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Armed with increasingly effective drug regimens, physicians have cut short-term rejection rates in the months after kidney transplantation in half. Yet recent analysis of a national database reveals the odds the lifesaving organs will ultimately fail years later have risen, University of Florida researchers report in the March issue of the American Journal of Transplantation.

Whether a patient experiences episodes of acute rejection has long been viewed as a key measure of the long-term success or failure of a kidney transplant. Experts say preventing acute rejection, especially in the year after transplant surgery, is critically important to ensuring organs remain healthy. Whether acute rejection occurs also has been viewed as a way of predicting whether donated organs will continue to thrive. From 1988 to 1995, as acute rejection rates improved, so did long-term graft survival, lending credence to the concept.

But the UF findings, which focused on patients who received transplants between 1995 and 2000, are causing physicians to rethink matters. In fact, some say the findings highlight the need to design studies to evaluate other factors that might more accurately predict patient outcome over time.

鈥淎ll the therapies we use are aimed at decreasing acute rejection, with the assumption that if you decrease acute rejection you鈥檙e going to improve outcome,鈥� said Bruce Kaplan, M.D., medical director of renal and pancreas transplantation at UF鈥檚 College of Medicine. 鈥淎ll the drug trials now are aiming at lower and lower acute rejection rates with the idea that over a period of time if you decrease rejection you鈥檙e going to get better long-term outcome. What we see, at least from this paper, is it鈥檚 not a given.

鈥淭he achievement of ever-lower rejection rates does not necessarily lead to improved organ survival,鈥� Kaplan added. 鈥淒espite the advances, we鈥檙e in a period where we鈥檝e hit a pace of no improvement statistically in kidney survival and in patient survival. We looked at medical records from 1995 to 2000, a period of time no one had really looked at, and saw acute rejection rates had gone done by 50 percent.

The corollary should be of course that outcomes were getting much better or at least a little bit better. But what happened during that period of time is outcomes did not get better and were actually statistically significantly worse in some groups.鈥�

UF researchers also noted another disturbing trend: A greater number of patients failed to recover the organ function they had before suffering an episode of rejection.

鈥淲e noted that patients who did experience a rejection were left with more functional deterioration than most patients in the past,鈥� Kaplan said. 鈥淥f those who had a rejection in 1995, 70 percent returned to their previous function. By 2000, only about 40 percent returned to their previous status. So the nature of rejection may be changing as well.鈥�

Kaplan said the findings underscore the need to 鈥渓ook beyond the issue of acute rejection鈥� in future clinical trials.

鈥淚t鈥檚 not just a given that if we can decrease acute rejection then the outcomes in the long run will be better,鈥� he said.

About 50,000 patients are currently awaiting 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.

UF researchers analyzed data from the U.S. Renal Data System and the U.S. Scientific Renal Transplant Registry for transplants performed in the United States between 1995 and 2000 in more than 62,000 adults. Before arriving at their conclusions they made sure factors such as increasing age of the patient, the age of the donor organs or other diseases, such as diabetes, hadn鈥檛 influenced their results.

UF physicians compared patient survival, as well as death-censored graft survival 鈥� a measure that takes into account not only patients who lost the use of the transplanted kidney but also those who died 鈥� and overall graft survival among those who did not have acute rejection in the first year after transplantation, those who had acute rejection between six and 12 months and returned to baseline kidney function level, and those who had acute rejection between six and 12 months but failed to return to baseline level of renal function.

Researchers also conducted analyses after separating patients into groups depending on the degree their kidney function was affected. 鈥淚f you have an acute rejection that doesn鈥檛 give you functional deterioration 鈥� you treat it and it鈥檚 totally gone away 鈥� then in terms of your renal function there鈥檚 no negative impact on long-term graft survival,鈥� Kaplan said. 鈥淏ut if you have a rejection that leaves you with injury and decreasing renal function, those patients do very poorly. Those people are doing worse and worse every year.

鈥淚t is possible that many of the acute rejection episodes that were less severe in terms of effects on functional status are the ones that were reduced in the more recent era, while rejections with stronger functional impact persisted,鈥� he said.

Other theories point to the effects of increasingly common viral infections that attack the kidney and changing patterns in how patients are taking anti-rejection medicines. Some, for example, take smaller doses or differing combinations of the drugs, or eventually stop taking them altogether.

鈥淲hen you look at these big studies some people want to go too far and say this means things are definitely getting bad,鈥� Kaplan said. 鈥淏ut it鈥檚 more a chance to pause and say maybe some of the assumptions we made aren鈥檛 true, and maybe new things are popping up that we need to look at.鈥�

Mohamed H.Sayegh, M.D., director of the Transplantation Research Center at Harvard Medical School, called the research 鈥渋nteresting and important,鈥� adding, 鈥淭here has been reduction of short and of somewhat long-term acute rejection rates, most likely attributable to newer immunosuppressive strategies. However, this did not translate into better long-term outcome. The exact etiology of this unexpected finding is unclear. Importantly, these findings will stimulate the transplant community to re-evaluate their current thinking and hopefully develop strategies that will minimize clinical and subclinical acute rejection as well as reduce the negative impact of severe rejection episodes.鈥�