Organ transplantation

Organ transplantation is surgery in which a diseased or damaged organ is removed from a patient and replaced with a healthy organ from an organ donor. Allmajor organs, including the heart, lungs, liver, and kidneys, can be transplanted, and the success rate ranges from 90% to 50%, depending upon the organtransplanted. In the United States alone, greater than 20,000 organ transplantations are performed annually, and approximately 2,300 of these are heart transplants. Normally, organ transplantation is a last resort. It is performedonly on patients who are in the last stages of organ failure and for whom other treatments have not been successful. Although rejection of the transplanted organ by the immune system of the recipient (immunologic rejection) is a major problem in the field of organ transplantation, an even bigger challenge is the shortage of donor organs. In 1999 in the United States, more than 55,000 individuals were awaiting donor organs, and that number increases daily.

History and Success Rate of Organ Transplantation

Although the clinical practice of organ transplantation is only a few decadesold, attempts to replace a failing organ with a healthy one have occurred for centuries, and mythic literature often describes it as a cure for disease.The first successful organ transplant was a kidney transplant performed in 1954 in Boston, Massachusetts. In what is known as a "living related donor" transplant, one identical twin donated a healthy kidney that surgeons then transplanted into the other twin. In 1966, a transplant recipient at the University of Minnesota received a pancreas from a postmortem donor; in 1967, a livertransplant was performed at the University of Colorado in Denver, Colorado restoring normal liver function for 13 months. Also in 1967, the first human heart transplant was performed in Cape Town, South Africa, and normal heart function continued for 18 days. A heart/lung transplant at Stanford University Medical Center in 1981 achieved successful organ functioning for five years. In 1982, artificial heart recipient Barney Clark died 112 days after his surgery at the University of Utah, Salt Lake City; and, in 1984, a baboon-to-humanheart transplant was performed in Loma Linda, California in an attempt to save the life of a baby who died 20 days after the transplant. In 1985, an artificial heart "bridge" achieved normal heart function for nine days for a recipient awaiting a donor heart; in 1992, a baboon-to-human liver recipient died70 days post surgery, and a pig-to-human liver transplant patient died two days post surgery. A living related lung transplant in 1993 at the Universityof Southern California proved successful when both parents each donated a lung lobe to their daughter.

By the late 1990s, more than 2,300 heart transplants were performed annuallyin the United States alone, not to mention the transplantation of other organs. In a report from the U.S. Department of Health and Human Services in December 1997, the one-year and three-year survival rates for organ transplantation recipients had reached an all-time high. The highest survival rate was among kidney recipients, with 95% surviving one year and 89% still living after three years. Data gathered by the United Network for Organ Sharing (UNOS) from97,000 transplants performed at 742 different centers across the country compared the one year survival rates of transplant recipients from January 1988through April 1992 with survival rates from May 1992 to April 1994. The studyrevealed a 7% to 12% improvement, with heart-lung, lung, and liver transplant recipients showing the largest percentage of success rate increase.

This and several other studies revealed that survival rates vary between transplantation centers. Those centers with the lowest survival rate are historically those performing a lower volume of transplants. High-volume centers statistically are showing higher survival statistics. One study concluded that "the risks of mortality at one month and at one year were 'substantially higher' at low-volume heart transplant centers" (those performing fewer than nine transplants a year). While approximately half of all the heart transplantationcenters in the nation are classified as low-volume, in total they perform only 15% of all heart transplants. However, they average 24% patient deaths within a year after surgery compared with 18% for high-volume centers (a 33% increase). Low-volume liver transplant centers average approximately 32% mortality within 12 months post surgery compared to 25% at high-volume centers (a 28% increase), and low-volume pancreas centers 15% mortality within 12 months post surgery compared with 10% at high-volume centers (a 50% increase).

Immunosuppression

One of the biggest obstacles yet to be overcome in organ transplantation is immunologic rejection, an automatic response by the immune system of the recipient that attacks and destroys the "foreign" tissue of the new organ. Under normal circumstances, the immune system is designed to recognize, attack, anddestroy foreign invaders or abnormal cells, such as viruses, bacteria, infectious diseases, and cancer cells.

Each person's cells contain molecules unique to that individual, much like afingerprint, called major histocompatibility antigens (MHAs). When searchingfor a donor organ, physicians attempt to find a donor whose MHAs are as closea match as possible to those of the recipient. Regardless, the immune systemstill recognizes the difference, except between identical twins. Since the advent of organ transplantation, a great deal of research has focused on understanding the immune system in an attempt to prevent organ rejection. Immunosuppressive drugs have been developed that suppress the immune system and allowthe new organ to function properly. The first effective immunosuppresants were those used to treat cancer. These chemicals suppressed bone marrow function, including its ability to produce immune cells. The transplant recipient was then left totally vulnerable to any type of infection or disease.

In 1983, cyclosporine became the first immunosuppressive drug licensed for transplant recipients. This pharmacologic agent is more selective in its action, blocking only one component of the immune system called T cells, thus leaving the bone marrow in tact. Azathioprine, muromonab-CD3, and prograf are other immunosuppressants, all of which have greatly improved the short-term success rate of organ transplants. They do not seem, however, to be successful forlong-term survival. Half of the patents who receive donor kidneys, for example, experience organ rejection within 10 years, necessitating dialysis treatments or another transplant. Also, because the immune system is still not as responsive to other foreign invaders while the individual is on immunosuppressive drugs, the transplant patient is continually at high-risk of infections and developing cancer. The drugs must be taken on a lifelong regimen and, because they are highly toxic, often cause undesirable side effects such as destruction of the lungs, kidney damage, high blood pressure, osteoporosis, lymphoma, and coronary artery disease-which affects almost half of all transplant recipients.

Transplant recipients are carefully monitored for organ rejection with periodic biopsies in which small pieces of tissue removed from the transplanted organ are examined for microscopic cell damage. In this way, doctors can adjustor change, if necessary, the type of immunosuppressant drugs being administered.

Supply of Donor Organs

Apart from living donors, organ donors are people who are brain dead, which means the brain shows absolutely no signs of life and the person's body is kept alive by machines which breathe for them to keep their heart beating. Braindeath may occur from automobile or other accidents, stroke, gunshot wounds,and severe head injuries. People who wish to donate organs for transplantation may carry organ donor cards, or ensure their desires are know by their families. Families may also offer to donate the organ of their deceased loved one.

In the United States, more than 200,000 people have kidney failure and more than 60,000 die each year from liver failure. The number of individuals awaiting donor organs in 1997 was 55,000, and the gap between prospective donor recipients and donor organs is increasing. However, preliminary 1998 donor statistics from the UNOS shows an increase in cadaveric donors from 5,479 donors in 1997 to 5,788 donors in 1998. For the first time in history, the number oforgans recovered from cadaveric donors rose above 20,000. Public awareness campaigns by hospitals and other organizations nationwide are ongoing to help further increase the number of individuals who agree to become organ donors when they die.

Because healthy donor organs are in such short supply, strict rules dictate who should or should not receive a transplant. Patients who have conditions that might cause the new organ to fail should not receive transplants. Similarly, patients who may be too sick to survive the surgery or the side effects ofthe drugs they must take to keep their new organ working are not good transplant candidates.

Once a person has been approved for an organ transplant, he or she is placedon a waiting list at a transplant center. All patients on waiting lists are registered with the UNOS. UNOS runs a national computer network that connectsall the transplant centers and organ-donation organizations. When a donor organ becomes available, information about it is entered into the UNOS computerand compared to information from patients on the waiting list. The computer program then produces a ranked list of patients who are good candidates for that particular organ. Finding an organ that is a good match for the recipient's blood and MHA type is important, so the computer program takes that into account when producing the list. The ranking is also based on other factors, such as the size of the organ relative to the patient's size, and how badly thepatient needs a transplant.

When a good match is found, the donor organ is rushed to the transplant center where the patient is waiting, and the patient is prepared for surgery. Transplant patients usually are started on immunosuppressive drugs before or during the transplant operation. Because the chance of rejection is highest during the first few months after the transplantation, recipients are usually given a combination of immunosuppressive drugs in high doses during this time. Afterward, they must take lower doses of immunosuppressive drugs for the rest of their lives.

Like all surgery, organ transplantation carries the risk of complications, such as infection and bleeding. In addition, certain other complications can develop from specific types of transplants. In kidney transplants, for example,the ureter, which carries urine from the kidney to the bladder, may be damaged, resulting in urine leakage. However, this problem usually can be corrected with follow-up surgery.

Patients are monitored closely after transplant surgery for any signs of infection, rejection of the new organ, or other complications. The likelihood ofsuccess depends on a number of factors, including the patient's age and health, the type of organ transplanted, the match between donor and recipient, andhow well the patient follows the physician's instructions after surgery. Forsome types of organ transplantation, the results can be quite dramatic. Forexample, heart patients who could hardly get out of bed before the surgery begin feeling much better soon afterward. More than 70% are able to go back towork and resume normal activities, and many are even able to participate in sports.

Alternatives to Whole Organ Transplantation

The lives of up to 35,000 patients every year in the United States could be improved with a heart transplant. With only 2,000 to 2,500 hearts donated annually, demand far exceeds supply and approximately 30% of heart transplant candidates die before a donor organ is available. In an effort to reduce this rate, physicians often use what are known as "short-term bridges." These are battery-operated mechanical pumps called left ventricular assist devices (LVADs), that take over the pumping action of the heart's main pumping chamber. Historically, these machines were satisfactory only for a few weeks, after whichtime the patient developed life-threatening conditions including blood clotsand hemorrhaging. The machines also destroyed blood cells.

Currently on the market is an improved version of this device called the HeartMate. About the size of a fist, this device is actually implanted into the patient, does not destroy blood cells, and is attached to a large, portable console which houses the battery. Even more efficient models under developmentmay, in some instances, eliminate the need for heart transplantation in somepatients. The implantable device would be driven by a rechargeable battery carried in a shoulder harness or strapped around the waist.

In an effort to compensate for the shortage of donor livers, researchers arecontinually looking at alternatives to whole organs. In an article entitled "Right Lobe Living Donor Liver Transplantation in the journal Transplantation, doctors describe a method whereby just certain sections of the left lobe of the liver of a live donor are removed and transplanted into children needing a new liver. This has met with considerable success. Called a left lobectomy, the procedure is unable to provide enough tissue for an adult patient. However, because right lobectomy was anticipated to provide enough graft tissue, 25 right lobe transplants performed between adults resulted in an 88% survival of the graft recipient with no significant problems for the donor. Although three recipients-all high risk for liver transplants-died shortly after surgery from uncontrolled infections, all three grafts were functioning well.

Xenotransplantation

Xenotransplantation is the use of animal organs to save human lives. Many scientists and biotechnology companies are looking at xenotransplantation as a way to address the acute donor organ shortage situation. So far, such attemptshave proven unsuccessful because the immune system, which reacts strongly even to foreign human organs, reacts even more quickly and violently to cells from organs so genetically distant from human cells as those of a pig or baboon, for instance. This "hyperacute rejection" appears to be the response of certain antibodies which, when detecting tissue from another species, attack the internal wall of the transplanted organ's blood vessels, rejecting that organ within hours or even minutes. Even if this hyperacute attack can be controlled, the body still launches a long-term rejection response to animal organswhich is, again, stronger than to those of a human donor organ. In the 1992and 1993 transplant of baboon livers into two patients with hepatitis B at the University of Pittsburgh Medical Center, the transplants were successful and the patients died not from organ rejection but from "runaway" bacterial andfungal infections caused by common microbes present in the human body and the environment but which could not be controlled by the patients' immune systems because of the heavy doses of immunosuppresant drugs required to prevent organ rejection.

For several reasons, researchers now believe pig organs may be the most suitable xenotransplant possibility. Several laboratories are experimenting with "genetic engineering" which may make the animal organ more compatible to the human immune system. To achieve this, certain genes from the pig are deleted and certain human genes are added. One laboratory in England and another in the United states have already developed pigs in which human genes prevent activation of a response system which is hoped to help prevent hyperacute rejection in the transplant recipient.

Although no whole-organ experiments with xenotransplantation were being performed as of 1998, more than 200 people received xenografts of animal tissue and/or cells. Fetal pig neurons have been implanted into the brain of Parkinson's disease patients, and pig liver cells wrapped in plastic are used to cleanse the blood of liver failure patients until a human organ donor can be found.

In other approaches, researchers are infusing purified bone marrow cells fromthe prospective organ donor into the prospective recipient's bone marrow inan attempt to achieve "tolerance" by the recipient's immune system of the donor organ. If the donor cells live to produce mature blood cells, then the recipient's immune system becomes "chimeric", containing some of its own blood cells and some from the donor. In animal experiments, chimeric immune systemsaccept both same-species and xenotransplants. Three human-to-human heart transplants performed using this technique have already been successful.

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