Transplantation is a branch of medicine which is unique in one respect: treatment depends on using a nonrenewable part of one individual to treat another. Blood transfusion and bone-marrow transplantation are renewable sources of human tissue; they are not included in this account. The human body was not designed to receive grafts from others. Organs and tissues differ among individuals because of certain cell wall markers, or tissue "groups," known as the HLA antigens. These factors are inherited, half from the mother, half from the father. Each person has 8 such factors (out of about 90 known possible factors, in the population); these give us our HLA profile. We can each be identified by HLA profile because the likelihood of another unrelated person having the same 8 factors is very small.
The human immune system is designed to recognise foreign proteins - or antigens - and to form an immune response against them. Immune responses also protect us from abnormal cancer cells which might arise within us from time to time. These cells, too, are recognized as foreign and attacked, provided they retain these recognition markers. The secret of successful transplantation is to control the immune system by immunosuppression in such a way that the body will not reject the graft, but will still be able to resist infection and recognize cancer cells. It would be highly advantageous if this could be done selectively, ie, dampening immunity only to the antigens of the graft, leaving other components of immunity intact. This cannot be achieved in humans yet, but it is an ultimate research goal.
Some immunosuppressive agents are "chemical," such as cyclosporin and azathioprine. Others, such as anti-lymphocyte globulin (ALG) or antibodies to T3 lymphocytes (OKT3), are highly selected antibodies of animal origin and are designed to block the immune response in very precise and selective ways. Immunosuppression is a changing field of medical therapy, though cyclosporin is justly famous as its use has markedly improved survival in a number of areas of organ transplantation.
The number of transplants performed in Canada increases slightly each year. Between 1987 and 1997, there was a 44% increase overall, and an increase of 36% between 1992 and 1997. During this 5-year period, liver transplantation increased 327%, total lung transplantation increased 614%, and pancreas transplantation increased tenfold. Heart transplantation increased only 21% and renal (kidney) transplantation 17%. The rate of organ donation in Canada remains static, indicating that the increase in liver, lung and pancreas transplantation reflects the development and maturation of Canadian transplant programs.
At the end of 1997, over 12 000 Canadian patients had a functioning transplant graft. There are over 1800 liver and 1300 heart recipients and nearly 9000 kidney recipients, representing the survival of 67% of all livers, 67% of all hearts and 50% of all kidneys donated in Canada to the end of 1997. In that year, the majority of transplant recipients (86%) were between 18 and 64 years of age, predominantly male (64%), with a particular male predominance in heart transplants (84%). Male recipients predominated to a lesser extent in renal (64%), liver (60%) and lung (85%) transplants.
Transplantation of Specific Organs
Kidney transplants developed first because the organ has an abundant blood flow (required for urine formation), has a single artery and vein (usually), is less prone to postoperative infections (maximal with the lung), and has an effective "back-up" system, the artificial dialysis machine, to provide kidney function while awaiting subsidence of a wave of rejection activity.
Transplantation has evolved from being experimental or "last ditch" to being the preferred treatment for most patients with chronic kidney failure. In the early days, many live donors (family members) were used, but the main emphasis in the last 2 decades has been in using cadaveric kidneys. This has led to special criteria for the diagnosis and certification of death from acute cerebral causes (or brain death), as well as means of explaining this to the public and to recently bereaved families in seeking their permission to use the organs after death. All transplant centres now have special persons for this work and its coordination.
Those who obtain good function after transplantation enjoy vigorous health and have very few restrictions. Those who receive kidneys from family members have better results than cadaveric kidney recipients.
Those who do best are those whose original disease was confined to the kidneys. Those with renal failure on the basis of DIABETES MELLITUS, for example, still suffer the other complications of that disease, even when the kidney problem has been successfully treated by a transplant.
Transplantation of Specific Tissues
Grafting the cornea is a well-established procedure. Immunologic rejection is not a problem for most patients, as the proteins of the cornea usually do not elicit a "foreign antigen" reaction and, in any event, the antibodies and educated lymphocytes have difficulty in mounting an attack in such a bloodless tissue.
Corneas are not in such a short supply as some other organs as they can be removed up to 6 hours after death, and from those who are older than donors of internal vital organs. Immunosuppressive drugs are not required for the uncomplicated corneal transplant.
Organ Procurement and Storage
The whole of transplantation medicine depends on public acceptance and understanding. It takes time to accept new concepts of death; there is much need for open discussion. In recent decades, however, the Canadian public has accepted the practices of clinical transplantation as shown by willingness to give organs from the bodies of their loved ones, after death. No one appreciates this more than the community of those who wait for these gifts for "restored life." Despite this, there is a marked shortage of vital internal organs for transplantation. This is largely because only 1-2% of those who die in hospitals do so under conditions which render their dead bodies suitable for organ procurement.
Unexpected death is tragic and emotionally shocking. Yet, in this atmosphere of grief, fear, bewilderment and uncertainty, it is necessary to ask the family to give their dead relative's organs for those in need. This can be a searing experience; suffice it here to note that it is easy to understand why only about 10-20% of that 1-2% become organ donors. However, if the figure were raised to 80% of 1-2%, shortage of organs would largely cease to be a problem. For those reasons, organ procurement is becoming an increasing responsibility for hospital administrators and the health-care professions.
Organ storage is a very difficult area of research in which there has not been much progress. The ideal would be long-term preservation of organs in the ultra-low temperatures of liquid nitrogen (around -1700C), but the science of cryobiology is not able to do this for complex highly differentiated organs, except for very small portions. At present, kidneys can be preserved at 40 C for 48-72 hours, but heart, heart-lung and liver transplants must be carried out as soon as possible, within only a few hours of the donor's death.
The Canadian Organ Replacement Register
CORR is the national information system for organ failure, transplantation, organ waiting list and organ donation. It records, analyzes and reports the level of activity and outcome of vital organ transplantation and renal dialysis activities. CORR was incorporated in 1990 and became a registry of the Canadian Institute for Health Information (CIHI) in 1995. The collection of statistics on chronic renal failure began with the Canadian Renal Failure Register under the auspices of Statistics Canada. In 1996, all CORR assets were transferred to CIHI; CORR's Board of Directors retain responsibility for the register's policies and the CORR Advisory Committee is responsible for data collection, analysis and prioritization of ad hoc reports.
The Register reports to the physicians and surgeons of the Canadian Society of Nephrology and the Canadian Transplantation Society and works closely with other health-care providers, including members of the Canadian Association of Transplantation and the Canadian Association of Nephrology Nurses and Technicians. CORR provides information to hospital administrators, government officials and researchers. It is sponsored by the Kidney Foundation of Canada and many pharmaceutical corporations.
Ethical Issues in Organ Transplantation
Ethical problems abound in transplantation. They fall into 3 areas: those which surround the diagnosis of death from cerebral causes, those which relate to organ procurement, and those which deal with organ allocation and program funding. In short, when may organs be taken? Who owns them, after procurement? How should they be equitably distributed? Are there limitations to the rights of donor families? What are the rights of waiting potential recipients? Can we afford these costly programs from which relatively few persons derive benefit?
Decisions on these matters involve members of our society outside those in medicine or health care. Resolutions evolve differently in different communities and cultures. Special problems are encountered when organs are transported between cultures or "moral communities."
The Future of Transplantation Medicine
Speculation on medical advances is fascinating, but unreliable. Nevertheless, contemporary predictions include the following: that organ grafts will be accepted from other species, xenografts; that certain species, probably primates, will be bred for this purpose; that brain tissue will be used for treatment of certain neurological diseases (this, in fact, has already started), though restoration of cerebral cognition by grafting will not be achieved; that organ transplants will vie with gene therapy in treating enzymatic and other genetic disorders, as the control over the immune system will become highly selective and safe; that grafts of ovarian and testicular tissue will be available for treatment of sterility and associated endocrine deficiency, though this raises very serious ethical issues which must be carefully regulated by society. Indeed, ethical regulation of the field will become increasingly important if science and technology are to confer increasing benefit upon us.
Most skin grafting involves the use of the patient's own skin to repair defects. These are known as skin autografts and present no immunological problem. In treatment of extensive and severe burns, skin allografts (obtained from skin banks of cadaveric skin) are used as burn dressings. No immunosuppression is used as it is expected that the allografts will be lost, though they may last for several vital weeks, and can then be replaced if needed. Skin banks are becoming more common and several exist in Canada.
Bone is used as a graft to bridge gaps in bone resulting from the effects of trauma or cancer surgery. The bone is not used as a living graft and no immunosuppression is used. Rather, the pores of the bone become permeated with bone cells of the recipient, replacing the bone cells of the donor. Thus the recipient uses the graft as a scaffold onto which cells later grow to turn it eventually into autologous bone.
On 3 December 1967, the world's attention was focused on the Groote Shure Hospital, Cape Town, by the announcement of the first successful human-to-human cardiac transplantation, though prior animal work in the US had painstakingly established the technique. Stimulated by this success, nearly 50 centres performed over 100 similar transplantations in 1968 (the number rising to 250 by the end of 1970), but most patients died from rejection or infection. In 1968-69, of 20 such procedures in Canada (Montréal and Toronto), most patients succumbed within 1 year, though each centre had a lone long survivor of over 4 years. No further cardiac transplantations were done in Canada until 1980.
During the 1970s, a group at Stanford in the US continued working out the diagnostic and management strategies and also first introduced cyclosporin to the regimen. Their success led to a renaissance of cardiac transplantation activity around the world. In April 1981, the procedure was reintroduced into Canada at University Hospital, London. By September 1987, 150 cardiac transplantations had been performed in Canada. Currently, there are now more than 304 centres performing heart transplants.
Combined heart and lung transplantation was first performed in 1969; 2 more were done by the end of 1971. The longest survivor was 23 days. No further attempts were made until 1981 when the Stanford group, having obtained successful heart/lung survivals in primates, began using the procedure.
In May 1983, Canada's first combined heart and lung procedure was performed at University Hospital, London. Because of the unique exposure of the lung to the external environment via the airways, infection is a major problem. In addition, the lung is also prone to severe rejections.
Liver transplantation has special problems: the organ deteriorates quickly in the donor; the surgeon must match the replacement organ for size; there is need for careful maintenance of the gall bladder and biliary drainage system; there are specially complicated disturbances of the blood clotting - coagulation - which may lead to severe postoperative bleeding; and there is no substitute or artificial back-up system to tide over periods of liver rejection. It is not surprising that programs for liver replacement have been established more slowly.
Pancreas transplants are undertaken because of their content of insulin-secreting islands of tissue, known as the Islets of Langerhans, but the digestive secretions of the organ have to be drained somewhere and that has proved to be the principal problem. Efforts have been made to drain these secretions into the bladder, the bowel and to the skin. In all but a few centres, results have been disappointing and pancreas transplantation is not widely practised.