National Trial Gives 'Unprecedented' Support for Steroid Withdrawal in Kidney Transplant Patients

CINCINNATI—Preliminary results of a study led by University of Cincinnati (UC) scientists suggest that reducing corticosteroid treatment in kidney transplant patients significantly lowers the toxic side effects of anti-rejection drugs without affecting survival rates.

Steroids are typically given in combination with other drugs that help suppress the body’s immune system and allow the transplanted organ to function properly. Previous research has linked them to an increased risk for cardiovascular disease, high cholesterol and blood pressure, weight gain, diabetes and cataracts. In adolescent and pediatric patients, the drugs can even hinder physical growth.

“When you ask transplant patients about their medicines, they say the drug they dislike most is steroids. They don’t want to take steroids because of what the drugs do to their bodies,” says Steve Woodle, MD, director of transplantation at UC and principal investigator for the study. “They see how the drug’s toxicity affects their bodies—their faces swell, they gain weight, they bruise easily—and they know steroids are the cause.”

Despite the known negative side effects, says Woodle, physicians have feared that removing them would increase the risk for organ rejection.

“This study shows that, when used in combination with the right immunosuppressive agents, we can minimize that risk for rejection while also reducing the negative side effects associated with steroid use,” says Woodle.

Specifically, he says, a seven-day treatment with synthetic steroids known as corticosteroids, in conjunction with immunosuppressive agents, is as effective as long-term corticosteroid therapy in kidney transplant patients three years after transplant.

The Cincinnati team’s findings were reported today (July 24) at the meeting of the World Transplant Congress in Boston, Mass.

This UC-led multicenter trial is the first in which corticosteroids were removed prior to 90 days after kidney transplant and is one of four double-blind, randomized trials of its kind ever conducted. The results presented were for the first three years of the projected five-year investigation.

The researchers found that patients who received just seven days of the corticosteroid prednisone after kidney transplant had the same transplant organ survival rate and functionality as those placed on continuous corticosteroids. In addition, patients on short-term steroids experienced significantly less cardiovascular risk, including cholesterol levels, blood pressure and weight gain.

These findings, Woodle says, contradict results from a 1995 Canadian study that claimed steroid-free patients begin to lose their transplant organs three years after surgery.

“For many years, people have believed that increased risk of losing the kidney transplant was a side effect of removing steroids,” explains Woodle. “Our study is the first to refute that. After three years, we’ve seen no statistical difference in graft survival or function. However, we need to see if this effect continues out to five years.”

Woodle’s team found that biopsy-proven acute rejection rate for steroid-free patients was 16 percent—just slightly higher than the nationwide average of 15 percent. Steroid-free patients, however, reaped substantial health benefits, including reduced cardiovascular risk and weight gain.

Based on the three-year study results, the researchers determined that patients on the steroid withdrawal regimen had less significant weight gain than those on long-term steroids. Steroid-free patients had fewer cardiovascular complications, including newly developed diabetes.

In addition, UC researchers found that African-Americans—long excluded from transplant research trials because of a perceived risk for increased acute rejection—are not at any greater risk for rejection than Caucasians and actually enjoy even greater benefits in terms of cardiovascular risk reduction.

“This study demonstrates that there is no harm from removing steroids after just seven days,” says Rita Alloway, PharmD, a research professor at UC and coinvestigator on the study.  “Now we need to further quantify the benefits of steroid-free regimens and their impact on health risks to provide the very best, holistic care to our patients.”

The national trial enrolled 397 patients who were then randomized to either a seven-day or lifetime course of corticosteroid therapy, which started within the first three days of transplant.

Patients in both treatment groups received the steroids in combination with twice daily tacrolimus (Prograf) and mycophenolate mofetil (CellCept), immunosuppressive agents designed to help lower the body’s natural immunity to the transplant organ.

All patients in the UC-led trial will reach the required five years of treatment in November 2007. The study will remain blinded until that time. Researchers will continue to track transplant patients for the life of their transplant.

When the trial enrolled its first patient in 1999, says Woodle, only about 5 percent of patients went home from the hospital on this drug combination. Now almost 60 percent of kidney transplant patients take this steroid-free immunosuppressive combination.

“We know that steroid-free regimens are being employed with increased frequency across the United States,” he says. “This study provides the strongest possible evidence in support of that trend and gives physicians the justification they need to continue prescribing steroid-free regimens.”

Woodle says steroid-free regimens could reduce health care costs from transplant-related health problems (heart disease, diabetes, obesity) and improve quality of life issues for patients in the future.

“We’re trying to reduce the dosage and ultimately get rid of steroids. If we can get over that barrier, then all transplant patients can reap the benefits of being steroid free,” he adds.

A multicenter effort, this trial was conducted at 26 medical centers across the United States including UC and the Universities of Washington, Utah and Tennessee-Memphis.

Collaborators designing and conducting the study include William Fitzsimmons, PharmD, Richard Miller, MD, Roy First, MD and John Holman, MD, all of Astellas Pharmecuticals.  Woodle and researchers at the participating institutions received honoraria and nominal research grants from the study sponsor, Astellas Pharmaceuticals, maker of tacrolimus.

UC researchers will present a total of 55 abstracts and oral presentations at this year’s World Transplant Congress meeting—10 of which relate to the corticosteroid withdrawal trial.