Pathology => Medical Transplant
Medical Transplantation, transfer of a living tissue or organ to an injured or ill person to restore health or reduce disability. Over the past 45 years, surgeons have made great strides in their ability to implant organs in people who are seriously ill. At least 21 different organs-such as hearts, livers, and kidneys-and tissues-such as corneas and bone marrow-can now be successfully transplanted into patients who can then expect to survive for years or even decades. Each year, more than 20,000 internal organs are successfully implanted into patients in the United States. Improved surgical techniques are partly responsible for the success of organ transplants, but a more important factor is the development of drugs that can suppress the body's rejection of the implanted organ without also leaving the patient highly susceptible to infections.
But this success also created a major problem: as the demand for organs grew, it soon outstripped the supply of donated organs. By early 1999, nearly 62,000 Americans were on a waiting list for organs or tissues. Each year, close to 4,000 die before a donated organ can be found. In order to match the scarce supply of donated organs with critically ill patients, in 1984 Congress passed the National Organ Transplant Act to regulate the transplant business. The United Network for Organ Sharing (UNOS) serves as the umbrella organization for organ procurement and transplantation centers around the nation.
When a physician determines that a patient requires a transplant, the patient's medical information is sent to the closest transplant center. At the transplant center, candidates are evaluated and ranked according to medical criteria. The patient's medical records are then sent to UNOS for inclusion on its computerized waiting list.
When a donated organ becomes available, it is offered to patients on a waiting list in the donor's local area. A match is made if laboratory tests show that the recipient is compatible with the available organ, reducing the risk that the organ will be rejected, and if the patient is healthy enough and available to undergo major surgery immediately. If the highest-ranked patient on the list does not meet these criteria, the organ is offered to the next patient on the list. If no one locally can use the organ, it is offered regionally. If it cannot be used regionally, the organ is offered to the highest-ranking patient elsewhere in the United States. In 1998 the U.S. government ordered UNOS to change its regionally based allocation procedure to a national one, in which a donated organ or tissue would be offered to the person in most need, no matter where the patient lives.
Most transplanted organs are from people who have died recently, particularly people involved in accidents injuring the head. Once all brain activity stops in a patient, the person is considered legally dead. When the brain dies, the rest of the body is kept alive temporarily until organs can be removed. Someone from either the hospital staff or a local organ procurement organization asks the victim's family for permission to harvest the organs. To save time and increase the supply of organs, many states encourage people to sign and carry donor cards that indicate their willingness to donate their organs in the event of an accidental death. This information can also be displayed on the driver's license in many states.
Some organs and tissues can be donated from living donors. For example, millions of people each year donate blood. After donating about 500 ml (about 1 pt) of blood, the donor's body quickly grows new blood cells to replace the donated ones. The donor suffers no ill effects of donating blood. Other organs that can come from living donors include the kidney and the liver.
For medical transplantation to be successful, physicians must elude the combative efforts of the body's complex immune system, which fights to protect the body from infections of all sorts. Central to the functioning of the immune system is its ability to distinguish between invading or foreign matter, which should be attacked, and matter that is a normal part of the body, which should not be attacked. This recognition system uses specific markers called histocompatibility antigens that are on the surface of all cells in an individual's body. The immune system attacks anything that lacks these histocompatibility antigens or has antigens different from those found in the rest of the body, such as those found on invading viruses, bacteria, or other microorganisms. This recognition system causes the immune system to attack transplanted tissues that have different antigens because it has no way to distinguish between harmful and beneficial foreign matter.
There are over 200 different histocompatibility antigens, with each individual having a specific set of them. The odds that two unrelated people will have the same set of histocompatibility antigens are about one in 30,000. Transplant surgeons attempt to match histocompatibility antigens of the donor and the recipient as closely as possible in order to minimize rejection. In most cases, the match will not be exact, and the recipients must take drugs to suppress the immune response. The first drugs that were used were azathioprine and prednisone. But these drugs suppress the entire immune system, leaving the recipient vulnerable to infections and certain cancers. They also have toxic side effects.
A major breakthrough in immune suppression was the development of cyclosporine, a natural product derived from a fungus found in soil. Cyclosporine suppresses the part of the immune system involved in organ rejection with less severe impact on other parts of the immune system. A few years later, another fungal product, tacrolimus (FK-506), was found that is even better for kidney, liver, heart, and lung transplants. However, patients who take these two drugs still face some increased risk of infection and cancer, and the drugs can cause kidney damage. Doctors often use a combination of immune-suppressing drugs to limit these side effects.
TYPES OF TRANSPLANTS
Kidneys are the most common organs to be transplanted. Kidneys remove waste products from the blood stream. If they fail, often as a result of diabetes mellitus or cancer, a person can die from the buildup of these toxic materials. The waste products can be removed artificially through a process called kidney dialysis, but the patient must be hooked up to the dialysis machine two to three times each week for as long as 12 hours at a time. Kidney transplants free the recipient from dependence on dialysis. If the kidney is rejected, the patient must go back on dialysis or receive another transplant. The first successful transplant of any organ was performed in 1954, when American surgeon Joseph Murray successfully transplanted a kidney donated from the recipient's twin brother.
In the United States, more than 12,000 kidney transplants were performed in 1997, and the one-year survival rate for kidney transplant patients is about 96 percent. Some kidney transplant patients have survived more than 25 years. Because people have two kidneys but need only one, a living relative often serves as a donor, retaining one kidney for his or her own use. About one-third of transplanted kidneys come from living relatives and about two-thirds are from someone who recently died.
Many patients whose kidney failure was caused by diabetes mellitus receive a pancreas transplant at the same time. The pancreas normally secretes insulin, a substance that helps the body use and store sugars. In some diabetics, insulin-secreting cells in the pancreas are destroyed by the body's immune system. In many cases, the disease can be controlled with shots of insulin. However, if the diabetic requires a kidney transplant, the surgeon will often transplant a pancreas at the same time. In 1997, there were 209 pancreas transplants and 841 simultaneous kidney and pancreas transplants performed in the United States. The one-year survival rate for pancreas transplant patients is about 93 percent.
Heart transplants are perhaps the most dramatic of all organ transplants because without a functioning heart, a patient cannot survive more than a few minutes. The heart is also more sensitive to a lack of blood than other organs, and can be preserved for only a few hours without damage. The first successful heart transplant was conducted in December 1967 by South African surgeon Christiaan Barnard. It was not until cyclosporine was approved for clinical use in the United States in 1983 that heart transplants gained widespread use. Most patients are able to resume a normal life about six months after surgery, and about 83 percent of them survive the first year. In 1997, more than 2,300 patients received heart transplants in the United States.
Liver failure caused by cirrhosis, cancer, or hepatitis can be fatal. The liver is the only internal organ with the capacity to regenerate. This capacity provides the surgeon additional flexibility in treating liver damage. For instance, if the damage is not very severe, a temporary transplant can take over the liver's function while the patient's own liver recovers. It is also possible to remove part of a liver from a living donor and transplant it. After the surgery both the donor's liver and the transplanted portion will grow to full size. In 1997, more than 4,100 livers were transplanted, of which about 50 came from living donors. The one-year survival rate is about 87 percent.
Lung transplants are used to replace a single diseased lung, and sometimes both lungs. In some cases lung disease has damaged the heart, and these cases may benefit from a combined heart-lung transplantation. Successful lung transplants are hampered by the difficulty in preserving a lung from a person who has recently died so that it is still viable by the time a proper recipient is found. In 1997, 930 lungs were transplanted in the United States. The one-year survival rate for lung transplants is about 77 percent.
Other organ transplant surgeries are being developed and some are still in the experimental stage. In 1997, 66 small intestines were transplanted in the United States to replace organs damaged by disease. Reliable survival data for intestine transplant patients are not yet available because the procedure is still experimental.
The most common tissue transplant is blood transfusion, commonly used to replace blood lost by a person in an accident or during surgery. Other tissues commonly transplanted include bone marrow, corneas, skin, bone, cartilage, tendons, and blood vessels.
Bone marrow is the living tissue found in the center of many large bones of the body. Special cells in the bone marrow, called stem cells, are the source of both red blood cells, the primary component of blood, and white blood cells, the workhorses of the immune system. Certain blood diseases, including leukemia and sickle-cell anemia, are the result of the stem cells in the bone marrow producing faulty blood cells. In some cases, these diseases can be treated by destroying all of the patient's bone marrow and replacing it with new donor bone marrow that does not produce the faulty blood cells. Bone marrow transplants are also used in fighting breast and other cancers because intensive radiation or chemotherapy used to cure the cancer also kills the patient's bone marrow, which must then be replaced with a transplant.
Bone marrow transplants require a closer matching of donor and recipient than is the case with other types of transplants. If the match is not good enough, the recipient's body may reject the bone marrow or the white blood cells generated by the donor marrow can attack the recipient's body, a phenomenon known as graft-versus-host disease.
About 30 percent of patients who require a bone marrow transplant have a close family member who is suitably matched. The rest must find a suitable donor. In the United States, the federal government has established the National Donor Marrow Program registry, which currently lists more than 2 million potential donors. About 1,000 transplants occur every year in the United States. The success rate of a transplant depends on the disease being treated. Transplants to treat sickle-cell anemia have a 90 percent success rate, but success rates are only in the 30 to 60 percent range for other diseases.
The cornea is the transparent front covering of the eye and is necessary for vision. Cornea transplants replace corneas that have become cloudy, swollen, or painful, usually as a long-term complication from cataract surgery. Corneas can also become scarred after an injury or require replacement because of birth defects. Cornea transplants are very successful, with a success rate of more than 90 percent if the cornea is placed on the eye in such a manner that blood vessels do not come into contact with it. Without blood vessels, the body cannot send immune cells to attack the cornea. About 35,000 cornea transplants are performed every year. Eye surgeons can also transplant scleral tissue, the fibrous tissue that forms the white of the eye. Sclera transplants are used to treat glaucoma patients and those requiring reconstructive eye surgery.
Skin was the first tissue transplanted, and researchers used skin transplants in the late 1950s and early 1960s to decipher the immune system response to transplants. Most skin transplants are so-called autografts, in which skin is taken from one site on the recipient's body and grafted onto an injured site, thus avoiding the problems with rejection. However, in cases where the amount of skin needed is greater than the recipient can provide, such as in burn victims with extensive burns, skin from donors is used. Donated skin is useful, even if not properly matched, since it provides temporary protection from infection while new skin grows. By the time the graft is rejected, new skin is present. Surgeons in the United States transplanted about 700 sq m (7,500 sq ft) of skin in 1997.
OTHER ORGAN AND TISSUE SOURCES
In addition to organs donated from humans, researchers are exploring the use of partially or wholly artificial organs manufactured in the laboratory. The use of organs from other species of mammals, a technique called xenotransplantation, is also being researched.
&DEG; Artificial Organs and Tissues
One way to get around the shortage of donors is to use wholly or partially artificial organs made of plastic, metal, and other synthetic materials. A kidney dialysis machine, for example, is an artificial organ, even if it is too large to implant in the body. In 1982 American physician William DeVries implanted a crude artificial heart into the chest of dentist Barney Clark. But Clark survived for only 112 days and the heart itself, powered by an air pump that required its own cart, proved impractical. Although subsequent researchers have built smaller, more efficient hearts, none of these devices have proved successful. Instead, emphasis has shifted to the use of left-ventricular assist devices (LVADs), which are implanted beside a patient's heart to help it pump blood. LVADs keep patients alive until a donor heart is available. Many artificial devices work to restore the operation of malfunctioning organs without replacing the whole organ. Examples include artificial heart valves and pacemakers to help the heart function properly, and cochlear implants to restore hearing.
Other researchers are working to build replacement organs and tissues from human cells, a technique known as tissue engineering. The Food and Drug Administration (FDA) has approved two types of artificial skin made by growing a relatively small number of human skin cells on an artificial surface in the laboratory. The cells multiply and grow into a useful skin covering that can be used to cover larger areas than are possible with a simple autograft. Researchers hope to develop other types of artificial organs as well, such as artificial pancreases in which insulin-secreting pancreatic cells are enclosed in a porous membrane that enables nutrients, but not immune cells, to reach the cells while insulin diffuses out.
Some scientists hope to use embryonic stem cells, which are found in very early stage human embryos and are capable of developing into almost any type of cell in the body, to overcome the shortage of donor organs. If researchers learn how to make embryonic stem cells develop into specific tissues, the cells could be used to produce new organs or to repair organs, such as the heart, that cannot regenerate.
The shortage of donors has led some surgeons to consider using animals as donors. Chimpanzee kidneys were successfully transplanted in 1963, with one recipient living for nine months after the surgery. Although the kidneys were not rejected, they proved too small to keep the recipient alive. Efforts to transplant chimpanzee and baboon hearts into humans in the 1960s and 1970s also failed because the hearts were too small. The first successful baboon organ transplant occurred in 1984, when a baboon's heart was transplanted into a two-week-old premature baby whose heart was congenitally malformed. The baby survived for 20 days before her body rejected the organ. Because of problems with the small size of chimpanzee and baboon organs, doctors are now turning to other species as potential organ donors.
One animal receiving a lot of attention from the medical community is the pig. Pigs have organs that are the right size for human use, they have large litters, and they mature quickly so there is a ready supply of donating animals. Human bodies do not reject some pig tissues, such as heart valves. Surgeons in the United States transplant about 60,000 pig heart valves into humans annually. However, other transplanted pig organs undergo a phenomenon called hyperacute rejection. The recipient's immune system recognizes that the blood vessels in the transplanted organ are foreign and shuts off blood flow to the new organ within hours or even minutes, causing the transplanted organ to blacken and die. Recently, scientists have used genetic engineering techniques to breed pigs whose blood vessels contain the marker antigens found in human blood vessels. Livers from these pigs have been successfully connected to the bloodstream of several patients to clear toxic wastes while the patients' own livers recovered. Fetal pig brain cells have also been used to treat Parkinson's disease, and research is underway on using other organs from these pigs.
One of the big drawbacks of xenotransplants is the fear that unknown, possibly deadly viruses could be transferred from animals to humans. Once the animal viruses get into humans, they might spread to other humans. In 1997, scientists showed that pig viruses could infect humans with unpredictable results. The unresolved questions surrounding xenotransplantation mean that future research must be done cautiously.
&DEG; ETHICAL ISSUES
A number of ethical issues haunt the transplant field. With few exceptions, donated organs go to the patient who is nearest death, even though a healthier patient might benefit more by living longer after the transplant. People who need a second, third, or fourth transplant because their prior transplants failed usually gain top priority, even though they are not likely to do as well as patients who have not already had a transplant. Some critics object to giving organs to patients whose organ failure was the result of their own actions, such as cirrhosis of the liver resulting from alcohol abuse.
Money is also a major issue. Access to transplantation is impossible without access to good primary medical care and good insurance, both of which are largely unavailable to the poor. To be placed on the waiting list, patients must show they can pay for the transplant. In 1998 a kidney transplant cost about $35,000 and a liver transplant as much as $200,000 in the first year after the surgery. Many insurance companies do not cover such costs, particularly for the new procedures, such as lung, pancreas, or multiple organ transplants, which are still considered experimental.
Although organs cannot be bought and sold legally in the United States, there is evidence that a black market in organs exists in China and other countries. Persistent allegations have been made of people traveling to China and paying for organ transplants. Human rights groups have reported evidence that the bodies of executed prisoners are the source for most of the organs transplanted in China. In February 1998 two men were arrested in New York City, accused of being involved in the trade of organs from executed prisoners in China.
In the United States, where organ donation is voluntary, ethical questions arise over the nature of the consent and the use of incentives. Intensive donor solicitations in recent years have not made much of a dent in the shortages of organs. Even though many people sign organ donor cards, their families are often reluctant to grant permission at the moment of crisis. Some ethicists debate whether family members should have the right to refuse donation if the deceased signed an organ donor card. Presumed consent laws, in which everyone would be considered willing donors unless they have specifically said they were unwilling, have been tried in Europe and South America, and on a limited basis in Pennsylvania and Maryland. Some experts have suggested financial incentives, such as cash rebates, estate tax discounts, or payment for burial expenses. Others have suggested broadening the criteria used to determine death beyond the lack of all brain activity. This would permit a surgeon to use organs from anencephalic children, who are born without a brain, and from people in a persistent vegetative state.
The implantation of tissues from aborted fetuses into the brain has proved a possible treatment for both Parkinson's and Huntington's disease, but the treatment has raised its own set of ethical questions. The foremost is the question of abortion itself. The possibility of using embryonic stem cells to create replacement organs has faced opposition for similar reasons. Some researchers believe that this issue can be surmounted by growing cells in the laboratory or by genetically engineering a patient's own skin cells. Fetal pig cells have also been used as a treatment for Parkinson's and Huntington's disease, but that raises other ethical issues regarding the treatment of animals.
The first reliable report of a transplant surgery is from 1823 when German surgeon Carl Bunger performed plastic surgery on a woman's nose, grafting skin from her thigh. By 1863, French physiologist Paul Bert had demonstrated that tissues transplanted from one person to another are rejected. Forty years later, German biologist Carl O. Jensen found that this rejection was carried out by the immune system.
During the early 20th century, researchers such as the French surgeon Alexis Carrel and American physiologist Charles Guthrie developed the surgical techniques needed for performing transplants, but rejection remained a problem. In 1958 French immunologist Jean Dausset discovered the histocompatibility system for tissue matching. Minimizing histocompatibility differences, along with the development of the first immunosuppressive drugs azathioprine and prednisone, made transplants possible in the 1950s. Nonetheless, they remained relatively rare until Swiss biochemist Jean Borel discovered the remarkable immunosuppression properties of cyclosporine in 1972. Cyclosporine revolutionized the field when it was marketed in 1983, making transplants more common.