney disease.

Sharma adds that the subsequent step is to carry out a larger clinical study and to classify personalized biomarkers, to verify which patients are most apt to demonstrate improvement on the drug. "This drug might also be useful in treating other types of fibrotic disease," he added.

"We have previously found that pirfenidone slows progressive loss of kidney function in another chronic kidney disease, called focal segmental glomerulosclerosis," Jeffrey B. Kopp, MD, NIH/NIDDK intramural researcher and Capt., USPHS, was quoted as saying. "By extending these findings to the most common chronic kidney disease -- diabetic kidney disease -- the present study suggests that pirfenidone may have broad utility to help patients maintain kidney function longer."

SOURCE: Journal of the American Society of Nephrology (JASN), April 21, 2011