New marrow brings hope for kidney recipients

Jennifer Searl was lucky -- she was alive because of a donated kidney from her father -- but the young woman seemed anything but fortunate as she hobbled around the University of New Hampshire two years ago. The powerful drugs Searl took to prevent her body from rejecting the donated organ had caused such painful growths on the bottom of her right foot that she could barely walk, and she had developed cataracts in both eyes. Worse, the drugs had failed to prevent long-term rejection, and her new kidney was failing anyway.

Today, Searl, 23, represents unusual hope for thousands of transplant recipients who endure a lifetime of antirejection drugs that keep them alive at the cost of increased risk of heart disease, diabetes, anemia, infections, and other serious health problems. Sixteen months ago, Searl underwent a groundbreaking surgery: a second transplant of a kidney accompanied by the donor's bone marrow. The operation at Massachusetts General Hospital allowed her to stop taking antirejection drugs altogether, and she feels better than she has in nearly a decade.

"It's been unbelievable," said Searl, the captain of her high school tennis team before kidney disease forced her to give up sports. "I work out every morning, and things that used to be so hard for me are nothing to me now . . . With kidney failure, you sleepwalk. I have this odd sense of being awake."

So far, eight patients have undergone the procedure, which requires them to get a simultaneous bone marrow transplant to "educate" their body that the kidney they are receiving is not an invader and should not be rejected. One patient, Janet McCourt, has lived more than five years since the operation and her kidney shows no sign of rejection even though she hasn't taken immunosuppressive drugs since late 1998. Five other transplant patients, including Searl, are also living without the drugs, while the remaining two underwent the procedure too recently to be sure of the outcome.

"It is very encouraging if [Mass. General] has got that many patients where that seems to have worked," said Dr. Clyde Barker, a transplant surgeon at the University of Pennsylvania in Philadelphia. "Tolerance so that kidneys or other organ grafts are accepted without the continued use of immunosuppressives has been a goal almost from the beginning of transplantation."

The surgeons and researchers at Mass. General won't disclose the complete results of their human experiments until a conference in Boston this summer, but more than a decade of animal research supports the underlying theory of "induced tolerance." They say their approach could be in wide use within a few years for transplants of kidneys as well as other organs. Already, once-skeptical colleagues are beginning to send potential patients their way. "When we first started to do this, many [kidney specialists] said, `I wouldn't refer my patient for that sort of thing,' " said Dr. A. Benedict Cosimi, chief of transplant surgery at Mass. General. "Now we are getting calls from all over."

However, the researchers need more proof that their approach is worth the hardship for patients, who must undergo several extra steps than they would with a conventional transplant: a bone marrow infusion coupled with radiation treatment and low-dose chemotherapy to eliminate some of the patients' own marrow cells.

"You are trading initially a lot more treatment for eventually being off immunosuppressives for the rest of your life," explained Dr. David Sachs, director of Mass. General's Transplantation Biology Research Center.

The body's tendency to attack transplanted organs has been a major obstacle for surgeons since the world's first successful kidney transplant in 1954 at what is now Brigham and Women's Hospital. Surgeon Joseph E. Murray got around the issue by having an organ donor who was the identical twin of the patient, so the transplanted kidney was genetically identical to the one it replaced. But transplanted organs that are not identical provoke white blood cells from the bone marrow called T-cells to mobilize in an attempt to repel the invader. Fear of such an attack, which can lead to fatal organ rejection, discouraged Boston surgeons from carrying out the city's first heart transplant for almost 20 years.

Today, nearly all of the more than 20,000 people in the United States who receive transplants each year take some combination of antirejection drugs such as Azathioprine or Prednisone for the rest of their lives. But few transplant surgeons are satisfied either with the side effects -- including vulnerability to heart disease and a permanently weakened immune system -- or the drugs' failure to protect organs from chronic rejection. Though 90 percent of donated kidneys are working at the end of a year, about 3 percent a year fail due to chronic rejection, according to Cosimi, making it highly likely that a patient will need a second kidney transplant within a decade. In a nation where 56,000 people are awaiting a kidney, that second organ isn't always available.

Doctors at the University of Pittsburgh Medical Center, one of the leading transplant centers, have switched many patients to greatly reduced antirejection drugs by giving them a treatment that wipes out many of their T-cells before the transplant. More than 60 percent of transplant patients are able to take as few as one to two pills per week compared with several a day under conventional approaches, said Dr. Ron Shapiro, director of kidney transplant at the hospital's Starzl Transplantation Institute.

But Mass. General's approach has an even more ambitious goal, training the patient's immune system to accept the new organ without a fight. Shapiro calls it "one of the most exciting things out there."

The bone marrow transfusion is key, giving the patient immature T-cells from the organ donor. Inside an organ called the thymus, other marrow cells from the transfusion, called dendritic cells, block T-cells from the patient that would otherwise attack tissues from the donor. This "educates" the thymus not to release T-cells that would attack the new organ, while leaving plenty of other T-cells to fight off diseases.

Initially, Mass. General offered the new transplant approach to only a very narrow group: patients who had a cancer of the blood called multiple myeloma that had helped to destroy their kidneys while also making them ineligible for a conventional transplant. For these people, the marrow transplant not only helped their body tolerate the new organ, but it treated their cancer as well.

McCourt, a 57-year-old contractor from Pembroke, went first, receiving marrow and a kidney from her sister in 1998. Initially, McCourt had hoped only to live long enough for her pregnant daughter to give birth to a grandchild, but McCourt is thriving. "It's wonderful. Not only is she tolerant to her kidney and back to her regular life, but . . . she is at least in long-term remission from her multiple myeloma," said Sachs of Mass. General.

Searl, by contrast, is a more typical transplant patient: Diagnosed with kidney disease at age 12, she received a kidney from her father in 1993. For a couple of years, she felt much better, but then chronic rejection set in, coupled with mounting side effects from the antirejection drugs, including enormous warts that covered her right leg and foot, making walking difficult.

Her mother, Joan Searl, a nurse, suggested Jennifer for a kidney-marrow transplant when she met one of the Mass. General surgeons in an elevator. Initially, the team was concerned about operating on Searl since she would be the first patient who was eligible for a conventional transplant. But Jennifer was so debilitated by the antirejection drugs that she was adamant about trying an approach that might free her of them.

So, Jennifer underwent chemotherapy and radiation treatment to prepare for a bone marrow transfusion. On Sept. 17, 2002, she received both the marrow and a kidney from her mother. Sixteen months later, Jennifer's kidney is working fine, the disabling warts on her foot are gone, and she's getting married in March. Medically, she demonstrated that the procedure can work for a much broader spectrum of patients than people suffering from cancer and kidney failure at the same time.

"Jennifer is a pioneer," said Cosimi. He explained the potential impact of the treatment, saying, "There may be only 10 Janet McCourts out there at any one time, but there are 50,000 Jennifers."

Sachs and Cosimi say their animal studies suggest their approach would work equally well on other organ transplants. However, because of the five days required to prepare the patient, they require a living donor, which narrows the organ possibilities to livers and kidneys for now. But Cosimi is optimistic that deceased donors can eventually be used; he notes that animal studies are underway to see if tolerance can be induced long after the transplant by infusing them with bone marrow from the same donor.

Ultimately, Sachs hopes the procedure may solve the biggest problem in transplant surgery, the organ shortage, by reducing the need for second transplants and allowing more use of animal organs.

Scott Allen can be reached at allen@globe.com.