What is transplantation?

The Immune System and Transplantation

Transplantation antigens are proteins expressed on the surface of an individual’s cells. Every individual has a unique set of these proteins, called human leukocyte antigens (HLAs), which are encoded on chromosome 6. Each parent contributes one HLA-containing chromosome, and both chromosomes are expressed in the offspring. The purpose of these antigens is to help the body recognize what is “self” and what is not. In this manner, bacteria and other pathogens harmful to the individual can be sensed as “nonself” and destroyed by the immune system.

When an organ is transplanted between unrelated people (allotransplantation), it will not be recognized as self in the recipient’s body, and the immune system will start to attack it in a process called rejection. In the same way, transplants between identical twins, with the same HLA proteins on their cells, will be recognized as self and not be rejected.

White blood cells (lymphocytes) are intimately involved in the body’s immune response. They protect the individual from invading bacteria, viruses, and fungi. Lymphocytes can be divided into two subsets: B and T cells. The T cell is the main cell involved in the recognition and destruction of allotransplants. Receptors found on the T lymphocyte cell surface are stimulated by the foreign antigens found on allotransplants. With T-cell stimulation, events are initiated that lead to the allotransplant’s destruction.

With the knowledge that T cells are responsible for rejection, methods of modulating T-cell activity were developed. One of the first approaches was to destroy them using total-body irradiation. This method had only limited success, and the side effects of the radiation were severe. Attention then turned toward drugs that acted directly on T cells.

Azathioprine was one of the first drugs to be used successfully. By preventing the biosynthesis of essential components of cell growth, azathiaoprine inhibits T cells from replicating. Steroids
were next found to have immunosuppressive properties. Azathiaoprine and steroids at one time were used in combination to prevent rejection in human kidney allografts. Although these drugs were effective, they were not specific for T cells. Other cells were affected, and both immunosuppressive drugs had serious side effects in high doses. In 1978, a T-cell-specific inhibitory drug was tried clinically for kidney allotransplants. This drug, named cyclosporine, has since become the mainstay of immunosuppressive therapy for all vascularized allotransplants. In most transplant centers, patients who have received allotransplants are given a combination of the above three drugs, since each drug works differently on T-cell function. The harmful side effects of these drugs can be minimized by using all three in smaller amounts, thus preventing the side effects from larger doses.

With the advent of cyclosporine, patients receiving kidneys without matching HLAs do almost as well in the short term (one to five years) as those receiving HLA-matched kidneys. Transplanted kidneys with HLAs in common, however, function significantly longer (ten years). Therefore, physicians try to match HLAs between donor and recipient. Most organs available for transplantation are from cadavers. It takes days to tissue-type the cadaver, find a compatible recipient, and transport the organ to him or her. Kidneys are the only organ that can be stored this long and still function. Therefore, only kidneys are matched for HLAs. With the liver, heart, and pancreas, only blood type is matched between donor and recipient. Currently, kidneys may be stored up to three days. The liver and pancreas must be transplanted within eighteen to twenty hours.

Indications and Procedures

With the advent of dialysis in 1960, renal failure
is no longer fatal and patients can live by having their blood filtered several times per week. Kidney transplantation, however, offers a significant improvement in the quality of life compared with dialysis. Unfortunately, while more than 16,000 patients in the United States receive kidney transplants each year, another 93,000 patients remain on waiting lists. There is much room for greater success.

Two donor options are available to the recipient awaiting a kidney transplant: living related and cadaveric. The first option involves removing a kidney from a willing family member and transplanting it into the recipient. Removing one of two donor kidneys does not significantly affect a healthy individual. The second option is for the recipient to be placed on a waiting list for a cadaveric kidney. When a cadaveric kidney that is of a compatible blood type for a particular recipient becomes available, arrangements are made to admit this patient to the hospital for transplant.

Approximately30 percent of all kidney transplants are living related. The advantages of a living related transplant are twofold. First, the waiting period for a cadaveric kidney is eliminated, as the operation can be scheduled as soon as the recipient has been evaluated. Second, kidneys from living related donors tend to work immediately and have better long-term results. Because of organ shortages, some medical centers will allow unrelated volunteers to donate a kidney to a recipient. Such transplants usually occur between spouses.

A typical kidney transplant operation takes three hours to perform. Usually, the patient’s own kidneys are not removed, and the transplanted kidney is placed in the pelvis. The vessels of the new kidney are sewn into the iliac blood vessels of the leg. After the transplant procedure, patients stay in the hospital ten days before returning home. They must take medications every day to prevent rejection but otherwise are independent.

Orthotopic liver transplantation

is now considered the optimal form of therapy for end-stage liver disease in adults and children. Since no machine exists to take the place of the liver, transplantation is the only alternative in patients with liver failure. Cadaveric livers are the source for transplants because individuals have only one liver. Because of a shortage in cadaveric organs, many patients die each year waiting for a liver transplant. For this reason, a few medical centers have experimented with living related liver transplants, usually from parent to child. In this operation, one of the two lobes of the donor’s liver is removed and transplanted to the recipient. The remaining liver in the donor will grow back to normal size in one week.

A liver transplant is one of the most difficult operations to perform. Unlike heart operations, there is no machine to take the place of the liver during surgery, and speed is vital. The liver is the largest organ in the body, weighing about 5 pounds in an adult. Because the liver is so large, and its blood supply complex, it is necessary to remove the patient’s own liver during the transplant. The average time for a liver transplant varies, ranging from five to thirty hours. The worst complication of liver transplant is failure to function after surgery. The only treatment is to find another liver for transplantation before the patient dies.

Pancreas transplants are done exclusively for patients with complications of insulin-dependent diabetes mellitus
(IDDM). Around half of the new cases of IDDM per year will develop complications such as renal failure and blindness. There is no way to predict which patients will develop these complications. Currently, combined pancreas-kidney transplants are done for diabetics who experience renal failure. The transplanted pancreas prevents damage from recurring in the new kidney and also makes the individual insulin-independent. Pancreas transplants are not performed for diabetics without complications because the risk of immunosuppression is not worth the benefit of insulin independence.

Unlike with liver transplants, short operative time for pancreas-kidney transplantation is not essential to patient survival. Both the pancreas and the kidney are placed into the pelvis, and the pancreas is anastomosed (sewn) to the right iliac vessels and the kidney to the left. Operative time is about ten hours. As with kidney transplants, the patient’s own pancreas and kidneys are left in place because there is no advantage to removing them.

The transplantation of bone marrow, sometimes called hematopoietic stem cell transplantation (HSCT), is less demanding than transplantation of vascularized organs. The bone marrow is composed of stem cells that are primarily responsible for developing into red and white blood cells. A stem cell is any cell from which a whole population of different cells may develop. Transplant recipients, who usually have a blood disease such as leukemia, undergo a process of chemoradiotherapy to destroy their own stem cells. Once it is certain that all their own cells are destroyed, the donor cells are injected into the long bone of the leg. Following HSCT, the recipient may be immunologically incompetent for some time. The functioning of the immune system is vital to the success of this type of transplant. The white blood cells begin to reappear in the blood during the second or third week after the transplant. Although many lymphocytes begin functioning as soon as they are generated, the T and B cells do not become active until later. This is primarily due to the suppression of WBC function due to the presence of immunosuppressive drugs.

Fetal tissue transplantation therapy is related to stem cell therapy in that vascularized organs are not transplanted. Fetal tissue cell lines, sometimes called pluripotent stem cells, have the ability to develop into any cell types found in the adult human body: brain cells for Alzheimer sufferers, pancreas cells for diabetics, heart cells for cardiac patients, and more. There are four sources for pluripotent stem cells: preimplanted human embryos from in vitro fertilization (IVF), umbilical cord blood, cadaveric human fetal tissue, and human germ cell tumors. Although potentially very valuable, research in this area has become an ethical firestorm due to the embryonic source of the tissues. There is the worry that to obtain these cells researchers may actively begin aborting human embryos. Despite this controversy, the stem cell treatment holds such therapeutic promise that no one has yet abandoned the concept.

In 2011, researchers at the University of Wisconsin announced they had successfully transplanted into a mouse brain neurons made from human embryonic stem cells. These neurons could both send and receive nerve impulses, proving that when neurons derived from human embryonic stem cells were transplanted, they could fully integrate and behave like any other neuron, which in turn makes treating neurological disorders such as Parkinson's disease, ALS, and epilepsy more feasible. Use of embryonic stem cells is a controversial issue, which resulted in a ban on federal funding of embryonic stem cell research during the early 2000s. In 2009, the federal position was reversed by President Barack Obama. The ethical debate surrounding embryonic stem cell research, however, continues.

Perspectives and Prospects

There are a number of ethical problems connected to organ transplantation. Primary among these is the problem of donor selection. Cadaverous donors sometimes present the problem of whether sufficient permission was given to donate organs. Without full consent of the donor, it is considered unethical to harvest tissues. In cases where the potential donor died without giving consent, very often relatives who knew of their wish will give consent in their stead. In the case of living donors who are donating kidneys or bone marrow, questions will sometimes arise of their ability to give full consent; for example, whether the donor is fully competent and informed of what consent means. These questions of competence will usually arise with the mentally ill, but often arise when the donor potentially has been coerced by physicians or relatives. Coercion on anyone’s part eliminates full consent from the donor.

Another ethical dilemma is the use of human newborns or late stage embryos as organ donors. Is it ethically permissible to use a fetus as an “organ farm”? There have been reports in the last several years of parents with a terminally ill child conceiving another child to act as an organ donor. Although most often these donor infants become family members, they are sometimes aborted because the needed organ can only be obtained in that way. The bioethicist Mary Anne Warren has argued that the mere “potential to become a person”—unaccompanied by awareness, consciousness, and perception—does not entitle one to life compared to that of a person who needs a transplant. Warren finds no ethical objection to killing a fetus, an “entity below the level of personhood,” in order to save the life of a grown human being. Whether or not there is abortion involved in the harvesting process, the ethicist Daniel C. Maguire submits that “person” is a relative term and even baby persons are intrinsically related to other persons. Maguire argues that using the uterus as an organ farm or the “objectified” fetus as an organ bank is intrinsically wrong at the level of consent. What right does anyone have to presume the permission of the baby to donate an organ to a sibling or even a parent? He suggests that the privacy and autonomy of the baby be protected until it grows and can itself consent to an organ donation.

Maguire’s argument has also been applied to the harvest and use of embryonic stem cells. When the cells are harvested directly from an embryo, whether that embryo was discarded from IVF or conceived for that specific purpose, the question of consent still remains unanswered.

Finally, allocation of transplanted organs has become increasingly difficult in recent years as the number of available organs has become overwhelmed by the number of potential recipients. A series of ethical questions has arisen in organ transplant allocation. Will the young or old recipient better benefit from a transplant? Should countries limit organ donations from their citizens to non-immigrant aliens? Should organ recipients of particular note, such as film stars and athletes, be moved ahead of “commoners” who are already on the waiting list? Should the location of the recipient affect the decision to provide an organ?

One principle that has been suggested as a guide to allocation is called “distributive justice.” Distributive justice suggests that donor organs should go to those most in need. Most countries have now devised rules by which available organs go to those who are the most critically ill. The problem with this selection strategy is that the patients who are in the greatest need are the least likely to survive long term. If the goal is to maximize the overall benefit to society, as the ethical theory of utilitarianism suggests, then this method reduces the overall advantage to society compared to a system that would donate to patients with a better prognosis.

The opposing theory, called “material justice,” suggests that patients who are likely to benefit most from transplantation get the organs first. This would maximize the benefit to society, which is risking less on a recipient with a better prognosis. One interpretation of this principle is that children with longer lives ahead of them would get preference for transplantation over adults or the elderly.

These two principles seem at odds with one another. Although the individual will benefit most from distributive justice, society may suffer, and the opposite might be true of material justice where society will benefit, but the individual may suffer. To make allocation as just as possible, the United Network for Organ Sharing (UNOS), the primary body which coordinates organ donors and recipients worldwide, has utilized a point system since August 1995. This point system creates a value for determining the suitability of a recipient for a particular donor based on number of years waiting, rank on the waiting list, HLA tissue mismatches, immune reactivity, and age.

Additionally, the geographic profile of the recipient can be problematic. If a potential transplant recipient has come to the United States from the developing world, where organ donors are rare, in the hope of more easily getting a transplant, should he or she be considered a serious candidate? Should that person be placed ahead of native or naturalized citizens on the waiting list? Should an American citizen and potential recipient living in an isolated geographic location be placed lower on a waiting list because of his or her isolation? These questions are difficult to answer because they bring geography and politics into the equation with medicine and human needs. In September, 2000, the US Department of Health and Human Services (DHHS) proposed rules to reduce the importance of geographic and political boundaries on organ allocation. The prime selection criterion—especially in heart and lung transplantation—would be altered by the DHHS primarily to reflect waiting time. Under these criteria, it would not matter where the candidate resided or where they originated. The only basis for selection would be their need and how long they had been waiting for a transplant.

It has been proposed that organ donors be allowed to sell transplanted organs to the highest bidder. This concept has been defended as “allowing the free market economy to flourish” and letting the poor have the right to “do with their bodies as they see fit.” One ethical difficulty with the idea of commercializing human organ sales is that those who are richest will tend to receive the “best” organs. Organ allocation would suffer from these sales, and just distribution would become meaningless. No longer would the most needful recipient get an organ, but rather those who could most afford it would benefit. Furthermore, the poor would be victimized, become commodities, and would be dehumanized as they potentially become organ farms.

Bibliography

Brunicardi, F. Charles, et al., eds. Schwartz’s Principles of Surgery. 9th ed. New York: McGraw-Hill, 2010.

Chen, Yi-Bin. "Bone Marrow Transplant." MedlinePlus, February 7, 2012.

Chopra, Sanjiv. The Liver Book: A Comprehensive Guide to Diagnosis, Treatment, and Recovery. New York: Simon & Schuster, 2002.

Mulholland, Michael W., et al., eds. Greenfield’s Surgery: Scientific Principles and Practice. 4th ed. Philadelphia: Lippincott-Raven, 2006.

National Research Council. Institute of Medicine. Stem Cells and the Future of Regenerative Medicine. Washington, D.C.: National Academy Press, 2002.

Organ Donor. http://www.organdonor.gov.

"Pancreas Transplant." Mayo Clinic, September 22, 2011.

Sacks, Kevin. "Kidney Transplant Committee Proposes Changes Aimed at Better Use of Donated Organs." New York Times, September 21, 2012.

Stewart, Susan K. Autologous Stem Cell Transplants: A Handbook for Patients. Highland Park, Ill.: Blood and Marrow Transplant Information Network, 2000.

Toouli, James, et al., eds. Integrated Basic Surgical Sciences. New York: Oxford University Press, 2000.

Townsend, Courtney M., Jr., et al., eds. Sabiston Textbook of Surgery. 19th ed. Philadelphia: Saunders/Elsevier, 2012.

Trzepacz, Paula T., and Andrea F. Dimartini, eds. The Transplant Patient: Biological, Psychiatric, and Ethical Issues in Organ Transplantation. New York: Cambridge University Press, 2011.

Welsh, Jennifer. "Growing Brains in Bio Labs, One Cell at a Time." FoxNews, May 23, 2011.