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David Geffen School of Medicine
 

New Life for Orphan Organs

As tens of thousands of people nationwide wait to receive scarce organs, doctors at UCLA are taking steps to ease the shortage by finding innovative ways to make use of hearts, livers, lungs and kidneys that might otherwise be discarded.

By Lyndon Stambler
Illustration by Kirk Caldwell
Photography by Ann Johansson and Mitch Tobias

MedMag-FallWinter11-OrphanOrgansIT WAS THE LATE 1980S, just a few years after he established UCLA’s heart-transplant program, and cardiothoracic surgeon Hillel Laks, M.D., was confronted with a dilemma.

His patient, a 14-year-old boy, had only a single ventricle in his heart instead of two, and he was deteriorating fast. UCLA had initially turned the boy down for a transplant because he was so sick that he did not meet the criteria for transplantation, but the boy’s mother was determined.

“Can’t you find him a heart, any heart?” she pleaded. “Give him a chance.”

Dr. Laks pushed to have the young man admitted to the program, to receive a heart that no one else could use. Because the boy was malnourished and small, the team found a donor heart from a smaller female. The transplant went ahead and, to everyone’s surprise, the boy survived another nine years – enough time to learn to ride a motorcycle and have a girlfriend.

“He had a life,” Dr. Laks recalls. “Sometimes it comes down to the question: Are you a champion of the rules or a champion of the patient? I tend to be a champion of the patient.”

That experience led Dr. Laks to think about how it might be possible to deepen the pool for donor hearts, which, with organs in short supply, always has been quite shallow. In 1992, he launched the nation’s first Alternative Heart Transplant Program to utilize “marginal” organs from older or higher-risk donors for patients who otherwise would not be accepted for transplantation. He successfully performed a five-vessel bypass to repair a donor heart that would have been rejected, to transplant into a patient who himself would not have been accepted.

Other UCLA transplant surgeons and researchers have joined Dr. Laks in efforts to expand the pool of acceptable organs and recipients, taking steps that are appropriate for each type of organ. With the national waiting lists for solid-organ transplants soaring from 30,000 15 years ago to 121,000 today, the surgical teams for liver, lung and kidney transplantation all have adopted their own creative protocols to save lives by making use of less-than-perfect organs that might at other times have been tossed away.

“There’s no way to get enough donors,” says Ronald W. Busuttil, M.D., Ph.D., executive chairman of surgery at the David Geffen School of Medicine at UCLA and founder of the UCLA Liver Transplant Program. “You’ve got to make everyone a potential donor.

THE PHRASE TO DESCRIBE THE USE OF MARGINAL ORGANS FOR TRANSPLANTATION is Extended Criteria Donation (ECD), a term that reflects a trend by clinicians to utilize these organs and to do so with measurably positive results. They might include organs from an older donor or one with risk factors such as hypertension or stroke.

MedMag-FallWinter11-Dr. Ardehali“The concept of ECD became a reality at UCLA,” says cardiothoracic surgeon Abbas Ardehali, M.D., director of the Heart, Lung and Heart-Lung Transplant Programs at UCLA. “This strategy saves lives.”

Organs typically are procured from donors following brain death, when brain function has ceased but the heart is still beating and circulating blood, which helps to preserve the tissues. But due to the nationwide shortage of potential donors, organs also are sometimes procured following cardiac death, making preservation and renewal before transplantation all the more important.

Ischemic reperfusion injury (IRI) – damage that can occur when blood is reintroduced to a lifeless organ – is a critical issue in all solid-organ transplantation, but particularly so when it comes to marginal organs, notes Dr. Busuttil. Holding a Blackberry in one hand to represent a liver, Dr. Busuttil explains: “When you put blood back into the organ, a tremendous chaos goes on in the organ. If the organ is marginal, that chaos results in non-function. We attempt to modify it in some way, so that when you transplant that organ, it doesn’t fall apart.”

Chemokines, or adhesion molecules, can gum up the workings of the donor tissues. “Rather than having free-flowing blood, it’s like the 405 Freeway at rush hour,” Dr. Busuttil says. “We are trying to declog the hepatic sinusoids (low-pressure vascular channels), so that blood can get through and the organ can work.”

Part of the challenge when working with less-than AAA-rated organs is to find new ways to keep them viable. To that end, Dr. Busuttil’s work in the lab for nearly three decades has resulted in a translational clinical trial, using a molecule known as a P-selectin blocker (recombinant P-selectin glycoprotein ligand, or rPSGL-ig) to block adhesion molecules and improve the blood flow. Positive results from that trial were recently published in the American Journal of Transplantation.

The surgeons do not, of course, work in isolation. They often partner with teams of research scientists to refine techniques and to create new innovations in transplant surgery. Before new modalities to improve therapeutic outcomes can be used at the bedside, “things need to be done at the benchside,” says Jerzy Kupiec-Weglinski, M.D., Ph.D., director of the Dumont-UCLA Transplant Research Laboratories.

Dr. Kupiec-Weglinski’s work has, for example, been essential to Dr. Busuttil’s P-selectin studies. While at Harvard’s Brigham and Women’s Hospital, Dr. Kupiec-Weglinski researched the molecule, and he brought that work with him to UCLA, where he has continued testing the compound for use in preventing IRI. “The results were very promising,” Dr. Kupiec-Weglinski says. “We published those results in the leading transplant journals in this country, and a couple of years later, Dr. Busuttil and his team incorporated this compound in their clinical transplantations. There were more than 50 patients treated with the rPSGL-ig, with very good results. This is a perfect example of a successful transition of the idea and the compound from bench to bedside.”

MedMag-FallWinter11-Dr. Hillel LaksSince IRI is common to all organ transplants, rPSGL-ig, or a cocktail of drugs, might further enhance the use of ECD organs. That would most certainly be a benefit for liver transplantation, where the demand has climbed from 4,000 in 1988 to more than 20,000 in 2010. Between 5,000 and 6,000 livers are procured each year; roughly 750 were discarded last year. Approximately 15,000 people die each year waiting for a suitable donor liver.

UCLA has been using several techniques to expand the use of donor livers. One approach that has helped to mitigate the shortage is split-liver transplantation, wherein a single liver is divided for transplantation into two recipients; however, less than 7 percent of donor livers are found to be suitable for this procedure. “It’s got to be a perfect liver, and you’ve got to have two perfect recipients,” Dr. Busuttil says.

Another approach is accepting organs procured after cardiac death. While this might cause some damage to the organs, they still work well if they are paired with the proper recipients, Dr. Busuttil says. Donation-after-cardiac-death transplantation requires an extraordinary amount of skill and judgment – experience that the surgeons at UCLA have developed through decades of research and clinical practice.

Dr. Busuttil and others at UCLA also have pioneered the use of anti-viral agents against cytomegalovirus and hepatitis B to keep organs from failing. “If we could take the hundreds of livers that are discarded each year and manipulate them in some way, either with the selectin blocker or other techniques, then we’re making a significant impact because we’re increasing the number of donors,” Dr. Busuttil says. “It’s not enough, but it’s certainly better than it was.”

The need is amply illustrated with a visit to the liver-transplant Intensive Care Unit at Ronald Reagan UCLA Medical Center. On this day in August, all 24 beds are filled, either with patients who are waiting for or who have recently received a new liver. Those awaiting transplantation have ghastly dark complexions, and they are among the sickest patients in the nation, with Model for End-Stage Liver Disease scores approaching 40, while the average for the nation is about 20.

As Robert Galindo, a transplant recipient who now counsels other patients, says, “If I were on my death bed, I’d go with an ECD liver,” and indeed for many of these very ill patients, that might be the approach that saves their lives. “ECD livers, under the appropriate circumstances and in expert hands, work as well as standard organs,” says liver-transplant surgeon Fady Kaldas, M.D.

“All organs are stressed during the donor’s death process,” Dr. Kaldas says, noting that the body will secrete metabolites following death, whether from a stroke or a gunshot wound. “It doesn’t mean it’s a bad organ. Generally, there is no difference between an extended-criteria and a standard-criteria liver in outcome. When we deem a liver usable, it’s usable.”

DR LAKS HAS PERFORMED HUNDREDS OF THE 1,500 HEART TRANSPLANTS that have been done at UCLA since he started the program in 1984. Early on, he was troubled that he could not help some people simply because they were too old or did not have a bright prognosis. The son of teachers, Dr. Laks grew up in South Africa with the notion that “if something isn’t working, there is almost always a solution. It’s a complex process, not a cookbook approach.”

Today, Dr. Laks is the Chancellor’s Professor of Cardiothoracic Surgery, an award that is reserved for “scholars of international distinction who are recognized and respected as teachers of exceptional ability.” His lifelong inclination toward innovation helped to earn him that coveted title. It was in 1992 that he began performing quadruple bypass operations to repair “marginal” hearts. Using veins taken from the recipient patient, he would perform the bypass on a table just moments before transplanting the heart. In this way, he began to help older patients who would not have qualified before for transplantation. One man who received such a transplant in his mid-70s lived into his 80s.

MedMag-FallWinter11-Dr. BusuttilDr. Laks and his team developed other creative ways to help their patients. One who had hepatitis C received a heart from a hepatitis C-infected donor. In some cases, a smaller recipient who needed less pumping capacity was matched with an older donor who had high blood pressure.

These patients often are among the cohort rejected by other transplant centers. “They are so sick, they come to us as their last resort,” says Dr. Ardehali, who performs up to 50 heart and lung transplants a year.

Nationwide, there are some 3,195 people on the waiting list for hearts and 1,790 on the waiting list for lungs, according to the non-profit United Network for Organ Sharing (UNOS). Each year, between 500 and 2,000 people die while waiting for hearts, and between 500 to 1,000 die waiting for lungs.

To optimize recipients’ chances, it has become vital to find ways to preserve potential donor hearts and lungs. In a so-called “beating-heart transplant,” for example, UCLA uses a device with multiple features and oxygenators to keep the donor heart pumping from the time it is procured to the time it’s implanted. “It is our belief that if we can maintain the donor heart in a near-normal physiological state, it will be a better organ to be transplanted,” says Dr. Ardehali, who is the principal investigator for a multi-center study on “beating-heart transplantation.”

Another innovation introduced by Dr. Laks was the use of modified reperfusion of the heart with blood from which the white cells had been removed. This proved to be highly effective, and Dr. Ardehali has now applied a similar technique to the lungs, also with excellent results. “We believe the white blood cells injure the graft, so we remove them,” Dr. Ardehali says. “We provide sugar and substrate. We modify the content of the blood that the organ needs initially. We add some measures to dilate the blood vessels.”

UCLA also has been fine-tuning the use of immunosuppression medications.

Such measures to procure and preserve donor organs are especially important if, for example, the lungs came from a donor who had pneumonia or contusions or if a heart has some blockage. “The goal is to try to expand the donor pools by utilizing hearts and lungs that were otherwise not being used,” Dr. Ardehali says. “Our experience has shown that the results are still good.”

In a UCLA study that followed 42 lung-transplant recipients who had received ECD organs, the three-month survival rate was 97.6 percent. Another study of ECD heart recipients found a five-year survival rate of nearly 60 percent, compared with the national average of about 72 percent for recipients of non-ECD hearts.

KIDNEY/PANCREAS-TRANSPLANT PATIENTS are among the happiest people on earth, says surgeon Gerald Lipshutz, M.D. ’93. “They come to us, and they’re on dialysis and they’re diabetic. And when they walk out of the hospital after surgery, they no longer need dialysis, they no longer need insulin,” he explains.

But here, too, the shortage of organs has a profound impact. More people are waiting for kidneys than for any other organ – more than 95,000. Of those, fewer than 15,000 each year will get a transplant. The wait in Southern California can be as long as eight to 10 years.

MedMag-FallWinter11-Dr. LipsutzAs with hearts and livers and lungs, UCLA has taken some innovative steps to address the kidney shortage. They include transplanting pediatric kidneys into adults or using two “marginal” kidneys. A more controversial approach is using kidneys from donors whom the Centers for Disease Control and Prevention consider high-risk due to behaviors that place them at greater risk of viral infectious disease. The organs in these cases are tested by sophisticated methods to detect viruses and, if cleared, can be used if the recipient, who is fully informed, gives consent. “The testing is 21st century, leaving little doubt that an infection exists,” Dr. Lipshutz says.

UCLA has also created a donor chain for kidney transplantation, in which an altruistic person, often a complete stranger, donates a kidney. That organ is given to a recipient who already has a kidney available that is not a perfect match. The recipient then passes on the incompatible kidney to another recipient, and so on. Such donor chains have resulted in successful transplants for up to six kidney patients. “It’s such a simple idea, so elegant and so creative, yet extremely powerful in its effect,” says Albin Gritsch, M.D., surgical director of the UCLA Kidney Transplant Program. “It is a huge move in a positive direction for patients with kidney failure.”

And to deal with the issue of blood-group incompatibility, UCLA has developed a program to allow a loved one to donate a kidney, even if his or her blood group doesn’t match that of the recipient. It starts with desensitizing the immune system of the recipient by filtering and removing antibodies. Doctors then use intravenous immunoglobulin to keep the cells from making more antibodies. “We can change their immune system just enough, so that they can get this alternative-blood-type organ,” Dr. Lipshutz says. The procedure also has been used in limited cases for liver transplants.

A modified approach has been used for people who have developed so many antibodies that “it’s almost as if they’re allergic to other people,” Dr. Lipshutz says. “On the operating table, they would reject any organ.” Guillermo Montoya was one of those patients. He had received a transplant in 1991, but it failed after 10 years, putting him back on the list. But because he had developed a high level of resistance, none of the organs that came available were deemed suitable for him.

Earlier this year, UCLA contacted Montoya, now 64 years old, to tell him that a kidney was available, but it was not a perfect match. “Do you want to risk it?” they asked.

“Why not,” Montoya responded.

Dr. Lipshutz and his team began the process, called plasmapheresis, to reconfigure Montoya’s immune system to accept the organ. “We did some filtering of his blood to remove antibodies and gave him other medication,” Dr. Lipshutz says. “It’s very time intensive for both the patients and for the doctors. Here we were able to take someone who never would have received a transplant because of immunologic reasons, and he was transplanted.”

On March 30, 2011, Montoya received his new kidney. While the recovery was difficult, doctors cleared him two months later to resume physical activities like going to the gym.

“Now I’m great, thank God,” Montoya says.

Treatments like plasmapheresis are a high-tech approach done at only a few centers. Newer hopes lie in the emerging realm of stem-cell technology. When that day comes, surgeons like Dr. Lipshutz might find themselves out of a job.

“I joke that in 100 years, people will nudge each other and say: ‘Can you believe what they did 100 years ago?’” Dr. Lipshutz says. “’They did organ transplants. Why didn’t they just grow new ones, like we do now?’”

Lyndon Stambler is a freelance writer and teaches journalism at Santa Monica College.

 





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