Panacea or peril? Do new treatments save lives or do they endanger them?

Living donor programs still risky

With the U.S. donor organ allocation system in a continuing state of crisis, listing thousands more desperate patients than organs available for donation, more and more transplant programs are turning to living donor programs to rescue people almost certain to die on the waiting list.

Once only considered for kidney donation, healthy people now also are giving portions of their lungs, livers, pancreas, and intestines to friends and relatives in need of a transplant. But is it a promising new technology or a case of too much too soon?

Risks to donor not evaluated

According to statistics kept by the Richmond, VA-based United Network for Organ Sharing, the organization that contracts with the U.S. Department of Health and Human Services to administer the organ transplant waiting list, living organ donation increased by 16% between 1999 and 2000, to 5,500 operations, the largest increase ever in a single year. Last year, in the state of New York, a third of all liver transplants came from live donors.

But, even though the operations provide lifesaving miracles for people who are at death’s door and free up more cadaveric organs for people who do not have such an option, many experts are critical of the rapid expansion in the use of organ grafts from living donors. The risks to the donor, on whom an unnecessary, major surgical procedure is performed, are not being properly evaluated. And there is almost no regulation on which centers are qualified to perform these procedures, they warn.

An editorial by Cronin and colleagues from the University of Chicago1 in the May 24 issue of the New England Journal of Medicine criticized the growth in the number of programs attempting adult-to-adult living liver transplant in particular.

"Since 1997, more than 30 U.S. transplantation programs have performed more than 400 of these procedures," the authors wrote. "Although six of these programs have performed only one procedure each, one program has performed more than 100. Twenty-three centers are planning to start such programs. Liver transplantation in adults with the use of grafts from living donors may initially have been regarded as a technical extension of the procedure for transplanting liver grafts from living donors into children. However, we are unaware of any formal analyses of whether it is ethical to perform the operation, even if donors and recipients provide informed consent."

Risky procedures, little data

Unlike living kidney donation, which has been performed in the United States since 1954, adult living liver donation is a much riskier procedure, and there are little published data on rates of complications, and mortality, among the donors, explains Elizabeth Pomfret, MD. Pomfret is a liver transplant surgeon and director of the live donor program at the Lahey Clinic in Burlington, MA.

The adult procedure is even significantly much riskier than adult-to-child living donation, which was pioneered in this country at the University of Chicago in the early 1990s and has since gained wide acceptance.

Because the liver has the ability to regenerate, the removal of the left lobe of the liver from an adult — a relatively small segment — can be transplanted into a child, giving the child a liver that is sufficient and will grow as the child grows. The adult operation requires a much more sizeable graft of liver tissue, the larger right lobe, from the donor, explains Pomfret.

"We have some experience looking at people who have given their left lateral segment, a much smaller piece of liver than we are talking about with adult live donor transplants where we are talking about typically somewhere between 50%-60% of the adult liver volume," she explains. "It is really a significant operation, there is potential for death, potential for a bad outcome."

The pediatric procedure was studied in a clinical trial at the University of Chicago, and the results were published before other institutions began performing the procedure. But now, Cronin and co-authors state, the adult operation is widely being performed without enough clinical data on which patients make good candidates and exactly what surgical techniques are best.

"Morbidity attributable to surgical resection in donors of grafts for adult recipients has been reported to be as high as 50%, with complications including wound infection, injury to the nerves of the brachial plexus, and portal-vein thrombosis," the authors wrote. "The most serious potential consequence of a right lobectomy or an extended right hepatectomy is death due to an intraoperative complication or postoperative liver failure. Although a right lobectomy performed in a healthy donor should carry a low risk of death, the mortality rate has not been clearly established. On the basis of discussions at professional meetings, as compared with reports in the literature, we are concerned that some centers may not be reporting deaths in a timely manner."

Due to the seriousness of the situation, the authors called for the Centers for Medicare and Medicaid Services (CMS), formerly the Health Care Financing Administration, and private insurers to collect data on complications associated with the surgeries and limit coverage of the procedures to only those performed at designated "centers of excellence."

National database needed

While there is a need for more and better information about the procedure, Pomfret says she is wary of inviting government restriction of a lifesaving treatment. "Whenever you talk about regulation, it gets kind of dicey. I think that, there needs to be some sort of comprehensive database, a registry if you will, where anybody doing live donor liver transplant is submitting their patients and their results," she says.

"This is more to allow those of us in the community doing this to be able to really quote numbers that are reasonable to people considering doing this. The rate of complications are X," she says. "Out of however many procedures that have been done worldwide or in the United States, there have been this many donors who have died, this many donors have required a liver transplant themselves because of complications, there have been this many major complications, this many minor complications.’ That sort of information needs to be available." Pomfret says she also is concerned about the number of small transplant programs "dabbling" in this surgery.

The Lahey Clinic has had extensive experience with performing liver and kidney transplants and has performed around 40 living donor adult liver transplants, she notes.

"What is important is there has to be tremendous skill in the team doing liver transplantation and liver resectional surgery, because the live donor operation is very different than the transplant operation," she emphasizes. "Our program is the largest in New England, and I think — at this point — the third largest in the United States, and there are only a handful of programs that would have that significant volume."

Attending meetings of transplant professionals, she has heard reports of donors taken to surgery only to have the team discover a problem that makes the resection impossible, she says.

"We have never had that happen," Pomfret states. "We have an extensive evaluation that has ruled those things out without ever going into the operating room. That is not the case with many other programs, where there are clearly reports of people going into the operating room, being well under way with the operation, and finding something that — as far as I am concerned — probably should have been able to be diagnosed preoperatively."

Failures not documented

Equally disturbing, she says, is the fact that these failed attempts are likely not documented when these centers report their complication rates. "I consider that to be a major complication, but it is one that sometimes isn’t put into the complication pool," she says. "It’s like, Oh yeah, there are those aborted hepatectomies.’"

The American Society of Transplant Surgeons established a registry for adult-to-adult living liver donation surgeries. But, according to Pomfret, the database does not contain enough information yet to be useful.

"Most of the data we have come from the transplant meetings that we all attend and that is where you are hearing things like, They’ve done this many operations, that there have been two people who have required liver transplants as a result of complications worldwide, three reported deaths in the donor population worldwide, rumors of more.’ But, I think that is a problem when you have just have these rumors to go on."

New lung procedure quietly gains ground

An even newer transplant procedure involves two living donors donating portions of a lung to create a set of lungs for a patient whose own pair are failing. Known as a living lobar transplant, there is even less information in the medical literature about who is performing these procedures, what the rates of complications are, and which patients should be candidates.

"No one knows the exact number or the success rates at other institutions because those numbers have not been published," says Soon Park, MD, assistant professor of cardiovascular and thoracic surgery at the University of Minnesota in Minneapolis. "We have not published because our numbers are so small. We have performed three operations, and all of these patients and donors are doing well. But our program is still in its infancy."

The procedure, performed on patients whose lungs are failing and are not likely to live the two or three years it often takes to get a set of cadaveric lungs, involves taking a lower lobe from one lung of two separate donors. "What the procedure is about is taking a lobe, which is half of a lung. Take one lobe from each of two donors and then in the recipient you take both lungs out and put two lobes. So, essentially they are getting one lung, comprised of two lobes, one on each side," explains Park.

The surgery was pioneered by Vaughn Starnes, MD, and colleagues at the University of Southern California, and researchers there have published some information, he says. Their data indicate that recipients of living lobar transplants do roughly as well as patients who receive bilateral cadaveric lung transplants, he says. "As far as the recipient is concerned, it gives them a survival benefit as well as enhanced quality of life."

For the donors, however, the risks are significant, he admits. The procedure involves major surgery and will take between 15% and 20% of their lung tissue, which does not regenerate the way that the liver does.

"The impact on lung function is fairly minimal, however," Park says. "People can even live with one lung. In patients who have lung cancer, John Wayne is a good example, one lung is sometimes removed. It is a big operation, but once patients survive the surgery, they do reasonably well. We don’t ask that of donors, of course, we take much less from them."

Most donors are able to return to leading normal lives after recovering from the surgery, he adds. And, his center has seen no complications among their donors. But, a report last year by researchers at Barnes-Jewish Hospital in St. Louis detailed complications among 62 donors who had undergone the procedure there.2

In their report, 38 of the 62 had complications, including 12 major problems and 55 minor ones. The major complications included a hemorrhage that required transfusions and a nerve injury that partially paralyzed the donor’s diaphragm. Minor complications included pneumonia, temporary problems with heart rhythm, and infections of the pericardium.

Is it ethical?

The problem for many in the transplant community is that complications in living donors are health problems caused by physicians in previously healthy people — the opposite of the mandate to "first, do no harm." But, for physicians in the transplant community faced with patients with little hope and donors asking to take the risk to save a loved one, going ahead with these procedures offers a chance they feel compelled to pursue, both for the individual patients and for the thousands more who must wait for a cadaveric organ.

"Clearly, there is a lot of debate about whether it is reasonable to take otherwise healthy people and expose them to significant risks, of liver transplantation, for example, solely for the good of another," says Pomfret.

"It is the heart of a lot of ethical debates. But, I think that most people agree, at this point, who are doing this, that, if the donation is done in such a way that there is a genetic or significant emotional relationship between donor and recipient, then there is a rationale to allowing that person to take that risk."

Both Park and Pomfret say they recommend limiting these procedures to patients who really have no other alternative — who most likely face death if they wait for cadaveric organs. And, both say it is essential that centers offering these procedures devote significant resources to ensuring that the donors are not coerced into offering the donation and that they fully understand the risks. (See "Living donors require adequate protection," in this issue.)

Given that 10%-20% of patients seeking lung transplants die on the waiting list and that lungs can be harvested from only 10%-15% of cadaveric organ donors, Park feels that the procedures have a place.

"I would not say that this is something that should be recommended as being an alternative to seeking cadaveric lung donation," Park says. "But, given that the availability of organs is so low, and the death rate on the waiting list is so high, I think it should be done in limited situations, and, possibly, expanded as we learn more."

References

1. Cronin DC II, Millis JM, Spiegler M. Transplantation of liver grafts from living donors into adults — too much, too soon. N Engl J Med 2001; 344(21):1,633-1,637.

2. Battafarano RJ, Anderson RC, Meyers BF, et al. Perioperative complications after living donor lobectomy. J Thorac Cardiovasc Surg 2000; 120:909-915.

Sources

Soon Park, MD, University of Minnesota, Department of Surgery, MMC207, 420 Delaware St. S.E., Minneapolis, MN 55455.

Elizabeth Pomfret, MD, Lahey Clinic, 41 Mall Road, Burlington, MA 01805.