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The influence of nonhepatic splanchnic venous blood on dog liver morphology and biochemical content was investigated by performing partial portacaval transposition, anastomosing the supra-adrenal inferior vena cava to either the right or left branch of the main portal vein. In the resulting preparation, nonhepatic splanchnic venous blood supplies one portion of the liver and systemic venous blood perfuses the remaining fraction,. Seven dogs were studied for 70 to 94 days, 3 with right and 4 with left transposition. No clinical abnormalities were noted. Transient enzyme elevations were seen early after operation but reverted to normal. The most striking feature was the gross and microscopic atrophy and deglycogenation which occurred in the part of the liver receiving systemic venous blood. Blood flow studies were performed in 8 additional dogs with an electromagnetic square wave flowmeter. Flow was measured in both right and left portal vein branches before and 1 to 4 hours after partial transposition to either the right (4 dogs) or left (4 dogs) main branch. Flow rates were increased in 11 instances and remained essentially the same in 5. In 2 more dogs, a jugular venous autograft was placed between the abdominal aorta and the right or left main portal vein branch. Atrophy and deglycogenation in the portion receiving arterial blood was comparable to that described above in liver fractions perfused with systemic venous blood. The evidence from these and earlier experiments that splanchnic venous blood contains a hepatotrophic substance is discussed. © 1967.

Six patients with terminal uremia due to glomerulonephritis or pyelonephritis were treated with heterografts from East African baboons. Immunosuppressive therapy was provided both before and after operation with azathioprine and prednisone and postoperatively local transplant irradiation and actinomycin C were administered intermittently. The individual rejection episodes in the post-transplant period could be reversed relatively easily but these reemred vigorously and repetitively, making it impossible to relax the stringent requirements of antirejectmion therapy. The continued need for high-dose immunosuppressive therapy precipitated lethal infections in the majority of cases. The patients lived for 19 to 98 days after heterotransplantation. Four died with the baboon kidneys still in placc after 19, 23, 35, and 49 days. In the other two cases the heterografts were removed after 60 and 49 days respectively, at a time when urine excretion was still present, and homografts from volunteer convict donors were placed on the opposite side. Both the latter recipients died of septic complications following the second operation, after 39 and 44 days. Complete cessation of heterograft urine excrelion appeared only in two cases, although rend function was failing in the remainder prior to death or before removal of the heterografts. The relation of renal function to changes in heteroagglutinin and hemagglutinin titers is described. After residence in the host for 19 to 60 days, all the heterotransplants were heavily infiltrated with plasma cells and large lymphoid cells with pyroninophilic cytoplasm. There was also disruption of peritubular capillaries, interstitial edema, widespread tubular damage, swelling of endothelial cells lining arterioles, fibrinoid necrosis of the walls of arterioles and interlobular arteries, and narrowing and obstruction of interlobular arteries by fibrin and platelet deposits on the intima. The pre-glomerular vascular lesions were accompanied by f

An investigation was conducted of the influence of portacaval transposition upon carbohydrate metabolism in 45 dogs. In 17 dogs, hepatic glycogen content was measured before and from 45 to 75 days after transposition. A reduction in glycogen content, principally in the TCA soluble fraction, was noted in 14 animals. The mean loss of total glycogen was 51 percent, and the mean loss of TCA soluble glycogen was 70 percent. In control animals hepatic deglycogenation did not occur. Despite the reduction in hepatic glycogen content, the animals were capable of glucagon-induced glycogenolysis using very small test doses. After transposition, a greater response to intraportal injection was noted as compared to that obtained with systemic venous infusions. Other alterations in carbohydrate metabolism were also measured. These included a reduction in the duration and magnitude of the hyperglycemic response to oral glucose loads. The profile of glycemic response under these conditions was studied, and demonstrated to be greatest in the portal vein, least in the peripheral venous blood, and of intermediate magnitude in the peripheral arteries. Based upon the hepatic deglycogenating effect of portacaval transposition in dogs, this operation was used for the treatment of an 8 1 2-year-old child with glycogen storage disease and concomitant portal cirrhosis. The portacaval transposition was performed in preference to a standard portacaval shunt. The enzyme defect in the patient was extensively studied before and after transposition. Prior to surgery, she was demonstrated to have Type IIIB glycogenosis (amylo-1,6-glucosidase deficiency confined to the liver). Eight and one half months after operation, the quantities of glycogen in liver and muscle and the enzyme activities showed no significant alteration. The clinical response to portacaval transposition was gratifying. There has been a decrease in the hepatosplenomegaly, rapid growth, a diminution in the pre-existing hypersplenism

Horse antihuman and antidog antilymphocyte globulins were shown to possess leukoagglutinating antibodies when tested against the white cells from a number of other divergent species. In addition, the white cells of individuals within the species against which immunization was originally conducted were variably affected by the immune globulin. The latter observation suggests that these globulins could be more effective in some cases than in others if they were used therapeutically for their immunosuppressive qualities. © 1967.

The feasibility of hepatic homotransplantation has been clearly established in principle inasmuch as several animals are still alive almost 3 years after complete hepatectomy and liver replacement. Both orthotopic and auxiliary operations are complicated surgical techniques. Nevertheless, the results in dogs are comparable to those which can be obtained with homotransplantation of the kidney. In man the problem is more difficult. In patients who have a need for such operations, there is invariably a metabolic disorder more complex than that caused by renal failure. In addition, the new organ must function efficiently from the beginning since its complete functional failure leads to death within a few hours. There is no recourse to an artificial liver to maintain life until the reversal of an injury which is caused by either ischemia or rejection. Nevertheless, research of several kinds may soon make possible the successful use of hepatic transplantation procedures for the definitive treatment of human liver disease as exemplified by the reports in this symposium concerning new techniques of organ preservation, histocompatibility analysis, and immunosuppression. © 1967 by The Williams and Wilkins Co.

An attempt was made to determine whether 36 long-term kidney homograft recipients and their donors were compatible for 7 major leukocyte groups. It was found that 21 of these recipients were surviving 2 to 3 years in spite of incompatibility for 1 or 2 major leukocyte antigens. Survival of mismatched grafts does not itself indicate that the antigens being measured are not transplantation antigens, for it was shown that the 15 recipients with no groups of mismatch were clinically superior to those with group incompatibilities. Moreover, histopathologic scores given to biopsy specimens taken 2 to 3 years after transplantation were significantly correlated with the number of group mismatches. Because the leukocyte groups were determined by cytotoxicity reactions of peripheral blood lymphocytes, the results may have been influenced considerably by chimerism in chronically dialyzed uremic patients or change in lymphocyte antigenicity or susceptibility to lysis upon prolonged immunosuppressive treatment. Although the possibility of these complications could not be ruled out in all instances, it was shown that 52 dialyzed uremic patients and 49 patients who had been treated with immunosuppression for over 1 year did not possess more or less antigens than a random population of normal individuals. It is concluded that: (1) the major leukocyte antigens are histocompatibility antigens, and (2) since survival can be attained at times despite mismatches for these groups, the antigens are of intermediate strength and kidney homograft rejection may occur if excessive numbers of antigens are incompatible or if particular combinations of antigens are mismatched. © 1966 by The Williams and Wilkins Co.

Infectious diseases occurred in 26 of 30 renal homotransplantation patients and contributed to eight of the 12 deaths in this series. There were 52 infections, 17 occurring before and 35 after transplantation. Infections were produced primarily by staphylococci, Pseudomonas species, and the enteric gram-negative bacilli. Staphylococcal infections occurred in 17 of 19 carriers of this organism and in only one of 11 noncarriers. Thirty-three of the 35 postoperative infections followed the intensification of immunosuppressive therapy for treatment of attempted homograft rejection. Granulocytopenia, steroid-induced diabetes, and hypogammaglobulinemia, from suppressive drug therapy, routinely preceded the onset of these complications. The infections, largely of endogenous origin, occurred when the host's defense mechanisms were depressed. © 1964, American Medical Association. All rights reserved.

A clinically distinct pneumonitis occurred in six renal transplant recipients receiving azathioprine and prednisone immunosuppressive therapy. The patients ranged in age from 3 to 20 years. The onset was 42 to 102 days postoperatively, coinciding with decrease in prednisone dosage below approximately 1 mg per kilogram of body weight per day. Mild nonproductive cough, fever, and cynanosis were present. Chest x-rays demonstrated extensive hazy to nodular infiltrates usually involving both hila and lower lung fields. Cold agglutinins were present in five patients. Pulmonary function studies demonstrated an alveolar capillary block. The duration of illness was 12 to 34 days and was not influenced by antibiotic therapy. Autopsy of the single case in which death occurred revealed Pneumocystis carinii pneumonia and disseminated cytomegalic inclusion-body disease. © 1964, American Medical Association. All rights reserved.

Twenty patients were treated with antilymphocyte globulin (ALG) which was prepared from the serum of immunized horses. The ALG was used as an adjuvant to azathioprine and prednisone and its use limited to 4 months. The surviving patients are now 1 to 7 months postoperative. There was 1 death, the consequence of a technical accident. The function in the remaining 19 patients is excellent, despite reduced doses of azathioprine and especially prednisone. Biopsies were obtained in the first 8 consecutive cases from 108 to 145 days after operation. There was no evidence in the specimens of either Masugi-like or serum sickness nephritis. © 1967 by The Williams and Wilkins Co.

From March 1962 to April 1963, 118 patients were treated with renal transplantation, 3 with kidneys from identical twins, 9 with cadaveric homografts, and 106 with homografts from volunteer donors. Sixty-two of the patients are still alive after nine months to almost five years. The only completely satisfactory group was that of the identical twin recipients. The results after homotransplantation have not materially improved during this time despite the acquisition of increased experience, adjustments of timing and dosage of azathioprine and prednisone, and attempts to identify biologically suitable donors in advance of operation by tissue typing. It is suggested that an impasse has been reached, beyond which further reduction in mortality and morbidity will depend primarily upon the effective application of new immunosuppressive techniques. © 1967 by The Williams and Wilkins Co.