Antibody reduces incidence of acute rejection in high-risk kidney transplant patients

November 08, 2006

Nearly 70 percent of kidney transplant patients get short-term drug therapy initially administered during surgery to help prevent rejection. In the first head-to-head comparison of the two drugs most commonly given to ward off acute kidney rejection, an international study led by researchers at Washington University School of Medicine in St. Louis shows that one - anti-thymocyte globulin - is superior. The results also suggest the drug could potentially save millions of dollars in health care costs by preventing the all-out immune attacks that can eventually lead to kidney rejection.

The study, published in the Nov. 9 issue of the New England Journal of Medicine, included only patients who were at high risk for acute rejection and for delays in graft function, in part because their kidneys came from cadaver donors. One year after transplant, patients who received anti-thymocyte globulin (Thymoglobulin®) had a significantly lower incidence of acute rejection, 15.6 percent, compared to 25.5 percent of patients receiving basiliximab (Simulect®). Anti-thymocyte globulin was even more effective at preventing episodes of acute rejection that require additional antibody therapy to stem the immune assault. Only 1.4 percent of patients who received anti-thymocyte globulin experienced such acute rejection versus 8 percent who got basiliximab.

"Acute rejection is a major risk factor for eventually losing a kidney," says Daniel C. Brennan, M.D., professor of medicine and director of transplant nephrology at Washington University School of Medicine. "Our study shows that anti-thymocyte globulin is an important weapon for fighting kidney rejection. A 10 percent difference in acute rejection between the two groups may not seem like a lot, but in these high-risk patients, it is very significant."

The study involved 278 patients in the United States and Europe who were randomly assigned to receive either anti-thymocyte globulin or basiliximab. This short-term induction therapy is commonly given during kidney transplant surgery and in the first several days afterward to prevent acute rejection prior to the start of more potent, long-term immunosuppressive therapy.

The study found no significant difference between the drugs in terms of delayed graft function, defined as the kidney's inability to make urine within the first week following transplant surgery. About 40 percent of patients in both groups experienced a delay in graft function. Brennan attributes this to the extended period of time the kidneys were kept on ice before transplant surgery, an average of 25 hours for patients in the anti-thymocyte group and 28 hours for the basiliximab group.

"The longer a kidney is kept cold outside of the body, the higher the risk of delayed graft function," Brennan says. "There is only so much a drug can do to overcome an extended 'cold time.' However, if the delay in graft function does not lead to acute rejection, usually there is no long-term effect on the kidney."

There were no significant differences between the groups in terms of graft loss or patient death, which would not be expected after following patients for only 12 months post-transplant. The investigators will continue to monitor patients' kidney function, however, to determine the long-term benefit of the drugs. "Based on the effectiveness of anti-thymocyte globulin, we expect that it will be more effective over time in preventing graft loss and reducing patient deaths," Brennan says.

An estimated 20 to 60 percent of kidney transplant patients will experience an episode of acute rejection, most often within the first six months following transplantation. It occurs when the body recognizes its new organ as a foreign invader and launches an intense immunologic attack aimed at destroying the donated tissue. If the immune system is not kept in check with drug therapy, an acute episode of rejection can become chronic, eventually leading to the loss of the organ.

Anti-thymocyte globulin is a polyclonal rabbit antibody that targets T cells, which are the body's first line of defense against anything foreign, including a donated organ. It reduces a patient's T cell count to zero, leaving them at risk for infection. Indeed, patients receiving anti-thymocyte globulin had more infections but most were managed effectively. Basiliximab is a monoclonal antibody that targets IL-2, a protein on the surface of T cells.

Although anti-thymocyte globulin is more expensive than basiliximab, Brennan believes it will save health care dollars in the long run. Anti-thymocyte globulin is given in three to four doses, costing a total of $6,000 to $8,000 per patient. In comparison, basiliximab is given in two doses and costs a total of about $4,000 per patient. But if a patient's immune system begins to attack the donated kidney, health care costs spiral. Surgery to remove a rejected kidney costs an estimated $30,000 and one year of dialysis is about $100,000, Brennan estimates.

"The cost to society for every episode of kidney rejection is extremely high," Brennan says. "While further study is warranted, we suspect anti-thymocyte globulin will be important not only for patients at high risk for rejection but for all kidney transplant patients."
The study was sponsored by Genzyme, the maker of anti-thymocyte globulin. The drug is approved by the U.S. Food and Drug Administration for the treatment of kidney transplant rejection but not for the prevention of rejection. However, once a drug is approved for a particular use, doctors can prescribe it for other uses.

Editor's note: Dr. Brennan has received grant support, consulting fees and lecture fees from Genzyme and Novartis, the maker of basiliximab.

Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Washington University School of Medicine

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