Biomedicine and Health: Organ Transplantation

Introduction

Organ transplantation or grafting has developed into a promising therapy for many ill patients. Every year more and more organs are grafted, saving thousands of lives. The idea of transplanting organs has existed since the 1880s, but was dismissed as a utopian dream until the late 1900s. Today's highly engineered “spare-part” surgery is the result of more than 100 years of scientific research, technological progress, and many experiments.

In the United States alone, over 90,000 people were on waiting lists for organs in 2004, and this number is rising. Even though transplantation seems to be ordinary in our times, it entails many ethical and legal questions, including how donor organs should be distributed among patients. In view of this increasing demand, it is no surprise that a black market for transplantable organs has emerged in some developing countries, where desperately poor donors are willing to part with a kidney when the price is right. Quite often, however, they become victims of organized crime.

Historical Background and Scientific Foundations

At the end of the nineteenth century, doctors began to dream of curing patients by replacing diseased organs or tissues with new ones. But this only makes sense when one can understand that damage to an organ leads to certain diseases that can be cured by transplantation. This idea was new in the 1890s, and one not readily accepted. The Swiss surgeon Otto Lanz (1865–1935) warned his colleagues in 1894 that a therapy “which endeavors to replace the organ itself that has lost its function to the organism” shouldn't be dismissed.

Until the nineteenth century disorders like cretinism (now known as congenital hypothyroidism) were assumed to be caused by climate, way of life, nutrition, housing, or other factors. In the second half of the nineteenth century physicians began to discover the determining causes for different diseases. Cretinism, for example, was associated with a dysfunctional organ, in this case the thyroid gland.

As a result, in 1883 a thyroid gland was the first organ transplant tested in animals. If symptoms exhibited before the removal of an organ disappeared when a new one was implanted, this would be evidence that the malfunctioning organ was, in fact, causing the disease. Experimental animal transplants were attempted unsuccessfully in the years after 1883 with a series of organs, including the adrenal gland, lung, heart, and pancreas.

Sir Victor Horsley (1857–1916), an early neurosurgeon, also conducted extensive research on thyroid function in both animal and human subjects. He proved that removing the thyroid gland resulted in tremors, rigidity, paralysis, and, in human patients, a reduction of cognitive ability. By transplanting thyroid tissue, Horsley showed that short-term relief for the symptoms of both myxedema and cretinism could be achieved by replacing diseased thyroids with healthy ones. The transplants always failed before long, however.

French surgeon Alexis Carrel (1873–1944) also experimented with transplantation. He performed a canine heart transplant in 1905; the patient survived for only a few hours afterward. His pioneering method of suturing blood vessels, for which he was awarded the Nobel Prize in 1912, proved fundamental in later transplants. Like Horsley, Carrel noticed that attempted organ transfers always failed, often replaced by scar-like connective tissue. This phenomenon, which occurred in both allografts (between animals of the same species) and xenografts (between animals of different species), was an immune reaction in which the recipient's body rejected foreign tissues. Today it is known as graft-versus-host disease.

Although scientists tried to solve the problem by matching hosts and donors and weakening the host's immune system, nothing worked. Hope for success dimmed and by the 1930s, transplantation medicine had almost been abandoned. While surgeons knew how to transplant an organ, their knowledge about the immune system was too limited to solve the problems of organ rejection.

Despite this, kidney transplants were attempted in the postwar years. Finally, the first successful kidney transplant was made in 1954 at Peter Bent Brigham Hospital in Boston. Both the donor and recipient were identical twins, so immune rejection was not a factor. The recipient lived for another 8 years, and the operating surgeon, Joseph E. Murray (1919–), received a Nobel Prize in 1990 for his discoveries in organ transplantation. At this point, however, since the problem of graft-versus-host disease hadn't been solved, only transplantation between identical twins was possible. Something was needed to weaken the host's immune defense and allow it to tolerate the transplanted organ, but immunosuppression attempted with nuclear radiation destroyed too much healthy cellular tissue.

The development of immunosuppressive drugs, which finally allowed the first kidney transplant between nonrelated individuals in 1962, was the beginning of a new era for transplantation. Research began to focus on immunological and tissue matching, because grafting an organ from a donor whose tissues resembled the recipient's increased the chance of success appreciably. Organizations were established to match donors and recipients. One is the Eurotransplant International Foundation, established in 1967.

The first heart successful heart transplant was performed by South African surgeon Christiaan Barnard (1922–2001) in 1967; the patient lived for 18 days after the surgery. But before the discovery of immuno-suppressive drugs like Cyclosporine in the 1980s, such grafts were rare.

By 2004, about 9,000 kidneys and 2,000 hearts were transplanted in the United States each year. Today kidney, liver, heart, lung, pancreas, cornea, and bone marrow are all transplanted.

Physicians determine whether transplantation is indicated, if it is possible, and whether the patient is stable enough to endure the operation. Patients who can no longer undergo dialysis, for example, may need a kidney transplant. Patients in the terminal stage of heart disease that can no longer be treated medically are candidates for a heart transplant. Corneal transplants are indicated when the cornea has become damaged but the eye itself is still healthy. Skin tissue grafted in plastic and cosmetic surgery is usually from the same individual (an autograft).

Surgical techniques have advanced to the point that transplantation is increasingly an alternative to complex therapy and not merely a last-ditch effort to save the patient's life. Sometimes, however, transplantation may be necessary but prevented by circumstance. Such situations include tumors that would spread under the influence of immunosuppressives, vascular diseases that make it difficult to connect the organ to the bloodstream, or a patient with tuberculosis or HIV/AIDS who has difficulty healing.

The Procedure

Both the quality of the donated organ and the method used to remove it must be chosen carefully. The donor cannot have any infections, chronic diseases, or cancer. Organs can come from living or deceased donors.

Once removed, the organs must be stored at 39°F (4°C), kept in a special solution, and implanted within a few hours if they are to function properly. A heart, for example, must be transplanted within 6 hours after being removed from the donor's body.

When implanted, some organs are placed at their natural location—orthotopic—or a different one—

IN CONTEXT: JOSEPH E. MURRAY PERFORMS THE FIRST HUMAN KIDNEY TRANSPLANT

Joseph E. Murray (1919–) was born in the small town of Milford, Massachusetts, 30 miles southwest of Boston. His father was a lawyer and district court judge and his mother was a schoolteacher. Even as a child, Joseph knew he wanted to be a surgeon. In high school he was fascinated by the natural sciences, but studied Latin, Greek, philosophy, and English in college, assuming that he would have ample science training at medical school. He said that his four years at Harvard Medical School were all he ever dreamed of, despite the long hours of study and hospital work. In his free time he attended concerts at Symphony Hall, played squash, or went on bicycle trips. At one Boston Symphony Orchestra concert he met Bobby Link, to whom he was married in June 1945. They had six children, three boys and three girls, all of whom went on to careers in education, medicine, nursing, business, or science.

Murray's interest in tissue and organ transplantation emerged during his time in the military. During World War II he served as a lieutenant at the Valley Forge General Hospital in Pennsylvania, a major plastic and reconstructive surgery center. Murray spent all of his free time in these wards, where he was confronted with hundreds of battle casualties. He enjoyed talking to the patients and watching the results of reconstructive surgery. For severe burns, skin grafts were taken from other persons to serve as temporary surface cover. Watching the slow rejection of these tissues, Murray wondered how the body could distinguish skin other than its own.

Working as a surgeon/scientist, Murray met many non-clinical researchers, including Sir Peter Medawar (1915–1987), an immunologist who went on to win a Nobel Prize for medicine in 1960. On December 23, 1954, Murray and J. Hartwell Harrison performed the first successful kidney transplant at Peter Bent Brigham Hospital in Boston. A kidney from Ronald Herrick was transplanted into his identical twin brother Richard. This avoided graft-versus-host disease altogether. Murray's success encouraged further research. In the 1960s the discovery of chemical immunosuppressive drugs enabled him to carry out transplants from unrelated donors. In 1990 he was honored with the Nobel Prize in medicine for his pioneering work in organ and cell transplantation.

heterotopic. The kidney and the pancreas, for example, are not implanted at their former locations, but further caudal (below their original place) and connected to the pelvic vessels. This is because the recipient's own kidneys are not removed. In this area it is easy to connect the organ to the vessels and the bladder. The right kidney is implanted near the left groin and vice versa. Finally the iliac artery and the iliac vein are connected to the renal artery and vein and the urinary duct is implanted into the bladder.

IN CONTEXT: IMMUNOSUPPRESSIVES

To make transplantation between unrelated persons possible, treatment with immunosuppressive drugs is absolutely essential. Without their use a transplanted organ would simply be rejected and die. The drugs are used both to fight existing immune reactions and to prepare the host's immune system before transplantation.

Corticosteroids and antimetabolites were the first immuno-suppressives used. Corticosteroids are already present in the body in much lower doses, where they support the growth of T-cells, which function in the immune system to detect foreign cells and alert the immune defense. Corticosteroids can also interfere with communication between the immune cells and obstruct their production, enabling the body to tolerate a transplanted organ. In addition to these desirable effects, however, corticosteroids also weaken bones and connective tissue. Antimetabolites inhibit the production of new genetic material, which is needed in order to produce new immune cells. Unfortunately, they also hinder the division of other fast-growing cells like bone marrow, which produces red blood cells.

In the 1980s another drug significantly improved the success rate for transplantation. Cyclosporine A is a metabolic product of funguses. Unlike the other drugs, it blocks the release of the immune reaction by obstructing the production of certain substances. Cyclosporine prevents the body from reacting to antibodies brought into the body with a transplant, but still allows the patient to mount an immune defense to other foreign antibodies. Like the other drugs, however, cyclosporine has side effects: It can damage the liver and kidneys.

Transplant patients who receive an organ from someone not related to them are treated with a mixture of different immunosuppressives. At first they get very high doses; later these are reduced to minimize damage to the patient's other organs. Although side effects have not been eliminated, these drugs are of enormous importance for modern transplant surgery.

A liver transplant is one of the most difficult, especially since the original organ must also be removed to make room for the donor organ. The new liver must be connected to the hepatic artery, the portal vein, and the bile duct; many other vessels must also be reconstructed. The time between removal of the old and reinsertion of the new organ is limited and mortality is comparatively high. Transplants from living donors allow small liver segments to be transferred from a parent to a child or the other way round.

Obviously, in heart transplants only deceased (after brain death has occurred) donors are possible. Before the heart is removed from the donor, its great blood vessels are dissected. While it is still beating, several liters of a cold special solution are injected directly into the aorta. This leads to cardiac arrest. Then the big vessels are cut through and the heart is removed. Reinsertion must be done within only a few hours. During the operation, the recipient is connected to a heart-lung machine. After the diseased heart is removed, the new organ is implanted in the chest cavity. Once all blood vessels have been connected, a heartbeat is induced with electric stimulation. To ensure the proper function, a pacemaker is implanted temporarily; it will activate automatically in case the heart rate is too low.

What Happens to the Transplant Inside the New Body?

The success of a transplant depends on many factors. Immune reaction can lead to a rejection, but immunosuppressive drugs leave the patient prone to infection. The organ might contain viruses or may not function again. The usual host of postoperative technical problems are also still possible.

Usually it takes some days until a transplanted kidney or liver starts working. Patients with heart transplants normally feel much better immediately afterward. Graft-versus-host disease, in which the implanted tissue attacks the host, can occur with bone marrow grafts, when T-cells—part of the donor's immune system—might still be present in the transplanted tissue and attack the tissues of the host. Unless the recipient is treated with an immunosuppressive drug, any foreign tissue will arouse a defense reaction and the recipient's body will start rejecting the transplanted organ.

The level of genetic affinity is of particular importance. An autograft is transplanted tissue, such as skin or a vein, from one part of the body to another. A transplant from one identical twin to another is an isograft. In times before chemical immunosuppression only these two types of transplants were successful. Today most of the grafted organs are allografts, which means their only link is that they are from the same species. Transplantation of tissue from one species to another is called a xenograft; these still fail all the time. An exception are porcine (pig) heart valves transplanted into humans; these are quite common and successful.

The immune system is activated when the foreign cells enter the recipient's bloodstream. When immune cells encounter the foreign antigens, the immune system is activated and starts attacking all cells with that antigen. Numerous cellular and noncellular elements are involved in this defense reaction. Transplant patients are given blood tests right before the operation to rule out existing antibodies that would act against the new cells in the transplant. If the test is positive, the operation cannot be performed because it would instantly lead to a destruction of the organ. Rejection can be avoided with immunosuppressive drugs, although they make the recipient prone to infections. Cornea transplants are exceptions, however, because cornea tissue isn't connected to the bloodstream and doesn't contain immune cells, eliminating the risk of rejection. Corneal grafts even between unrelated persons are successful without immunosuppression.

Organ Allocation

Because there are more people waiting for transplants than there are organs available, an allocation system is necessary. This process has three steps. A patient must first be declared eligible for a transplant by the attending physician and sent to a transplant center. The attending physician has the role of a doorman—a role that can be misused. (In the past, for example, dialysis patients sometimes suspected they were not declared candidates for a kidney transplant because doctors and hospitals earned a lot from their expensive treatment.) Once declared eligible for a transplant, the patient takes the second step: getting on the waiting list. The transplant center verifies their eligibility and rules out factors that would make transplantation impossible. The third step is organ allocation to patients on the list. To guarantee an impartial, fair, and consistent process, some basic principles are necessary.

Ideally, a patient's individual harm or benefit should be assessed without considering the needs of other applicants. Knowing how few organs are available, however, may indicate that another patient might benefit more from a transplant. Trying to make the best of a scarce resource, physicians follow the principle of utilitarianism, which directs actions to maximize good for the largest possible population.

One principle used to allocate kidney transplants, for example, determines how well the donor and recipient tissues match—compatibility should be as high as possible. Another ethical principle is the prevention of harm, which favors children, adolescents, and emergency cases (even though most urgent cases usually don't have the best prognosis). In the case of heart and liver transplants especially, the conflict between urgency and likely success is enormous. Candidates with extremely rare tissue features, who have little hope of a tissue match among donors, are another difficult category. Doctors must balance many different criteria to obtain the best solution possible. Other factors, such as how long the patient has been waiting, or whether the need for a transplant has been caused by alcohol or drug abuse must also be evaluated.

Ethical Concerns

Organ transplantation requires that both the donor's and recipient's rights be protected. A living donor faces risks from both the operation and the organ or tissue removal, for which they cannot be compensated. The advantage of a living donor is a shorter waiting time and a better result, because all steps of the procedure can be synchronized. From an ethical point of view, minimizing the donor's risk must be a priority, because organ removal technically constitutes “harm,” contradicting the medical principle that medical procedures should only be undertaken for the patient's benefit.

For this reason, the donor must understand the risk he or she is undertaking and agree to the surgery. But while donors have the ultimate right to self determination, family pressure and feelings of guilt can force people to become donors. Another issue is the problem of organ trading, which is prohibited in most industrial countries. This includes commercial purchase and trade as well as paying individual compensation for donated organs. Minors and mentally handicapped persons are not allowed to be donors.

In less-developed parts of the world, organ trading is customary. In these places living organ donation is the only way transplants can be performed, since the logistics for transporting organs from deceased donors and the technology to record brain death are often lacking. Under such conditions a flourishing market for organs has developed, despite the danger to the donors. Medical treatment after the operation and real information about the risks involved are often insufficient. Donors get far less for their organ than the recipient pays, while brokers and physicians may benefit greatly. The bottom line, however, is that in these countries there is no other way for recipients to gain organs, and it is a source of income for poor people. In light of these abuses, some Indian transplant surgeons advocate a government-controlled organ trade, called “rewarded giving.”

Cadaver donation is another way to gain organs. Death is usually declared when brain function has ceased, even if blood circulation, respiration, and other functions are still artificially enabled. Brain death can only be detected within the scope of highly developed intensive medicine, and only after all other situations, such as coma or intoxication, have been ruled out and the donor's organs are released, once the appropriate family or donor consent has been obtained.

Modern Cultural Connections

Sensational discoveries in the field of immunology helped make organ replacement therapy possible. This was especially true of the first chemical immunosup-pressive drugs, which enabled organ grafting between unrelated persons.

Thanks to new pharmaceutical products and surgical techniques, modern transplant surgery now saves the lives of otherwise terminally ill patients. But it also offers ethical challenges: Should human embryos be cloned to grow “spare parts”? Should organs be bought and sold as commodities? The European Society for Organ Transplantation (ESOT) has stated that transplantations involving payment for donor organs are unacceptable, and that clinicians must ask hard questions to avoid being involved in the sale of donor organs.

Future developments may include better drugs for controlling the immune system and reducing the risk of rejection. Synthetic lab-grown organs, which Alexis Carell could only dream about in the 1920s, could avoid ethical dilemmas. Lab-grown bladders, for example, have been implanted successfully. Another possibility is the use of genetically engineered animal organs for human transplantation. Which of these efforts will succeed is still unknown, but even if technical limits can be solved the ethical barriers still exist. Despite these moral and physical difficulties, however, organ replacement is one of the most promising therapies for some fatally ill patients.

See Also Biomedicine and Health: Antibiotics and Antiseptics; Biomedicine and Health: Immunity and the Immune System; Biomedicine and Health: Surgery; Biomedicine and Health: The Germ Theory of Disease.

bibliography

Books

Finn, Robert. Organ Transplants: Making the Most of Your Gift of Life. Patient Centered Guides, 2000.

Hakim, Nadey S. Introduction to Organ Transplantation. London: Imperial College Press, 1997.

Land W., and J.B. Dosetor. Organ Replacement Therapy: Ethics—Justice—Commerce. First Joint Meeting of ESOT and EDTA/ERA. New York: Springer-Verlag, 1991.

Periodicals

Ginn, S.R., and J.A. Vilensky. “Experimental Confirmation by Sir Victor Horsley of the Relationship between Thyroid Gland Dysfunction and Myxedema.” Thyroid 16, no. 8 (August 2006): 743–747.

Morris, Peter J. “Transplantation—A Medical Miracle of the 20th Century.” New England Journal of Medicine 351 (December 2004): 2,678–2,680.

Web Sites

American Society of Transplantation. “Conversations in Transplantation: Advances in Transplant Research.” http://a-s-t.org/index2.cfm?Section=knowledge_center&Sub1Section=podcast&content=index.cfm (accessed April 1, 2008).

National Kidney Foundation of East Tennessee. “Transplantation.” http://www.kidneyetn.org/nkfetxplant.html (accessed January 5, 2008).

New York Organ Donor Network. “Organ and Tissue Donation.” http://www.donatelifeny.org/organ/organ.html (accessed April 1, 2008).

Scientific Registry of Transplant Recipients. “National Transplant Statistics.” http://www.ustransplant.org/national_stats.aspx (April 1, 2008).

Florian Steger

Matthias Schrempf