C. W. Putnam

PORTACAVAL SHUNT IN HYPERLIPOPROTEINÆMIA

Abstract A 12-year-old girl with homozygous type-II hyperlipoproteinaemia, which was refractory to medical treatment, had significant improvement in her serum lipid abnormalities during a trial of parenteral hyperalimentation. Subsequently, end-to-side portacaval shunt caused striking reduction of the serum-cholesterol and low-density (beta) lipoprotein elevations, regression or disappearance of xanthomatous skin and tendinous lesions during the 61/2 months since operation, and relief of severe cardiac symptoms apparently as resorption occurred of xanthomatous deposits in the aortic valve and around the coronary arteries. Liver biopsy at 51/2 months showed several changes, including depletion of rough endoplasmic reticulum; this finding was consistent with the possibility that the portal diversion caused the desired therapeutic effects by inhibiting synthesis of hepatic cholesterol or low-density lipoprotein.A 12-year-old girl with homozygous type-II hyperlipoproteinaemia, which was refractory to medical treatment, had significant improvement in her serum lipid abnormalities during a trial of parenteral hyperalimentation. Subsequently, end-to-side portacaval shunt caused striking reduction of the serum-cholesterol and low-density (beta) lipoprotein elevations, regression or disappearance of xanthomatous skin and tendinous lesions during the 61/2 months since operation, and relief of severe cardiac symptoms apparently as resorption occurred of xanthomatous deposits in the aortic valve and around the coronary arteries. Liver biopsy at 51/2 months showed several changes, including depletion of rough endoplasmic reticulum; this finding was consistent with the possibility that the portal diversion caused the desired therapeutic effects by inhibiting synthesis of hepatic cholesterol or low-density lipoprotein.

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.

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

A decade followup in early cases of renal homotransplantation

Sixty-four consecutive patients underwent renal homotransplantation 10 1/6 to 11(1/2) years ago, 46 from related and 18 from nonrelated living donors. Thirty-six of these recipients were alive when this series was presented to the American Surgical Assocation in 1965. Now, nine years later, 26 (72%) of the 36 still survive, in 22 instances with function of their original grafts. The 10 who died in the interim tended to have subnormal renal function or graft failure. However, the actual causes of death included 2 or more examples each of myocardial infarction, hepatitis, or other systemic infections. The prognosis for achieving a one decade survival was not obviously related to HL-A tissue match. The best results were with related kidneys, within which subgroup 24 (52%) of the original recipients are still alive. However, there was no particular category of consanguineous donor that had a marked superiority. Only 2 of 18 nonrelated recipients are still alive. All 36 patients who were alive in 1965 had a biopsy of their renal homograft. Kidneys that were destined to function for a decade tended to have relatively minor histopathologic abnormalities. If serious glomerular lesions were found, the outlook for long graft survival was grave. Vascular lesions had a somewhat less serious import. Mononuclear cell infiltration, tubular atrophy, and interstitial fibrosis proved prognostically to be the least significant. Long-term followup of these early cases has shown the durability of chronic renal homografts, particularly if these are from related donors, and has demonstrated the very high degree of rehabilitation that could be achieved even in the early days of renal homotransplantation.