UF researchers find national kidney transplant failure rate is rising

Armed with increasingly effective drug regimens in the past decade, 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 life-saving 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 an episode of acute rejection has long been viewed as an early measure of the long-term success or failure of a kidney transplant because of the structural damage it causes. Experts say preventing acute rejection, therefore, 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 too 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 data highlight the need to design studies to evaluate other factors that might more accurately predict patient outcome over time.

“Since 1995, a number of new potent immunosuppressive medications have been newly approved by the Food and Drug Administration in the U.S.,” said the study’s principal investigator Herwig-Ulf Meier-Kriesche, M.D., an associate professor of medicine and clinical director of renal transplant at UF. “These drugs were chosen mostly because of their ability to reduce acute rejection episodes proven in prospective clinical trials. In fact, we observed that subsequently with the clinical use of these new agents important reductions in the rejection rates have been achieved in the U.S. transplant population, cutting the occurrence of this traumatizing and possibly damaging event in half.

“On the other hand, we did not observe the improvement in transplant kidney survival many physicians would have hoped for based on the improvement in rejection rates,” said Meier-Kriesche, also the paper’s lead author. “Our data in fact reinforce the idea that acute rejection is only part of the issue. In kidney transplant patients we have to keep a delicate balance between too little immunosuppression and the potential for acute rejection, and too much immunosuppression and possible consequences like infections and malignancies that can jeopardize kidney and patient survival.”

All the drug trials now are aiming at lower and lower acute rejection rates with the idea that over time if rejection decreases long-term outcome will improve, said study co-investigator Bruce Kaplan, M.D., medical director of renal and pancreas transplantation at UF’s College of Medicine.

“What we see, at least from this paper, is it’s not a given,” he said. “The achievement of ever-lower rejection rates does not necessarily lead to improved organ survival. Despite the advances, we’re in a period where we’ve 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.”

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

“We noted that patients who did experience a rejection were left with more functional deterioration than most patients in the past,” Kaplan said. “ So the nature of rejection may be changing as well.”

Kaplan said the findings underscore the need to “look beyond the issue of acute rejection” in future clinical trials.

“It’s not just a given that if we can decrease acute rejection then the outcomes in the long run will be better,” 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. The trend is fueled by the failure of transplanted kidneys and thus the return to the waiting list of many of patients who already have undergone transplantation, Meier-Kriesche said. Because the availability of donor kidneys is strikingly low - each year, only 14,000 kidney transplants are performed in the United States - it is crucial to make existing transplant kidneys last as long as possible to reserve the new transplants to new patients with end-stage renal disease, he said.

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’t influenced their results.

UF physicians compared patient survival, death-censored graft survival — a measure that takes into account not just patients who lost the use of the transplanted kidney but also includes those who died — and overall graft survival for those who did not have acute rejection in the first year after transplantation, those who had acute rejection between six and twelve months and returned to baseline kidney function level, and those who had acute rejection between six and twelve 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.

“If you have an acute rejection that doesn’t give you functional deterioration — you treat it and it’s totally gone away — then in terms of your renal function there’s no negative impact on long-term graft survival (at least for the first 6 years after transplantation),” Kaplan said. “But 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.

“It 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,” he said.

Other theories to explain the lack of recent improvement despite the availability of new antirejection drugs point to the effects of increasingly common viral infections that can attack the kidney as more potent immunosuppressive medications are administered.

Additionally, long-term medication regimens have been changing dramatically in the United States, without clear evidence about long-term safety and efficacy of theses new strategies. For example, many patients are prescribed in the long-term smaller doses or differing combinations of the drugs, or eventually stop taking them altogether.

“When you look at these big studies some people want to go too far and say this means things are definitely getting bad,” Kaplan said. “But it’s more a chance to pause and say maybe some of the assumptions we made aren’t true, and maybe new things are popping up that we need to look at.”

Mohamed H.Sayegh, M.D., director of the Transplantation Research Center at Harvard Medical School, called the research “interesting and important,” adding, “There 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.”