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ScienceWeek
HISTORY OF MEDICINE: ON TRANSPLANTATION
The following points are made by Peter J. Morris (New Engl. J. Med. 2004 351:2678):
1) Fifty years ago, on December 23, 1954, a kidney was transplanted from one healthy identical twin to his twin who was dying of renal disease. The surgery was performed at the Peter Bent Brigham Hospital in Boston, and John Merrill, Joseph Murray, and Hartwell Harrison[1,2] led the clinical team. The operation was successful, renal function was restored in the recipient (although he would later have both his own kidneys removed in order to control hypertension), and the donor suffered no ill effects. This was the first successful transplantation, performed against a background of failure. For this reason, it created enormous excitement, both in the media and among medical professionals, at a time when the pioneers of kidney transplantation were despondent about the possibility of any real clinical application.
2) This successful transplantation occurred some 50 years after Emerich Ullmann (1861-1937) performed the first experimental transplantation of a kidney between dogs in Vienna in 1902. A few years later, in 1906, Mathieu Jaboulay (1860-1913), professor of surgery in Lyon, France, connected the renal vessels of a sheep and a pig kidney, respectively, to the brachial vessels of two patients who were dying of renal failure. Neither kidney worked, but these were the first transplants, albeit xenografts, that had been placed in humans. The techniques used to join the vessels together were those developed and described by Alexis Carrel (1873-1944), who had been a young surgeon in Jaboulay's unit, and in fact, the techniques of vascular anastomosis described by Carrel are exactly those still used in renal transplantation today. By the time of Jaboulay's transplantations, Carrel had moved to Chicago to work with Charles Guthrie (1880-1963), studying experimental organ and even limb transplantation.
3) Carrel subsequently moved to the Rockefeller Institute in New York, but he continued his organ-transplantation work until the beginning of the First World War. Indeed, in a prescient lecture in 1914, he said that the technical problems of transplantation were essentially solved, but until some method was developed to prevent the reaction of the organism against the foreign tissue, there would be no clinical application of organ transplantation. Between the wars, experimental transplantations were occasionally performed, but there was no advance in knowledge. There was a serious clinical attempt by a Russian surgeon, Yu Yu Voronoy (?-?), who transplanted cadaveric kidneys into six human recipients, but without success.[3]
4) The modern era of clinical transplantation began in Paris and Boston after the Second World War, and one highlight of postwar efforts was the small series of transplantations of cadaveric kidneys performed by David Hume (1917-1973) at Peter Bent Brigham Hospital in Boston.[2-4] No immunosuppression was used, but some kidneys did function for days or weeks, and one for several months -- no doubt because of the immunosuppression resulting from the profound uremia in the recipients.[4] Enormously encouraged by the successful transplantation between identical twins that had shown that renal failure could be reversed completely, those pursuing immunosuppression, in Boston and Europe, now directed all their efforts at total-body irradiation. Although such irradiation did achieve immunosuppression, however, it also produced profound marrow aplasia, which led to patients' deaths from overwhelming infections. By the early 1960s, it was clear that total-body irradiation was not the solution.[5]
References (abridged):
1. Merrill JP, Murray JE, Harrison JH, Guild WR. Successful homotransplantation of the human kidney between identical twins. JAMA 1956;160:277-282
2. Tilney NL. Transplant: from myth to reality. New Haven, Conn.: Yale University Press, 2003
3. Hamilton D. Kidney transplantation: a history. In: Morris PJ, ed. Kidney transplantation: principles and practice. 5th ed. Philadelphia: W.B. Saunders, 2001:1-8
4. Hume DM, Merrill JP, Miller BF, Thorn GW. Experiences with renal homotransplantation in the human: report of nine cases. J Clin Invest 1955;34:327-382
5. Hamilton D. Reaching for the impossible: the quest for tissue replacement. In: Ginns LG, Cosimi AB, Morris PJ, eds. Transplantation. Boston: Blackwell Science, 1999:1-19
New Engl. J. Med. http://www.nejm.org
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Related Material:
SKIN CANCERS AND ORGAN TRANSPLANTATION
The following points are made by S. Euvrard et al (New Engl. J. Med. 2003 348:1681):
1) Long-term survival after organ transplantation is increasing. As a result, many patients have long-term complications of transplantation. Adequate graft function requires lifelong immunosuppressive treatment, and the resultant modification of the immune system is associated with an increased risk of various cancers, particularly those involving viruses. Skin cancers are the most common malignant conditions in transplant recipients and account for substantial morbidity and mortality in such patients.
2) Squamous-cell and basal-cell carcinomas account for more than 90 percent of all skin cancers in transplant recipients. The incidence of these carcinomas increases with the duration of immunosuppressive therapy, ultimately affecting 50 percent or more of white transplant recipients. For example, the cumulative incidence of skin cancer in transplant recipients in Queensland, Australia, increases from 7 percent after 1 year of immunosuppressive therapy to 82 percent after 20 years. Among Dutch transplant recipients, the incidence of skin cancer at one year is 0.2 percent and the long-term incidence is 41 percent.
3) Squamous-cell carcinoma is the most common skin cancer in transplant recipients, occurring 65 to 250 times as frequently as in the general population. The incidence of basal-cell carcinomas is reportedly increased by a factor of 10 in transplant recipients. The risk appears to increase linearly for basal-cell carcinomas and exponentially for squamous-cell carcinomas; thus, the ratio of squamous-cell to basal-cell carcinomas in patients without transplants (1:4) is reversed in transplant recipients. The relative risk of squamous-cell carcinoma after transplantation is higher for men than for women, except for cancers of the lip. Curiously, skin cancers appear to be extremely rare in Japanese patients with transplants.
New Engl. J. Med. http://www.nejm.org
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Notes by ScienceWeek:
The skin cancer called "basal-cell carcinoma", rare in Blacks and Asians, is the most common malignant skin tumor in Whites. This cancer arises from the undifferentiated basal keratinocytes of the epidermis. Such cancers rarely metastasize but may be highly invasive locally, when they are called "rodent ulcers". The lesions are prevalent in fair-skinned persons and on areas of skin that receive the greatest exposure to sunlight. Treatment with inorganic arsenical drugs and exposure to ionizing radiation (e.g., x-rays) may also be contributing factors.
The skin cancer called "squamous-cell carcinoma" is less common than basal-cell carcinoma but has a higher rate of metastasis. Squamous-cell carcinoma is common in children with xeroderma pigmentosum, who are unable to repair DNA damage caused by ultraviolet radiation. In most persons, such an inability to repair DNA damage is due to a deficiency of an endonuclease enzyme. In adults, squamous-cell carcinoma rarely occurs in the absence of an external cause, and protracted exposure to sunlight is the usual cause of this disease. Chronic scarring from burns, as well as reactions to vaccinations, radiation dermatitis, and chronic ulceration may also be risk factors for squamous-cell carcinoma of the skin.
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Related Material:
ON KIDNEY TRANSPLANTATION FROM DONORS WITHOUT A HEARTBEAT
The following points are made by M. Weber et al (New Engl. J. Med. 2002 347:248):
1) The number of patients awaiting organs for transplantation has grown dramatically during the past two decades, triggering interest in expanding the pool of organs beyond those obtained from brain-dead donors with a heartbeat. Alternative sources of organs include elderly, brain-dead donors whose hearts continue to beat, living donors, and donors without a heartbeat. A successful program of transplantation from donors without a heartbeat could increase the number of kidneys available for transplantation by 30 percent.(1)
2) Death in donors without a heartbeat is defined as an irreversible cessation of circulatory and respiratory function,(2) whereas brain death in donors with a heartbeat is determined according to neurologic criteria. Therefore, by definition, a donor without a heartbeat has had a prolonged phase of hypotension (one that lasts several minutes) followed by cardiac arrest before organ harvesting. Insufficient perfusion or complete lack of perfusion of such organs has long been thought to cause irreversible damage, resulting in poor short-term and long-term outcomes after grafting.(3) With the exception of recent limited experience in liver transplantation,(4) the use of organs from donors without a heartbeat has been restricted to the kidneys, since dialysis is available for support in case the graft does not function after transplantation.(5)
3) The authors report they conducted a matched, single-center study of kidney transplants obtained from donors without a heartbeat and those from donors with a heartbeat, with a 15-year follow-up period. Between 1985 and 2000, 122 kidney transplantations involving donors without a heartbeat were performed at the University of Zurich, in Switzerland. Outcomes of these procedures were compared with those of 122 transplantations of kidneys from donors with a heartbeat. The recipients were matched according to age, sex, number of transplantations, and calendar period of transplantation. The authors conclude that although the incidence of delayed graft function is significantly higher with kidneys from donors without a heartbeat than with kidneys from donors with a heartbeat, there is no difference in long-term outcome between the two types of graft.
References (abridged):
1. Sanchez-Fructuoso AI, Prats D, Torrente J, et al. Renal transplantation from non-heart beating donors: a promising alternative to enlarge the donor pool. J Am Soc Nephrol 2000;11:350-358.
2. Guidelines for the determination of death: report of the medical consultants on the diagnosis of death to the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. JAMA 1981;246:2184-2186.
3. Kahan BD, Ponticelli C. Selection and operative approaches for donors: non-heart-beating cadaveric donors. In: Kahan BD, Ponticelli C, eds. Principles and practice of renal transplantation. London: Martin Dunitz, 2000:149-50.
4. D'allessandro AM, Hoffman RM, Knechtle SJ, et al. Liver transplantation from controlled non-heart-beating donors. Surgery 2000;128:579-588.
5. Wijnen RMH, Booster MH, Stubenitski BM, de Boer J, Heineman E, Kootstra G. Outcome of transplantation of non-heart-beating donor kidneys. Lancet 1995;345:1067-1070.
New Engl. J. Med. http://www.nejm.org
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