Giving a Piece of Yourself

BY ROBIN EISNER
IN AUGUST OF 2003, CATHERINE MERNAR, THEN 47, WAS QUITE ILL from liver disease. The Bayonne, N.J., resident went to see Robert S. Brown Jr., M.D., M.P.H., associate professor of medicine and surgery at P&S and chief of the Center for Liver Disease & Transplantation at New York-Presbyterian Hospital. Dr. Brown told her she might have nine months to a year to live if she didn't get a liver transplant. Having already waited about seven years, she knew the time to get a cadaveric liver in the New York metropolitan area could be longer than nine months.
Dr. Brown offered her an alternative: Obtain a transplant from a living donor. In 1998, New York-Presbyterian became one of the first hospitals in the country to perform adult-to-adult living liver transplantation. Jean C. Emond, M.D., the Thomas S. Zimmer Professor of Surgery and surgical director of the Center for Liver Disease and Transplantation, helped pioneer the procedure in children in the 1980s and expanded its application to adults. After Mrs. Mernar discussed her condition with her family, her sister, Regina Gill, then age 41, volunteered to be her living donor.
"I did a lot of research," says Mrs. Gill, a wife and mother of three children who works in the bond market and lives six blocks from her sister. "I talked to other hospitals and people who had undergone the procedure. But the level of confidence the doctors at New York-Presbyterian Hospital were able to instill in me made making the decision that much easier."
"It was a heroic thing Regina did for her sister, because of the potential risk to her, and she is a mother of three young children," says Milan Kinkhabwala, M.D., adjunct assistant professor of surgery, surgical director of the liver transplantation program, and one of the doctors who performed the surgery.
Today, hundreds of "heroes" like Mrs. Gill are donating their organs while they are still alive to family members, friends, and sometimes even strangers, as waiting lists for organs continue to grow. Columbia University Medical Center and New York-Presbyterian physicians are leading the effort to use living donor organs and to improve methods to increase the number of available organs from living and cadaver donors. They are spearheading new techniques, such as "kidney swaps" and expanded donor organ transplantation, and researching new ways to protect patients and donors after transplantation.

Liver Transplantation
Sisterly Love
Sisterly Love: Regina Gill, left, and Catherine Mernar
The first successful liver transplantation was reported in 1968 and by the 1980s the procedure had become the standard treatment for end-stage liver failure for both children and adults. But almost immediately, children experienced a crisis in supply, as children in need of livers always outnumbered pediatric donors. By the mid-1980s, nearly half the children who needed a liver transplant died on the waiting list. As a response to the crisis, Dr. Emond and a colleague at the University of Chicago developed the live donor procedure for children in the late 1980s after they found their first series of patients using livers from live donors fared just as well as patients who received livers from cadavers.
Before joining P&S, Dr. Emond directed pediatric liver transplantation at the University of California-San Francisco, where Dr. Brown was one of his trainees in pediatric and adult liver transplantation. Before he joined P&S, Dr. Brown built the liver transplantation program at the University of North Carolina, Chapel Hill, into a thriving success. Dr. Emond and Dr. Brown, by then preeminent liver disease experts, combined forces and joined P&S in 1997 and 1998, respectively, to create one of the first fully multidisciplinary liver disease centers in the nation.
The Columbia center's first liver transplant using a living donor was performed in January 1998 to replace the scarred and cirrhotic liver of a 1-year-old girl who was suffering from biliary atresia, a rare but devastating congenital condition that affects about 400 newborns in the United States every year. The child's father became the donor because his blood type matched his daughter's. The successful transplant turned the girl from someone expected to live only six months into someone with a normal life expectancy. The father returned to work about six weeks after the operation.
Successful adult transplants using live donors have followed. Since the mid-1990s, when the first living donor liver transplantations were performed in adults, more than 2,000 patients nationwide have received livers from living donors.
Clearly, living donor operations save lives but the surgery performed on the donor appears to run counter to the tenet of medicine to "first do no harm." For transplantation into an adult, 60 percent of the healthy donor's liver is removed from the organ's right lobe. The donor regenerates most of the lost tissue in a few weeks, though the long-term outcomes to the donor are still unclear. A survey by Dr. Brown of U.S. liver transplantation programs, published in the Feb. 27, 2003, issue of the New England Journal of Medicine, found serious complications in 14 percent of donors and a rehospitalization rate of 8.5 percent.
Most of the controversy in the public's mind, though, has centered on the risk of death to the donor. After a 57-year-old donor died at another New York hospital in 2002 (the second of two donor deaths) New York state enacted some of the toughest guidelines in the country for living donations and issued a report outlining recommended procedures for such operations. "The guidelines used by New York state were based on those that had been at NYPH," says Dr. Kinkhabwala. "We now teach a course for other centers about how to ethically and safely perform living donor liver transplants."
One of those guidelines is to have different teams of doctors independently monitor the health of the donor and the recipient, before the first incision is made. "The separation ensures that a doctor caring for the recipient would not exert any pressure on the donor to undergo the procedure," says Dr. Kinkhabwala. Both donor and recipient are informed of all the possible risks of the operation. The two teams also make sure the donor and recipient have sufficient financial and social resources during recovery.
Mrs. Gill, the liver donor for her sister, said she was told of every possible risk she could face as a result of the procedure. "The hospital was very careful in not making me feel any pressure about my decision," Mrs. Gill says. "They seemed to give me every opportunity to opt out." A blood test for Mrs. Gill indicated she had a marker for rheumatoid arthritis, which the doctors warned might develop due to the stress of the procedure. "I said, 'I might get rheumatoid arthritis even if I don't go on with the operation'."
Mrs. Gill chose to accept the risks, but nationwide, the number of living donor liver transplantations has declined from a peak of 518 in 2001 to 323 in 2004. Raising the number of living donor liver transplants may depend on more accurate data on the risks to the donor and developing ways to reduce those risks. Dr. Emond is co-chair of a nine-center NIH study of outcomes for donors and recipients of live liver donor transplantation. "Our goal is to gather accurate data in a disciplined way so we can give liver transplant patients and potential donors solid information about the risks and benefits of this innovative and controversial procedure," Dr. Emond says.
Donors also may be heartened by new findings by Dr. Brown that show the overall death rate for recipients with potential living donors is less than that of recipients who received an organ from a cadaver. "Most studies in the past that compared adult living donor liver transplantation to deceased liver donor transplant focused on post-transplant survival," Dr. Brown says. But the studies did not take into account that people die while on cadaveric waiting lists and that living donations have a shorter waiting period. "This kind of data might help educate people about the benefits of living liver donation," says Dr. Brown.
To further improve the quality of life for donors of livers, Dr. Kinkhabwala is refining minimally invasive methods, such as laparoscopy, for the procedure. "I am working with a doctor in Paris to learn the technique, first for patients with cancer and then for donors," says Dr. Kinkhabwala.

Kidney Transplants
Living donors of kidneys have benefited from laparoscopic surgery for some time, thanks to Lloyd Ratner, M.D., who, with a colleague, performed the world's first laparoscopic donor operation in 1995 at Johns Hopkins. Dr. Ratner, director of renal and pancreatic transplantation, has been at Columbia since September 2004. Approximately 70 percent of living kidney donor procedures are now done laparoscopically.
In 2001, Dr. Ratner also pioneered a method called a kidney swap or paired kidney exchange, which increases the pool of donor kidneys available. The kidney swap allows two patients who have found donors who are medically suitable but blood group-incompatible to swap their donors. After initiating such exchanges in both Baltimore and Philadelphia, Dr. Ratner performed New York state's first kidney swap at New York-Presbyterian Hospital on Sept. 29, 2004.
During a swap, the four patients undergo surgery in neighboring operating rooms. Once the donor kidneys are removed laparoscopically, they are put on ice and given to the surgeons waiting to perform the transplants in the adjacent operating rooms. Kidneys in the recipients usually are not removed. Doctors make an incision in the recipient's abdomen and place the kidney in the pelvis, rather than at the organ's usual location in the rear of the upper abdomen. A vein and an artery from the kidney are sewed to the patient's iliac vein and artery and the donor kidney's ureter is connected to the recipient's bladder.
Dr. Ratner says the anonymity between the two sets of donors and recipients is needed to prevent anyone from backing out at the last minute in case they don't get along and to prevent any kind of coercion. The participants can meet after the operations are over. Not many facilities are big enough to have four transplant teams simultaneously working together. "Columbia/NYPH has the manpower and resources to do this," says Dr. Ratner. "One of the reasons I came here was to establish the swap program."
In the late 1990s, Dr. Ratner also advanced kidney transplantation by allowing more recipients access to living organs through use of plasmapharesis, which removes antibodies from the blood of recipients that would cross react with the donor kidney and cause immediate irreversible rejection of the donor kidney by the recipient. Some patients have antibodies from a previous transplant, from pregnancy (approximately 30 percent of pregnant women develop antibodies against their fetus), and from transfusions, explains Dr. David J. Cohen, associate professor of clinical medicine and medical director of renal transplantation.
A donor's white blood cells, acting as surrogate kidney tissue, are tested against a recipient's plasma to see if they cross react. If they do, the recipient's antibody levels are measured and plasmapheresis is performed before the transplantation to remove them. Plasmapheresis also is done after the transplant. With time, antibodies return and cause rejection in approximately half the patients and plasmapheresis must be repeated to successfully treat the rejection. Eventually, though, the antibodies disappear as the patients receive immunosuppressants that curb immune cells from making antibodies.
Still another innovation Dr. Ratner has brought to kidney transplantation is taking two cadaveric kidneys from an older donor and putting them into a recipient. A single kidney from an older individual frequently will not provide enough kidney function to keep a recipient healthy. For example, after age 40, kidney function decreases every decade by 10 percent. By the time someone is 70 years old, kidney function is down to 70 percent, with each kidney operating at 35 percent. Preservation and rejection may bring it down to only 25 percent of normal. But in 1993, Dr. Ratner performed the first operation to transplant two deceased donor kidneys from an older individual into a recipient to provide sufficient functional kidney mass. It is now an accepted practice.

Improving Liver and Kidney Quality
Like their colleagues in the renal transplant program, the liver transplantation team is trying to make the best of suboptimal donor organs. Dr. Brown is beginning to work with a form of liver dialysis called MARS, or Molecular Absorbant Recirculating System, for patients who have end-stage liver disease, with the hope that those who undergo the procedure might be able to use a less than ideal donor liver from a deceased donor.
Other important research areas are rejection treatment and immunosuppressant therapy. In 1977, Columbia doctors began the use of polyclonal antibodies to treat rejection in kidney transplant patients. The medical center "was a pioneer in using biological agents against lymphocytes as a way to prevent rejection," says Mark A. Hardy, M.D., the Auchincloss Professor of Surgery and director of renal transplantation. Now the renal team also is using Thymoglobulin, a polyclonal antibody drug that works against T-cells in recipients of kidneys. Researchers are studying whether a monoclonal antibody, Campath-1H, in addition to other immunosuppressants can help prevent or treat rejection in recipients of living kidneys. "Clearly over the years immunosuppression has changed in renal transplantation and the effort to induce tolerance and minimize immunosuppression in this field continues, and our institution has continued to lead this effort," adds Dr. Hardy.
Another investigation is examining whether removal of steroids from the immunosuppressant cocktail will reduce hepatitis C recurrence in living and deceased donor liver transplant recipients. Still another is examining whether anti-VEGF, an anti-angiogenesis drug that is an antibody to vascular endothelial growth factor, will prevent the spread of liver cancer. Anti-angiogenesis agents aim to treat cancer by preventing the growth of the blood supply the tumor uses to expand. Findings from the anti-VEGF trial could be used in patients awaiting liver transplantation, as 20 percent to 30 percent will get cancer.
Dr. Cohen is involved in a variety of clinical trials investigating the best use of immunosuppressants for recipients of living kidneys. One study will look at the longterm effects of starting patients on tacrolimus and microphenylate, two immunosuppressants, and then switching to rapamycin and microphenylate. Tacrolimus can damage the kidney, so it is believed patients would do better on rapamycin. Another trial is examining the effectiveness of a completely new type of immunosuppressant, called a jak3 inhibitor, which works by inhibiting the pathway that stimulates lymphocyte activity.

Postop
Jan. 26, 2005, marked the first anniversary of the operations Mrs. Mernar and Mrs. Gill underwent. The only ill effect Mrs. Gill says she faces from the procedure is the pull from the scar on her abdomen when she does sit-ups at the gym. Mrs. Mernar says she has more energy now than she has had in 20 years. Besides being a mother, she works in a law office and teaches computer skills at her children's elementary school. Both plan on participating in research at Columbia that studies the outcomes of living donor transplantation, hoping to help others who may consider the procedure.
Looking back, both agree that one of the toughest parts of the whole experience was the emotional aspect. "It was hard for me to see my sister going through pain," Mrs. Mernar says. "Cathy never asked me to do this," Mrs. Gill says. "The most difficult things for me were getting her to say yes and talking with my husband and children about it. But when I had my doubts before the operation, I took comfort in knowing that had I died, I'd taught my kids the best lesson any mother could."

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