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University of Pittsburgh Researchers Report in The Lancet Findings of Clinical Approach That Radically Reduces Drugs Transplant Patients Take

PITTSBURGH, May 1, 2003 Measurable improvements in quality of life and long-term survival could be achieved in organ transplant patients if clinicians were to adopt two prescriptive changes in their treatment approach, say University of Pittsburgh Medical Center (UPMC) researchers in the May 3 issue of the Britishmedical journal The Lancet.

The authors from UPMCs Thomas E. Starzl Transplantation Institute report initial results involving 82 patients who had kidney, liver, pancreas and small bowel transplants and were treated under a clinical protocol developed by the Pittsburgh team. Just before transplantation, each patient received 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 were treated with just one anti-rejection drug that was administered at radically reduced levels and given progressively more sparingly over time. Eleven of their patients were on just one pill once a week with no signs of organ rejection or other complications, the researchers reported.

Our findings suggest that improvements in clinical transplantation might be within easy grasp by simple modification of timing and dosage, stated lead author Thomas E. Starzl, M.D., Ph.D., professor of surgery, and colleagues.

The protocol developed by the Pittsburgh team is based on two principles: pre-treatment of the recipient and the administration of as little immunosuppression as possible after transplantation. The regimen of T-cell depletion as a pre-treatment and the use and tapering of a single drug has become the standard of care for most of UPMCs transplant patients. Unlike their counterparts at other centers, the majority of UPMCs liver, kidney, pancreas and small bowel transplant patients have been taking lower doses of one drug rather than the typical cocktail of two or three agents.

For example, 39 of 47 (83 percent) of the surviving kidney transplant patients were being treated with one drug, usually tacrolimus, and 25 of these were able to begin weaning of the drug to every-other-day dosage.

The intent throughout was to find the minimum amount of immunosuppression consistent with the avoidance of irreversible graft damage, wrote the authors.

Progress was followed in 50 kidney (including 10 kidney/pancreas), 17 liver, 4 pancreas and 11 small bowel transplant recipients who were administered pre-treatment with rabbit antithymocyte globulin.

For patients in whom it was thought to be safe, the process of weaning was begun about four months after transplantation. Because the treatment was already lighter than in the past, members of UPMCs transplant teams approached the spacing of doses with caution. Doctors or patients anxiety about spaced dosing frequently delayed its initiation, stated the authors, who added this was most often the case if a patients initial organ function was not optimal in the early period after transplantation.

But the process paid off for most of its patients. Of the 82 recipients of various organs, 78, or 95 percent, were alive at one-year and between 1318 months after transplantation. At one year, 73 of the patients (89 percent) had functioning grafts, and at the 13-18 month follow-up period, graft survival was 88 percent. Of the 72 recipients with functioning grafts, 43 were on spaced doses of tacrolimus. Eleven patients required just one dose per week, 15 were on doses taken twice a week, 11 patients three times a week and the remaining six patients were taking tacrolimus every other day.

In the 25 surviving kidney transplant patients who were on single-drug therapy, one was taking tacrolimus every other day, six patients were taking it three times a week, 11 patients were on a twice-a-week dose, and seven were taking the anti-rejection drug just once a week.

Similar results were achieved in other organ transplant recipients as well. Eleven liver recipients had initiated weaning, and at follow-up, three were down to a once-a-week dose, two to twice a week, four to three times a week, and two patients were taking tacrolimus every other day. Five of 12 pancreas recipients were successfully treated under the protocol, with two on a once-a-week dose, two on a three-times-a-week regimen and one patient requiring a dose every other day. Six of eight small bowel transplant recipients were on spaced doses: two at twice a week, one at three times a week and three patients every other day.

For patients whose spacing reached one dose per week, we did not advise drug discontinuance, stated the authors. Our animal studies indicate that a maintenance dose of tacrolimus given just once a week can prevent the undesirable outcome of chronic rejection, so we believe it wise for the time being to aim for the lowest dose possible short of complete drug discontinuance in our patients, further explained Ron Shapiro, M.D., professor of surgery and director of kidney transplantation at the Starzl Institute.

To determine the limits of their treatment, the transplant team engaged in closer-than-usual monitoring of their patients for evidence of increased activity of the recipient immune cells, but increased immune activation was not always associated with graft dysfunction or thought to be of serious consequence to the patient. In such cases, treatment was not intensified. For the patients experiencing bona fide rejection episodes, the rejections were treated with the addition of steroids, or if necessary, stronger drugs, and for as brief a period as possible. After rejection was resolved, many of the patients returned to the single-drug regimen and weaning was reconsidered.

It is widely believed that in order to protect their donor organs from rejection, transplant patients must take potent immunosuppressive drugs for the rest of their lives. While these drugs have been quite successful in addressing early acute rejection, they are not a panacea. Later-developing rejection, called chronic rejection, is difficult to treat and is the most common reason for retransplantation.

Furthermore, the drugs, which are usually given in very high doses, can make patients vulnerable to serious infections, malignancies and other complications.

According to the authors, the common practice of giving several drugs in the early period after transplantation may actually prevent acceptance of the transplanted organ by preventing a process known as immune tolerance and thereby creating a near-certain life-long dependence on anti-rejection drugs. The reason is that over-immunosuppression eliminates the all-important, initial immune reaction against the donor organ, which under the right circumstances, proceeds to clonal deletion, or selective removal of a subset of T cells that are directed against the donor tissue. Without this activation and deletion process, T cells targeted against the graft will persist, and drugs will always be required to keep them at bay.

The study was funded in part by a grant from the National Institutes of Health. No support of any kind was requested or received from pharmaceutical industry sponsors.

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