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Rejecting defeat

Scientist triumphs after setback in kidney transplant method

Email|Print| Text size + By Patricia Wen
Globe Staff / January 24, 2008

Dr. David H. Sachs was full of optimism when the third patient in his $1 million study was wheeled into the recovery room at Massachusetts General Hospital after an experimental kidney transplant.

The first two patients had thrived, adding credibility to an unorthodox idea that Sachs had pioneered over his career, that transplanting a donor's bone marrow along with the kidney could solve the problem of organ rejection, sparing patients a lifetime of powerful antirejection drugs.

But 10 days after the third patient's surgery, Sachs's phone rang at his spacious lab overlooking Boston Harbor. A colleague reported that William Andrews, a 43-year-old father of two, was rejecting the kidney.

Sachs and his research team remember the darkness of the ensuing months in 2003, when they abruptly suspended their transplants for nearly two years. Andrews was demoralized and on dialysis, his sister's donated kidney seemingly wasted. Over and over, Sachs paced the corridors of his lab asking himself, "What did we miss?"

Today, capping a comeback from the crisis, Sachs and his team are reporting that they unraveled the explanation for Andrews's rejection. After they tweaked their protocol, adding a drug to avert what happened to Andrews, two new patients have thrived without the long-term need for antirejection drugs, according to a paper published in the New England Journal of Medicine.

Overall, four of Sachs's five patients have experienced no organ rejection, a particularly striking accomplishment because they all received kidneys that were different from their own tissue type. Transplants of such mismatched organs are the most common and the most likely to be rejected, even when patients take immunosuppressive drugs.

"I had confidence we would figure it out," said the 66-year-old Harvard Medical School professor, who has dedicated more than three decades to conquering organ rejection. He said the results restored his faith that his once-radical idea will eventually become mainstream, making organ transplants safer and more available.

Transplant surgeons said Sachs's study represents a pivotal moment in organ transplantation, demonstrating that it is feasible to eliminate immunosuppressive drugs with their debilitating side effects, such as skin warts, cataracts, and increased risks of heart disease, diabetes, and serious infections. If the results are borne out in a larger group of patients, the Mass. General technique has the potential to help transplant recipients live longer. Within 10 years, half of all transplanted organs fail because of chronic rejection, a bleak predicament in this era of organ shortages.

"This is landmark work," said Dr. Joshua Miller, an organ transplant researcher at Northwestern University's Feinberg School of Medicine in Chicago.

Other researchers cautioned that only the healthiest patients may be able to endure the rigorous treatments, including chemotherapy and radiation, that precede the transplant.

Andrews said that going through the experimental protocol was not easy and that being an example of a failed case was even harder. But he sees his difficult experience as a contribution to medical research, saying how impressed he was that the Mass. General staff worked tirelessly on his case.

"They did not want to accept defeat," said Andrews, who ultimately received a replacement kidney in 2004 using conventional treatment with antirejection drugs.

Sachs is no stranger to the emotional roller coaster of experimental medicine and the intellectual nimbleness required to overcome setbacks. Since he was a young Harvard medical student in the mid-1960s, hearing his first lecture on organ transplantation, Sachs has set out to tackle "the most important problem that could be solved." In his mind, that was the persistent problem of organ rejection.

Sachs, director of the Transplantation Biology Research Center at Mass. General, had faith that a donor's bone marrow, from which immune cells originate, could play a pivotal role in giving transplant patients "induced tolerance" to a donated organ.

Under Sachs's approach, five days prior to transplant surgery, patients begin to undergo low-dose chemotherapy to kill off some of their marrow cells and make room for injection of the donor's bone marrow.

The patients also receive a drug and radiation to the thymus to eliminate a type of immune system cell, known as a T cell, that typically attacks any tissue perceived as foreign.

On the day of the procedure, surgeons attach the new kidney while injecting the donor's bone marrow into a blood vessel in the patient's arm. The donor's bone marrow mixes with the patient's, creating a temporary state called mixed chimerism. This tricks the patient's immune system into recognizing for years - and possibly forever - the donated organ as part of the self.

After the surgery, the immune system is still in a period of adjustment, and doctors give patients antirejection drugs that are gradually tapered off. Most patients were off the drugs by the ninth month.

Sachs first tried this approach successfully on mice, pigs, then monkeys. In 1998, he won approval to try his treatment on a select group of Mass. General patients with severe kidney failure, all of whom were offered matching kidneys from close relatives. When these six patients did well, Sachs moved on to the most ambitious test of his method, trying it out on patients with mismatched donors.

Starting in 2002, the method worked nearly flawlessly on Jennifer Searl, 28, a librarian from Peabody, and Christopher McMahon, 26, a retail store manager from Tewskbury.

Sachs and his colleagues felt something close to restrained euphoria. At a New Year's Eve party in 2002, Sachs and the chief surgeon on the research team, Dr. Benedict Cosimi, who share a small boat that they years ago named "Tolerance," gave a toast to the initial success of the experiment.

Then in October 2003, Andrews, a software engineer with polycystic kidney disease, went in for his experimental procedure. When the surgery was complete, spirits were high.

"Everybody thought it was a success," Andrews recalled.

But within two weeks of the surgery, Dr. Tatsuo Kawai, one of Sach's research colleagues, was handed test results showing that Andrews's urine output had dropped and that his blood contained high levels of toxins. An ultrasound scan showed the new organ was losing blood flow.

"The kidney's rejecting," Kawai remembered saying to himself.

He phoned Sachs, who was in his lab at one of Mass. General's research facilities in the Charlestown Navy Yard, with the news.

"It hurt," Sachs recalled. "You want to see everyone succeed."

For several months, Sachs and his team tried various drugs on Andrews, hoping to reverse the rejection. But by spring 2004, doctors began dialysis, conceding defeat in saving Andrews's new kidney. Because of the failure, Andrews was no longer eligible for another try with the experimental treatment.

The outcome for Andrews hit everyone on the research team hard.

"It was the lowest moment," Sachs recalled.

He said these studies put "people's lives in your hands" and are full of unpredictability.

Sachs and his dozen colleagues on the project began brainstorming about what went wrong, trying to salvage a lesson, if not Andrews's kidney. After intensive study, they concluded that another type of immune cell, the B cells, played a critical role in his organ rejection. They theorized that Andrews's body harbored B cells that ultimately produced antibodies against his sister's kidney, a scenario they did not anticipate because B cells had played no role in organ rejection in any of their previous studies.

To prevent rejection in new cases, the team revised the protocol to give all patients a drug prior to surgery that depletes B cells. Before they could proceed with the study, they had to win approvals from several regulatory agencies, which ensure patient safety.

Meanwhile, Sachs was delighted when he heard that Andrews's cousin had stepped forward to offer a kidney.

In August 2004, that conventional transplant surgery went smoothly, and Andrews went back to work "feeling great," while accepting his fate of being on antirejection drugs.

By 2005, the regulatory agencies approved the revised plan. In February 2005, surgeons operated on Derek Besenfelder, 28, a communications specialist from Los Angeles, and then in January 2006, they did transplant surgery on Matthew Knowles, 48, of Marshfield. Both have returned to their normal lives.

"I'm in perfect health," said Knowles, a supervisor for a gas company. "I don't take a pill a day. It's a miracle."

The four successful transplant patients have so far lived between 15 months and nearly five years without antirejection drugs.

Other researchers are also experimenting with ways to create permanent tolerance to donated organs, using slightly different approaches. Today's New England Journal includes two case studies from these other groups.

Sachs hopes to expand the study to include 20 new patients with mismatched donors. His greatest hope is that someday his novel treatment will extend to other organs.

"It's a wonderful feeling when you see people returning to their normal lives," he said.

Patricia Wen can be reached at wen@globe.com.

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