Journal of the Royal Society of Medicine Volume 71 July 1978
479
The state of British medicine -7
Organ transplantation Professor R Y Caine MS FRS Department of Surgery, Addenbrooke's Hospital Hills Road, Cambridge CB2 2QQ
Organ transplantation has come of age and this would seem to be an appropriate time to look at what has been achieved. I will also try to point out some of the disappointments to those engaged in this work and hazard predictions for the future. At the beginning of this century Alexis Carrel worked out a technique of kidney grafting based on his methods of vascular suturing. In the early 1950s technical success with experimental kidney grafts could be expected, but it was clear that this was not enough to ensure satisfactory function of a transplanted organ. As with skin grafts, so with vascularized organ transplants: after an initial period of temporary 'take', changes occurred in the recipient which led to rapid and inexorable destruction of the graft. A second graft from the same donor was destroyed more quickly than the first, so the phenomenon fitted into the requirements of an immune reaction. Murray et al. (1958), at the Peter Bent Brigham Hospital in Boston, were able to avoid this biological hazard in the first successful clinical organ graft by transplanting a kidney, where no immune reaction could occur, namely where the donor and recipient were identical twins. Some of their earliest patients are now alive, the longest survivor having continuing good kidney function twenty-one years after operation. Two developments in the 1950s led to more widespread therapeutic kidney grafting. First, Scribner et al. (1960) in Seattle applied the principle of recurrent dialysis using an indwelling cannulation prosthesis for vascular access, to maintain patients without renal function in reasonable health. Secondly, effective immunosuppressive drugs became available in experimental animals with organ grafts, namely the use of steroids coupled with the thiopurine antimetabolite, azathioprine (Imuran), a close chemical relative of 6-mercaptopurine. Thus it became possible for desperately ill patients suffering from uraemia to be restored to health and maintained fit for surgery whilst the kidney transplant operation was planned and performed. Both immunosuppressive agents mentioned are sometimes totally ineffective when given at the maximum tolerated dosage. Nevertheless, more than 25 000 kidneys have now been transplanted in patients who have been treated primarily using azathioprine and steroids and the results have been encouraging enough for the procedure to be accepted as established rather than experimental therapy. Results between close relatives are particularly good. Kidney transplantation has been one of the most comprehensively documented new forms of treatment. A registry was set up initially in Boston and it then moved to Chicago. Follow up has been remarkably thorough from all over the world. With grafts between identical twins, where the organ from a living volunteer donor is likely to be in perfect condition when transplanted, 86% of the grafts were functioning at two years. The percentage of functioning grafts in the other donor categories are shown in Table 1. The longest functioning transplant coming from a blood relative who was not an identical twin is eighteen years, and the longest survival with a kidney from an unrelated cadaver donor is fourteen years. A kidney from a cadaver donor, in addition to having increased sensitivity to 0 1 41-0768/78/0071-0479/$O 1.00/0
OC, 1978 The Royal Society of Medicine
480
Journal of the Royal Society of Medicine Volume 71 July 1978
rejection, may also suffer damage prior to its removal and during its transportation to an appropriate recipient. Most patients in terminal renal failure do not have the luxury of a willing and healthy identical twin donor, nor for that matter is it very common for there to be a suitable close blood relative. Therefore, transplantation of kidneys from cadavers is the most common form of renal graft practised. Table 1. Kidney transplants: functioning grafts
Sibling Parent Cadaver
Table 2. Kidney transplants: patients surviving
Functioning grafts
Patients surviving
1 year
5 years
1 year
5 years
75% 70% 50%
60% 50% 30%
85% 85% 70%
70% 60% 50%
Sibling Parent Cadaver
Advances Since 1960, when effective immunosuppression became available, improvements in results of kidney grafting have been rather modest. Once the management of immunosuppressive agents became established with the principle of trying to preserve the patient rather than the graft if rejection becomes difficult to control, there was a marked improvement in patient survival. A rejected kidney can be removed and the patient restored to dialysis, and maintained on dialysis or offered a second transplant. It is of interest that second kidney transplants do no worse than the first, probably because of more careful selection of the second donor kidney. Many patients, however, following rejection of a kidney, develop cytotoxic antibodies in their sera which makes it extremely difficult to find a kidney which they will not react against violently, so there is a worldwide tendency for dialysis spaces to be filled with patients who are untransplantable in practical terms. The patient survival shown in Table 2 is, nevertheless, a remarkable achievement when compared with the 100% mortality that patients with chronic renal failure suffered prior to the introduction of dialysis and transplantation. Kidney disease in young patients is not uncommon. It has been estimated that in the United Kingdom 2000-3000 people between the ages of 5 and 55 could benefit from kidney transplantation, whereas only 500-600 transplants are performed each year. The hospital and surgical facilities and personnel are available and both doctors and Government are agreed that shortage of donor organs is a severe impediment to the treatment of patients with renal failure. The law governing the removal of organs from dead bodies was framed before organ grafting was established (Human Tissue Act 1961). The urgency in removal of organs after death was not then appreciated. Nevertheless, it is quite clear that if the deceased's wishes in his lifetime were known and he willed that organs should be transplanted after death, then organ removal is justified without any further enquiry. When, however, as is usually the case, the deceased's wishes are not known, then permission to remove organs must be sought from relatives, though which relatives is not specified. If, 'after having made such reasonable enquiry as may be practicable-' the relatives cannot be contacted, then 'the person lawfully in possession of the body' can give permission. This has been assumed to be the administrative head of the hospital. The law has never been tested in court and the key words 'reasonable' and 'practicable' have not been defined. In the past decade there has been much discussion on the law, the general ethical principles involved, the role of the coroner and methods of establishing that death has occurred. Following publication of a document by the British Transplantation Society (1975), the Department of Health have issued guidelines on the interpretation of the Human Tissue Act
Journal of the Royal Society of Medicine Volume 71 July 1978
481
1961, and the diagnosis of death. There is widespread acceptance that complete and irreversible brain death constitutes death of the individual and there has been clarification of the coroner's role aimed at increasing the number of suitable organs donated. Provided their duty is not interfered with, most coroners are helpful to the needs of transplantation. Removal of organs from patients who are dead but who are still on ventilators with intact circulations, has greatly reduced the incidence of primary organ failure, which used to be of the order of 17% of cases in the United Kingdom. Damage from ischaemia was such a serious and frequent finding in kidneys removed in Britain that several centres in Europe refused on principle all kidneys removed from United Kingdom hospitals. The Government's policy of encouraging donor cards has improved the goodwill of the public to transplantation; however, it is doubtful whether the carrying of donor cards has in itself made an important impact on the number of kidneys available. The discussion, distribution and collection of cards has made many people, who would otherwise not have been concerned, take organ donation as a serious matter to be discussed with close relatives. There would seem to be a consensus of opinion amongst transplanters that apathy in the medical profession has been the main cause of the shortage of organs. Doctors looking after patients in intensive care areas are often unwilling to be involved in extra work, some of it harrowing, to help a patient they have never seen. Recently kidney patients' organizations have been formed and their voices are more likely to be heard than those of surgeons practising transplantation. The main advances, therefore, have been not so much fundamental, but rather practical improvements in the administration of drugs and patient care and help from Government and patients themselves in improving the supply of donor organs.
Disappointments A new era of immunology began when Medawar and his colleagues (Billingham et al. 1954) demonstrated experimentally that rejection could be prevented by introducing transplant antigens of the subsequent graft into the organism before the immune system had developed the process called 'immunological tolerance'. A huge body of data has now been accumulated at both chemical and cellular levels on the nature of the immune response and methods of interfering with immune reactions. A simple schema shown in Figure 1, which appeared to us straightforward and potentially controllable, has now been replaced by a complicated theory
Afferent arc
Graft Immune
\
reacting centre Cellular immune mechanisms Killer cells
Proliferation ofa
B
small percentage of T and B lymphocytes specifically committed
00 °
00 Circulating antibody
&3 Circuatin ant y Y globulin secreting
CIA,, -tterent arc Figure 1. Rejection schema. (Reproduced from Calne 1974, by kind permission)
cells
482
Journal of the Royal Society of Medicine Volume 71 July 1978
involving many different cell types, antibodies and other humoral factors all interlinked with each other, some leading to increased aggression of the immune response, others to the reverse. For the practising clinician, learning current views has doubtful value, since the state of play is changing continuously, as is the nomenclature. Moreover, most of the experimental work has been performed in artificial animal models, far removed from a sick patient. The frontiers of human genetics have also been pushed forward as a result of interest in serological tissue typing of white cells. Certain patterns have been recognized to predispose to diseases, the most well known example being ankylosing spondylitis; the chromosome on which the major histocompatibility complex is carried has been discovered. What value is all this knowledge in trying to help a patient who requires a transplant? The answer is disappointingly limited, but the story is not entirely gloomy. If the major histocompatibility complex is matched between donor and recipient siblings, which occurs in 25% of cases, a kidney transplant will have a very high chance of success (of grafts from HLA identical siblings, 85% are functioning at one year, 75% at five years), although the recipients will require immunosuppressive therapy and rejection can occur. A similar degree of tissue typing between unrelated donors gives less satisfactory results. This implies that there are important transplantation antigens which are not detected by current techniques. Following multiple pregnancies, blood transfusions or previous rejection of a graft, circulating antibody can be produced in high titres that cause hyperacute destruction of the kidney graft. Cross-matching of recipient serum for donor cells is important to such sensitized patients. Unfortunately there are so many transplantation antigens that it is usually difficult to obtain a good match from an unrelated donor. However, some phenotypes are relatively common, so that if there is widespread sharing of information and transfer of kidneys to appropriate recipients, better results can be obtained than when kidneys are transplanted at random. This argument is a justification for the expensive, computerized, organ transplant centres which, in addition to correlating the information on tissue typing of potential donors and recipients, also arrange the most efficient method of transportation of the kidneys. Simple flushing of the kidney in a cold solution and storage in a sterile container surrounded by ice will permit up to twenty-four hours of preservation time, provided the kidney was not damaged before removal. Such a long preservation time is permissible if the kidneys come from a donor who has been maintained on a ventilator. Longer periods of preservation, up to three days, can be achieved with complicated perfusion machines which are expensive and require trained technical personnel in order to prevent mechanical and electrical faults. In Europe, the simpler method of storage is preferable, although machines allow the transplant operation to be scheduled on ordinary operating lists. Much confusion has arisen concerning the role of blood transfusions given to patients prior to transplantation. It is known that blood transfusions may result in the patient producing cytotoxic antibodies in the serum. To transplant such a patient across a positive cross-match is courting disaster. If, however, the patient has received blood transfusions and has not produced antibodies, then the results of organ grafts are better than in non-transfused patients. A few years ago clinicians were warned by the specialists in tissue typing of the dire consequences of giving blood transfusions. Now the admonitions are just as threatening, but are directed against those who do not give blood transfusions! It is quite clear that the story must be more complicated than just giving or not giving blood. Nontoxic and predictable donor-specific immunosuppression is the goal of transplantation research. It is likely that some degree of specific immunosuppression occurs spontaneously in many patients who have good functioning transplants in the presence of tissue-typing incompatibilities. Whether the donor-specific immunosuppression is brought about by suppressor cells, enhancing antibodies or a combination of both, or by other unknown factors, is not clear. In vitro tests, which are believed to be correlates of the in vivo immune reaction, are being used to study the progress of patients before and following transplantation. It is hoped that these investigations may help explain how donor-specific immunosuppression occurs
spontaneously.
Journal of the Royal Society of Medicine Volume 71 July 1978
483
The only other vital organs to have been transplanted successfully are the heart and the liver, there being no long-term survivors following lung or intestine grafts. Shumway and his colleagues (Schroeder et al. 1976) in Stanford have transplanted more than 100 hearts and the results obtained now are better (57% one year survival) than the average results of kidney transplantation from cadaver donors. They have also managed to overcome the distressing and distorted public image of heart transplantation. Nevertheless, the heart is rather susceptible to rejection, perhaps more so than the kidney, and it is a tribute to the immense attention to detail and clinical care of the Stanford workers that their results are so good. One patient is alive eight years after heart grafting. Liver transplantation fortunately has been- continuing with a low publicity profile, exciting little emotional reaction. Starzl in Denver has transplanted 120 livers (Putnam et al. 1977) and in the Cambridge/King's College Hospital series we have transplanted eighty (Calne & Williams 1977). The main indications have been primary malignancy of the liver and parenchymatous liver disease, particularly nonalcoholic cirrhotic processes. The chief causes of death were complications from biliary drainage and recurrence of tumour in malignant cases. A new technique for biliary drainage, where the gallbladder is used as a conduit between the donor and recipient common ducts (Figure 2), has been far more satisfactory. Recently we have shown that the liver can be preserved for more than ten hours in a similar way to the kidney, by cool flushing and ice storage. Livers can be removed some distance away and can then be transported to our hospital for the grafting operation. This has increased the supply of donor livers and permitted operation on patients who would otherwise have died whilst waiting. Recently, results have improved (Calne & Williams 1977) and it is clear that the liver is far less likely to be rejected than the kidney. Less than 10% of grafted livers have uncontrollable rejection, whereas, as has been mentioned, 50% of kidneys from cadaver donors are rejected within a year. Recipients of liver grafts usually require less immunosuppressive drugs than patients with kidney grafts. One of the Denver cases is the longest surviving patient with a liver graft and is now leading a normal life more than seven and a half years after transplantation. Another Denver patient has given birth to a normal child (T E Starzl, personal
communication).
Armwtomoi*o
/,e,.,i,? S
gaUbl t~~~~~~~~~~~d
to..
bid
s000: 1: s ? ,,.,As,, - ,04:.
Figure 2. Pedicle graft conduit with donor gallbladder. Hartmann's pouch is anastomosed to donor common duct and fundus anastomosed to recipient common duct. Irrigating T-tube is inserted with irrigating arm through upper anastomosis. Blood supply to gallbladder is carefully preserved. (Reproduced from Calne & Williams 1977, by kind permission)
484
Journal of the Royal Society ofMedicine Volume 71 July 1978
The future It may be that a completely new principle will be discovered in transplantation immunology which will provide safe and predictable control of rejection. In the absence of such an advance, it would seem likely that in vitro monitoring of the immune response should permit more appropriate immunosuppressive treatment, since the present policy of giving the maximum tolerated dosage of immunosuppressive drugs may, in addition to damaging cells that cause rejection, also impair the development of natural suppressive mechanisms. In vitro culture techniques using material taken from recipients and potential donors may allow prediction of which patients would do well and which badly, without having to give blood transfusions. Such an advance would be very important as it would prevent patients being sensitized and subjected to unnecessarily painful and distressing operations. Patients who are unsuitable for transplantation would be kept on maintenance dialysis. A study of recipients of liver grafts compared with those of kidneys could shed light on the interesting observation of the low incidence of uncontrollable rejection of liver grafts. This might provide a tool for the control of rejection. I would predict that more donor organs will become available in the near future and in vitro techniques will considerably improve results of organ grafting. Livers and hearts will be transplanted in increasing numbers and with better results as patients are operated on before they are moribund. I hope someone will find a new and safe immunosuppressive drug. The fact that there has been a singular lack of success in this direction in the past does not make me too pessimistic, since recent advances in pharmacology have resulted in the treatment of so many diseases for which previously no effective therapy was available, and besides, surgeons are traditionally and of necessity optimistic. A particularly interesting new compound cyclosporin A has been shown to prolong organ graft survival in animals and will soon be investigated in man (Calne & White 1977). Comment In my opinion, the Department of Health has now produced reasonable medical and supporting resources to treat patients by dialysis and transplantation, but the needs of the patient can be fulfilled only if organ donation from all suitable cadaver donors becomes accepted as routine. My personal suggestion would be to establish a register of 'opters-out'. This could be consulted and, in the absence of recorded objection and using the various safeguards already mentioned, would then allow the lawful removal of organs from dead patients to proceed. This type of legal framework has been accepted in several European countries, including Denmark, France and Austria, but to gain approval in the United Kingdom it would require much more publicity of a favourable nature on the plight of patients not receiving treatment and what could be available to them if organ donation were more generally forthcoming, as well as a more helpful and less apathetic attitude to aiding organ donation from the medical profession itself.
References Billingham R E, Brent L, Medawar P B & Sparrow B M (1954) Proceedings of the Royal Society B 143, 43 British Transplantation Society (1975) British Medical Journal i, 251 Caine R Y (1974) Organ Grafts. Edward Arnold, London; p 20 Calne R Y & White D J G (1977) IRCS Journal of Medical Science 5, 595 Caine R Y & Williams R (1977) British Medical Journal i, 471-476 Murray J E, Merrill J P & Harrison J H (1958) Annals of Surgery 148, 343 Putnam C W, Halgrimson C G, Koep L & Starzl T E (1977) World Journal of Surgery 1, 165 Schroeder J S, Rider A K, Stinson E B & Shumway N E (1976) Transplantation Proceedings 8, 58 Scribner B H, Buri R, Caner J E, Hegstrom R E & Burnell J M (1960) Transactions of the American Societyfor Artificial Internal Organs 6, 114
479
The state of British medicine -7
Organ transplantation Professor R Y Caine MS FRS Department of Surgery, Addenbrooke's Hospital Hills Road, Cambridge CB2 2QQ
Organ transplantation has come of age and this would seem to be an appropriate time to look at what has been achieved. I will also try to point out some of the disappointments to those engaged in this work and hazard predictions for the future. At the beginning of this century Alexis Carrel worked out a technique of kidney grafting based on his methods of vascular suturing. In the early 1950s technical success with experimental kidney grafts could be expected, but it was clear that this was not enough to ensure satisfactory function of a transplanted organ. As with skin grafts, so with vascularized organ transplants: after an initial period of temporary 'take', changes occurred in the recipient which led to rapid and inexorable destruction of the graft. A second graft from the same donor was destroyed more quickly than the first, so the phenomenon fitted into the requirements of an immune reaction. Murray et al. (1958), at the Peter Bent Brigham Hospital in Boston, were able to avoid this biological hazard in the first successful clinical organ graft by transplanting a kidney, where no immune reaction could occur, namely where the donor and recipient were identical twins. Some of their earliest patients are now alive, the longest survivor having continuing good kidney function twenty-one years after operation. Two developments in the 1950s led to more widespread therapeutic kidney grafting. First, Scribner et al. (1960) in Seattle applied the principle of recurrent dialysis using an indwelling cannulation prosthesis for vascular access, to maintain patients without renal function in reasonable health. Secondly, effective immunosuppressive drugs became available in experimental animals with organ grafts, namely the use of steroids coupled with the thiopurine antimetabolite, azathioprine (Imuran), a close chemical relative of 6-mercaptopurine. Thus it became possible for desperately ill patients suffering from uraemia to be restored to health and maintained fit for surgery whilst the kidney transplant operation was planned and performed. Both immunosuppressive agents mentioned are sometimes totally ineffective when given at the maximum tolerated dosage. Nevertheless, more than 25 000 kidneys have now been transplanted in patients who have been treated primarily using azathioprine and steroids and the results have been encouraging enough for the procedure to be accepted as established rather than experimental therapy. Results between close relatives are particularly good. Kidney transplantation has been one of the most comprehensively documented new forms of treatment. A registry was set up initially in Boston and it then moved to Chicago. Follow up has been remarkably thorough from all over the world. With grafts between identical twins, where the organ from a living volunteer donor is likely to be in perfect condition when transplanted, 86% of the grafts were functioning at two years. The percentage of functioning grafts in the other donor categories are shown in Table 1. The longest functioning transplant coming from a blood relative who was not an identical twin is eighteen years, and the longest survival with a kidney from an unrelated cadaver donor is fourteen years. A kidney from a cadaver donor, in addition to having increased sensitivity to 0 1 41-0768/78/0071-0479/$O 1.00/0
OC, 1978 The Royal Society of Medicine
480
Journal of the Royal Society of Medicine Volume 71 July 1978
rejection, may also suffer damage prior to its removal and during its transportation to an appropriate recipient. Most patients in terminal renal failure do not have the luxury of a willing and healthy identical twin donor, nor for that matter is it very common for there to be a suitable close blood relative. Therefore, transplantation of kidneys from cadavers is the most common form of renal graft practised. Table 1. Kidney transplants: functioning grafts
Sibling Parent Cadaver
Table 2. Kidney transplants: patients surviving
Functioning grafts
Patients surviving
1 year
5 years
1 year
5 years
75% 70% 50%
60% 50% 30%
85% 85% 70%
70% 60% 50%
Sibling Parent Cadaver
Advances Since 1960, when effective immunosuppression became available, improvements in results of kidney grafting have been rather modest. Once the management of immunosuppressive agents became established with the principle of trying to preserve the patient rather than the graft if rejection becomes difficult to control, there was a marked improvement in patient survival. A rejected kidney can be removed and the patient restored to dialysis, and maintained on dialysis or offered a second transplant. It is of interest that second kidney transplants do no worse than the first, probably because of more careful selection of the second donor kidney. Many patients, however, following rejection of a kidney, develop cytotoxic antibodies in their sera which makes it extremely difficult to find a kidney which they will not react against violently, so there is a worldwide tendency for dialysis spaces to be filled with patients who are untransplantable in practical terms. The patient survival shown in Table 2 is, nevertheless, a remarkable achievement when compared with the 100% mortality that patients with chronic renal failure suffered prior to the introduction of dialysis and transplantation. Kidney disease in young patients is not uncommon. It has been estimated that in the United Kingdom 2000-3000 people between the ages of 5 and 55 could benefit from kidney transplantation, whereas only 500-600 transplants are performed each year. The hospital and surgical facilities and personnel are available and both doctors and Government are agreed that shortage of donor organs is a severe impediment to the treatment of patients with renal failure. The law governing the removal of organs from dead bodies was framed before organ grafting was established (Human Tissue Act 1961). The urgency in removal of organs after death was not then appreciated. Nevertheless, it is quite clear that if the deceased's wishes in his lifetime were known and he willed that organs should be transplanted after death, then organ removal is justified without any further enquiry. When, however, as is usually the case, the deceased's wishes are not known, then permission to remove organs must be sought from relatives, though which relatives is not specified. If, 'after having made such reasonable enquiry as may be practicable-' the relatives cannot be contacted, then 'the person lawfully in possession of the body' can give permission. This has been assumed to be the administrative head of the hospital. The law has never been tested in court and the key words 'reasonable' and 'practicable' have not been defined. In the past decade there has been much discussion on the law, the general ethical principles involved, the role of the coroner and methods of establishing that death has occurred. Following publication of a document by the British Transplantation Society (1975), the Department of Health have issued guidelines on the interpretation of the Human Tissue Act
Journal of the Royal Society of Medicine Volume 71 July 1978
481
1961, and the diagnosis of death. There is widespread acceptance that complete and irreversible brain death constitutes death of the individual and there has been clarification of the coroner's role aimed at increasing the number of suitable organs donated. Provided their duty is not interfered with, most coroners are helpful to the needs of transplantation. Removal of organs from patients who are dead but who are still on ventilators with intact circulations, has greatly reduced the incidence of primary organ failure, which used to be of the order of 17% of cases in the United Kingdom. Damage from ischaemia was such a serious and frequent finding in kidneys removed in Britain that several centres in Europe refused on principle all kidneys removed from United Kingdom hospitals. The Government's policy of encouraging donor cards has improved the goodwill of the public to transplantation; however, it is doubtful whether the carrying of donor cards has in itself made an important impact on the number of kidneys available. The discussion, distribution and collection of cards has made many people, who would otherwise not have been concerned, take organ donation as a serious matter to be discussed with close relatives. There would seem to be a consensus of opinion amongst transplanters that apathy in the medical profession has been the main cause of the shortage of organs. Doctors looking after patients in intensive care areas are often unwilling to be involved in extra work, some of it harrowing, to help a patient they have never seen. Recently kidney patients' organizations have been formed and their voices are more likely to be heard than those of surgeons practising transplantation. The main advances, therefore, have been not so much fundamental, but rather practical improvements in the administration of drugs and patient care and help from Government and patients themselves in improving the supply of donor organs.
Disappointments A new era of immunology began when Medawar and his colleagues (Billingham et al. 1954) demonstrated experimentally that rejection could be prevented by introducing transplant antigens of the subsequent graft into the organism before the immune system had developed the process called 'immunological tolerance'. A huge body of data has now been accumulated at both chemical and cellular levels on the nature of the immune response and methods of interfering with immune reactions. A simple schema shown in Figure 1, which appeared to us straightforward and potentially controllable, has now been replaced by a complicated theory
Afferent arc
Graft Immune
\
reacting centre Cellular immune mechanisms Killer cells
Proliferation ofa
B
small percentage of T and B lymphocytes specifically committed
00 °
00 Circulating antibody
&3 Circuatin ant y Y globulin secreting
CIA,, -tterent arc Figure 1. Rejection schema. (Reproduced from Calne 1974, by kind permission)
cells
482
Journal of the Royal Society of Medicine Volume 71 July 1978
involving many different cell types, antibodies and other humoral factors all interlinked with each other, some leading to increased aggression of the immune response, others to the reverse. For the practising clinician, learning current views has doubtful value, since the state of play is changing continuously, as is the nomenclature. Moreover, most of the experimental work has been performed in artificial animal models, far removed from a sick patient. The frontiers of human genetics have also been pushed forward as a result of interest in serological tissue typing of white cells. Certain patterns have been recognized to predispose to diseases, the most well known example being ankylosing spondylitis; the chromosome on which the major histocompatibility complex is carried has been discovered. What value is all this knowledge in trying to help a patient who requires a transplant? The answer is disappointingly limited, but the story is not entirely gloomy. If the major histocompatibility complex is matched between donor and recipient siblings, which occurs in 25% of cases, a kidney transplant will have a very high chance of success (of grafts from HLA identical siblings, 85% are functioning at one year, 75% at five years), although the recipients will require immunosuppressive therapy and rejection can occur. A similar degree of tissue typing between unrelated donors gives less satisfactory results. This implies that there are important transplantation antigens which are not detected by current techniques. Following multiple pregnancies, blood transfusions or previous rejection of a graft, circulating antibody can be produced in high titres that cause hyperacute destruction of the kidney graft. Cross-matching of recipient serum for donor cells is important to such sensitized patients. Unfortunately there are so many transplantation antigens that it is usually difficult to obtain a good match from an unrelated donor. However, some phenotypes are relatively common, so that if there is widespread sharing of information and transfer of kidneys to appropriate recipients, better results can be obtained than when kidneys are transplanted at random. This argument is a justification for the expensive, computerized, organ transplant centres which, in addition to correlating the information on tissue typing of potential donors and recipients, also arrange the most efficient method of transportation of the kidneys. Simple flushing of the kidney in a cold solution and storage in a sterile container surrounded by ice will permit up to twenty-four hours of preservation time, provided the kidney was not damaged before removal. Such a long preservation time is permissible if the kidneys come from a donor who has been maintained on a ventilator. Longer periods of preservation, up to three days, can be achieved with complicated perfusion machines which are expensive and require trained technical personnel in order to prevent mechanical and electrical faults. In Europe, the simpler method of storage is preferable, although machines allow the transplant operation to be scheduled on ordinary operating lists. Much confusion has arisen concerning the role of blood transfusions given to patients prior to transplantation. It is known that blood transfusions may result in the patient producing cytotoxic antibodies in the serum. To transplant such a patient across a positive cross-match is courting disaster. If, however, the patient has received blood transfusions and has not produced antibodies, then the results of organ grafts are better than in non-transfused patients. A few years ago clinicians were warned by the specialists in tissue typing of the dire consequences of giving blood transfusions. Now the admonitions are just as threatening, but are directed against those who do not give blood transfusions! It is quite clear that the story must be more complicated than just giving or not giving blood. Nontoxic and predictable donor-specific immunosuppression is the goal of transplantation research. It is likely that some degree of specific immunosuppression occurs spontaneously in many patients who have good functioning transplants in the presence of tissue-typing incompatibilities. Whether the donor-specific immunosuppression is brought about by suppressor cells, enhancing antibodies or a combination of both, or by other unknown factors, is not clear. In vitro tests, which are believed to be correlates of the in vivo immune reaction, are being used to study the progress of patients before and following transplantation. It is hoped that these investigations may help explain how donor-specific immunosuppression occurs
spontaneously.
Journal of the Royal Society of Medicine Volume 71 July 1978
483
The only other vital organs to have been transplanted successfully are the heart and the liver, there being no long-term survivors following lung or intestine grafts. Shumway and his colleagues (Schroeder et al. 1976) in Stanford have transplanted more than 100 hearts and the results obtained now are better (57% one year survival) than the average results of kidney transplantation from cadaver donors. They have also managed to overcome the distressing and distorted public image of heart transplantation. Nevertheless, the heart is rather susceptible to rejection, perhaps more so than the kidney, and it is a tribute to the immense attention to detail and clinical care of the Stanford workers that their results are so good. One patient is alive eight years after heart grafting. Liver transplantation fortunately has been- continuing with a low publicity profile, exciting little emotional reaction. Starzl in Denver has transplanted 120 livers (Putnam et al. 1977) and in the Cambridge/King's College Hospital series we have transplanted eighty (Calne & Williams 1977). The main indications have been primary malignancy of the liver and parenchymatous liver disease, particularly nonalcoholic cirrhotic processes. The chief causes of death were complications from biliary drainage and recurrence of tumour in malignant cases. A new technique for biliary drainage, where the gallbladder is used as a conduit between the donor and recipient common ducts (Figure 2), has been far more satisfactory. Recently we have shown that the liver can be preserved for more than ten hours in a similar way to the kidney, by cool flushing and ice storage. Livers can be removed some distance away and can then be transported to our hospital for the grafting operation. This has increased the supply of donor livers and permitted operation on patients who would otherwise have died whilst waiting. Recently, results have improved (Calne & Williams 1977) and it is clear that the liver is far less likely to be rejected than the kidney. Less than 10% of grafted livers have uncontrollable rejection, whereas, as has been mentioned, 50% of kidneys from cadaver donors are rejected within a year. Recipients of liver grafts usually require less immunosuppressive drugs than patients with kidney grafts. One of the Denver cases is the longest surviving patient with a liver graft and is now leading a normal life more than seven and a half years after transplantation. Another Denver patient has given birth to a normal child (T E Starzl, personal
communication).
Armwtomoi*o
/,e,.,i,? S
gaUbl t~~~~~~~~~~~d
to..
bid
s000: 1: s ? ,,.,As,, - ,04:.
Figure 2. Pedicle graft conduit with donor gallbladder. Hartmann's pouch is anastomosed to donor common duct and fundus anastomosed to recipient common duct. Irrigating T-tube is inserted with irrigating arm through upper anastomosis. Blood supply to gallbladder is carefully preserved. (Reproduced from Calne & Williams 1977, by kind permission)
484
Journal of the Royal Society ofMedicine Volume 71 July 1978
The future It may be that a completely new principle will be discovered in transplantation immunology which will provide safe and predictable control of rejection. In the absence of such an advance, it would seem likely that in vitro monitoring of the immune response should permit more appropriate immunosuppressive treatment, since the present policy of giving the maximum tolerated dosage of immunosuppressive drugs may, in addition to damaging cells that cause rejection, also impair the development of natural suppressive mechanisms. In vitro culture techniques using material taken from recipients and potential donors may allow prediction of which patients would do well and which badly, without having to give blood transfusions. Such an advance would be very important as it would prevent patients being sensitized and subjected to unnecessarily painful and distressing operations. Patients who are unsuitable for transplantation would be kept on maintenance dialysis. A study of recipients of liver grafts compared with those of kidneys could shed light on the interesting observation of the low incidence of uncontrollable rejection of liver grafts. This might provide a tool for the control of rejection. I would predict that more donor organs will become available in the near future and in vitro techniques will considerably improve results of organ grafting. Livers and hearts will be transplanted in increasing numbers and with better results as patients are operated on before they are moribund. I hope someone will find a new and safe immunosuppressive drug. The fact that there has been a singular lack of success in this direction in the past does not make me too pessimistic, since recent advances in pharmacology have resulted in the treatment of so many diseases for which previously no effective therapy was available, and besides, surgeons are traditionally and of necessity optimistic. A particularly interesting new compound cyclosporin A has been shown to prolong organ graft survival in animals and will soon be investigated in man (Calne & White 1977). Comment In my opinion, the Department of Health has now produced reasonable medical and supporting resources to treat patients by dialysis and transplantation, but the needs of the patient can be fulfilled only if organ donation from all suitable cadaver donors becomes accepted as routine. My personal suggestion would be to establish a register of 'opters-out'. This could be consulted and, in the absence of recorded objection and using the various safeguards already mentioned, would then allow the lawful removal of organs from dead patients to proceed. This type of legal framework has been accepted in several European countries, including Denmark, France and Austria, but to gain approval in the United Kingdom it would require much more publicity of a favourable nature on the plight of patients not receiving treatment and what could be available to them if organ donation were more generally forthcoming, as well as a more helpful and less apathetic attitude to aiding organ donation from the medical profession itself.
References Billingham R E, Brent L, Medawar P B & Sparrow B M (1954) Proceedings of the Royal Society B 143, 43 British Transplantation Society (1975) British Medical Journal i, 251 Caine R Y (1974) Organ Grafts. Edward Arnold, London; p 20 Calne R Y & White D J G (1977) IRCS Journal of Medical Science 5, 595 Caine R Y & Williams R (1977) British Medical Journal i, 471-476 Murray J E, Merrill J P & Harrison J H (1958) Annals of Surgery 148, 343 Putnam C W, Halgrimson C G, Koep L & Starzl T E (1977) World Journal of Surgery 1, 165 Schroeder J S, Rider A K, Stinson E B & Shumway N E (1976) Transplantation Proceedings 8, 58 Scribner B H, Buri R, Caner J E, Hegstrom R E & Burnell J M (1960) Transactions of the American Societyfor Artificial Internal Organs 6, 114
