1965. Factors determining short and long term survival after orthotopic liver homotransplantation in the dog

Abstract

In an effort to answer many unresolved questions concerning orthotopic homotransplantation of the canine liver, a complete reappraisal of this preparation was under-taken in early 1964 in both the untreated and modified host. A particular effort was made to (A) reduce the operative mortality; (B) interpret the significance of pathologic changes in the homograft and in the recipient tissues; (C) define the presence or absence of a graft-host reaction; (D) study the effect of variations in therapy upon results; (E) assess the hepatotoxic properties of azathioprine; (F) determine if and with what regularity hepatic rejection could be reversed and chronic survival attained; and (G) find if and when a state of relative host-graft non-reactivity developed some time after homotransplantation. METHODS Mongrel dogs weighing 8.3 to 27.3 kilograms were used. All animals had hematologic and liver function determinations before and at regular intervals after the experiments were begun. Red cell survival studies were performed with a Cr 51 technique. 6 Tetracycline and chloramphenicol were routinely administered. Azathioprine * was employed in most experiments with a dose of 2 to 8 mg. per kilogram per day. Insofar as possible, the induction of leukopenia was avoided. Azathioprine and antibiotic therapy was discontinued at 120 days in all surviving animals. Other variations in therapy are described below. Tissues were examined with light and electron microscopy. For homotransplantation, livers were obtained from donors of dissimilar appearance, but of approximately the same weight as the recipients. Prior to removal, the donor liver was cooled by perfusion of chilled Ringer's lactate solution through the portal vein. The technique of transplantation 24 resulted in an essentially normal blood supply (Fig. 1). The intervals of ischemia were almost all less than one hour. Cholecystoduodenostomy was established for internal biliary drainage. Azathioprine toxicity study In 18 non-transplanted dogs the effects of 40 days of azathioprine were studied. The animals were divided into 3 groups of 6 each which received: Group I. Daily azathioprine (2 to 4 mg. per kilogram).

The Role of Organ Transplantation in Pediatrics

“…In dogs this drug has been shown to be a significant liver poison which causes hepatic injury within a few days after beginning administration. 58 The high degree of toxicity is apparently speciesspecific for the dog, but four adults in our experience have suffered severe liver injury after months or years of azathioprine therapy; one of these patients died of a combination of liver failure and bacterial sepsis. 61 Thus far this has not been observed in patients of 18 years or less.…”

“…58 With both organs the severity of the subsequent rejection is highly variable in individual experiments, a finding undoubtedly explained by differences in the quality of chance histocompatibility matching as discussed earlier. In a recently reported series of nearly a hundred canine liver homotransplantations in which azathioprine alone was given for immunosuppression, approximately 20 per cent of the recipient animals had no clinical evidence of rejection (Fig.…”

“…of potassium. 58 Serious errors of fluid therapy can be introduced, however, unless repeated plasma and urine electrolyte determinations are carried out. One of the deaths in the present series (LD 26) occurred as a result of an acute electrolyte disorder during the first postoperative day.…”

“…The most incisive experiments have involved orthotopic transplantation in which the recipient animal's own liver is excised and replaced with a homograft obtained from an unrelated mongrel animal 31,35,36,37,50,51,58 with a technique similar to that depicted in Figure 38. With this preparation there is no equivocation about the presence or absence of transplant viability, since survival provides incontrovertible proof of continuous homograft function.…”

“…58 It seems probable that all homografts, even those in which function is not demonstrably impaired, undergo early invasion by pyroninophilic mononuclear cells, the maximum infiltration usually being between the first and third weeks. After this time the predominant histologic features in most homografts were those of repair and regeneration, with either absent or relatively minor degrees of continuing destruction.…”