Sep. 4, 2003 ANN ARBOR, MI – As if the ordeal of waiting for, receiving and living with an organ transplant weren't enough, a new study finds that people who get a second chance at life from new hearts, lungs, livers or intestines are very likely to have their lives cut short by failing kidneys.
In fact, 16.5 percent of all non-kidney transplant recipients develop chronic kidney failure, and almost a third of those patients go on to develop full-blown end-stage renal disease, according to new data published in the New England Journal of Medicine by researchers from the University of Michigan Health System.
And those whose kidneys begin to fail after their transplant face a much larger risk of dying than those whose kidneys stay healthy, the study finds. Only a second transplant -- to put in a new kidney -- mitigates the fatal consequences of ESRD.
The researchers weren't able to pinpoint the exact causes of the kidney failure seen in the study of 69,321 people who received transplants of any solid organ except kidney or pancreas between 1990 and 2000. But in the largest-ever study of its kind, they identified several factors that put patients at a higher risk of kidney failure and death: older age; being a woman; pre-transplant hepatitis C infection, high blood pressure or diabetes; and kidney problems before or immediately after transplant.
They also know that some kidney damage is caused by the very drugs that all transplant recipients take to prevent their bodies from rejecting their new organs.
"Every doctor involved in transplant sees these patients come through clinic, but there has never been a detailed attempt to quantify the issue," says Akinlolu Ojo, M.D., Ph.D., the associate professor of nephrology at the U-M Medical School who led the study. "We can see now how large the problem is, what the risk factors are, and what the implications and costs might be for the dialysis and transplant systems. We can also see that damage caused by anti-rejection drugs is one of the reasons for this effect, but not the only reason."
In the lead editorial that accompanies the paper, two Harvard University transplant experts call the findings "cause for concern." The U-M team and editorialists both say the results have implications for counseling given to patients awaiting a transplant, the design of less-damaging anti-rejection treatment regimens, and the decision of when to place transplant recipients with failing kidneys on the kidney transplant list.
The results that Ojo and his colleagues report in the new paper come from a cross-analysis of data contained in three national databases.
The researchers relied heavily on the detailed medical information about all American solid-organ transplant recipients contained in the Scientific Registry of Transplant Recipients. The SRTR is administered on behalf of the U.S. government by the University Renal Research and Education Association, a not-for-profit health research foundation, in collaboration with the U-M. The SRTR is run with oversight and funding from the Health Resources and Services Administration, a division of the U.S. Department of Health and Human Services.
"We compiled SRTR data on all the patients who had never received a kidney or pancreas transplant before they received their heart, lung, liver, intestine or combination heart-lung transplant," says senior author Robert Merion, M.D., a transplant surgeon and professor of surgery at the U-M. "These data allowed us to calculate a measure of kidney function, called glomerular filtration rate, that indicates kidney failure of varying degrees in a standard way." A small number of patients who had combination heart-liver, liver-kidney or heart-kidney transplants were excluded.
The team then cross-referenced those patients with the federal Centers for Medicare and Medicaid Services list of all those who received treatment for end-stage renal disease during the same time period. Treatment could include dialysis or kidney transplant. They also searched the Social Security Administration's list of deaths, so that they had complete information on which transplant recipients had died for any reason during the study period, which ended in 2001.
Besides the overall incidence of kidney failure, which increased steadily as time went on and led to an escalating rate of ESRD and a 4.5-times-greater overall death risk, the researchers found many other trends that may be significant for pre-and post-transplant treatment.
For example, the risk of developing chronic kidney failure varied greatly depending on the type of organ received. Only 6.8 percent of heart transplant patients had developed kidney failure by the third anniversary of their transplant, as compared with 10 percent of lung recipients, 13.9 percent of liver recipients and 14.2 percent of intestine recipients. By the fifth year, nearly 11 percent of heart recipients had failing kidneys, as opposed to nearly 15 percent of lung recipients, 18 percent of liver recipients and 21.3 percent of intestine recipients.
The researchers were able to obtain data on use of anti-rejection drugs in the immediate post-transplant period for nearly all the patients in the study. Because almost all transplant recipients in the 1990s took one of three such drugs -- cyclosporine, tacrolimus or sirolimus -- it was impossible to tell exactly how much they may have contributed to an individual's kidney failure.
The only statistically significant finding related to anti-rejection drugs was that the excess risk of developing chronic kidney failure was greater among liver transplant recipients who took cyclosporine than among those who took tacrolimus. Sirolimus was introduced toward the end of the study period; only 1 percent of patients in the study took it, so comparisons with other drugs did not produce statistically significant findings.
Both the researchers and the editorialists call for further studies of the outcomes for patients taking these three drugs, and newer regimens with less-toxic medications.
The findings regarding kidney transplant for patients whose kidneys entered end-stage failure were interesting, says Ojo, who treats many kidney transplant candidates and recipients.
"For years, we had been finding that non-kidney transplant patients had been coming back to clinic in need of dialysis or a kidney transplant," he notes. "These data show that each year, one percent of all the transplant patients who had chronic kidney failure progressed to end-stage renal disease, and that those patients who received a kidney transplant soon after this progression had a lower overall death risk than those who received dialysis."
However, Ojo and his colleagues say, the ongoing shortage of kidneys from living and deceased donors already means that many kidney transplant candidates do not get an organ in time. The same is bound to be true for many non-kidney transplant recipients who find themselves needing a new kidney.
And, the cost of dialysis and transplants for these second-time-around transplant candidates could add millions to the already costly Medicare system that insures kidney failure patients. Already, the nation's 300,000 ESRD patients make up only 0.8 percent of Medicare recipients, but account for 6 percent of all Medicare costs -- more than $13 billion annually.
In all, the researchers call for better counseling of non-kidney transplant candidates, to make sure they understand the risk that among other complications, their kidneys may fail as a result of their life-saving transplant. They also call for better understanding of the co-existing risk factors -- especially diabetes, hypertension and hepatitis C infection -- that might influence an individual's risk of developing kidney failure after a transplant. And, they say that transplant teams should do more to prevent kidney-harming complications during and immediately after surgery to give a patient a new heart, liver, lung or intestine.
In addition to Ojo and Merion, the study's authors include U-M nephrologists Alan Leichtman, M.D. and Eric Young, M.D., M.S.; emeritus U-M nephrology professor and current URREA president Friedrich K. Port, M.D., M.S.; URREA founder and former U-M professor Philip J. Held; U-M School of Public Health professor Robert A. Wolfe, Ph.D.; and research associates Julie Arndorfer, M.P.H. and Laura Christensen, M.S.
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