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UF researchers report: Immunosuppressant drug prevents late rejection of transplanted kidneys


UF researchers report: Immunosuppressant drug prevents late rejection of transplanted kidneys

A drug that suppresses the immune system and prolongs the survival of donated kidneys in patients in the first months after transplantation also has the ability to block organ rejection over the long haul, University of Florida researchers have found.

The drug, mycophenolate mofetil, has been shown to decrease acute rejection by 50 percent compared with an older agent commonly used, azathioprine, also known as Imuran. In addition, the relative newcomer has been associated with longer kidney survival compared with azathioprine.

Previous research indicated that in some cases patients could eventually stop taking mycophenolate mofetil, which goes by the trade name CellCept, particularly because most episodes of rejection occur within the year after transplantation. That has left physicians who care for kidney transplant patients with many questions, said Dr. Bruce Kaplan, a professor of medicine, and of pharmacology and therapeutics at UF’s College of Medicine.

The UF study, published in this month’s issue of the American Journal of Transplantation, also has prompted new theories about the physiologic processes that lead to the severe scarring of the kidney that doctors call chronic rejection, which can cause the organ to malfunction or even fail. The UF findings suggest that some chronic rejection actually may be the culmination of a series of episodes of acute rejection, an abrupt immunologic attack on the donated kidney led by a vanguard of immune cells bent on destroying it. Acute rejection often can be reversed by medicines that temper this assault.

"Chronic rejection, next to the patient dying, is the most common reason patients lose their transplanted kidney," said Kaplan, also medical director of the kidney and pancreas transplant program at the UF Shands Transplant Center. "Physicians have yet to pinpoint its precise cause, and there is no known treatment for this type of injury. Acute rejection appears to be linked to that. People with acute rejection have a higher risk of developing this process.

"We believe that part of the link is people who develop acute rejection are more at risk of a later rejection, and it’s caused by the cumulative damage that’s occurring as opposed to something magical that happens with just one acute rejection episode," he said. About 50,000 patients await kidney transplantation--a number expected to double by 2010, according to the United Network for Organ Sharing. Yet the availability of donor kidneys is strikingly low. Each year, only 10,000 kidney transplants are performed in the United States. Although remarkable advances in organ transplantation have made headlines in recent decades, preventing the body from recognizing a transplanted organ as foreign has impeded long-term survival for many patients.

"One of the big questions has been how long you should stay on this drug CellCept," Kaplan said. "What does this drug, if you stay on it for a year, two years or three years, do to rejections that happen late? Everybody used to say rejection occurs within the first six months and if it doesn’t, it won’t happen later. But we found that acute rejection can actually happen two or three years down the line."

Kaplan, together with Dr. Herwig-Ulf Meier-Kriesche, an associate professor of medicine at UF and clinical director of renal transplant at Shands at UF medical center, worked with colleagues at the University of Pennsylvania Cancer Center to analyze U.S. Renal Data System data from nearly 48,000 patients who received a single kidney transplant between 1988 and 1998. The study was funded in part by a grant from Roche Laboratories, which manufactures CellCept.

Researchers compared patients who continuously took mycophenolate mofetil or the traditional drug, azathioprine, for a year to see whether either therapy lowered the incidence of late acute rejection, defined as rejection occurring beyond the first year after transplantation. They also assessed how patients who took either drug for two years fared.

Compared with azathioprine, mycophenolate mofetil was associated with up to a 72 percent decreased risk of developing late acute rejection. In addition, the incidence of acute rejection episodes two and three years post-transplantation was significantly lower in patients on mycophenolate mofetil.

"CellCept blocks rejection in the first year--halves it over the old drug--and virtually eliminates rejection in the second and third year if you stay on it, even if you’ve had a rejection in the first year," Kaplan said. "But if you had an episode of rejection in the first year and you are on the older therapy, your rejection rate in the second year is about 10 percent. That would indicate these patients are at high risk, and the older drug is not protecting them from late rejection, which often goes unchecked because by that time they are seeing physicians in the community and they may not be tracked as often. This wasn’t really appreciated before."

The occurrence of acute rejection may actually signal a patient’s likelihood of developing rejection a year or more after transplantation, and a therapy that prevents rejection early may be a marker for a therapy that prevents rejection later, Kaplan added. Physicians likely will track transplant patients much more closely over the long term, he said, adding that further study is needed to determine the optimal duration of treatment with mycophenolate mofetil.

"It may make people hesitant to stop the drug," Kaplan said. "More importantly, it may change the way people think about lowering doses."

In recent years, several newer agents have been shown to reduce the early acute rejection rate better than traditional medications, but it has been harder to demonstrate they have a long-term positive effect, as would be expected, said Dr. J. Harold Helderman, medical director of the Vanderbilt University Transplant Center.

"(With CellCept) the effect toward increased long-term organ survival was greater than predicted by merely reducing acute rejection early and thus potentially is an issue of the specific molecule used," he said. "The transplant community has been struggling with how long to use these new and more expensive immunosuppressant medications like CellCept. The newer work demonstrating the importance of low-level but persistent risk for acute rejection and its inhibition by CellCept is additional evidence for the strong recommendation that this particular medication be continued when tolerated by patients."

Melanie Fridl Ross | EurekAlert!
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