Experience in RENAL
THOMAS E. STARZL, Ph.D., M.D.
PROFESSOR OF SURGERY,
UNIVERSITY OF COLORADO SCHOOL OF MEDICINE;
CHIEF, SURGICAL SERVICE,
VETERANS ADMINISTRATION HOSPITAL, DENVER, COLORADO
W. B. SAUNDERS COMPANYLondon1964
Although the possibility of organ homotransplantation has intrigued surgeons since antiquity, major strides toward this end have been achieved only in the past few years. Initially, progress was limited by lack of understanding of the processes involved in homograft rejection. Prior to the beginning of the Second World War, many physicians believed that homograft rejection was the consequence of a primary technical failure. In 1944 and 1945, Medawar published the classic studies which not only defined the events that transpired after the placement of skin homografts, but provided a rational explanation for the rejection process. He demonstrated that homografts behaved initially in much the same manner as autografts, but that they were eventually sloughed after a varying period of time. The histologic alterations in the transplants consisted of mononuclear cell infiltrates, a variety of vascular lesions, and eventual distortion or destruction of the normal architecture.
IMMUNOLOGIC REACTION OF HOST
Medawar's studies provided strong evidence that these phenomena were due to an immunologic reaction of the host to the foreign tissue (Fig. 1). The key observation in support of this concept was that once a homograft had been placed, a second graft from the same donor was destroyed in an accelerated fashion (second set reaction), suggesting the acquisition of host immunity. The immunity conferred by contact with the first graft was of long duration, and applied to all tissues subsequently transplanted from the same donor. The sensitization was specific, inasmuch as homografts from other donors were not rejected in an accelerated manner. A feeble quantitative effect was noted by Medawar, with more rapid rejection of larger than of smaller grafts.
These important observations were soon extended by Dempster and by Simonsen to whole organ homografts of the kidney, in which the mode of revascularization is quite different. Free skin grafts survive without immediate restitution of blood supply, revascularization occurring from the graft bed over a period of days. With kidneys, a blood supply is promptly restored by means of surgically performed vascular anastomoses. Despite this difference the fate of renal homografts was comparable in most respects to that previously described for skin.
The delay between exposure to a foreign graft and rejection has prompted comparisons between homograft immunity and the delayed tuberculin type sensitivity. However, the precise details of homograft immunity are not known. The nature and location of the antigen and of the resultant antibodies are matters on which there are conflicting opinions. There is abundant evidence that the reticuloendothelial system plays an important role in rejection (Fig. 1). After the placement of skin grafts, the regional lymph nodes become enlarged and packed with large lymphoid, reticulum, and plasma cells, while a similar reaction is seen in the subjacent graft bed. All vascularized homografts are ultimately invaded by lymphocytes and plasma cells during rejection. Work by Weaver, Algire, and Prehn has focused attention upon the small lymphocyte as the ultimate cellular agent of destruction (Fig. 2).
Although it has been customary to think of homograft rejection primarily in terms of a host cellular response, recent evidence has pointed to the possibility that humoral factors may also be of great practical importance. Najarian and Feldman's investigations, which demonstrated the invocation of a presumed host humoral rejection factor by specifically sensitized tissues isolated in millipore chambers, is particularly pertinent in this respect.
Clinically, Murray and his associates and Hamburger have also drawn attention to the probability that sudden homograft failures could be due to humoral factors only, not only because of the rapidity of destruction of some grafts, but because histologic evidence of cellular infiltration has often not been present under these circumstances. Finally, evidence to be described within our own experience has suggested that some deleterious effects upon the homografted kidney must be explicable by mechanisms other than cellular invasion. These various lines of inferential evidence have led to considerable speculation that an important, if not vital, element of the rejection process may be an immunologically mediated process which involves the blood vessels, leading to a vascular catastrophe which either occurs independently or concomitantly with cellular invasion.
Methods of Altering Host's Reaction
Because of the evidence indicting an immunologic etiology for homograft rejection, it was natural that attention should be focused upon means of altering the immunologic capacity of the prospective host.
Total Body Irradiatior,. Host conditioning with total body irradiation was extensively evaluated for this purpose in the early 1950's. Successes in experimental animals were rare because irradiation so injured the treated animal that survival in a normal environment was impossible. The method of total body irradiation was given a clinical trial by Murray and his associates at the Peter Bent Brigham Hospital in the mid 1950's. Although only one success was attained, this was a signal event since the recipient of this homograft from his nonidentical twin brother is still alive and is the first example of a chronically successful human homotransplantation between a donor and recipient who were genetically different. The most common cause of failure was bone marrow depression, agranulocytosis, and overwhelming infection. Subsequent efforts by European investigators, notably Kiiss and Hamburger, were somewhat more successful. Nevertheless, the prospect of achieving consistent success with this approach has ultimately appeared to be virtually hopeless.
Drug Immunosuppressiorz. A new chapter in immunosuppressive therapy was opened in 1959 by the work of Schwartz and Dameshek, who demonstrated an obtundation of immunologic response in animals which were exposed to foreign protein antigens while receiving 6mercaptopurine. One year later, Schwartz and Dameshek, Calne, and Zukoski independently demonstrated that this drug prolonged homograft survival. Still later, Calne and Murray demonstrated an improved effect with a chemical compound closely related to 6mercaptopurine, termed azathioprine, especially if it were combined with weaker antirejection agents such as actinomycin C and azaserine. These drugs, alone or in combination, were superior to irradiation in that their effects were more incisively directed. It was possible with these agents to inhibit homograft rejection without the production of agranulocytosis. Thus, for the first time, rejection could be prevented or delayed without rendering the host totally nonreactive against other environmental antigens.
CURRENT STATUS OF RENAL HOMOTRANSPLANTATION
Despite these encouraging findings, it was not yet possible to obtain consistent success with homotransplantation procedures, either in experimental animals or in man. Like the elusive jigsaw puzzle, in which many of the pieces had been fitted into their appropriate slots, the picture was not yet complete. The pioneer efforts of Murray, Kuss, Hamburger, and Hume had all demonstrated that a renal homotransplant was capable of protracted function in the occasional case. If this could be achieved sporadically, it seemed reasonable to expect that the proper manipulation of a number of small details might provide a consistently successful solution. Despite this expectation, almost all renal homotransplants had failed when, in the spring of 1963, Goodwin and Martin compiled the known renal transplants from various centers throughout the world. Less than 10 per cent of those cases treated to that time had survived for as long as three months.
The courageous and often tragically unsuccessful attempts of the early pioneers provided a vast, although frequently uncatalogued, background of valuable information upon which future progress might be built. Quite apart from the information obtained concerning the prevention of homograft rejection, important strides were taken of a purely technical nature. The surgical technique described by Kuss in 1951 was popularized as a result of its use by Murray and Harrison for the transplantation of kidneys between pairs of identical twins (isografts) in 1954. Subsequent repeated successful experiences with identical twins have contributed much to the definition of effects of ischemia upon subsequent renal function, the response of the host patient to sudden alleviation of his complex metabolic disorder, and the unique problems of pre and postoperative care presented by these chronically and terminally ill upon prior to March 31, 1964, is included in the appendix, brought up to date to June 1, 1964. In this tabular summary (Chap. 28), the patients are listed in four groups depending on the source of the donated organs. The categories are:
1, living donors (LD); 2, cadaveric donors (CD); 3, simian (baboon) donors (SD); 4, identical twin donors (ITD). Each illustration in the book is coded so that by crossreferencing to the appendix, the current status of an individual patient can be readily determined. Thus, further details of the patient identified as LD 2 in Chapter 2 (Fig. 3) can be quickly obtained by consulting the same number in the appendix.
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19. Zukoski, C. F., Lee, H. M., and Hume, D. M.: The prolongation of functional survival of canine renal homografts by 6mercaptopurine. Surg. Forum 11:470, 1960.