Charles G. Halgrimson

Long-term survival after renal transplantation in humans: With special reference to histocompatibility matching, thymectomy, homograft glomerulonephritis, heterologous ALG, and recipient malignancy

AT the University of Colorado Medical Center, 189 patients have been given kidney homografts at a remote enough time to permit relatively long follow-up in the event of continued survival. On the basis of this experience, a reassessment will be attempted of the practical value of renal transplantation. In addition, the effect of various factors upon short and long-term survival will be examined including the organ source, the quality of HL-A antigen matching, thymectomy before or after transplantation, the addition of heterologous antilymphocyte globulin (ALG) to the immunosuppressive regimen, the development of glomerulonephritis in the transplants, and the occurrence of a significantly increased incidence of de novo malignancies in the recipients.

Portal diversion for the treatment of glycogen storage disease in humans.

Seven patients with Types I, III, or VI glycogen storage disease were treated with portal diversion from 5 1/2 mth to 9 1/2 yr ago. The first 2 patients had portacaval transposition with 1 early death. The last 5 patients had the technically safer procedure of end to side portacaval shunt without any deaths and with no late findings of hepatic encephalopathy. The convalescence of the patients with either kind of portal diversion was characterized by accelerated body growth and bone mineralization, incomplete relief of hypoglycemia and metabolic acidosis, striking amelioration of the hyperlipidemia of Type I disease, liver shrinkage in Types I and VI disease, and variable relief of such diverse other derangements as abnormal bleeding and elevated serum uric acid concentrations. The liver concentrations of glycogen were not affected by portal diversion. Hepatocytes were decreased in size in subsequent biopsies, thereby accounting for the reduction of liver size in most of the cases without a major alteration in glycogen. There was a high incidence of pre existing coincidental liver disease in patients, including transaminase elevations and hepatic fibrosis or even cirrhosis. These abnormalities were particularly striking in Type III patients but did not appear in any of the cases to be made worse by portal diversion. The observations in these 7 patients and in 6 more reported from other centers and followed up with personal examination indicate that portal diversion should have an important role in carefully selected cases of glycogen storage disease. Recent work was reviewed which suggests that the effects of portacaval shunt are due more to the rerouting of pancreatic hormones around the liver than to the bypassing of alimentary glucose.

Clotting Changes, Including Disseminated Intravascular Coagulation, during Rapid Renal-Homograft Rejection

Abstract One of two patients in whom early homograft rejection developed after renal transplantation had many antidonor antibodies before operation. By the measurement of gradients across intracorp...

Canine and human liver preservation for 6 to 18 hr by cold infusion.

SUMMARY Forty-one dog livers were preserved with cold, lactated Ringers, plasma, or intracellular (Collins) solutions. Consistent survival was obtained with all three solutions for 9 hr. After 18 hr, the plasma and Collins solutions permitted survival, with the Collins solution having a slight overall advantage. The method using Collins solution has been used to preserve seven human livers in Los Angeles, to transport the organs to Denver, and to transport them as orthotopic grafts from 6 hr, 45 min to 10 hr later.

Iatrogenic alterations of immunologic surveillance in man and their influence on malignancy.

The surveillance hypothesis of the immunologic control of malignancy has far-reaching clinical implications, of which two major and essentially opposite ones will be considered in this communication. The first concerns the growth of tumors in patients with surveillance failure. From the premise of Burnet (1957, 1963, 1967, 1970) and Thomas (1959), it could have been predicted and was (Thomas 1959, Starzl 1964b, Schwartz et al. 1966) that an increased incidence of de novo tumors would develop in people with naturally occurring immunologic deficiency diseases or in patients whose immune reactivity was deliberately depressed in order to permit their acceptance of organ homografts. The hazard of malignancy consequent to spontaneous deficiency is so well known (Page et al. 1963, Green et al. 1966, Dent et al. 1968, Huber 1968) that it will not be reviewed here. However, the analogous data in iatrogenically immunosuppressed transplant recipients that have accumulated since 1968 will be brought up to date. In addition, some comments will be made about the accidental transplantation of tumors to immunologically depressed humans and about the growth of metastases or residual tumor under these same conditions. The second general topic of this report, and a far more interesting one from a therapeutic point of view, is the expectation that the artificial endowment of immunologic surveillance in a patient whose natural defense system had failed to prevent neoplasia might then have an inhibitory or even destructive effect upon the established growth. Of course, a necessary condition to evaluate this latter possibility is the successful transplantation of immunologically competent tissue such as spleen or bone marrow while at the same time avoiding the kind of fatal graft-versus-host reaction that has defeated essentially all efforts at bone marrow grafting for whatever purpose except between a few HL-A identical siblings. As a first step toward this previously unattainable goal, suggestions will be made for the application to the bone marrow problem of immunosuppressive regimens that have been evolved in the successful transplantation of whole organs such as the kidney, liver, and heart.

CYCLOPHOSPHAMIDE AND HUMAN ORGAN TRANSPLANTATION

Abstract Cyclophosphamide, a drug that has not previously had an important role in whole-organ transplantation, was given as a primary immunosuppressant to one liver and eleven kidney recipients, in combination with prednisone and horse antilymphocyte globulin. One of the patients died despite good renal-graft function. Two kidneys from a common cadaveric donor failed. The other nine patients have excellent function of their homografts after 2-3 months. Cyclophosphamide was substituted for azathioprine in one hepatic and five renal recipients who were suspected of having liver toxicity from azathioprine 3 months to almost 8 years post-transplantation. Graft function was maintained after this change, and the evidence of liver injury subsided.

Thoracic duct fistula and renal transplantation.

Thoracic duct drainage (TDD) was established for 21 – 115 days in 40 kidney recipients with an average removal per patient day of 4.7 I lymph and 1.88 billion cells. Cellular and humoral immunity were depressed. TDD and immunosuppressive drugs were started at transplantation in 35 recipients of cross-match negative grafts. Although the results were better than in precedent non-TDD controls, eight patients rejected their grafts before a full TDD effect, and three of the eight developed predominantly anti-B lymphocyte cytotoxic antibodies which were probably responsible for positive cross-matches with their next donors. With continuing TDD, all eight patients had good initial function after early retransplantation. In five more “nontransplantable” patients with performed cytotoxic antibodies, TDD was started 30–56 days before transplantation. In these five pretreated patients, antibodies persisted with positive antidonor cross-matches. Hyperacute rejection occurred repeatedly in two patients with high anti-T (and anti-B) titers, but was surmounted in three patients with lower titers. From the clinical and immunologic data, we have concluded that TDD should be used for pretreatment of all cases with or without prior antibodies, and have suggested an adjustable management plan that takes into account new developments in antibody monitoring.

Obstructive Cholangitis Secondary to Mucus Secreted by a Solitary Papillary Bile Duct Tumor

A middle-aged woman had repeated episodes of common bile duct obstruction and cholangitis caused by profuse secretion of mucus by a solitary papillary tumor in the left hepatic duct. This complication usually occurs only with papillomatosis. The tumor initially appeared to be benign but subsequently was proven to be an invasive adenocarcinoma. Although the tumor recurred after surgical resection, her course remained uneventful without spread of the neoplasm for 3 yr.

Immunosuppression, liver injury, and hepatitis in renal, hepatic, and cardiac homograft recipients: with particular reference to the Australia antigen.

RENAL homograft recipients have been reported to have a high incidence of livu disease in the post-transplantation period.2f• 29. 31. 56. 65, 70 It was assumed that the immunosuppressive agents were responsible, either by their hepatotoxicity or because the consequent weakening of the host immune system permitted the frequent development of virus hepatitis. An accurate distinction between these two general possibilities was not feasible until recently. Then, with the description of tests which permitted identification of the hepatitis associated or Australia (Au) antigen, 7 , 9, 58 it became possible to deciSively study at least one variety of virus hepatitis in transplant recipients. In this communication, a series of observations related to the problem of hepatic damage with or without hepatitis in a large transplantation program will be presented. These observations will include: (1) The

SURVIVAL OF A HOMOLOGOUS PARATHYROID IMPLANT IN AN IMMUNOSUPPRESSED PATIENT

Abstract A patient who had undergone subtotal Summary parathyroidectomy while on chronic haemodialysis became severely hypocalcaemic after receiving a well-functioning cadaveric renal graft. After a homologous parathyroid implant, there was a biochemical improvement in the patient, and at biopsy 6 months later the parathyroid graft was histologically normal. 21 months after the implant, serum calcium and phosphorus remain normal without calcium supplementation.