Groth, CG

Halgrimson, CG

Husberg, B

Kashiwagi, N

Penn, I

Putnam, CW

Starzl, TE

English

Name not available

Notes on some immunosuppressive agents and their use in human liver transplant recipients

D-Scholarship@Pitt

Notes on Some Immunosuppressive Agents and Their Use in Human Liver Transplant Recipients C. G. Groth, N. Kashiwagi, B. Husberg, C. W. Putnam, C. G. Halgrimson, I. Penn, T. E. Starzl In this presentation, three aspects of immunosuppressive treatment will be dealt with: first, recent experience with the use of cyclophosphamide in whole organ graft recipients; second, some interrelationships between the major immunosuppressive drugs and the liver; and finally, the im-munosuppression used recently for hepatic transplant recipients. General Experience with Cyclophosphamide Cyclophosphamide has long been known to be an extremely effective immunosup-pressant in rodents. In humans, the drug has been used extensively for cancer chemo-therapy and for the treatment of auto-immune disorders. Several years ago cyclo-phosphamide was introduced by Santos and his associates into to the field of clini-cal bone marrow grafting. There are prob-ably tho reasons why cyclophosphamide has not been applied to clinical whole organ transplantation until recently. First, This work was supported by research grants from the Veterans Aministration, by grants RR-OOOSI and RR-00069 from the general cli-nical research centers program of the Division of Research Resources, National Institutes of Health, and by grants AI-AM-08898, Am-07772, and HE-091l0 of the United States Public Health Service. a few trials in human kidney transplan-tation almost a decade ago were complica-ted by severe drug toxicity. Second, cyclo-phosphamide was found not to prolong renal homograft survival in dogs. Although the latter findings were due to a species peculiarity, they were apparently extra-polated to the human situation. For 16 months, cyclophosphamide has been used to replace azathioprine in a se-ries of whole organ graft recipients in Denver [71. Prednisone and antilymphocyte globulin (ALG) has been administered as previously described. The daily dose of cyclophosphamide tolerated without undue toxicity has been 0.5-1 mg/kg or approxi-mately half of that usually tolerated of azathioprine. Using such doses, bone mar-row depression was observed about as frequently as with the old triple drug regi-men containing azathioprine. Other side effects from cyclophosphamide were rare and consisted mainly of gastrointestinal symptoms. In renal homograft recipients, the results with cyclophosphamide have been very similar to those achieved previously with azathioprine. With a follow-up of 4 to 16 months, the kidney survival among 39 recipients of related grafts is 82 010 and the patient survival is 90 0/0. In a group of 36 recipients of non-related cadaveric kidneys, ." 222 73 % have functioning grafts and 78 % of the patients are alive. Approximately half of the latter patients were retransplanted for the second to fifth time, and in these cases, the kidney survival was only 59 %. In contrast, the patients undergoing pri-mary cadaveric renal transplantation have a kidney survival exceeding 80 %. Kidney recipients have been treated with cyclophosphamide rather than azathioprine for as long as Ph years. However, it is our present practice to use cyclophosphamide for approximately 2 months and then switch to azathioprine. This will be described in the last section of this article. Immunosuppression and the Liver Hepatotoxicity is obViously an undesirable feature of any drug to be used in liver transplant recipients. Furthermore, if the activation or the degradation of the drug occurs mainly in the liver, this will have special implications in such patients. Azathioprine may be hepatotoxic in hu-mans. In controlled studies in animals, the usual signs of toxicity are rises in serum transaminases and the alkaline phosphatase [8], although in one study an increase in bilirubin was also noted [1]. In humans, azathioprine is by no means as hepatotoxic as in dogs. Yet, there have been a number of cases in which azathioprine may have played a role in causing liver injury after renal transplantation [9,10]. Administration of the main metabolite of azathioprine, 6-mercaptopurine, has also been shown to cause liver damage, as for instance, when used in leukemic patients [4]. Although cyclophosphamide, given in very high doses, has been found to cause liver damage in rodents, patients have been treated with the drug for several years without evidence of significant liver tox-icity [5]. In the Denver kidney transplant Notes on Some Imr.1Unosuppressive Agents recipients, the incidence of liver dysfunc-tion was similar whether azathioprine or cyclophosphamide was used [7], but the numerous factors involved make an eva-luation of the effect of the individual drugs difficult. Corticosteroids, including prednisone, may cause hepatomegaly and fatty degene-ration of the liver in animals, but the incidence of this complication in humans under prolonged treatment is difficult to determine. There is no evidence that ALG has a significant hepatotoxic effect [2]. The reverse question concerning the ef-fect of the liver on the metabolism of immunosuppressive drugs, might also be of consequence in hepatic transplant recip-ients. The way in which this factor could influence the daily doses of azathioprine in both dogs and man has been speculated upon [6, 9]; the same considerations apply to cyclophosphamide. Cyclophosphamide becomes an active immunosuppressive agent first after an in vivo activation pro-cess in which the liver plays an important role [3]. Consequently, the drug might be-come less activated and thus decreasingly immunosuppressive if the liver function deteriorates. To date, there is no direct evidence from experience with hepatic transplantation that this occurs, but the possibility will have to be borne in mind in future cases. Alternatively, since the degradation and detoxification of azathioprine, cyclophos-phamide, and prednisone occurs mainly in the liver, it could be suggested that the effe,::t of the drugs would become enhanced with liver dysfunction. In fact, some evi-dence has been adduced that renal trans-plant recipients require reduced immuno-suppression, particularly of azathioprine, when afflicted with severe liver dysfunc-tion. However, the practical implications of the described interactions between the im-~ otes on Some Immunosuppressive Agents I\unosuppressive drugs and the liver for tie care of the hepatic transplant recipient ~main obscure. 'resent Practices of Immunosuppression Immunosuppression in hepatic transplant f""cipients has been founded on experience ~Ecumulated in large series of renal trans-rlant patients. Before 1966, treatment was ,ith azathioprine and prednisone and no long term survivals were obtained. In the first triple drug regimen intro-duced in 1966, azathioprine was given con-tinuously in the maximum dose tolerated Nithout leukopenia, the prednisone dose was adjusted according to the vigor of rejection, and ALG was given in a standard ::lose for the first 2-4 postoperative months. [ntravenous Actinomycin C and local graft ~radiation were occasionally used as sup-plemental immunosuppressive measures iuring homograft rejection. In many cases, the course of ALG was prolonged to several months or even years. In addition, the practice was introduced of giving large doses of intravenous corti-costeroids, first prednisone and later methyl-prednisone, for rejection or sometimes pro-phylactically. With this program, one year survival of 25 Ofo to 30 Ofo was achieved from 1967 to 1970. In the last 16 months, azathioprine has been replaced with cyclophosphamide during the initial postoperative treatment. In the References: 1. Aronsen, K. r., B. Hl<sberg and B. Pilll: Immunosuppressive treatment in non-trans-planted dogs. Acta chir. scand. 135; 475, 1969 223 first liver transplant patients on this regi-men, the cyclophosphamide was continued for 9 months. More recently, the protocol has been adjusted in that cyclophosphamide is now given only for the first 1 to 2 months, following which a change is made to azathio-prine. The rationale for such a successive use of two cytotoxic agents lies in their dissimilarity of structure and of action. Cyclophosphamide is an alkylating agent and azathioprine is a purine analogue. The two drugs are thought to act at different stages of the cell cycle and might thus have a reinforcing effect when given serially. The consecutive use of drugs in order to achieve "longitudinal synergism" in con-trast to the synergism of simultaneously administered agents is common in cancer chemotherapy. With this new practice, we have limited ALG to the first few post-operative months. A total of 15 recipients of orthotopic hepatic grafts have now been treated with a drug regimen including cyclophosphamide. Six of the patients are alive and well with a follow-up of 2-16 months. Summary Recent experience with the use of cyclo-phosphamide in whole organ graft recipients is described. The interrelationship between the major immunosuppressive drugs and the liver is discussed. Recent practice for clinical immunosuppression is outlined. 2. Aronsen, K. F., B. Husberg, 7. Hagerstrand, 7. C. Norden and B. Pihl: Enzyme histo-chemical studies of the liver during im-munosuppressive treatment in dogs. Acta chir. scand. 136; 529, 1970 K~ -:: I .• ~l-,. ... ~ ~ T • , . ~ _ .. ;.1 ,r, ,-224 3. Brock. N .• R. Cross. H. 7. Hohorst. H. O. Klein and B. Schneider: Activation of cyclo-phosphamide in man and animals. Cancer 27; 1512. 1971 4. Einhorn. M. and l. Davidsohn: Hepatotox-icity of mercaptopurine. JAMA 188; B02. 1964 5. Calle. P.: EinfluB der Endoxan-Langzeitbe-handlung auf die Leberfunktion. Wien. Klin. Wschr. 77; 644. 1965 6. Mitchell. C. C .• A. L. W. F. Eddleston. M. C. M. Smith and R. Williams: Serum immuno-suppressive activity due to azathioprine and its relation to hepatic function after liver transplantation. Lancet 1; 1196. 1970 7. StarzI. T. E .• C. W. Putnam. C. C. Halgrim-son. C. P. Schroter. C. Martineau. B. Lau-nois. 7. L. Corman. I. Penn. A. S. Booth 7r .• K. A. Porter and C. C. Croth: Cyclophos-Notes on Some Immunosuppressive Agents phamide and whole organ transplantation in humans. Surg. Cynec. Obstet. 133; 9B1. 1971 B. StarzI. T. E .• T. L. Marchioro. P. D. Taylor, T. D. Faris. T. 7. Herrman. C. Hlad and W. R. Waddell: Factors determining short and long term survival after orthotopic liver homotransplantation in the dog. Sur-gery 58; 131. 1965 9. Starzl, T. E. and C. W. Putnam: Experience in Hepatic Transplantation. Philadelphia, Saunders. 1969 10. Torisu, M. Yokoyama. H. Amemia. P. F. Kohler. C. Schroter, C. Martmeau. l. Penn. W. Palmer, C. C. Halgrimson, C. W. Putnam and T. E. Starz!: Immunosuppression, liver injury and hepatitis in renal. hepatic. and cardiac homograft recipients: With parti-cular reference to Australia antigen. Ann. Surg. 174; 620, 1971 

http://d-scholarship.pitt.edu/3679/1/31735062108984.pdf

Notes on some immunosuppressive agents and their use in human liver transplant recipients

Abstract

Similar works

Full text

Available Versions

Name not available

Name not available

D-Scholarship@Pitt