Edward B. Hager

Immunologic Rejection of Human Cancer Transplanted with a Renal Allograft

Abstract Metastatic carcinoma of the bronchus, inadvertently transferred to a patient when a kidney was transplanted from a cadaveric source, underwent immunologic rejection in the new host. This metastatic focus in and around the transplanted kidney did not appear until 18 months after the allograft was placed. When immunosuppressive therapy was discontinued, the previously functioning kidney was promptly rejected whereas tumor growth did not appear to be altered. After removal of the kidney, however, the residual cancer disappeared. The patient received a second kidney transplant nine months after removal of the first. There has been no evidence of further metastatic cancer despite resumption of a full program of immunosuppression.

Major surgery in patients on maintenance hemodialysis

Abstract The hospital records of thirty-three patients with chronic renal failure undergoing forty-four major operations and requiring pre- and postoperative hemodialysis were reviewed. The patients were evaluated as to preoperative preparation, intraoperative course, and the development of postoperative complications. Dialysis was performed within twenty-four hours prior to surgery in thirty instances. Most patients were hypertensive. Mean preoperative laboratory values included: blood urea nitrogen of 54 mg. per cent, creatinine of 9.0 mg. per cent, potassium of 4.8 mEq./L., and carbon dioxide of 24 mM/L. Hematocrit averaged 28 per cent. Preoperative anesthetic medications consisted for the most part of a short-acting barbiturate and atropine. Halothane was the general anesthetic most commonly used in conjunction with nitrous oxide. Except for two instances of cardiac arrest (one resulting in death), there were few intraoperative problems. These two cases are described in detail. Postoperative fever was present in twenty-six patients, atelectasis in twenty, wound infection in six, bleeding in four, and pericarditis appeared after surgery in eleven. In six patients thrombosis of the arteriovenous cannulas developed within one week of operation. All postoperative complications were minor and most patients demonstrated excellent wound healing. Twenty-three patients had dialysis within twenty-four hours of surgery. The most common indication for dialysis was a rapidly rising serum potassium level. From our experience, we would recommend that the following conditions prevail in patients on dialysis who are to undergo major surgery: (1) dialytic treatment should be carried out on the day prior to surgery; (2) there should be adequate control of hypertension, either by ultrafiltration or antihypertensive medication; and (3) serum potassium concentration should be below 5.5 mEq./L. on the day of surgery. With careful attention to fluid balance, an awareness of the propensity of these patients to the development of electrolyte-induced cardiac abnormalities, and with the institution of early postsurgical dialysis, the outlook for recovery from operation in the patient on maintenance dialysis would appear to be excellent.

IMMUNOLOGIC SUICIDE AND STUDIES ON THE ROLE OF ANTIBODY AND COMPLEMENT IN CANINE KIDNEY HOMOGRAFT REJECTION

Traditional characteristics of the so-called homograft rejection reaction are: (1) destruction of the engrafted tissue by a process that intimately involves the host’s immune mechanisms, ( 2 ) absence of graft directed antibody in the serum of the host, (3) invasion of the graft by cells of host origin, and (4) heightened response of the host to a subsequent exposure to the antigens of the same donor. If an animal be immunized with antigens which bear similar structural conformation to antigens found on the surface of his own cells, antibody formed in response to such a stimulus would be expected to show an affinity for the host’s own cell surface antigens, in addition to a specific affinity for the original immunizing antigen. This concept forms the basis of a theory first described five years ago by Robert A. Nelson, Jr.lj2 to explain the above phenomena of socalled homograft immunity, and represents the framework upon which our own work of the past two and one-half years is based. Simply stated, this hypothesis holds that if the donor and host share antigenic similarities, antibody formed will not normally be found present in the serum of the host, but will be attached to host cells, and will reach the graft by means of mobile, sensitized, (antibodycoated) host cells. Upon reaching the graft, the antibody will recognize the better structural fit of the graft antigen, and will readily transfer off to this ”specific” antigen. The ultimate destructive pathway for the rejection of the graft is presumed to be via the complement sequence of the host. A vitally important corollary of this concept is that if host tissue cells become coated with sufficient antibody, immune lysis of these “sensitized” cells may ensue through action of the host complement components-“immunologic suicide.” By use of the immune adherence technique, we demonstrated in 19619 and 1962* that antibody could be found not only on the surface of cells found within a rejecting homograft, but on cells of the host’s own tissues as well. At that time, we also demonstrated that canine platelets carry homograft antigens capable of sensitizing a host against a subsequent kidney graft from the platelet donor. The present reports represent continuation and development of these previous studies.

CURRENT EVALUATION OF HUMAN KIDNEY TRANSPLANTATION

Four years elapsed between the first monozygQtic twin in 1954 and the first dizygotic twin tran~plant.~.~ Only two years later, successful transplants were reported from a m ~ t h e r , ~ sibling,e and a nonconsangiuneous relative.‘ All recipients, except the monozygotic twin, received sublethal total-body irradiation to suppress the host response. These nontwin successes (success being defined as survival over one year) were only a few of a much larger number of illfated attempts and even in these patients, renal function continued to decrease as time passed. The introduction of immunosuppressive drug therapys-10 led to a better early function of greater numbers of kidney transplants from diverse sources. The prolonged survival of a cadaveric kidney in a man treated solely by drugs11-13 further stimulated clinical activity, so that today human kidney transplantation is a partial reality. A recent conference on the present status of human kidney transplantation, held under the auspices of the National Academy of Science-National Research Council, has been summarized and re~0rted.l~ This current report attempts to evaluate human kidney transplantation from two viewpoints: a restricted view of our own group activity and a wider glance at the field at large. At the Peter Bent Brigham Hospital, 81 patients have received kidney transplants; this includes 24 sets of twins (TABLE 1). Total-body irradiation for immune suppression was abandoned two years ago because of repeated failures. Immunosuppressive drug therapy, cautiously started in April 1960, has been used in 31 patients. Two of this group received two kidney transplants on separate occasions. The first 10 recipients received expendable kidneys, either from cadavers or from elective therapeutic nephrectomies, the so-called “free” kidney. Although drug toxicity and many physiological problems were associated with the early experience in the adaptation of dog data to man, four of these kidneys had measurable function. One is still functioning at 22 months, The reversal of a rejec tion reaction by drug treatment, the first known instance of such an event, occurred in our second patient.15 This was an extremely pertinent observation and indicated that immunological rejection was not an inexorable “all-or-none” process which, when once initiated, proceeded inexorably to destruction; on the contrary, rejection became analagous to a disease process amenable to proper and timely therapy. The first kidney transplant to receive azathioprine, a 6‘4” male with a kidney from a six-year-old child (see Reference 11, patient D. T.), had good renal function for a month and died of drug toxicity. The patient who received a cadaver kidney in April 1962 still survives, although function has decreased to such an

Treatment of chronic renal failure by transplantation and dialysis: two decades of cooperation.

The overall transplant experience at the Peter Bent Brigham Hospital which extends over twenty years has been reviewed; the course of all patients was updated to a followup of at least one year (through October 1973). A total of 388 patients received 427 renal isografts and allografts between March 1951 and October 1972. Of these, 58% were still alive at the end of the followup period, 50% with a functioning graft. The results of patient and allograft survival early (1959-1968) and later (1968-1973) in the experience have been compared. The significant decline in patient mortality, especially among recipients of cadaver allografts, demonstrates improved treatment of complications and increased availability of dialysis. The improvement of allograft function during the two time periods is less striking but still significant. Overall social and work rehabilitation following transplantation was evaluated in 284 patients, 86% of whom became at least as well adjusted as they had been prior to the development of renal failure. The incidence and individual causes for mortality and complications of transplantation have been compared to results from the National Dialysis Registry, figures comparable to those of the dialysis program at this institution. Transplantation and dialysis must be used conjointly and in a complimentary manner as part of the total treatment for those with end-stage renal failure.

Immunosuppressive effect of epsilon amino caproic acid (EACA)

Summary o 1. Prolongation of skin homograft survival was observed in some rabbits given 300 to 500 mg. of epsilon amino caproic acid per kg. per day. 2. EACA inhibits complement activity in vitro and may, at high concentration with the formation of antigen-antibody complexes. 3. No effect of EACA on of antibody was noted. Similarly, there appeared to be no alteration of preformed antigen-antibody complexes by EACA.

Isolation and characterization of antibodies and other immunologically reactive substance from rejecting renal allografts

Summary Tissue bound, complement fixing (and presumably cytotoxic) antibodies were regularly found in rejecting canine renal allografts. Techniques for the elution and characterization of these antibodies and other immunologically reactive substances from kidneys undergoing rejection are described. Physicochemical characteristics of the antibodies eluted from rejecting homografts conform to the electrophoretic and ultracentrifugal criteria for 19 S (IgM) and 7 S (IgG) immunoglobulins. Biologic activity of these antibodies includes a preferential affinity for donor kidney antigen as well as cross-reactivity with antigen from “indifferent donors.” Consistent demonstration of affinity for host antigen helps substantiate the concept of autoimmunity in allograft rejection. Antibody cross-reacted best with donor lung and platelets and had lesser reactivity against donor bladder, liver and spleen. A small molecular weight complement fixing substance was found in all rejecting kidneys, but it was not present in normal tissue. This dialyzable substance inactivates complement when reacted with kidney or platelet “antigen” but exhibits no donor specific affinity. A large molecular weight inhibitor of complement hemolytic activity was regularly found in all kidney tissue, rejected or normal.

Current Status of Renal Transplantation

The record of success in renal transplantation has been somewhat improved but is still far from satisfactory. Once a recipient has been selected, he must be brought into optimum physical condition with hemodialysis. After transplantation, acute rejection episodes must be treated vigorously but treatment should not endanger life. Late complications include infection, indolent low-grade rejection, glomerulonephritis and drug toxicity.