Drug May Slow Kidney Disease in Patients with Diabetic Nephropathy

Drug May Slow Kidney Disease in Patients with Diabetic Nephropathy

Mar 7, 2011 1:05 PM

SALT LAKE CITY—Chronic kidney disease related to diabetes (so-called diabetic nephropathy) often involves an inevitable path to dialysis or kidney transplantation for millions of people worldwide.

But if the results suggested by a recent clinical drug trial can be confirmed in a larger study, many of those patients may find hope in a medication that researchers believe can slow the course of kidney disease. Called atrasentan, the drug would actually reduce the progression of kidney disease related to diabetic nephropathy, which is a common complication of diabetes that can also damage nerves and injure blood vessels, the eyes, heart, and other organs.

The trial, published Thursday, March 3, 2011, in the Journal of the American Society of Nephrologists online, was led by University of Utah nephrologist and professor of internal medicine Donald E. Kohan, M.D., Ph.D.

“There has been only modest success in slowing down progressive kidney disease related to diabetic nephropathy,” Kohan says. “But there is evidence for optimism that this drug will be effective in slowing the progression of the disease in patients with diabetic nephropathy.”

Kohan led a trial of the drug with 89 patients who had chronic kidney disease and diabetic nephropathy. To gauge whether the disease was being slowed, he and his colleagues at Abbott Laboratories – the maker of atrasentan – and Northwestern University measured the presence of albumin, a protein that builds to excess levels in the urine when the kidney isn’t functioning correctly. Too much albumin in the urine, called albuminuria, can be a marker of the presence and progression of chronic kidney disease, according to Kohan. “Sometimes when you reduce albuminuria, you reduce the progression of kidney disease,” he says.
 
Study participants were divided into four groups, with three receiving different dosages of atrasentan and the fourth getting a placebo. The results showed that, depending on the dosage of atrasentan given, the albumin level in the urine was reduced from 30 percent to 50 percent below a baseline measurement in patients who received the drug, while the decline in those who received a placebo was 17 percent. Of the three dosages of atrasentan that were given, the mid-level amount (0.75 mg) proved to be the most effective.

Some study participants did experience fluid retention, but atrasentan proved to be generally safe for the participants, the researchers wrote. 
Atrasentan was given on top of medications often prescribed for high blood pressure: angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB). Both of those drugs can modestly slow the progression of diabetic nephropathy. If atrasentan becomes available to patients with diabetic nephropathy-related chronic kidney disease, it would be prescribed in addition to either of these medications, according to Kohan.

Atrasentan is in a class of drugs called endothelin-A receptor antagonists. Endothelins are peptides produced by the endothelium, the thin lining of cells in blood vessels, and play an important role in blood flow by causing blood vessels to dilate or constrict. But when overproduced, endothelins can cause too much blood vessel constriction, contributing to high blood pressure and leading to heart, lung, and kidney problems.
 
Endothelins bind two receptors, A and B, which generally signal blood vessels to constrict and dilate, respectively. Endothelin-A receptor antagonists, such as atrasentan, work by blocking the A receptor signal and preventing vessel constriction. In addition, endothelin-A receptor activation leads to tissue scarring and abnormal cell growth so antagonism of this receptor could potentially prevent progressive kidney injury.
 
Before atrasentan could be widely given to kidney disease patients with diabetic nephropathy, a much larger clinical trial (phase three) must replicate the results of the phase 2 study. Abbott Laboratories is planning such a trial and Kohan will participate in that one.
“If a phase-3 clinical trial shows that atrasentan does slow the progression of chronic kidney disease, it would be the only effective therapy, besides ACEs and ARBs, for patients with diabetic nephropathy,” Kohan says.

Kohan, who has studied endothelins for more than 20 years, is among a handful of experts in those molecules and their role in regulating kidney function. He frequently presents at international conferences, and in 2005 chaired the International Conference on Endothelins. Kohan also serves as a paid consultant to Abbott Laboratories.



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