University of Pittsburgh Reports Results of Bold Approach That Has Lung Transplant Patients Taking Fewer Anti-Rejection Drugs
WASHINGTON, June 2, 2003 Surgeons at the University of Pittsburgh Medical Center (UPMC) have instituted a new clinical protocol that has the potential to redefine the standard of care for lung transplant patients. Bucking conventional thought that successful lung transplantation can only be achieved with a three-punch assault on the immune system, the new protocol is a departure from the triple-drug therapy in place at nearly every other transplant center.
Instead, UPMC surgeons favor a regimen involving fewer pills that are given less often over time. The protocol is an important achievement for lung transplant patients, in whom studies that seek to reduce or eliminate anti-rejection drugs are rarely performed out of fear that the lungs, already the most vulnerable organ to rejection, would succumb to an irreversible immune system attack, placing patients at risk for death. Ironically, lung recipients have the greatest incidence of immunosuppression-related complications, such as infection and chronic kidney dysfunction, providing incentive to search for alternative immunosuppression approaches.
Results of the first 20 patients treated using the new approach are being presented at the American Transplant Congress, the joint scientific meeting of the American Society of Transplant Surgeons and the American Society of Transplantation. The scientific sessions run through June 4 at the Marriott Wardman Park Hotel in Washington, D.C.
According to Kenneth R. McCurry, M.D., director of lung and heart-lung transplantation at UPMC, 18 of 20 patients are doing well taking lower-than-normal doses of one mainstay anti-rejection drug, tacrolimus, as opposed to the usual three-drug combination that is given twice a day. Two patients died, one of a common complication associated with nonfunction of the organ, and the other from causes that have yet to be determined. While eight of the 18 currently remain on a twice-a-day regimen of the single drug, five are taking tacrolimus once a day and five just four times a week. In addition, all 18 patients are on a daily 5-milligram dose of prednisone, a negligible dose compared to the more typical 20 milligram dose that is usually given.
"The reason the lung transplant patients are taking low-dose prednisone, unlike the other organ recipients at UPMC, is because the majority were taking steroids prior to their transplants and abrupt discontinuance would likely lead to adrenal insufficiency, whereby their own adrenal gland's ability to produce the steroid would be impaired. Still, it's noteworthy that after transplantation the patients are being treated with very low doses of the steroid, which is basically what the adrenal gland produces each day anyway," explained Dr. McCurry, who also is assistant professor of surgery at the University of Pittsburgh School of Medicine.
The clinical protocol, developed by Thomas E. Starzl, M.D., Ph.D., and the Pittsburgh team, is based on two principles: pre-treatment of the recipient and the administration of as little immunosuppression as possible after transplantation. Just before transplantation, each patient receives a one-time dose of a drug that depletes T cells - key immune system cells that are known to target the donor organ - and following their transplants, patients are treated with just one anti-rejection drug that is administered at radically reduced levels and given progressively more sparingly over time. In the case of lung recipients, low doses of prednisone are given as well.
"Follow-up has ranged from only between six and 10 months, but we believe that having our patients on fewer and lower doses of tacrolimus and minimal prednisone has already offered them tremendous advantages. Down the road, we should expect that they will be at much less risk for developing the types of complications associated with high levels of immunosuppression, such as kidney dysfunction, which is quite common in lung recipients.
Those complications associated with steroids, including hypertension and osteoporosis, should be fewer as well," said Dr. McCurry.
Comparing outcomes of the 20 patients to 15 patients who were treated using conventional triple-drug therapy before the new protocol was introduced, acute rejection rates were comparable. But, suppressing acute rejection was never meant to be a goal of the protocol, says the transplant team. The surgeons believe that some level of immune activation is needed for long-term organ acceptance and fault conventional approaches that "over-immunosuppress" patients for inhibiting this activation process.
While it is too soon to gauge whether chronic rejection rates will be less in these patients, that certainly is the hope, says Dr. McCurry. Chronic rejection, which occurs in 50 percent of all lung transplant patients who survive more than five years - a rate higher than for other organs, also is more difficult to treat and often leads to organ failure and death. It is the most common cause of death for lung recipients beyond two to three years of transplantation.
"At this point, many of our patients are doing extremely well on low levels of immunosuppression and we have strong evidence that this approach may be very beneficial to patients. Even reducing the steroids in these patients is a somewhat remarkable feat, since so-called steroid sparing has only been successful in kidney and liver recipients. Perhaps in the future we can further taper their drugs, but for now, it's one step at a time," said Dr. McCurry.
Since July 2001, more than 550 transplant patients receiving kidney, liver, pancreas, small intestine or lung transplants at UPMC have been treated under the new protocol. The totals include more than 35 lung transplant recipients.