SEMINARS IN LIVER DISEASE-VOL.
12, NO. 1, 1992
Maintenance lmmunosuppression After Liver Transplantat ion JOHN R. LAKE, M.D., JOHN P. ROBERTS, M.D., and NANCY L. ASCHER, M.D., Ph.D.
From the Department of Medicine and Surgery and Liver Transplantation Program, University of California, Sun Francisco, Sun Francisco, California. Reprint requests: Dr. Lake, Liver Transplant Services, University of California at San Francisco, 533 Parnassus, San Francisco, CA 94143-0780.
HISTORY Many of the immunosuppressive regimens and agents currently used in liver transplant recipients reflect regimens and agents developed for renal transplantation. The earliest combination regimen used in liver transplantation was a combination of azathioprine and prednisone. This regimen in the 1970s yielded the first long-term survival of hepatic allografts. However, graft loss was relatively high, and, moreover, relatively high doses of prednisone were necessary to maintain immunosuppression in these patients. These high doses of prednisone led to significant long-term morbidity. The introduction of cyclosporine into the immunosuppressive regimen of liver allograft recipients revolutionalized our approach to immuno~uppression.~ Foremost, the introduction of cyclosporine into the immunosuppressive regimen has led to the marked improvement in graft and patient survival that has been seen throughout the 1980s and importantly also paved the way for the development of new immunosuppressive strategies, such as synergistic regimens and sequential therapy, which has already contributed to decreased morbidity related to the immunosuppressive regimens. In the 1990s we will see the introduction of an even greater number of agents. This should allow for the tailoring of immunosuppressive regimens to the individual patient. For example, it is anticipated that, although patients may receive relatively potent immunosuppressive regimens during the immediate post-transplant period when the risk of rejection is highest, those patients who do not develop rejection will be quickly switched to alternative regimens, which will provide less immunosuppression but will likewise decrease the morbidity of the immunosuppressive agents. Alternatively, those patients who demonstrate a greater number or more severe episodes of rejection will be switched to a more potent agent, or agents, that, although running the risk of greater side effects, nonetheless, will, it is hoped, provide adequate immunosuppression and thereby prevent graft loss. For historical purposes, it is important to mention a variety of strategies that were once tried but have largely been abandoned due to either a high frequency of complications or poor outcome. These include thoracic duct drainage and total lymphoid irradiation; although lym-
Copyright O 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
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Liver transplantation evolved throughout the 1980s from a therapeutic modality only for those with the most advanced liver failure to therapy for many patients with end-stage liver disease and complications sufficiently severe to markedly impair their quality of life.'-7 In 1990, more than 2500 liver transplants were performed throughout this country and this is a testimony to the improved survival rates currently seen with the procedure. The most dramatic change in liver transplantation throughout the 1980s was the improvement in survival. One-year survival rates were only approximately 30% in 1980 and currently many of the better programs are reporting I-year survival rates of better than 80%. The development of better regimens for immunosuppression and improved immunosuppressive agents, particularly cyclosporine, has been responsible for a substantial part ~ these current survival of this increase in s ~ r v i v a l . ' .With rates, the challenges of the 1990s will be focused on the development of new immunosuppressive agents and immunosuppressive regimens that will lower morbidity and also the costs of liver transplantation. It is also anticipated that some of the advances in the 1990s will include a better clarification of the synergy between the various immunosuppressive agents available, as well as the tailoring of immunosuppressive regimens to the individual clinical scenario. This article will largely focus on the agents used for immunosuppression, both those that are currently in use as well as some of the newer agents that we anticipate will be available within the next several years. We also will focus on the development of immunosuppressive regimens, since none of these agents is used alone. To understand immunosuppression in liver transplantation, it is important to understand the mechanisms involved in liver transplant rejection. These mechanisms are covered elsewhere in this issue of Seminars, but we will allude to them in our discussion of the mechanism of action for the individual agents.
phoid irradiation occasionally tries to make a reappearance.
AGENTS USED FOR IMMUNOSUPPRESSION IN LIVER ALLOGRAFT RECIPIENTS Corticosteroids Corticosteroids (prednisone and prednisolone) have been used as immunosuppressive agents since the earliest days of transplantation.'-8 Even today, almost every regimen incudes corticosteroids as a major component. Corticosteroids are used not only for maintenance immunosuppression, but also are used for treatment of established rejection as well. Corticosteroids act at a variety of levels in a cascade of immunologic events that lead to rejection. For example, corticosteroids appear to block the production of interleukin- 1 (IL- I ) . This inhibition of IL-1 production leads to impaired activation of the T-cell and its subsequent production of IL-2,9 which is important for clonal expansion in response to HLA class I1 antigens. Corticosteroids also appear to be cytotoxic to alloactivated lymphocytes.1° In addition, corticosteroids decrease HLA class I1 antigen expression," inhibit the inflammatory response of other cells (such as eosinophils), and prevent the migration of inflammatory cells into damaged tissues. Finally, corticosteroids also inhibit monocyte transformation into macrophages" and may inhibit the effects of other antigen-presenting cells as well. Corticosteroids are often given as a bolus intravenously either immediately prior to transplant surgery, during surgery, or immediately after surgery. Relatively high doses of prednisone or prednisolone are used during the early post-transplant period and the dose is rapidly tapered to the desired maintenance level. Generally, the dose is 5 to 10 mg of prednisone per day in adults and 0.1 to 0.2 mglkg per day in children. The side effects of corticosteroids are well known and include fluid retention, hypertension, hyperglycemia, impaired wound healing, myopathy, growth retardation in children, aseptic necrosis of the hip, cataracts, and decreased bone mineralization. It is these latter longterm side effects that are the most troubling and most disabling of the corticosteroids, and it is for that reason that a number of programs have attempted to develop regimens that eventually remove corticosteroids from the patient's immunosuppression regimen.
Azathioprine As alluded to earlier, azathioprine was part of the original regimen used for liver allograft immunosuppression and for years was a mainstay for immunosuppression of liver transplant recipients. More recently, azathioprine largely has been used as part of the so-called triple immunosuppressive regimen in combination with cyclosporine and prednisone. This immunosuppressive regimen likely represents the most common regimen currently used for immunosuppression of the allograft recip-
12, NUMBER I , 1992
ient. Azathioprine represents a modification of the parent compound, 6-mercaptopurine (6-MP), and is converted in vivo to 6-MP, which represents the active compound. Azathioprine is an antimetabolite and exerts its immunosuppressive effects through purine metabolism, and inhibiting cell division. Consequently, the most rapidly dividing cells in the body are most sensitive to this agent. Currently, azathioprine is used primarily as a steroidsparing agent, in combination with prednisone and cyclosporine. It can be administered either intravenously or by mouth and the dosages used are 1 to 2 mglkglday, generally given as a single dose. The side effects of this agent are directly related to its effect on cell proliferation and thus the cells that are most rapidly dividing are most likely to be affected. The major side effect of azathioprine is bone marrow suppression. In particular, azathioprine has its most significant effects on white blood cells. This effect is dose related and can be easily reversed either by temporary discontinuation or, more often, by decreasing the dose of azathioprine that is used. Azathioprine also has been shown to produce hepatotoxicity, which, in its earliest stages, resembles an ischemic insult to the liver. This may reflect a primary effect of azathioprine on central vein endothelial cells. Early on, azathioprine hepatotoxicity is manifested clinically as cholestasis and an increase in serum transaminase and alkaline phosphatase activities.13 In its later stages, it can lead to veno-occlusive disease, as has been described in renal transplant recipients.14 This effect of azathioprine appears to be idiosyncratic. The long-term side effects of azathioprine include an increase risk of malignancy and susceptibility to opportunistic infections.
Cyclosporine Cyclosporine represents the major advance in immunosuppression that occurred in the late 1970s and early 1980s." This agent has become a cornerstone of most immunosuppressive regimens currently in use today.' Cyclosporine is a lipophilic endecapeptide that comes both as an intravenous and oral preparation, either as an oil-based liquid or in capsule form.16 When given orally, cyclosporine is primarily absorbed in the small intestine. The bioavailability of orally administered agent is low, on the order of 10 to 30%.17 Since it is very lipophilic and comes as an oil-based preparation, it requires bile salts for maximal absorption. Cyclosporine absorption is inhibited by a variety of clinical conditions, including biliary diversion (such as T-tube drainage), diarrhea, steatorrhea, decreased gastric emptying, and short gut. In pediatric patients, the bioavailability of cyclosporine correlates directly with the length of the bowel in the individual patient. To facilitate the absorption of cyclosporine in a patient with biliary diversion, bile is refed, serving both to provide the bile salts for cyclosporine absorption and also to complete the small enterohepatic circulation of cyclosporine. In addition, the T-tube is capped as early as possible following transplantation to reestablish the normal biliary conduit.18 Cyclosporine has a measured half-life serum of 4 to 12 hours in most patients.'' Cyclosporine is metabolized
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by a variety of metabolic pathways, including hydroxtransplant appear to be at increased risk for post-transylation, demethylation, reduction, and c a r b o ~ y l a t i o n . ~ ~plant renal dysfunction, but this fails to explain all the To a large extent, cyclosporine metabolism is via the cases of cyclosporine nephrotoxicity that are seen. It is controversial as to whether cyclosporine nephrotoxicity P450 system2' and thus inducers or inhibitors of P450 is progressive in liver allograft recipients, as was prevican have dramatic effects on cyclosporine metabolism and blood cyclosporine levels. Agents that commonly afously shown for heart allograft recipient^.^^ If it is profect cyclosporine metabolism include diphenylhydangressive, it is very slowly progressive and it is extremely toin, phenobarbital, and r i f a m ~ i n . ~Cyclosporine ~,?~ is unusual that patients with initially stable renal funcexcreted into bile largely as metabolites, but there is a tion progress to require dialysis. Equally important is small enterohepatic circulation of the parent compound whether chronic cyclosporine nephrotoxicity is reversible with discontinuation of cyclosporine. Histologically, as well. Cyclosporine circulates bound to a variety of one can demonstrate interstitial fibrosis and vascular serum lipoprotein^.^^ Approximately half of cyclosporine in the bloodstream is attached to red blood cells and sclerosis in the kidney with chronic cyclosporine adminwhite blood cells.25 ' cyclosporine in paistration. In one s t ~ d y , ~stopping The immunologic effects of cyclosporine represent tients with a decrease in GFR of greater than 50% after 2 years had no effect on GFR and precipitated episodes a relatively specific effect on T lymphocyte^.^^ Intracellularly, cyclosporine binds to a cytosolic protein2' and of rejection in 6 of 12 of these patients, who previously had not had a rejection. In addition to the decrease in acts to inhibit T-cell proliferation by blocking transcripGFR, cyclosporine can also produce a type IV renal tution of IL-2 mRNA, leading to decreased IL-2 prod ~ c t i o nand ~ ~secretion by T cell^.'^.^'^^^ In the absence bular acidosis (RTA) with occasionally marked increases of IL-2 production, the clonal expansion of T lymphoin serum potassium concentration^.^^ This apparent RTA responds well to mineralocorticoid administration. cytes is inhibited. These effects of cyclosporine appear Cyclosporine is associated with a number of other to be relatively specific for T-helper cells. Besides its side effects,38 including hypertension, which is usually effect on 11-2 production, cyclosporine also inhibits the easily controlled by medication^:'^ hypercholesterolsecretion of a variety of lymphokines, including gamma interferon. l 6 emia, hypertrichosis, gingival h y p e r p l a ~ i a ,gout, ~ ~ and hepatotoxicity, which is usually manifested by minor inCyclosporine is absorbed poorly from the gastroincreases in serum liver enzymes and which responds simtestinal tract in the early post-transplant period. Thus, ply to lowering the cyclosporine d ~ s e . ~ ' , ~ ' many programs administer cyclosporine intravenously Central nervous system (CNS) toxicity is one of the during the immediate post-transplant period at a dose of more disabling side effects of c y ~ l o s p o r i n e .Neuro~~.~ 2 to 5 mglkglday often given in a continuous infusion. logic signs and symptoms seen following transplantation Oral cyclosporine is begun at a dose of 10 to 20 mglkgl include headache, sleep disturbance, psychosis, encephday in divided doses once gastrointestinal tract function alopathy, seizures, tremors, myoclonus, cortical blindreturns. Subsequent dosing of cyclosporine is adjusted n e ~ s , ~hemiplegias, ' spastic quadraparases, and coma.44 according to blood levels. Currently, two methods exist One of the more common and specific manifestations of for cyclosporine blood level determination: high-perforcyclosporine neurotoxicity that we have seen is a speech mance liquid chromotography (HPLC)3' and radioimapraxia. The etiology of the cyclosporine-associated munoassay (RIA). The older polyclonal RIA assay meaneurotoxicity is unclear, but patients with decreased sesured both parent compound and metabolites. However, rum magnesium concentration^^^ and decreased serum the newer monoclonal RIA available measures only parcholesterol levels44appear to be at increased risk for this ent compound and has an advantage over HPLC (which cyclosporine-associated neurotoxicity. CNS symptoms also only measures parent compound) by being techniare often associated with dramatic changes seen by comcally easier." The three most common clinical situations puted tomography or magnetic resonance imaging of the that lead to difficulty obtaining adequate cyclosporine brain and vary from minor white matter changes to hemlevels include cholestasis because of the impaired delivery of bile salts to the intestine and consequently poor orrhagic infarcts that reverse with time. While most patients with cyclosporine neurotoxicity completely recyclosporine absorption, biliary diversion, and P450 accover, some are left with residual gait, visual, or speech tivation. Cyclosporine is stored in body fat so that patients with increased body fat often take longer to disturbance^.^ achieve adequate cyclosporine blood levels than those Cyclosporine administration is also associated with with less body fat. malignan~ies;~' in particular, B-cell lymphoma. Many of these lymphomas are associated with Epstein-Barr virus The most important side effect of cyclosporine is infection and may respond to lowering the immunonephrotoxi~ity.~'-~~ Acutely, cyclosporine nephrotoxicity suppression and intravenous administration of high doses is manifested by a fall in urine output, impaired natruof a c y ~ l o v i r . ~ ~ resis, and a fall in glomerular filtration rate (GFR). This reflects the acute effects of cyclosporine on intrarenal Antilymphocyte Preparations blood flow and is rapidly reversed by a decrease in cyclosporine dosage. Virtually all patients develop some Currently, there are two forms of antilymphocyte decrease in GFR associated with cyclosporine adminispreparations available in this country: a monoclonal antration, which can vary from 10 to 70%. Individual sustibody directed against CD3-baring lymphocytes (OKT3) ceptibility to the nephrotoxic effects of cyclosporine is and polyclonal preparations generated by immunizing quite variable. Patients with impaired renal function pre-
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animals with various lymphocyte preparations (antithymocyte globulin or Minnesota antilymphoblast globulin [MALG]). Both of these have been incorporated into maintenance immunosuppression protocols, termed sequential therapy. In these protocols, patients are treated for relatively brief periods of time (less than 2 weeks) with one of these preparations in the immediate posttransplant period. The rationale for these regimens will be discussed later. Both of these agents are also used for treatment of established rejection. Polyclonal preparations suffer by being relatively non~elective.~' Thus, they tend to decrease total white blood counts and platelet counts as well. These preparations also require administration through a central venous catheter and have been reported to cause allergic skin reactions as well as serum sickness.50 0 K T 3 is given via peripheral intravenous access. 0 K T 3 is specific in its effects against CD3-baring T lymphocytes and thus does not affect total white blood counts or platelet counts. There is, however, a dramatic first-dose reaction that can be seen and consists of fevers, chills, hypotension, and occasionally pulmonary edema and bronchos p a ~ m . It~ 'appears that the severity of this reaction can be decreased by pretreatment with corticosteroids. These effects lessen with each successful dose and may be related to the release of lymphokines as a result of 0 K T 3 administration. Other side effects of 0 K T 3 include diarrhea, and an aseptic meningitis, which is typically seen on days 4 to 5 of 0 K T 3 administration and manifested by headache and neck stiffness. The use of 0 K T 3 is limited by the development of antimurine antibodies, since 0 K T 3 is a mouse monoclonal antibody.52Low titers of antibody can be overcome by increasing the dose of OKT3. Both preparations also have been associated with an increased risk of cytomegalovirus infections when used as treatment for established rejection episodes." 0 K T 3 also has been associated with an increased risk of B-cell lymphoma.48
12, NUMBER 1 , 1992
prine, and prednisone. The theory behind adding azathioprine to prednisone and cyclosporine was that this would allow utilization of lower doses of each individual drug and, it was hoped, lower long-term side effects. This regimen also has been associated with a lower incidence of retransplantation and chronic rejection. The arguments against triple therapy include that it represents increased immunosuppression and thus the risk of opportunistic infections or malignancies may be higher. Finally, because of the effect of intravenous cyclosporine on urine output and renal function in the early transplant period, sequential protocols have been developed.50 Patients undergoing liver transplantation are often very edematous and require relatively large quantities of blood products during the transplant procedure. Thus, patients will undergo marked fluid shifts during the immediate post-transplant procedure and commonly patients require substantial diureses. The use of intravenous cyclosporine impairs the action of diuretics so that the principal advantage of sequential therapy is to avoid the use of intravenous cyclosporinc and to allow beginning cyclosporine only once renal function has returned to normal. A few programs, including our own, utilize quadruple immunosuppression (sequential therapy) as our standard maintenance immunosuppression protocol and many use such a protocol for patients with impaired renal function pretransplant. Both MALG and 0 K T 3 have been incorporated into sequential regimen^.^^.^^ It is unclear whether these regimens lead to less rejection overall, but they certainly appear to delay the onset of rejection by 1 to 2 weeks in these patient^.""'^^^ Most sequential regimens delay the administration of cyclosporine until day 5 to day 14 following transplant. In addition, whether avoidance of intravenous cyclosporine will lead to better long-term renal function is unclear. The criticism of the use of antilymphocyte preparations for maintenance immunosuppression has been that this could lead to an increased frequency of post-transplant malignancy and opportunistic infections. This, however, does not appear to be the case in the published series.5b
COMBINATION THERAPY Every regimen currently employed for liver allograft immunosuppression represents a combination of these individual agents. It is difficult to compare the relative efficacy and side effects of the various regimens, since there have been few randomized trials that have compared the different regimens head to head. The earliest regimen employed was azathioprine and prednisone with or without an antilymphocyte preparation. Although successful, this regimen was associated with a relatively high incidence of graft loss secondary to refractory allograft rejection and also required relatively high doses of prednisone (10 mg or greater in adults) with significant long-term corticosteroid toxicity. Later regimens utilized cyclosporine and prednisone.j4 With this regimen, there was a decreased incidence of graft loss and improved survival, but still this regimen required relatively high doses of cyclosporine and prednisone with its subsequent long-term toxicity. This led to the development of so-called triple therapy regimens, which included cyclosporine, azathio-
NEW AGENTS FOR IMMUNOSUPPRESSION There are a number of immunosuppressive agents currently undergoing testing in this country. Most are still at the stage of laboratory and animal testing and will not be discussed here. Two agents, however, FK 506 and RS-61443, are currently in clinical testing and the preliminary results with these agents will be discussed. FK 506, a very promising drug, is a macrolide produced by a Streptomyces species that was discovered in Japan.s9 It appears to have a similar mechanism of immunosuppressive action to cyclosporine. Like cyclosporine, it also inhibits IL-2 synthesis by lymphocytes and may decrease the expression IL-2 receptors on activated lymphocytes as well. Although similar in action to cyclosporine, FK 506 is 50 to 100 times more potent by weight. In vitro, FK 506 has been used to prevent allograft rejection in a variety of animal models, including
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heart, renal, and liver a l l ~ g r a f t s . ~ There ~ - ' ~ is also in vitro information that FK 506 can be synergistic with cy~losporine.~~ Clinical studies of FK 506 began at the University of Pittsburgh in 198864and currently over 1000 patients have been treated at that institution thus far. The results, as recently reported at an international symposium on FK 506 in Pittsburgh, suggest that in their hands, FK 506 produces better graft and patient survival and lower costs of transplantation. Our own experience as part of the United States multicenter, open-label, randomized trial indicates that FK 506, indeed, appears to be a potent immunosuppressive drug that produces results comparable to that of cyclosporine, in terms of rejection incidence and graft and patient survival. The initial hope was that FK 506 would be associated with fewer side effects and, in particular, less nephrotoxicity. However, it appears that FK 506 has a similar side effect profile to cyclosporine. In particular, FK 506 has both an acute and probably chronic nephrotoxicity. The acute nephrotoxic effects of FK 506 are very similar to cyclosporine in that they are greater with intravenous administration, they are dose-dependent, and are reversible with dose reduction. FK 506 does have a substantially lower incidence of hypertension and does not produce hypertrichosis. It also exhibits neurotoxicity and a CNS syndrome similar to cyclosporine has been seen with FK 506. FK 506 can also lead to glucose intolerance and in high doses causes diarrhea and poor appetite. Thus far, FK 506 has generally been used in combination with prednisone. However, a number of patients treated at the University of Pittsburgh have now been taken off prednisone and are currently managed with FK 506 as the sole immunosuppressive agent. FK 506 also may be effective as a rescue agent for patients with refractory rejection.64 RS-61443 is an ester of the parent compound, mycophenolic acid, which has a mechanism of immunosuppressive action that is distinct from cyclosporine or FK 506. RS-61443 is rapidly hydrolyzed following absorption by cytosolic esterases to yield the parent compound. LymphoRS-61443 is an inhibitor of purine ~ynthesis.'~ cytes, unlike most other cell types, possess a single pathway for purine synthesis and thus inhibition of this pathway will lead to a selective inhibition of lymphocyte proliferation. Although inhibition of T- and B-cell proliferation is the primary effect of the drug, it appears that the immunologic effects of this agent may be more complex. RS-61443 has been used successfully for immunosuppression in a variety of animal allograft models, including heart, pancreatic islets, and renal transplants. Clinical studies with RS-61443 as an immunosuppressive agent in transplantation are just beginning in this country. Its use to date has been largely as a rescue agent for patients either intolerant of cyclosporine or with refractory rejection. Primary trials in both kidney and liver allograft recipients are planned. The toxicity of this drug is minor. Despite its similar mechanism of action to azathioprine, RS-61443 in therapeutic doses does not lead to bone marrow suppression, nor does it exhibit nephrotoxicity or hypertension. The only side effects noted thus far include skin rash and
minor gastrointestinal upset. There already exists longterm follow-up information on the safety of the parent compound, mycophenolic acid. A cohort of patients with psoriasis have now been treated for almost 20 years with mycophenolic acid with essentially no serious long-term sequelae, although 12% of the patients had uncomplicated episodes of herpes zoster. The incidence of malignancy in that cohort does not appear to be different from the cancer incidence in the United States as a whole.65 How RS-61443 will be used as an immunosuppressive agent in maintenance protocols is unclear. It would seem logical to replace azathioprine with RS-61443 in a triple drug regimen that includes cyclosporine and prednisone.
''
THE FUTURE With the expanding number of agents available for immunosuppression in the near future, tailoring of immunosuppression for the individual patient will become a priority. Decisions as to what regimen and agents should be used will likely be based on pretransplant renal function, the presence or absence of rejection post-transplant, and severity of side effects that occur in an individual patient. Goals of new immunosuppressive agents and regimens certainly will include improved graft and patient survival, but patient morbidity and financial costs will play an increasing role in decision-making regarding choices for maintenance immunosuppression in the future.
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crease the expression of B,-microglobulin and histocompatibility antigens on human peripheral blood lymphocytes in vitro. Clin Exp Immunol44:239-246, 1981. Rinehart JJ, Wuest D, Ackerman GA: Corticosteroid alteration of human monocyte to macrophage differentiation. J Immunol 129:1436-1440, 1982. Sterneck M, Wiesner R, Ascher N, et al: Azathioprine hepatoxicity after liver transplantation. Hepatology 14:800-810, 1991. Read AE, Wiesner RH, LaBrecque DR, et al: Hepatic venoocclusive disease associated with renal transplantation and azathioprine therapy. Ann Intern Med 104:651-655, 1986. Calne RY, White DJG, Thiru S, et al: Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 2:1323-1327, 1978. Borel JF, Feurer C , Magnte C , et al: Effects of the new antilymphocytic peptide cyclosporin A in animals. Immunology 32:1017-1025, 1977. Burckart GJ, Venkataramanan R, Ptachcinski RJ, et al: Cyclosporine absorption following orthotopic liver transplantation. J Clin Pharmacol 26:647-65 1, 1986. Tredger JM, Naomumov NV, Steward CM, et al: Influence of biliary t-tube clamping on cyclosporine pharmacokinetics in liver transplant recipients. Transplant Proc 20(Suppl 2):5 12515, 1988. Ptachcinski RJ, Venkataramanan R, Burckart GJ: Clinical pharmacokinetics of cyclosporin. Clin Pharmacokinet 11: 107132, 1986. Maurer G , Loosli HR, Schreier E, et al: Disposition of cyclosporine in several animal species and man. I. Structural elucidation of its metabolites. Drug Metab Dispos 12:120-26, 1984. Bertault-Peres P, Bonfils C , Fabre G, et al: Metabolism of cyclosporin A. 11. Implication of the macrolide antibiotic inducible cytochrome P-450 3c from rabbit liver microsomes. Drug Metab Dispos 15:391-398, 1987. Keown PA, Laupacis A, Carruthers G, et al: Interaction between phenytoin and cyclosporine following organ transplantation. Transplantation 38:304-306, 1984. Van Buren D, Wideman CA, Ried M, et al: The antagonistic effect of rifampin upon cyclosporine bioavailability. Transplant Proc 16: 1642-1645, 1984. Gurecki J , Warty V, Sanghvi A: The transport of cyclosporine in association with plasma lipoproteins in heart and liver transplant patients. Transplant Proc 17: 1997-2002, 1985. Lemaire M, Tillement JP. Role of lipoproteins and erythrocytes in the in vitro binding and distribution of cyclosporin A in the blood. J Pharm Pharmacol 34:715-718, 1982. Lillehoj HS, Malek TR, Shevach EM: Differential effect of cyclosporin A on the expression of T and B lymphocyte activation antigens. J Immunol l33:244-250, 1984. Quesniaux VFJ, Schreier MH, Wenger RM, et al: Cyclophilin binds to the region of cyclosporine involved in its immunosuppressive activity. Eur J Immunol 17:1359-1365, 1987. Bunjes D, Hardt C , Rollinghoff M, et al: Cyclosporin A mediates immunosuppression of primary cytotoxic T cell responses by impairing the release of interleukin I and interleukin 2. Eur J Immunol 11:657-661, 198 1. Bickel M, Tsuda H, Amstad P, et al: Differential regulation of colony-stimulating factors and interleukin 2 production by cyclosporin A. Proc Natl Acad Sci USA 84:3274-3277, 1987. Borel IF, Feurer C , Gubler HU, et al: Biological effects of cyclosporin A: A new antilymphocytic agent. Agents Actions 6 : 4 6 8 4 7 5 , 1976. Kahn GC, Shaw LM, Kane MD: Routine monitoring of cyclosporine in whole blood and in kidney tissue using high performance liquid chromatography. J Anal Toxicol 10:28-34, 1986.
Schran HF, Rosano TG, Hassell AE, et al: Determination of cyclosporine concentrations with monoclonal antibodies. Clin Chem 33:2225-2229, 1987. Kahan BD, Flechner SM, Lorber MI, et al: Complications of cyclosporin therapy. World J Surg 10:348-360, 1986. Kahan BD: Cyclosporine nephrotoxicity: Pathogenesis, prophylaxis, therapy, and prognosis. Am J Kidney Dis 8:323331, 1986. June CH, Thompson CB, Kennedy MS, et al: Profound hypomagnesemia and renal magnesium wasting associated with the use of cyclosporine for marrow transplantation. Transplantation 39:620-624, 1985. Myers BD, Ross J , Newton L, et al: Cyclosporine-associated chronic nephropathy. N Engl J Med 31 1:699-705, 1984. Hay JE, Rorayko MK, Wiesner RH, et al: Withdrawal of cyclosporine from liver transplant recipients is immunologically unsafe and does not improve chronic renal dysfunction. Hepatology 14:53A, 1991. Grant D, Wall W, Duff J , et al: Adverse effects of cyclosporine therapy following liver transplantation. Transplant Proc 19: 3463-3465, 1987. Chapman JR, Marcen R, Arias M, et al: Hypertension after renal transplantation: A comparison of cyclosporine and conventional immunosuppression. Transplantation 43:860-864, 1987. Wysocki GP, Gretzinger HA, Laupacis A, et al: Fibrous hyperplasia of the gingiva: A side effect of cyclosporin A therapy. Oral Surg 55:274-278, 1983. Klintmalm GBG, Iwatsuki S , Starzl TE: Cyclosporin A hepatotoxicity in 66 renal allograft recipients. Transplantation 32:488489, 1981. Lorber MI, Van Buren CT, Flechner SM, et al: Hepatobiliary complications of cyclosporine therapy following renal transplantation. Transplant Proc 19:1808-18 10, 1987. Adams DH, Ponsford S , Gunson B, et al: Neurological complications following liver transplantation. Lancet 1:949-95 1, 1987. DeGroen PC, Aksamit AJ, Rakela J , et al: Central nervous system toxicity after liver transplantation: The role of cyclosporine and cholesterol. N Engl J Med 317:861-866, 1987. Rubin AM, Kang H: Cerebral blindness and encephalopathy with cyclosporin A toxicity. Neurology (Cleve) 37: 10721076, 1987. Thompson CB, June CH, Sullivan KM, et al: Association between cyclosporin neurotoxicity and hypomagnesanemia. Lancet 2:1116-1120, 1984. Penn I: Cancers following cyclosporine therapy. Transplantation 43:32-34, 1987. Starzl TE, Nalesnik MA, Porter KA, et al: Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1583-587, 1984. Heyworth MF: Clinical experience with antilymphocyte serum. Immunol Rev 65:79-97, 1982. Najarian JS, Simmons RL, Condie RM, et al: Seven years' experience with antilymphoblast globulin for renal transplantation from cadaver donors. Ann Surg 1984:352-368, 1976. Thistlewaite RJ, Stuart JK, Mayes JT, et al: Monitoring and complications of monoclonal therapy: Complications and monitoring of 0 K T 3 therapy. Am J Kidney Dis 11:112-119, 1988. Jaffers GH, Fuller TC, Cosimi AB, et al: Monoclonal antibody therapy: Anti-idiotypic and non-anti-idiotypic antibodies to 0KT3 arising despite intense immunosuppression. Transplantation 41572-578, 1988. Dummer JS, Hardy A, Poorsattar A, et al: Early infections in kidney, heart, and liver transplant recipients on cyclosporine. Transplantation 36:259-267, 1983.
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Starzl TE, Klintmalm GBG, Porter KA, et al: Liver transplantation with use of cyclosporin A and prednisone. N Engl J Med 305:266-268, 1981. Eld A, Gonzales LSU, Wiesner RH, et al: Prophylactic use of anti-lymphocyte globulin in patients undergoing orthotopic liver transplantation: Preliminary results. Hepatology 8:1288, 1988. Milis JM, McDiarmid SV, Hiatt JR, et al: Randomized prospective trial of 0KT3 for early prophylaxis of rejection after liver transplantation. Transplantation 47:82-88, 1989. Stock PG, Snover D, Payne W, et al: Biopsy-guided immunosuppressive therapy in the treatment of liver transplant rejection: An individualized approach. Clin Transplant 1:179186, 1987. Kelayoglu M, Strottz RJ, Hoffman RM, et al: Quadruple immunosuppressive therapy for liver transplantation. Transplant Proc 20(Suppl 1):524-529, 1988. Kino T, Hatanaka H, Miyata S, et al: FK-506, a novel immunosuppressant isolated from streptomyces. 11. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) 40: 1256-1265. 1987. Ochiai T, Nakajima K, Nagata M, et al: Effect of a new im-
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munosuppressive agent, FK-506, on heterotopic allotransplantation in the rat. Transplant Proc 19:1284-1286, 1987. Murase N, Todo S, Lee PH, et al: Heterotopic heart transplantation in the rat receiving FK-506 alone or with cyclosporine. Transplant Proc 19:71-75, 1987. Todo S, Podesta L, ChapChap P, et al: Orthotopic liver transplantation in dogs receiving FK-506. Transplant Proc 19 (Suppl 6):64-67, 1987. Ochiai T, Sakamoto K , Gunji Y, et al: Effects of combination treatment with FK-506 and cyclosporine on survival time and vascular changes in renal-allograft-recipient dogs. Transplantation 48: 193-197, 1989. Starzl TE, Makowka L, Todo S (Eds): FK-506: A potential breakthrough in immunosuppression. Transplant Proc 19 (Supp16):3-104, 1987. Mariani R, Fleischmajer R, Schragger AH, et al: Mycophenolic acid in the treatment of psoriasis. Arch Dermatol 113:930-932, 1977. Lynch WS, Hoenigk HH: Mycophenolic acid for psoriasis. Arch Dermatol 113:1203-1208, 1977. Epinette WW, Parker CM, Jones EL, et al: Mycophenolic acid for psoriasis. J Am Acad Dermatol 17:962-971, 1977.
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12, NO. 1, 1992
Maintenance lmmunosuppression After Liver Transplantat ion JOHN R. LAKE, M.D., JOHN P. ROBERTS, M.D., and NANCY L. ASCHER, M.D., Ph.D.
From the Department of Medicine and Surgery and Liver Transplantation Program, University of California, Sun Francisco, Sun Francisco, California. Reprint requests: Dr. Lake, Liver Transplant Services, University of California at San Francisco, 533 Parnassus, San Francisco, CA 94143-0780.
HISTORY Many of the immunosuppressive regimens and agents currently used in liver transplant recipients reflect regimens and agents developed for renal transplantation. The earliest combination regimen used in liver transplantation was a combination of azathioprine and prednisone. This regimen in the 1970s yielded the first long-term survival of hepatic allografts. However, graft loss was relatively high, and, moreover, relatively high doses of prednisone were necessary to maintain immunosuppression in these patients. These high doses of prednisone led to significant long-term morbidity. The introduction of cyclosporine into the immunosuppressive regimen of liver allograft recipients revolutionalized our approach to immuno~uppression.~ Foremost, the introduction of cyclosporine into the immunosuppressive regimen has led to the marked improvement in graft and patient survival that has been seen throughout the 1980s and importantly also paved the way for the development of new immunosuppressive strategies, such as synergistic regimens and sequential therapy, which has already contributed to decreased morbidity related to the immunosuppressive regimens. In the 1990s we will see the introduction of an even greater number of agents. This should allow for the tailoring of immunosuppressive regimens to the individual patient. For example, it is anticipated that, although patients may receive relatively potent immunosuppressive regimens during the immediate post-transplant period when the risk of rejection is highest, those patients who do not develop rejection will be quickly switched to alternative regimens, which will provide less immunosuppression but will likewise decrease the morbidity of the immunosuppressive agents. Alternatively, those patients who demonstrate a greater number or more severe episodes of rejection will be switched to a more potent agent, or agents, that, although running the risk of greater side effects, nonetheless, will, it is hoped, provide adequate immunosuppression and thereby prevent graft loss. For historical purposes, it is important to mention a variety of strategies that were once tried but have largely been abandoned due to either a high frequency of complications or poor outcome. These include thoracic duct drainage and total lymphoid irradiation; although lym-
Copyright O 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
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Liver transplantation evolved throughout the 1980s from a therapeutic modality only for those with the most advanced liver failure to therapy for many patients with end-stage liver disease and complications sufficiently severe to markedly impair their quality of life.'-7 In 1990, more than 2500 liver transplants were performed throughout this country and this is a testimony to the improved survival rates currently seen with the procedure. The most dramatic change in liver transplantation throughout the 1980s was the improvement in survival. One-year survival rates were only approximately 30% in 1980 and currently many of the better programs are reporting I-year survival rates of better than 80%. The development of better regimens for immunosuppression and improved immunosuppressive agents, particularly cyclosporine, has been responsible for a substantial part ~ these current survival of this increase in s ~ r v i v a l . ' .With rates, the challenges of the 1990s will be focused on the development of new immunosuppressive agents and immunosuppressive regimens that will lower morbidity and also the costs of liver transplantation. It is also anticipated that some of the advances in the 1990s will include a better clarification of the synergy between the various immunosuppressive agents available, as well as the tailoring of immunosuppressive regimens to the individual clinical scenario. This article will largely focus on the agents used for immunosuppression, both those that are currently in use as well as some of the newer agents that we anticipate will be available within the next several years. We also will focus on the development of immunosuppressive regimens, since none of these agents is used alone. To understand immunosuppression in liver transplantation, it is important to understand the mechanisms involved in liver transplant rejection. These mechanisms are covered elsewhere in this issue of Seminars, but we will allude to them in our discussion of the mechanism of action for the individual agents.
phoid irradiation occasionally tries to make a reappearance.
AGENTS USED FOR IMMUNOSUPPRESSION IN LIVER ALLOGRAFT RECIPIENTS Corticosteroids Corticosteroids (prednisone and prednisolone) have been used as immunosuppressive agents since the earliest days of transplantation.'-8 Even today, almost every regimen incudes corticosteroids as a major component. Corticosteroids are used not only for maintenance immunosuppression, but also are used for treatment of established rejection as well. Corticosteroids act at a variety of levels in a cascade of immunologic events that lead to rejection. For example, corticosteroids appear to block the production of interleukin- 1 (IL- I ) . This inhibition of IL-1 production leads to impaired activation of the T-cell and its subsequent production of IL-2,9 which is important for clonal expansion in response to HLA class I1 antigens. Corticosteroids also appear to be cytotoxic to alloactivated lymphocytes.1° In addition, corticosteroids decrease HLA class I1 antigen expression," inhibit the inflammatory response of other cells (such as eosinophils), and prevent the migration of inflammatory cells into damaged tissues. Finally, corticosteroids also inhibit monocyte transformation into macrophages" and may inhibit the effects of other antigen-presenting cells as well. Corticosteroids are often given as a bolus intravenously either immediately prior to transplant surgery, during surgery, or immediately after surgery. Relatively high doses of prednisone or prednisolone are used during the early post-transplant period and the dose is rapidly tapered to the desired maintenance level. Generally, the dose is 5 to 10 mg of prednisone per day in adults and 0.1 to 0.2 mglkg per day in children. The side effects of corticosteroids are well known and include fluid retention, hypertension, hyperglycemia, impaired wound healing, myopathy, growth retardation in children, aseptic necrosis of the hip, cataracts, and decreased bone mineralization. It is these latter longterm side effects that are the most troubling and most disabling of the corticosteroids, and it is for that reason that a number of programs have attempted to develop regimens that eventually remove corticosteroids from the patient's immunosuppression regimen.
Azathioprine As alluded to earlier, azathioprine was part of the original regimen used for liver allograft immunosuppression and for years was a mainstay for immunosuppression of liver transplant recipients. More recently, azathioprine largely has been used as part of the so-called triple immunosuppressive regimen in combination with cyclosporine and prednisone. This immunosuppressive regimen likely represents the most common regimen currently used for immunosuppression of the allograft recip-
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ient. Azathioprine represents a modification of the parent compound, 6-mercaptopurine (6-MP), and is converted in vivo to 6-MP, which represents the active compound. Azathioprine is an antimetabolite and exerts its immunosuppressive effects through purine metabolism, and inhibiting cell division. Consequently, the most rapidly dividing cells in the body are most sensitive to this agent. Currently, azathioprine is used primarily as a steroidsparing agent, in combination with prednisone and cyclosporine. It can be administered either intravenously or by mouth and the dosages used are 1 to 2 mglkglday, generally given as a single dose. The side effects of this agent are directly related to its effect on cell proliferation and thus the cells that are most rapidly dividing are most likely to be affected. The major side effect of azathioprine is bone marrow suppression. In particular, azathioprine has its most significant effects on white blood cells. This effect is dose related and can be easily reversed either by temporary discontinuation or, more often, by decreasing the dose of azathioprine that is used. Azathioprine also has been shown to produce hepatotoxicity, which, in its earliest stages, resembles an ischemic insult to the liver. This may reflect a primary effect of azathioprine on central vein endothelial cells. Early on, azathioprine hepatotoxicity is manifested clinically as cholestasis and an increase in serum transaminase and alkaline phosphatase activities.13 In its later stages, it can lead to veno-occlusive disease, as has been described in renal transplant recipients.14 This effect of azathioprine appears to be idiosyncratic. The long-term side effects of azathioprine include an increase risk of malignancy and susceptibility to opportunistic infections.
Cyclosporine Cyclosporine represents the major advance in immunosuppression that occurred in the late 1970s and early 1980s." This agent has become a cornerstone of most immunosuppressive regimens currently in use today.' Cyclosporine is a lipophilic endecapeptide that comes both as an intravenous and oral preparation, either as an oil-based liquid or in capsule form.16 When given orally, cyclosporine is primarily absorbed in the small intestine. The bioavailability of orally administered agent is low, on the order of 10 to 30%.17 Since it is very lipophilic and comes as an oil-based preparation, it requires bile salts for maximal absorption. Cyclosporine absorption is inhibited by a variety of clinical conditions, including biliary diversion (such as T-tube drainage), diarrhea, steatorrhea, decreased gastric emptying, and short gut. In pediatric patients, the bioavailability of cyclosporine correlates directly with the length of the bowel in the individual patient. To facilitate the absorption of cyclosporine in a patient with biliary diversion, bile is refed, serving both to provide the bile salts for cyclosporine absorption and also to complete the small enterohepatic circulation of cyclosporine. In addition, the T-tube is capped as early as possible following transplantation to reestablish the normal biliary conduit.18 Cyclosporine has a measured half-life serum of 4 to 12 hours in most patients.'' Cyclosporine is metabolized
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by a variety of metabolic pathways, including hydroxtransplant appear to be at increased risk for post-transylation, demethylation, reduction, and c a r b o ~ y l a t i o n . ~ ~plant renal dysfunction, but this fails to explain all the To a large extent, cyclosporine metabolism is via the cases of cyclosporine nephrotoxicity that are seen. It is controversial as to whether cyclosporine nephrotoxicity P450 system2' and thus inducers or inhibitors of P450 is progressive in liver allograft recipients, as was prevican have dramatic effects on cyclosporine metabolism and blood cyclosporine levels. Agents that commonly afously shown for heart allograft recipient^.^^ If it is profect cyclosporine metabolism include diphenylhydangressive, it is very slowly progressive and it is extremely toin, phenobarbital, and r i f a m ~ i n . ~Cyclosporine ~,?~ is unusual that patients with initially stable renal funcexcreted into bile largely as metabolites, but there is a tion progress to require dialysis. Equally important is small enterohepatic circulation of the parent compound whether chronic cyclosporine nephrotoxicity is reversible with discontinuation of cyclosporine. Histologically, as well. Cyclosporine circulates bound to a variety of one can demonstrate interstitial fibrosis and vascular serum lipoprotein^.^^ Approximately half of cyclosporine in the bloodstream is attached to red blood cells and sclerosis in the kidney with chronic cyclosporine adminwhite blood cells.25 ' cyclosporine in paistration. In one s t ~ d y , ~stopping The immunologic effects of cyclosporine represent tients with a decrease in GFR of greater than 50% after 2 years had no effect on GFR and precipitated episodes a relatively specific effect on T lymphocyte^.^^ Intracellularly, cyclosporine binds to a cytosolic protein2' and of rejection in 6 of 12 of these patients, who previously had not had a rejection. In addition to the decrease in acts to inhibit T-cell proliferation by blocking transcripGFR, cyclosporine can also produce a type IV renal tution of IL-2 mRNA, leading to decreased IL-2 prod ~ c t i o nand ~ ~secretion by T cell^.'^.^'^^^ In the absence bular acidosis (RTA) with occasionally marked increases of IL-2 production, the clonal expansion of T lymphoin serum potassium concentration^.^^ This apparent RTA responds well to mineralocorticoid administration. cytes is inhibited. These effects of cyclosporine appear Cyclosporine is associated with a number of other to be relatively specific for T-helper cells. Besides its side effects,38 including hypertension, which is usually effect on 11-2 production, cyclosporine also inhibits the easily controlled by medication^:'^ hypercholesterolsecretion of a variety of lymphokines, including gamma interferon. l 6 emia, hypertrichosis, gingival h y p e r p l a ~ i a ,gout, ~ ~ and hepatotoxicity, which is usually manifested by minor inCyclosporine is absorbed poorly from the gastroincreases in serum liver enzymes and which responds simtestinal tract in the early post-transplant period. Thus, ply to lowering the cyclosporine d ~ s e . ~ ' , ~ ' many programs administer cyclosporine intravenously Central nervous system (CNS) toxicity is one of the during the immediate post-transplant period at a dose of more disabling side effects of c y ~ l o s p o r i n e .Neuro~~.~ 2 to 5 mglkglday often given in a continuous infusion. logic signs and symptoms seen following transplantation Oral cyclosporine is begun at a dose of 10 to 20 mglkgl include headache, sleep disturbance, psychosis, encephday in divided doses once gastrointestinal tract function alopathy, seizures, tremors, myoclonus, cortical blindreturns. Subsequent dosing of cyclosporine is adjusted n e ~ s , ~hemiplegias, ' spastic quadraparases, and coma.44 according to blood levels. Currently, two methods exist One of the more common and specific manifestations of for cyclosporine blood level determination: high-perforcyclosporine neurotoxicity that we have seen is a speech mance liquid chromotography (HPLC)3' and radioimapraxia. The etiology of the cyclosporine-associated munoassay (RIA). The older polyclonal RIA assay meaneurotoxicity is unclear, but patients with decreased sesured both parent compound and metabolites. However, rum magnesium concentration^^^ and decreased serum the newer monoclonal RIA available measures only parcholesterol levels44appear to be at increased risk for this ent compound and has an advantage over HPLC (which cyclosporine-associated neurotoxicity. CNS symptoms also only measures parent compound) by being techniare often associated with dramatic changes seen by comcally easier." The three most common clinical situations puted tomography or magnetic resonance imaging of the that lead to difficulty obtaining adequate cyclosporine brain and vary from minor white matter changes to hemlevels include cholestasis because of the impaired delivery of bile salts to the intestine and consequently poor orrhagic infarcts that reverse with time. While most patients with cyclosporine neurotoxicity completely recyclosporine absorption, biliary diversion, and P450 accover, some are left with residual gait, visual, or speech tivation. Cyclosporine is stored in body fat so that patients with increased body fat often take longer to disturbance^.^ achieve adequate cyclosporine blood levels than those Cyclosporine administration is also associated with with less body fat. malignan~ies;~' in particular, B-cell lymphoma. Many of these lymphomas are associated with Epstein-Barr virus The most important side effect of cyclosporine is infection and may respond to lowering the immunonephrotoxi~ity.~'-~~ Acutely, cyclosporine nephrotoxicity suppression and intravenous administration of high doses is manifested by a fall in urine output, impaired natruof a c y ~ l o v i r . ~ ~ resis, and a fall in glomerular filtration rate (GFR). This reflects the acute effects of cyclosporine on intrarenal Antilymphocyte Preparations blood flow and is rapidly reversed by a decrease in cyclosporine dosage. Virtually all patients develop some Currently, there are two forms of antilymphocyte decrease in GFR associated with cyclosporine adminispreparations available in this country: a monoclonal antration, which can vary from 10 to 70%. Individual sustibody directed against CD3-baring lymphocytes (OKT3) ceptibility to the nephrotoxic effects of cyclosporine is and polyclonal preparations generated by immunizing quite variable. Patients with impaired renal function pre-
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animals with various lymphocyte preparations (antithymocyte globulin or Minnesota antilymphoblast globulin [MALG]). Both of these have been incorporated into maintenance immunosuppression protocols, termed sequential therapy. In these protocols, patients are treated for relatively brief periods of time (less than 2 weeks) with one of these preparations in the immediate posttransplant period. The rationale for these regimens will be discussed later. Both of these agents are also used for treatment of established rejection. Polyclonal preparations suffer by being relatively non~elective.~' Thus, they tend to decrease total white blood counts and platelet counts as well. These preparations also require administration through a central venous catheter and have been reported to cause allergic skin reactions as well as serum sickness.50 0 K T 3 is given via peripheral intravenous access. 0 K T 3 is specific in its effects against CD3-baring T lymphocytes and thus does not affect total white blood counts or platelet counts. There is, however, a dramatic first-dose reaction that can be seen and consists of fevers, chills, hypotension, and occasionally pulmonary edema and bronchos p a ~ m . It~ 'appears that the severity of this reaction can be decreased by pretreatment with corticosteroids. These effects lessen with each successful dose and may be related to the release of lymphokines as a result of 0 K T 3 administration. Other side effects of 0 K T 3 include diarrhea, and an aseptic meningitis, which is typically seen on days 4 to 5 of 0 K T 3 administration and manifested by headache and neck stiffness. The use of 0 K T 3 is limited by the development of antimurine antibodies, since 0 K T 3 is a mouse monoclonal antibody.52Low titers of antibody can be overcome by increasing the dose of OKT3. Both preparations also have been associated with an increased risk of cytomegalovirus infections when used as treatment for established rejection episodes." 0 K T 3 also has been associated with an increased risk of B-cell lymphoma.48
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prine, and prednisone. The theory behind adding azathioprine to prednisone and cyclosporine was that this would allow utilization of lower doses of each individual drug and, it was hoped, lower long-term side effects. This regimen also has been associated with a lower incidence of retransplantation and chronic rejection. The arguments against triple therapy include that it represents increased immunosuppression and thus the risk of opportunistic infections or malignancies may be higher. Finally, because of the effect of intravenous cyclosporine on urine output and renal function in the early transplant period, sequential protocols have been developed.50 Patients undergoing liver transplantation are often very edematous and require relatively large quantities of blood products during the transplant procedure. Thus, patients will undergo marked fluid shifts during the immediate post-transplant procedure and commonly patients require substantial diureses. The use of intravenous cyclosporine impairs the action of diuretics so that the principal advantage of sequential therapy is to avoid the use of intravenous cyclosporinc and to allow beginning cyclosporine only once renal function has returned to normal. A few programs, including our own, utilize quadruple immunosuppression (sequential therapy) as our standard maintenance immunosuppression protocol and many use such a protocol for patients with impaired renal function pretransplant. Both MALG and 0 K T 3 have been incorporated into sequential regimen^.^^.^^ It is unclear whether these regimens lead to less rejection overall, but they certainly appear to delay the onset of rejection by 1 to 2 weeks in these patient^.""'^^^ Most sequential regimens delay the administration of cyclosporine until day 5 to day 14 following transplant. In addition, whether avoidance of intravenous cyclosporine will lead to better long-term renal function is unclear. The criticism of the use of antilymphocyte preparations for maintenance immunosuppression has been that this could lead to an increased frequency of post-transplant malignancy and opportunistic infections. This, however, does not appear to be the case in the published series.5b
COMBINATION THERAPY Every regimen currently employed for liver allograft immunosuppression represents a combination of these individual agents. It is difficult to compare the relative efficacy and side effects of the various regimens, since there have been few randomized trials that have compared the different regimens head to head. The earliest regimen employed was azathioprine and prednisone with or without an antilymphocyte preparation. Although successful, this regimen was associated with a relatively high incidence of graft loss secondary to refractory allograft rejection and also required relatively high doses of prednisone (10 mg or greater in adults) with significant long-term corticosteroid toxicity. Later regimens utilized cyclosporine and prednisone.j4 With this regimen, there was a decreased incidence of graft loss and improved survival, but still this regimen required relatively high doses of cyclosporine and prednisone with its subsequent long-term toxicity. This led to the development of so-called triple therapy regimens, which included cyclosporine, azathio-
NEW AGENTS FOR IMMUNOSUPPRESSION There are a number of immunosuppressive agents currently undergoing testing in this country. Most are still at the stage of laboratory and animal testing and will not be discussed here. Two agents, however, FK 506 and RS-61443, are currently in clinical testing and the preliminary results with these agents will be discussed. FK 506, a very promising drug, is a macrolide produced by a Streptomyces species that was discovered in Japan.s9 It appears to have a similar mechanism of immunosuppressive action to cyclosporine. Like cyclosporine, it also inhibits IL-2 synthesis by lymphocytes and may decrease the expression IL-2 receptors on activated lymphocytes as well. Although similar in action to cyclosporine, FK 506 is 50 to 100 times more potent by weight. In vitro, FK 506 has been used to prevent allograft rejection in a variety of animal models, including
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heart, renal, and liver a l l ~ g r a f t s . ~ There ~ - ' ~ is also in vitro information that FK 506 can be synergistic with cy~losporine.~~ Clinical studies of FK 506 began at the University of Pittsburgh in 198864and currently over 1000 patients have been treated at that institution thus far. The results, as recently reported at an international symposium on FK 506 in Pittsburgh, suggest that in their hands, FK 506 produces better graft and patient survival and lower costs of transplantation. Our own experience as part of the United States multicenter, open-label, randomized trial indicates that FK 506, indeed, appears to be a potent immunosuppressive drug that produces results comparable to that of cyclosporine, in terms of rejection incidence and graft and patient survival. The initial hope was that FK 506 would be associated with fewer side effects and, in particular, less nephrotoxicity. However, it appears that FK 506 has a similar side effect profile to cyclosporine. In particular, FK 506 has both an acute and probably chronic nephrotoxicity. The acute nephrotoxic effects of FK 506 are very similar to cyclosporine in that they are greater with intravenous administration, they are dose-dependent, and are reversible with dose reduction. FK 506 does have a substantially lower incidence of hypertension and does not produce hypertrichosis. It also exhibits neurotoxicity and a CNS syndrome similar to cyclosporine has been seen with FK 506. FK 506 can also lead to glucose intolerance and in high doses causes diarrhea and poor appetite. Thus far, FK 506 has generally been used in combination with prednisone. However, a number of patients treated at the University of Pittsburgh have now been taken off prednisone and are currently managed with FK 506 as the sole immunosuppressive agent. FK 506 also may be effective as a rescue agent for patients with refractory rejection.64 RS-61443 is an ester of the parent compound, mycophenolic acid, which has a mechanism of immunosuppressive action that is distinct from cyclosporine or FK 506. RS-61443 is rapidly hydrolyzed following absorption by cytosolic esterases to yield the parent compound. LymphoRS-61443 is an inhibitor of purine ~ynthesis.'~ cytes, unlike most other cell types, possess a single pathway for purine synthesis and thus inhibition of this pathway will lead to a selective inhibition of lymphocyte proliferation. Although inhibition of T- and B-cell proliferation is the primary effect of the drug, it appears that the immunologic effects of this agent may be more complex. RS-61443 has been used successfully for immunosuppression in a variety of animal allograft models, including heart, pancreatic islets, and renal transplants. Clinical studies with RS-61443 as an immunosuppressive agent in transplantation are just beginning in this country. Its use to date has been largely as a rescue agent for patients either intolerant of cyclosporine or with refractory rejection. Primary trials in both kidney and liver allograft recipients are planned. The toxicity of this drug is minor. Despite its similar mechanism of action to azathioprine, RS-61443 in therapeutic doses does not lead to bone marrow suppression, nor does it exhibit nephrotoxicity or hypertension. The only side effects noted thus far include skin rash and
minor gastrointestinal upset. There already exists longterm follow-up information on the safety of the parent compound, mycophenolic acid. A cohort of patients with psoriasis have now been treated for almost 20 years with mycophenolic acid with essentially no serious long-term sequelae, although 12% of the patients had uncomplicated episodes of herpes zoster. The incidence of malignancy in that cohort does not appear to be different from the cancer incidence in the United States as a whole.65 How RS-61443 will be used as an immunosuppressive agent in maintenance protocols is unclear. It would seem logical to replace azathioprine with RS-61443 in a triple drug regimen that includes cyclosporine and prednisone.
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THE FUTURE With the expanding number of agents available for immunosuppression in the near future, tailoring of immunosuppression for the individual patient will become a priority. Decisions as to what regimen and agents should be used will likely be based on pretransplant renal function, the presence or absence of rejection post-transplant, and severity of side effects that occur in an individual patient. Goals of new immunosuppressive agents and regimens certainly will include improved graft and patient survival, but patient morbidity and financial costs will play an increasing role in decision-making regarding choices for maintenance immunosuppression in the future.
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