MODERN IMMUNOSUPPRESSION

ADVANCES IN LIVER TRANSPLANTATION

1089-3261/00 $15.00

+ .OO

MODERN IMMUNOSUPPRESSION David C. Cronin 11, MD, PhD, Thomas W. Faust, MD, Lynda Brady, MD, Hari Conjeevaram, MD, Sushi1 Jain, MD, Puneet Gupta, MD, and J. Michael Millis, MD

Immunosuppression strategies in liver transplantation been classified into relatively distinct periods. These phases are referred to as induction (initial), maintenance, and treatment of acute and chronic rejection. The induction phase refers to events immediately associated with implantation and reperfusion of the allograft. Traditionally, this phase is characterized by a high level of immunosuppression. The goal of this treatment phase is the induction of a state of acute immunologic nonresponsiveness or immunoparalysis that prevents early cellmediated rejection. Initial immunosuppression therapy based on a combination of high-dose glucocorticoids and calcineurin inhibitors has resulted in protection from acute cellular rejection that is comparable with the protection achieved with induction antilymphocyte based therapy? A nonantibody approach to initial immunosuppression has the benefits of a decrease in opportunistic infections, lower incidence of posttransplant lymphoproliferative disease,*17lower overall cost of therapy, and the reservation of antilymphocyte antibody therapy for steroid-resistant rejection episodes. Transition from induction therapy to maintenance immunosuppression is usually gradual and is begun before hospital discharge. Calcineurin inhibitors are the basis for the majority of maintenance immunosuppression protocols. The level of maintenance immunosuppression is adjusted according to the rejection history of the patient, underlying liver disease, the immunosuppression cocktail used, and the phlosophic bias of the program. In general, patients who experience episode(s) of early or severe acute cellular rejection are maintained on higher levels of immunosuppression for longer periods of time. As patients demonstrate stable graft function without episodes of rejection, most programs make every effort to gradually reduce the level of immunosuppression. By protocol or by experience, the therapeutic goal is

From the Section of Transplant Surgery, Department of Surgery (DCC, JMM); the Liver Study Unit, Department of Medicine, (TWF, HC, SJ);Pediatric Hepatology, Department of Pediatrics (LB, PG), University of Chicago, Chicago, Illinois

CLINICS IN LIVER DISEASE VOLUME 4 NUMBER 3 AUGUST 2000

619

620

CRONIN et a1

maintenance of the patient at the lowest level of immunosuppression necessary to avoid the onset of rejection and minimize the occurrence of immunosuppressant-related side effects. Further modifications are made based on the side effects experienced by the patients being treated, such as calcineurin-associated 193 Some patients have benefited from further reduction in nephrotoxi~ity.'~~, calcineurin exposure or from switching to alternative immunosuppression with the newer agents. There are a few therapeutic options for the treatment of acute cellular rejection in liver transplant patients. The mainstay of therapy is treatment with high-dose glucocorticoids.These agents are dosed as a pulse and taper or pulse without taper. Most episodes of mild-to-moderate rejection respond. Treatment for severe acute cellular rejection or steroid-resistant rejection may require use of antilymphocyte antibody therapy.179Tacrolimus has reportedly been used to reverse mild, moderate, and severe acute cellular rejection,s2and steroid-resistant rejections.118,122 Therapeutic options for the treatment of chronic allograft rejection, whch is defined as centrolobular dropout, loss of bile ducts, and foam cell arteritis, are much more limited. Agents that have demonstrated some therapeutic benefit are discussed. Many classifications have been used to group and discuss immunosuppressant agents used in transplantation; the authors group agents based on their mechanism of pharmacologic action. Under tlus classification both older and newer agents may appear in the same section. The pharmacology, pharmacokinetics, notable side effects, and toxicities of the immunosuppressive agents are described in this article. At the conclusion of each section the authors' current practice with these agents and treatment strategies are described. EARLY CELL CYCLE INHIBITORS Calcineurin Inhibitors (Cyclosporine, Tacrolimus)

Since its introduction, calcineurin inhibition has provided the immunosuppressant base for most antirejection therapeutic strategies. The benefit of calcineurin inhibition extends across all solid and cellular organ transplants. Additional benefits have accrued from improved understanding of intracellular signaling pathways as a consequence of uncovering the mechanisms of immunoNo doubt the discovery suppression mediated by cyclosporine and tacrolimus.lO1 and use of cyclosporine, the first calcineurin inhibitor used for immunosuppression, defined a new era in solid organ transplantation. The prominence of cyclosporine, however, is being eroded by tacrolimus. The following discussion highlights the basic concepts associated with cyclosporine and tacrolimus use. Although both agents act in a similar fashion, each possess many unique qualities that have clinical relevance. Pharmacology

Cyclosporine and tacrolimus, both calcineurin inhibitors, share a similar mechanism of action, the inhibition of cytokine gene transcription, primarily interleukin-2 (IL-2) in T lymphocytes. Inhibition of calcineurin, a calmodulindependent serine-theroinine protein phosphatase, occurs when it is bound to either tacrolimus-FK binding protein (FKBP) complex or the cyclosporinecyclophilin complex.17This drug-binding protein-calcineurin complex interferes

MODERN IMMUNOSUPPRESSION

621

with the dephosphorylation of nuclear factor of activated T cells (NF-AT). Nuclear factor of activated T cells, a cytosolic protein, must be dephosphorylated for translocation to the nucleus, where it is required for IL-2 gene transcription.18 FK binding protein and cyclophilin are two members of the immunophilin family of cytoplasmic intracellular proteins and serve as intracellular ligands for tacrolimus and cyclosporine, respectively.61,73 In vitro data demonstrate that the potency of tacrolimus at calcineurin inhibition is 10 to 100 times greater than cyc10sporine.Z~~ Tacrolimus interferes with the transcription of a variety of other cytokines, IL-3, IL-4, interferon-? (IFN-y), tumor necrosis factor-a (TNF-a), and granulocyte-macrophage colony-stimulating factor (GM-CSF)." Io6, 195 Additionally, tacrolimus is hepatotrophic*&Pa property not shared by cyclosporine. This tissue-specific distribution may partially explain the lower rates of allograft rejection obtained with tacrolimus. Pharmacokinetics

Although both agents share a similar pharmacology, they have very different pharmacokinetic profiles. Tacrolimus

The oral bioavailability of tacrolimus ranges from 5% to 67% with a marked 204 The absorption is reduced by food but variability in the rate of absorption.203, seems less dependent on the presence of bile.2" Tacrolimus undergoes extensive metabolism in the liver by the mixed function oxidase system, primarily the cytochrome P450-3A Additional metabolism can occur in the small bowel cytochrome system?6,97 More than 10 metabolites have been identified with varied immunosuppressant activity.167The P450-3A cytochrome system is responsible for metabolism of a wide variety of pharmacologic agents and can result in drug interactions.Il6Pediatric patients tend to clear tacrolimus at a faster rate than adults do on a body-weight basis."O Most tacrolimus is excreted as a conjugate in the bile (>95%),with less than 1% excreted unchanged in the urine?" The terminal elimination half-life of tacrolimus is approximately 11 hours. Measurement of trough levels has proved useful in dosage adjustment. Unlike cyclosporine, tacrolimus has a strong trough area-under-the-curve (AUC) correlation. As a result, trough levels are used to guide immunosuppressive effect and monitor toxicity. Cyclosporine

Two brand-name oral preparations of cyclosporine are available: Sandimmune and Neoral. Neoral is a cyclosporine microemulsion formulation, which is less dependent on the presence of intestinal bile for absorption than Sandimmune.lz9Both products are available in liquid and liquid-filled gel capsules. Additionally, generic formulations with apparent bioequivalence to cyclosporine microemulsion are being developed. Oral bioavailability of Neoral is generally better than that of the nonemulsified product: 43% versus 28%, respecti~ely.'~~ The range of bioavailability, however, is large: 17% to 68%. Food decreases the rate and extent of absorption. External biliary drainage has little impact on the extent and degree of absorption of Neoral but significantly decreases bioavailability of Sandimmune.'"

622

CRONIN et a1

First-dose pharmacokinetics of cyclosporine demonstrated a large volume of distribution (13L/kg). Chronic dosing, however, results in a steady state volume of distribution of 3L to 5L/kg. Similar to tacrolimus, cyclosporine is partitioned into plasma, serum, and erythrocytes. This partitioning quantitatively affects the value obtained when measuring trough levels. Whole blood measurement of cyclosporine trough values is more reliable and reproducible than serum or plasma. Similar to tacrolimus, cyclosporine undergoes extensive hepatic metabolism primarily by the P450-3A cytochrome isoenzyme system. Greater than two dozen metabolites have been identified, some possessing a degree of immunosuppressant activityJ6The clinical relevance has not been established. Pediatric patients seem to have a higher rate of drug clearance, which is ascribed to increased cytochrome activity in the gastrointestinal tract.212Less than 0.1% of cyclosporine is excreted unchanged in the urine. Microemulsion and nonemulsion formulation of cyclosporine demonstrate wide variability in intrapatient and interpatient pharmacokinetics. Clinically, this variability is reflected in a wide range of trough values for the same dose exposure, and less predictability in dosing between patients. Also, the correlation coefficient between trough measurement and AUC is much less dependable than that of tacrolimus. Toxicity

Hypertension is a frequent side effect with both agents.159, 193 Acute exposure can result in both hypertension and hypotension and is related to the level of drug exposure. Hypertension associated with chronic exposure to the calcineurin irhbitors is primarily a manifestation of nephrotoxicity. Hyperglycemia is more common in patients treated with tacrolimus and is caused by the effect of 71, I9O tacrolimus on p cells of the Nephrotoxicity with acute exposure is probably secondary to vasoconstriction of the afferent arterioles resulting in a decreased glomerular filtration rate,159,193 with acute elevation of blood urea nitrogen (BUN) and serum creatinine. Ths effect is dose related and proportional to the trough level of the drug; the effect is usually reversible with cessation or lowering of the dose of the agent. Chronic calcineurin exposure can result in more permanent changes in the kidney and include arteriolar hyalinosis, tubular vacuolization, and atrophy.6 Additionally, a variety of electrolyte disturbances are associated with use of the calcineurin inhibitors: hyperkalemia, hyponatremia, hypomagnesemia, and chronic depression of serum bicarbonate levelsJ1,lo9,139 The progressive deterioration in renal function has prompted some programs to institute alternative immunosuppression strategies in an effort to lower or avoid further exposure to calcineurin inhibitors." Neurotoxicity frequently presents as tremor and headache with an incidence 193 These side effects are more common at the initiation of approximately 50%.159, of therapy and are associated with high trough levels. More serious neurologic effects involve seizures, coma, and grey-white matter changes in the brain.53,76, lZ8, 194, 196 Reportedly there is an increased risk of cyclosporine-induced central nervous system toxicity among patients with low perioperative serum cholesterol levels.3oNo such correlation has been established for tacrolimus. Frequent gastrointestinal disturbances have been reported with these agents. These complaints are usually confined to diarrhea, dyspepsia, bloating, and vague abdominal pain and dis~ornfort.'~~, lg3 Most symptoms resolve with a decrease to dosage, alteration in the dosing interval; occasionally removal of the

MODERN IMMUNOSUPPRESSION

623

agents is necessary. The frequency of gastrointestinal complaints is increased in patients receiving mycophenolate mofetil in addition to a calcineurin inhibitor. Patients receiving cyclosporine have a higher incidence of gingival hyperplasia and hypertrichosis than those receiving t a ~ r o l i m u s .Although ~~~ both agents are associated with an overall increased risk of viral, bacterial, and fungal infectious complications, tacrolimus may have a higher incidence of post transplant lymphoproliferative disease (PTLD) than cyclosporine.28 Clinical Use European and American Large multicenter trials have compared the efficacy of tacrolimus and cyclosporine as primary immunosuppressant agents in liver transplantation'&, 159, 193, 214 with similar patient and graft survival with either agent. Patients treated with tacrolimus, however, experienced fewer episodes of acute cellular rejection, fewer episodes of steroid-resistant rejection, less exposure to muromonab-CD3 therapy, and lower cumulative steroid exposure.159* 193 Also, tacrolimus has been used effectively to treat acute allograft rejection alone and when combined with glucocorticoids.82Tacrolimus has been shown to reverse steroid-resistant rejection118,150 and reverse chronic allograft rejection in selected liver transplant recipients.174 The authors' protocol uses tacrolimus-based immunosuppression in all adult recipients of both cadaveric and live-donor primary liver allografts. Tacrolimus is given preoperatively before induction of anesthesia (0.075mg/kg) and continued enterally thereafter. The authors do not use the intravenous formulation. In the immediate posttransplant period the dose of tacrolimus is adjusted to maintain a target trough level of between 15 mg/mL to 20 ng/mL. Glucocorticoids are given as an intraoperative bolus and tapered rapidly to a maintenance dose of 20 mg/day by postoperative day seven. Using this protocol, the authors have required antilymphocyte therapy. Acute rejection in the early postoperative period is treated with an increase in tacrolimus dose or glucocorticoid bolus therapy, or both. On discharge, target trough level of tacrolimus is maintained between 8 ng/ mL to 10 ng/mL for the first 3 months. During that time, total steroid dose is gradually reduced to the lowest possible dose. Most patients are maintained long-term on tacrolimus (trough 5 ng/mL to 7 ng/mL) as the sole immunosuppressant. In the pediatric population the authors have chosen to use a Neoral-based immunosuppressive regimen in prepubescent patients and tacrolimus-based immunosuppression in older pediatric patients. This strategy is based on concern about the potential increase in PTLD with tacrolimus exposure in this high-risk population. Also, many adolescent children are troubled by the cosmetic side effects of cyclosporine and t h s may contribute to a higher incidence of noncompliance among patients in this group. Pediatric patients that develop steroidresistant rejection or chronic rejection are switched to tacrolimus-based immunosuppressive therapy regardless of age. LATE CELL CYCLE INHIBITORS Sirolimus Pharmacology Sirolimus, a macrolide antibiotic, is structurally similar to tacrolimus. Although sirolimus binds to the FKBezo5immunosuppressant activity is distinct

624

CRONIN et a1

from that of cyclosporine and tacrolimus.10The FKBP-sirolimus complex mediates a series of intracellular events that result in the inhibition of both T-cell and thymocyte proliferation and B-cell activation. Sirolimus inhibits the response of lymphocytes (both T and B cells) to cytokine stimulation and inhibits antibody production by B cells.lo4 Sirolimus acts by inhibition of intracellular signal transduction and subsequent proliferation mediated by IL-2 receptor stimulation of at least two cellcycle kinases, p7P6k(70-kD S6 k i n a ~ e )95~and ~ , p34cdc2126, IZ7, Sirolimus exerts its inhibitory effects late in the G1phase of the cell cycle,Zo5later than tacrolimus or cyclosporine. Activation stimuli that are resistant to calcineurin inhibition or cytokine stimulation, are sensitive to sirolimus. This late-stage inhibition allows greater lymphocyte activation than previously possible with calcineurin inhibitors. Presently, tolerance induction is believed to require active induction and calcineurin inhibitors have been demonstrated to interfere with tolerance induction. Late GI inhibition may allow the induction of tolerance in the responding lymphocyte population while simultaneously preventing the onset of acute cellular rejection. Pharmacokinetics

Pharmacokinetic evaluation of sirolimus has been derived from healthy volunteers and recipients of kidney tran~plants.4~ The results of a multicenter trial in liver transplant patients are awaited. Oral bioavailability is variable and is improved with high-fat meals."O Like cyclosporine and tacrolimus, sirolimus is metabolized through the cytochrome P450-3A system.167 The terminal half-life is long (63 to 68 hours) and allows for once-a-day dosing. Most of the drug is sequestered in erythrocytes with a blood serum ratio of 30.9.219This factor must be considered when interpreting the sirolimus blood or serum trough levels. Additionally, at plasma concentration steady state there is a strong correlation between the &hour trough value and the AUC.49,197 This relationship between trough and AUC make correlation between dose and observed immunosuppression or side effects more predictable. Toxicity

The most frequent major side effects observed among recipients of renal allografts treated with sirolimus were hyperlipidemia (elevated cholesterol and triglycerides), thrombocytopenia, and leukopenia. The incidence and severity of the side effects correlated with sirolimus blood trough leve1.64.-5 The diabetogenic, nephrotoxic, and hypertensive effects associated with cyclosporine were 86 not augmented by coadministration of sirolirnu~.~~, Clinical Use

To date, most clinical reports evaluating the efficacy of sirolimus as an immunosuppressant are derived from renal transplant recipients. Sirolimus in combination with cyclosporine and steroids results in a lower incidence of acute cellular rejection.=*85* 86 Experience with sirolimus in liver transplantation is limited. In a small pilot study Watson et a1 demonstrated that combination therapy with cyclosporine and sirolimus provide adequate steroid-free immunosuppression.Sirolimus used as the sole agent in maintenance therapy was adequate and well tolerated.210 Early results with combination therapy using sirolimus and tacrolimus in

MODERN IMMUNOSUPPRESSION

625

liver transplant recipients are encouraging.'08The side effect profiles do not overlap, and the addition of sirolimus provides a steroid and tacrolimus sparing effect. The center's experience with sirolimus has also been favorable. One group of liver transplant recipients in whom the authors have used sirolimus therapy are those patients with poor renal function in the immediate postoperative period. Patients with hepatorenal syndrome are considered candidates for sirolimus-based immunosuppression. Postoperative immunosuppression consists of anti-IL-2R mAb, steroids (pulse and taper) and sirolimus 5 mg/ day. With the return of renal function, tacrolimus is gradually added to the postoperative immunosuppression cocktail and the sirolimus dose is lowered. Side effects have been limited to thrombocytopenia and hyperlipidemia and are dose related. The number of patients treated, however, is small and follow-up is short. ANTIBODY THERAPY Antilymphocyte Antibodies: Muromonab-CD3 (Murine) Monoclonal, Thymoglobulin (Rabbit) Polyclonal, Lymphocyte Immune Globulin (Equine) Polyclonal

Antilymphocyte antibody therapy provides very potent immunosuppression in allograft recipients. Muromonab-CD3 is a murine monoclonal antibody specific for the E chain of the TCR/CD3 complex expressed on mature T cells and medullary thym0cytes.2~~ Recent additions to this class of drugs include the antibody products, lymphocyte immune globulin, and thymoglobulin. These newer agents are polyclonal and derived from equine and rabbit sources, respectively. Muromonab-CD3 exerts its immunosuppressive effect by binding to and modulating the CD3 complex on T cells. This antibody T-cell interaction results in trafficking of the T lymphocytes out of the circulation and down regulation of TCR mediated signaling.'6,215 Additionally, binding of the antibody to the CD3 complex results in liberation of a vast array of cytokines contributing to the cytokine release syndrome experienced by many patients treated with this agent. This syndrome can cause fever, rigors, chills, and malaise. Less frequently, patients experience pulmonary edema,3*, 165 cardiovascular collapse,g8, 180 seizures,**,170 and renal fai1u1-e.~ Patients are more likely to experience the cytokine release syndrome with the first doses of antibody when the number of susceptible T cells is largest. Use of the polyclonal products has primarily been restricted to the renal transplant pop~lation'~, 57 with few publications describing their use in liver tran~plantation.'~' The polyclonal antibody products have much broader antigen specificity. These antibodies bind to various cellular antigens on both T and B lymphocytes in addition to cellular antigens on platelets, erythrocytes, and leukocyte^.^^-'^ Their mechanism of immunosuppression is mediated primarily by IgG antibody binding resulting in opsonization or antibody-mediated complement lysis of the target cells. The nonspecific nature of the polyclonal antibody product contributes to the various blood dyscrasias associated with their use. Antilymphocyte antibodies provide potent immunosuppression and effective management of steroid-resistant acute cellular rejection31,59, 208, 209; however, other agents are now available with fewer adverse effects. Specifically, antilymphocyte antibodies do not provide benefit over standard calcineurin-based therapy?09Furthermore, use of muromonab-CD3 in steroid-resistant hepatic allograft

626

CRONIN et a1

rejection is a risk factor for cytomegalovirus disease.'53Among patients transplanted for end-stage liver disease secondary to hepatitis C, treatment with muromonab-CD3 predisposes the patients to early and severe recurrence of hepatitis C infection.la Prophylaxis with muromonab-CD3 in liver transplant patients offers no advantage over standard calcineurin-based therapy114,12' nor is muromonab-CD3 the only effective agent for rescue therapy for refractory rejection after liver tran~plant.~~, 11*, In light of the potential for serious adverse effects,'&, 173 predisposition for viral infection,8', 125 and availability of alternative, effective therapy, the authors avoid antilymphocyte induction, prophylaxis, or maintenance therapies in their liver transplant recipients. Acute cellular rejection is treated with steroid pulse and taper and in cases of steroid-resistant rejection tacrolimus has been used.**sFor 500 patients, over the past 6 years, the authors have used muromonab-CD3 therapy successfully in two cases of steroid-resistant, tacrolimus-resistant rejection. Within the authors' pediatric population, the authors' avoid exposure to muromonab-CD3 because of the increased risk for the development of EpsteinBarr virus (EBV) and cytomegalovirus (CMV)153infection and PTLD.9,137

Anti-Interleukin-2 Receptor Antibodies (Basiliximab, Daclizumab) Pharmacology

Recently two antibodies directed against the a subunit of the IL-2 receptor (CD25) have been added to the immunosuppressive armamentarium: basiliximab and daclizumab?, 137 Daclizumab is a humanized anti-IL-2 receptor monoclonal antibody (mAb) and basiliximab is a chimeric anti-IL-2 receptor mAb. Both products are IgGl monoclonal antibodies. These monoclonal antibodies are specific for the IL-2R (CD25, IL-2R-a) expressed only on activated T cells. Immunosuppression is mediated by binding to the IL-2 receptor in a nonactivating fashion, competing with IL-2 and thereby inhibiting IL-2 driven proliferation of the activated T lymphocyte. Interleukin-2 induced proliferation of activated (antigen stimulated) T lymphocytes is a critical step in clonal proliferation and acquisition of effector function. Pharmacokinetics

Although these two monoclonal antibodies share similar pharmacologic activity, they have different pharmacokinetic patterns. Basiliximab demonstrates a volume of distribution (Vd) equivalent to blood and plasma (4 to 5 L). At steady state, however, the Vd increases suggesting distribution outside the vascular compartment. Daclizumab demonstrates a smaller Vd than basiliximab at steady state but it still exceeds the vascular compartment. Increased Vd at steady state may be partially explained by redistribution of the antibodies into ascites fluid. Basiliximab clearance is not well correlated with body weight or age and has a terminal half-life of 4 to 14 days. By contrast, daclizumab has a terminal half-life of 20 days and has a clearance proportional to body weight. Degree and length of IL-2R saturation are relavant for immunologic efficacy. When given at the recommended dose and schedule both agents provide satura206 tion binding of IL-2 R for greater than 1 month after dosing.96,

MODERN IMMUNOSUPPRESSION

627

Toxicity

Both monoclonal antibody preparations are well tolerated. The frequency of opportunistic infections (viral or bacterial), malignancy, and posttransplant lymphoproliferative disease were not increased among study patients exposed to drug.132 Clinical Use

Early experience with these agents was obtained from multicenter and 85, I3O Both agents single center studies involving recipients of renal appear to lessen the incidence of acute cellular rejection among recipients of cadaveric renal allografts when added to baseline immunosuppression.2o7 Although the antibody design, affinity for the IL-2 receptor, and pharmacokinetics differ between the two products, both seem equally effective at safely reducing the onset of acute cellular rejection in kidney transplant recipient~.'~~ Use of anti-11-2-receptor blockade in recipients of hepatic allograft transplants is limited to a few single center reports to date?,92It seems that the addition of anti-11-2-receptor blockade to baseline immunosuppression can safely lower the incidence of acute cellular rejection early after liver transplantation. The administration schedule of the antibody, however, must be modified when used in liver transplantation. In the liver transplant recipient, unlike the renal transplant recipient, administration of the antibody must be delayed until reperfusion of the graft has been established because of the large volume of blood replacement associated with liver transplantation. Antibody may also be lost in ascites fluid?2 The authors' current practice is to use anti-11-2-receptor antibody therapy in patients at high risk for the development of posttransplant calcineurin-related side effects such as nephrotoxicity and neurotoxicity. Additionally, the authors have included anti-11-2-receptor therapy for patients undergoing simultaneous multiorgan transplants (liver combined with kidney, heart, or heart and kidney). The authors' have used both basiliximab and daclizumab under these circumstances with equal efficacy. Presently, the authors use basiliximab given in a dose of 20 mg by intravenous infusion after reperfusion of the graft or in the intensive care unit. This dose is repeated on postoperative day four. Patients treated receive simultaneous baseline immunosuppression with intravenous glucocorticoids. Use of the calcineurin inhibitors is begun cautiously with a target trough level of 12 ng/mL to 15 ng/mL (IMX) achieved by the fifth to seventh postoperative day depending on renal and neurologic function. ANTIMETABOLITES Mycophenolate Mofetil

Pharmacology

Mycophenolate mofetil (MMF) is the esterified prodrug of mycophenolic acid. This relatively new immunosuppressant can be classified as an antimetabolite with selectivity for lymphocytes, both T and B.4 Mycophenolate mofetil exerts its antiproliferative effect by reversible noncompetitive inhibition of inosine monophosphate dehydrogenase (IMPDH), which is responsible for de novo purine synthesis. Because lymphocytes lack the salvage pathway for purine synthesis, they are dependent on the de novo pathway and are sensitive to the

628

CRONIN et a1

antiproliferative effects of mycophenolic acid? Mycophenolate mofetil's more specific enzyme inhibition offer an advantage over azathioprine, which also inhibits 5-phosphoribosyl-l-pyrophosphate-amidotransferase and adenylosuccinate syntheta~e.'~~ Pharmacokinetics The prodrug, mycophenolate mofetil (MMF), is hydrolyzed to the active agent mycophenolic acid (MFA) in the liver. The ester prodrug formulation has significantly higher bioavailability than MPA. Mycophenolic acid is further metabolized to the inactive glucuronide conjugate (MPAG). MPAG is excreted into bile and subsequently deconjugated in the gut into MPA and reabsorbed into the enterohepatic circulation. Mycophenolic acid and MPAG are both highly protein bound, and high levels of MPAG can displace MPA, thereby increasing free drug and potential toxicity and Vd. The Vd of MPA is approximately 4 L. Most of the dose of MMF is excreted in the urine as MPAG with less than 1% as MPA. Mycophenolic acid has a half-life of approximately 18 Toxicity The most common adverse effects reported with MMF therapy are gastrointestinal, including diarrhea, nausea, abdominal pain, and constipation, whch are usually dose related. Leukopenia is another frequent side effect of therapy and mav reauire dose adiustment. Omortunistic infections have been more commoily &ported in s&dy patient; 'receiving higher dose therapy (3 g/ day).147,178 Clinical Use The current treatment indications, strategies, and study designs for MMF use in liver transplant vary. Indications for MMF in liver transplantation have included calcineurin la steroid reduction,16*,Ia8 treatment of steroid69, 87, 91 resistant rejection, or chronic The authors are presently conducting a prospective, randomized trail in stable, posttransplant liver patients experiencing calcineurin-induced nephrotoxicity. Primary end points will include recovery of renal function and incidence of acute and chronic rejection. Mycophenolate mofetil are combined with calcineurin inhibitors in a steroid-sparing protocol has also been attempted.162 The use of MMF for graft rescue to chronic rejection and resistant acute rejection has been reported with some s ~ c c e s s e s . ~ ~ In most studies the incidence of gastrointestinal side effects noted in the recipients of MMF is high. The gastrointestinal side effects seem to be more severe and more frequent in patients receiving both tacrolimus and MMF.69,77

TREATMENT OF REJECTION Steroids Corticosteroids were used in the early clinical trials of liver transplantation.la2Their efficacy in the treatment of acute cellular rejection is because of its powerful multifocal immune modulation.

MODERN IMMUNOSUPPRESSION

629

Immunosuppressive Properties of Steroids Depress delayed hypersensitivity Decrease the cytotoxic T-cell proliferation Inhibit effector cell cells in antibody-dependent cytotoxicity Inhibit production of IL -1 Inhibit production y-interferon* Prevents production of IL-2* Decreases local inflammation by decreasing migration of neutrophils and inhibiting lysosomal enzyme release by neutrophils T-cell sequestration and cytotoxicity Most centers use intravenous corticosteroids as first line therapy for patients experiencing an initial rejection episode. A multicenter trial of cyclosporine and tacrolimus revealed that corticosteroids were effective in reversing the rejection episode in 62% of patients although there was a sigvficant increase in the responsiveness in those patients receiving tacrolimus (78% versus 53%, P < 0.001).193 The treatment regimen used in this study consisted of one or two intravenous doses of 1000 mg of methylprednisolone followed by a 6-day taper starting at 200 mg/ day and ending at 20 mg/ day. Patients who experience another rejection episode within an arbitrarily defined period of 30 days are said to have steroidresistant rejection. The treatment of this type of rejection is not as uniform as the initial rejection episode. A traditional algorithm to treat rejection under a cyclosporine-based immunosuppressive regimen during the time of this study is shown in Figure 1. Tacrolimus Over the last several years there has been an increasing role for tacrolimus in the treatment of steroid-resistant rejection. Several groups have documented These effects may be secondary to the inhibition of IL - 1.

Steroids Response

No Response

Continue Baseline Immunosuppression

Response

No Response

OKT3

I

Continue Baseline Immunosuppression

Tncrolimus I

Continue Baseline Immunosuppression

Response Tacrolimus

No Response Retransplant

Figure 1. Traditional rejection therapy protocol. (From Millis JM: Treatment of liver allograft rejection. Liver Transpl Surg 5:S98-S106, 1999; with permission.)

630

CRONIN et a1

tacrolimus' use in this setting,55*56,90,113with a graft-salvage rate between 60% and 90%. The primary variable for response was the level of bilirubin at the initiation of tacrolimus therapy.89 A study at The University of Chcago to evaluate the role of tacrolimus in the treatment of steroid-resistant rejection revealed that tacrolimus was as effective as OKT3 in reversing the rejection episode and was more effective than continuing with a cyclosporine-based immunosuppression regimen118,120, Iz2 (see Fig. 2A and 2B). The lack of immunerelated complications had a dramatic effect on hospital charges during the first 6 months after transplantation. The mean hospital costs for patients receiving

11 -

2 a a

v

e:

2 1 B

P=ns*

T

10 -

T

+ Tacrolimus

9-

OKT3

8: 76-

54:

T

E

2 r2

3: 2101

SD 0

7

0

A

14

21

Days of Therapy 100 90 80 -

3 f

70

-C-

60-

-Ef Tacrolimus

50. 40-

OKT3

P
30 . 20 10 . 01

'

'

'

I

.

.

.

)

,.

'

t

'

.

.

I

"

.

)

"

~

1

Figure 2. A, Bilirubin response to treatment for steroid resistant rejection. 6, Incidence of recurrent rejection episodes after treatment for steroid resistant rejection. (From Millis JM: Treatment of liver allograft rejection. Liver Transpl Surg 5:S98-S106, 1999; with permission.)

MODERN IMMUNOSUPPRESSION

631

OKT3 was 356,023 versus 143,661 for the patients treated with tacrolimus, P <0.001.'~0

Our most recent experience has evaluated the use of tacrolimus for the primary treatment of acute rejection episode after liver transplantation, thereby eliminating the use of steroid cycle for these indication^."^ The authors' results, shown in Figure 3, demonstrate that patients on cyclosporine can be safely converted to tacrolimus for immune unresponsiveness in the early postoperative period. The University of Chicago's current algorithm for the treatment of rejection is shown in Figure 4A and 48. Antibodies OKT3

The recent literature concerning OKT3 for the treatment of rejection focuses on the side effects of therapy including recurrent hepatitis C and the development of EBV induced posttransplant lymphoproliferative disease.'38,164 But the early literature is replete with documentation concerning the efficacy of OKT3 in the treatment of steroid-resistant rejectionJ9,31, 48 The summary of these data indicates that 60% to 90% of patients treated with OKT3 demonstrate initial control of the rejection episode. As experience with OKT3 has grown, however, it is now associated with a number of undesirable side effects including recurrent hepatitis C and PTLD. Rosen identified the use of OKT3 to treat steroid-resistant rejection in patients with hepatitis C as a major risk factor for graft loss.'" Newel1 reported a significantly increased incidence of posttransplant lymphoproliferative disease after OKT3 use in pediatric liver transplant patients.138These associations have dramatically reduced the use of OKT3 in liver transplant patients.

- 2.0

10 12

s

a E

v

- 1.8 - 1.6 s' - 1.4 5E - 1.2 .-g - 1.0 g

8 -

v

El

a

.-12

6-

Lo

-0.8

a

E

2

$

42-

8

U

-0.6 1

- 0.4 -- 0.2

CI

2

Figure 3. Bilirubin (narrow line) and creatinine (heavy line) levels after treatment of initial rejection episode with tacrolimus. (From Millis JM: Treatment of allograft rejection. Liver Transpl Surg 5(suppl):S9&S106, 1999; with permission.)

632

CRONIN et a1

Steroids or Convert to Tacrolimus Response

No Response

Continue Baseline Im munosuppression

Response

No Response

L

Increase Tacrolimus Dose +Steroids+ MMF

A

Steroids Response

No Response

Continue Baseline Immunosuppression

Response

Tacrolimus-based Immunosuppression

B

Increase Tacrolimus

No Response OKT3 Response

Tacrolimus-based Immunosuppression

No Response

Retransplant

Figure 4. Current rejection therapy protocol. A, Cyclosporine based immunosuppression. B, Tacrolimus based immunosuppression. (From Millis JM: Treatment of liver allograft rejection. Liver Transpl Surg 5 5 9 8 4 106, 1999; with permission.)

IL-2Receptor Antibodies There currently is no information about the use of IL-2 receptor antibodies therapy for liver allograft rejection. As induction therapy, however, it may reduce the incidence of rejection following liver tran~p1antation.I~~ Mycophenolate Mofetil

Currently there is no proper trial establishing the use of mycophenolate mofetil to treat rejection in liver transplant patients. Mycophenolate mofetil is generally added to an existing regimen when rejection persists. Neuhaus's group has reported the use of mycophenolate mofetil in five patients with acute or chronic rejection and hepatitis C. They reported that all five patients resolved the rejection episode and were alive with good graft function at the time of publication. This is contrasted with 14 patients who were treated with OKT3; five of the patients died.149This report provides anecdotal information that mycophenolate mofetil may be useful in augmenting existing regimen for difficult-to-manage patients.

MODERN IMMUNOSUPPRESSION

633

DISORDERS THAT MAY REQUIRE MODIFICATION OF IMMUNOSUPPRESSION

Certain groups of patients pose a unique challenge after transplantation. Patients transplanted for end-stage primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis are at increased risk for rejection and disease recurrence. Cellular rejection may be more prevalent in patients transplanted for fulminant hepatic failure and for those who require retransplantation. Modifications in immunosuppression may be necessary for this subgroup of patients. Autoimmune Hepatitis

As with other putative autoimmune disorders, the significant recurrent autoimmune hepatitis (AIH) after transplantation remains controversial. Exclusion of acute rejection, viral hepatitis, drug effects, and biliary obstruction is imperative before making a diagnosis of recurrent disease (see article by Dr. Rosen). Neuberger et suggested that AIH may recur after transplantation. After weaning corticosteroids and cyclosporine, recurrence of symptoms in association with abnormal liver chemistry tests and positive serology was apparent. Liver biopsy revealed periportal inflammation and interface hepatitis. Clinical, biochemical, and histologic parameters improved after increasing corticosteroid dose and introduction of azathioprine. Wright et a1 reported 43 patients who underwent transplantation for AIH with a minimum of 10 months follow-up.218Autoimmune markers were present and serologic markers for viral hepatitis were absent in all patients; however, testing for hepatitis C RNA was not performed. Periportal inflammation and piecemeal necrosis, persistence of autoantibodies, and hyperglobulinemia suggested recurrent disease in 11 of 43 (26%) patients. Nine patients were HLADR3 positive recipients of HLA-DR3-negative grafts. In contrast, investigators from the Mayo Cinic reported that no patient who underwent transplantation for AIH had evidence of recurrent disease after a mean follow-up of 39 months.*66Positive autoantibodies, absence of viral infection, and periportal hepatitis without rejection defined disease recurrence. In this study, higher doses of azathioprine were used (2 mg/kg/d) in combination with corticosteroids and cyclosporine. Disappearance of autoantibodies and normalization of gammaglobulin levels were seen in the first year after transplantation. Biopsies failed to disclose recurrent AIH. The investigators concluded that triple therapy may prevent expression of AIH after transplantation. In a more recent study, the incidence of recurrent AIH, associated risk factors, response to treatment, and patient and graft survival after recurrence were assessed.156Recurrent disease was defined by sustained elevation of transaminases of at least 1-month duration, consistent histopathology, and positive autoimmune markers. Twenty-seven patients met inclusion criteria, 9 (33%) of whom developed recurrent AIH after a mean interval of 2.6 years with periportal and lobular hepatitis, piecemeal necrosis, and bridging fibrosis implying disease recurrence. The estimated risk of recurrence was 8% for the first year and 68% after 5 years. Recurrent disease was more frequent in HLA-DR3 positive recipients on less immunosuppression with longer follow-up. Half of the patients who received single therapy (cyclosporine) or double therapy (prednisone and cyclosporine) had recurrent disease, whereas none of the patients who were

634

CRONIN et a1

on triple therapy (prednisone and azathioprine and cyclosporine) exhibited recurrence. In three patients, recurrence was observed 3 to 6 months after stopping azathioprine or tapering corticosteroids; the other six patients had been on stable immunosuppression for at least 1 year. Recurrence was treated by either adding azathioprine and increasing corticosteroids (5 patients) or by adding or increasing corticosteroids (4 patients). Biochemical parameters improved with increased immunosuppression, but hepatic inflammation did not improve or worsened in most patients; however, with a mean follow-up of 2.4 years, there was no significant difference in patient or graft survival between recipients who developed recurrence and those who did not. The investigators concluded that recurrent AIH was frequent, the risk of recurrence increased over time as immunosuppressionwas reduced, and longer follow-up was required to assess the impact of recurrent disease upon patient and graft survival. In another study, 15 patients transplanted for AIH were followed for a mean of 4.8 years; 3 (20%) developed chronic hepatitis with histologic and serologic features of recurrent disease.I6O Piecemeal necrosis, portal lymphoplasmocytic infiltration, and lobular inflammation suggested recurrent AIH. All patients received corticosteroids, azathioprine, and cyclosporine.One patient was asymptomatic, and two patients experienced severe disease leading to graft failure. Nine patients (60%) experienced at least one episode of biopsy-proven acute rejection. OKT3 was necessary for four patients with corticosteroid-resistant rejection. Birnbaum et a1 described aggressive recurrence of AIH in a pediatric population." Five out of six children developed recurrent AIH at a mean of 11.4 months after transplantation. Two patients received tacrolimus-based immunosuppression, and four patients received cyclosporine-based immunosuppression; two of these latter patients required early tacrolimus rescue therapy for severe rejection. Two of the patients on tacrolimus and one of the patients on cyclosporine developed cirrhosis and were retransplanted withn 1 year of recurrence. Recurrent AIH developed in all three retransplanted patients. The investigators concluded that AIH recurred frequently in children, recurrence was associated with aggressive disease requiring retransplantation, and efforts to improve the immunosuppression regimen should continue. Caution must be exercised when weaning immunosuppression. Sempoux et a1 reported a case of recurrent AIH presenting with abnormal liver chemistry tests and lobular hepatitis after prednisolone, cyclosporine, and azathioprine doses were reduced.172In a recent study, corticosteroids were withdrawn 3 months after transplantation for AIH.Il7Thirteen of 47 patients (28%)developed recurrent disease after a mean of 29 months. Recurrence was based on the presence of autoantibodies, elevation of transaminases, portal mononuclear infiltrates and lobular inflammation with confluent or bridging necrosis, and a lack of serum markers of viral hepatitis. Ten patients responded to reintroduction of steroids; however, three patients required retransplantation for progressive disease. Acute rejection occurred in 87% of patients, with 58% of patients experiencing moderate-to-severerejection. Unfortunately, the immunosuppressive protocol after steroid withdrawal was not described. Hayashi et a1 assessed the incidence of rejection in patients transplanted for AIH and alcoholic cirrhosis.68Patients received prednisone (0.3 mg/kg per day) and either cyclosporine (12 mg/kg to 15 mg/kg per day) or tacrolimus (adjusted to obtain whole-blood trough levels of 12 mg/mL to 15 ng/mL). Acute rejection developed in 79% of 33 patients transplanted for AIH and 47% of 47 patients transplanted for alcoholic cirrhosis. In the AIH group, cyclosporine-basedimmunosuppression was associated with acute rejection in 89% of patients. Although

MODERN IMMUNOSUPPRESSION

635

the group receiving tacrolimus was small, only one of five (20%) developed acute rejection. In the AIH and alcoholic cirrhosis groups, 33% and 13% had steroid-resistant rejection, respectively. Contrary to most reports, Trouillot et a1 found that 17 of 25 patients (68%) transplanted for AIH could be withdrawn from corti~osteroids.~~~ Steroid withdrawal was initiated on patients with stable graft function who were more than 6 months post-transplant. In 20 patients, prednisone was reduced by 2.5-mg increments over several months; 19 patients received cyclosporine, and 1 patient received tacrolimus. Five additional patients were enrolled in a 14-day rapid prednisone taper protocol, in combination with mycophenolate for 6 months, and either tacrolimus or cyclosporine. The frequency of acute rejection was 33%. Of 14 episodes of rejection, 2 were steroid-resistant. Disease recurrence could not be adequately assessed because liver biopsies were not performed on asymptomatic patients. The investigators concluded that the benefit of steroid-free long-term maintenance immunosuppression outweighed the short-term risk of treatable acute rejection. In summary, recurrent AIH after transplantation is supported by most studies. Reported recurrence rates up to 33% are based on well-defined criteria. Differences in the immunosuppressive regime and length of follow-up influence recurrence rates. Weaning of immunosuppression should be approached with caution, but recurrent disease appears to respond to an increase in corticosteroids with or without azathioprine in most cases. The potential benefit of tacrolimus over cyclosporine in the prevention of recurrent disease is not clear. The incidence of acute rejection and steroid-resistant rejection is higher in patients transplanted for autoimmune hepatitis than in patients transplanted for diseases without an autoimmune basis. Which subset of patients with autoimmune hepatitis are likely to respond to a reduction in immunosuppression, and what is the optimal method of weaning, are questions which remain to be answered. Will the use of novel immunosuppressants reduce the risk of recurrent disease or cellular rejection? Longer follow-up will be necessary to assess the consequence of recurrent disease and rejection on patient and graft survival. Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is also thought to be a disease of disordered immune reg~lation.9~ Antimitochondrial antibodies (AMA) are present in 95% of patients. The relationship between AMA and bile duct injury is unclear, but immune attack of aberrantly expressed antigenic molecules on biliary epithelial cells is possible. Lymphocytic destruction of medium-sized bile ducts expressing increased amounts of Class I and I1 antigens is characteristic.99 Recurrence of PBC in the liver allograft has generated controversy since it was first reported by Neuberger et a1.'= They described three patients transplanted for PBC who were followed for 3.5 to 4.5 years. Maintenance immunosuppression consisted of prednisolone (15-20 mg / d) and azathioprine (75-150 mg/ d). Three years after transplantation, cholestasis, pruritus, and a progressive rise in previously decreased titers of AMA were observed. Biopsies revealed portal inflammation, bile duct injury, ductopenia, lymphoid aggregates, and granulomas. The abnormal biochemical and histologic findings were not found in five control patients who received transplants for other conditions. The investigators concluded that PBC recurred after transplantation. The same group reported a larger study of 23 patients on cyclosporinebased immunosuppression followed for 1 to 10 years after tran~plantation.'~~

636

CRONIN et a1

Six patients were maintained on cyclosporine and prednisone, 4 patients on cyclosporine alone, and the remaining 13 patients on cyclosporine, prednisone, and azathioprine. Histology compatible with recurrent PBC was seen in 9 of 10 biopsies. Ductular proliferation, granulomas, lymphocytic aggregates, and breaks in the bile duct membrane were highly suggestive of recurrent disease. Six patients transplanted for PBC were followed for 14 to 43 months by Dietze et al.38All patients received cyclosporine, azathioprine, and corticosteroids for the first year, followed by cyclosporine monotherapy. Two recipients displayed granulomatous destruction of bile ducts suggestive of recurrent disease. Rejection or infection was not suspected in either case. The investigators suggested that rapid progression to liver failure before transplantation may be associated with an increased risk of recurrence, and that recurrent disease may be attenuated by immunosuppression; however, the small number of patients and short follow-up precluded any conclusions regarding the impact of recurrent disease on long-term patient and graft survival. Hubscher et a1 found that 13 of 83 (16%) patients transplanted for PBC experienced rec~rrence.~~ Corticosteroids were discontinued by 3 months after transplantation in most patients. Of the 13 patients with recurrence, 8 patients received azathioprine (50-75 mg/ d) and cyclosporine (200-400 mg / d), 3 patients received only cyclosporine (400 mg/ d), and 2 patients received azathioprine (25-75 mg/d) and prednisone (5 mg/d). Disease recurrence was based upon histologic criteria. Granulomatous disruption of bile ducts, mononuclear infiltrates, lymphoid aggregates, portal tract granulomas, and ductopenia, were suggestive of recurrent PBC. The investigators implied that long-term azathioprine and cyclosporine may modify expression of recurrent disease within the graft. Others have noted that recurrent PBC may be dependent on the immunosuppressive regimen and method of weaning. Wong et a1 reported recurrent disease w i h n 1 year of transplantation in two recipients receiving tacrolimus.216 The first patient received prednisolone 20 mg/d and tacrolimus 10 mg/d; prednisolone was discontinued by 10 months posttransplant and tacrolimus was continued at a dose of 1 mg/d. The second patient received prednisolone 20 mg/d and tacrolimus 20 mg/ d. Prednisolone and tacrolimus were subsequently reduced to 7.5 mg and 3.5 mg/ d respectively. Both patients demonstrated florid granulomatous bile duct destruction and cholestasis. The investigators suggested that low dose tacrolimus may have been inadequate to suppress the underlying immunologic abnormalities associated with PBC. They also suggested that cyclosporine may be preferable to tacrolimus in patients transplanted for PBC. In another paper, 27 subjects with graft survival over 1 year were studied; 11 patients received cyclosporine and azathioprine, and 16 patients received t a c r o l i m ~ s .Corticosteroids ~~ were withdrawn at 3 to 5 months. All of the cyclosporine-treated patients and 13 of the tacrolimus patients had at least one episode of acute rejection. After the first year, 5 of 16 patients receiving tacrolimus developed hepatic granulomas on biopsy. Granulomas were not seen in recipients receiving cyclosporine. After 2 years, features suggestive of PBC recurrence (portal granulomas, lymphoid aggregates, bile duct damage) were present in 7 of 16 patients on tacrolimus and 1 of 11 patients on cyclosporine. The investigators concluded that PBC recurred more frequently and sooner in patients receiving tacrolimus, but graft survival was not affected in the mediumterm. Of note, details regarding the exclusion of other causes of granulomas were not provided. In a study by Mazariegos et al, 2 of 13 (15%)patients exhibited histologic evidence of recurrence 7 and 24 months after weaning from a cyclosporine-

MODERN IMMUNOSUPPRESSION

637

based regimen.Io7The possibility of late recurrence highlights the importance of using caution when selecting patients for withdrawal of immunosuppression.1n Several other reports have suggested an association between rapid corticosteroid withdrawal and PBC recurrence.Js,74, 134 In summary, recurrent PBC after transplantation is controversial. Liver biopsy remains the gold standard for diagnosis, but the interpretation of recurrence may be complicated by the effects of immunosuppression, which may delay or modify disease expression within the graft! Exclusion of other conditions mimicking PBC (acute and chronic rejection, graft versus host disease, biliary obstruction, viral hepatitis, drug effects) is important before making a diagnosis of PBC recurrence. If PBC recurs, intermediate-term patient and graft survival is excellent, but long-term studies are required to assess the impact of disease recurrence on the allograft. Patients transplanted for PBC seem to be at increased risk for rejection. How will newer immunosuppressants or rapid steroid withdrawal protocols affect the incidence and severity of recurrent PBC or rejection? Additional studies are required to answer these questions. Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic disease of unknown associated with fibrosing inflammation of intrahepatic or extrahepatic bile ducts. Disordered immune regulation may play a role. Cholestatic liver indices and perinuclear antineutrophil cytoplasmic antibodies are characteristic. Irregular ductal strictures, beading, dilatation, and pruning are seen on cholangiography, whereas biopsy reveals concentric rings of fibrous tissue with edema and inflammatory cells around interlobular bile ducts (fibrous cholangitis), and replacement of ducts with fibrous scars (fibroobliterative lesions). The recurrence of PSC after transplantation is controversial. Careful exclusion of other conditions identified with intrahepatic and extrahepatic biliary strictures is mandatory.168Bile duct strictures can occur secondary to ischemia from hepatic artery stenosis or thrombosis. Chronic rejection, ABO blood group incompatibility between donor and recipient, viral and bacterial infections, and preservation injury have all been associated with the development of biliary strictures after transplantation. Narumi et a1 studied 33 patients transplanted for PSC with a mean followup of 37 months.131Patients received azathioprine, prednisone, and cyclosporine posttransplantation. Diagnosis of recurrence was based upon biochemical, cholangiographic, and histologic criteria in the absence of other known causes for biliary strictures. Four of 33 (12%) patients developed periportal fibrosis and pericholangitis in conjunction with multiple nonanastomotic strictures. Of the patients with recurrent disease, two had moderate steroid-resistant rejection, and one had mild steroid-responsive rejection. Cold ischemia times were not prolonged, ABO-identical grafts were used, hepatic artery blood flow was normal, and CMV infection was not significant. In another study, recurrent disease was assessed in 127 patients who underwent transplantation for PSC.60Seventy-six patients received cyclosporine (to maintain a whole blood trough level between 250 ng/mL and 300 ng/mL), prednisone (20 mg/d), and azathioprine (1 mg/kg per day). Fifty-one patients received tacrolimus (to maintain a whole blood trough level of 5 ng/mL to 10 ng/mL) and prednisone (20 mg/d). Eleven of 127 (8.6%) patients exhibited cholangiographic and histologic evidence of recurrence with a median follow-

638

CRONINetal

up of 3 years. Recurrence was based upon clinical symptoms and signs of cholestasis, nonanastomotic strictures within intrahepatic or extrahepatic bile ducts, and periductal inflammation with fibrosis at least 6 months after transplantation. There was no significant difference in patient or graft survival between the group with recurrent disease and those in whom recurrence did not develop, although follow-up was short. Unfortunately, the investigators did not report whether recurrent PSC was more common in patients who received cyclosporine versus those who received tacrolimus. In a retrospective study of 100 patients transplanted for PSC, Jeyarajah et al found recurrent disease in 15.7% and chronic rejection in 13%0.~ Forty one patients developed steroid-resistant rejection, whereas 23 developed OKT3-resistant rejection. They also found that patients who developed recurrent PSC or rejection were more likely to have received cyclosporine; however, the number of patients who received tacrolimus was small and follow-up was short. Even with supportive data, the recurrence of PSC remains controversial because of lack of a gold standard for diagnosis. In order to accurately diagnose PSC recurrence, well-defined cholangiographic and histologic criteria are mandatory. As with PBC and AIH,the effects of immunosuppression may modify or delay disease expression within the graft. Additional studies are essential to determine the effect of corticosteroid withdrawal on rates of recurrence and rejection. Is there any difference between tacrolimus- and cyclosporine-based regimens in the management of PSC patients undergoing transplantation? Will newer immunosuppressive agents favorably influence the posttransplant course €or patients receiving allografts for end-stage PSC? Fulminant Hepatic Failure

The outcome of transplantation in patients with fulminant hepatic failure (FHF) has been generally inferior to that of transplantation performed electively for patients with chronic liver disease reflecting the impact of severe complications such as severe cerebral edema, on survival. However graft dysfunction and infections are also more prevalent in patients transplanted for FHF. Specific data regarding postoperative immunosuppression for these patients is limited.m More recently, 44 patients from the multicenter European tacrolimus liver study who had FHF were compared to 485 patients who received transplantations for other indication^.^^ Patients transplanted for FHF experienced more episodes of acute rejection and sepsis (57% and 32%)when compared with the control group (45% and 21%). At two-year follow-up, patient and graft survival rates in the FHF group (71% and 64%) were also inferior to the control group (78% and 73%). The frequency of retransplantation for FHF and non-FHF patients was 23% and lo%, respectively. In the FHF group, 21 patients received tacrolimus and 23 patients received cyclosporine. The incidence of acute rejection was less in patients who received tacrolimus when compared with patients who received cyclosporine (52% versus 61%); refractory acute rejection occurred in four (17%)patients receiving cyclosporine, but did not occur in patients receiving tacrolimus. Two patients who received cyclosporine developed chronic rejection within 2 years of transplantation, whereas chronic rejection did not occur in any patient receiving tacrolimus. Additionally, corticosteroid requirements were less in patients who received tacrolimus. There was no difference in patient or graft survival between the cyclosporine and tacrolimus groups. The results of these studies confirm that transplantation for FHF carries an inferior outcome when compared with transplantation for other indications. This

MODERN IMMUNOSUPPRESSION

639

may reflect a number of factors including use of suboptimal groups in the critically ill group of patients. Primary immunosuppression tacrolimus may be preferable to cyclosporine in this group. Retransplantation Patients undergoing retransplantation have a significantly inferior result compared with patients receiving a first graft; overall 1-year survival is 50% to 70%.40,94 Markmann et a1 retrospectively investigated preoperative criteria predictive of poor outcome after liver retran~plantation.'~~ Regression analysis identified older patient age, donor organ ischemia, requirement for preoperative mechanical ventilation, elevated total bilirubin, and elevated creatinine as independent variables predictive of poor survival. Primary immunosuppression after the first transplantation (tacrolimus versus cyclosporine) was not a significant factor. Further details regarding immunosuppression were not provided. In a study of 418 retransplantations, Doyle et a1 found variables similar to those of Markmann et a1 to be significant in determining patient survival; however, primary immunosuppression was a significant independent factor associated with subsequent graft failure.4O Cyclosporine was associated with greater graft loss within 1 year of retransplantation compared to tacrolimus. Additional details regarding immunosuppression were not provided. Van Hoek et a1 analyzed factors associated with ductopenic rejection after retransplantation.201Patients received either cyclosporine and prednisone, or cyclosporine, prednisone, and azathioprine. Of 34 retransplantations, 13 were performed for chronic rejection, 7 for hepatic artery thrombosis, 8 for primary graft failure, and 6 for other reasons. Multivariate analysis revealed chronic rejection in a previous graft and immunosuppression without azathioprine as independent risk factors for chronic rejection after retransplantation. Takaya et a1 compared results of retransplantation in patients receiving cyclosporine and steroids plus OKT3 or azathioprine (or both) to patients receiving tacrolimus and low-dose steroids.'89 The incidence of retransplantation within 6 months of primary transplantation was significantly higher in the cyclosporine group (15.4%)when compared with the tacrolimus group (8.6%). Primary nonfunction was the most common cause for retransplantation in both groups. One-month and 6-month patient survival after retransplantation were 69.1% and 54.6% in the cyclosporine group, and 85.7% and 62.9% in the tacrolimus group respectively, a difference that was not statistically significant. The causes of death after retransplantation were not described. MANAGEMENT OF LONG-TERM ADVERSE EFFECTS

Hypertension The development of hypertension after liver transplantation has been reported in 60% to 90% of patients receiving cyclosporine and 30% to 60% of patients receiving tacrolimus.2°,54, 66, 67, 77, I4O The pathogenesis of posttransplant hypertension is multifactorial. Corticosteroids contribute through sodium retention, increased plasma volume, and weight gain?" Cyclosporine has nephrotoxic effects, causing alterations in intrarenal vascular reactivity and vasoconstriction; consequently, glomerular filtration rate (GFR) and sodium excretion are impaired. Long-term cyclosporine use leads to glomerular sclerosis, tubular atro-

640

CRONIN et a1

phy, and interstitial fibrosis. Cyclosporine has been associated with suppression of the renin-angiotensin system, followed by an increase in extracellular volume." Also, cyclosporine may induce systemic arterial vasoconstriction through stimulation of endothelin release or inhibition of nitric oxide synthesis or re1 e a ~ e . The I ~ ~ mechanism of tacrolimus-associated hypertension is less clear, but is probably related to renal vasoconstriction and decreased GFR?O Tapering or withdrawing steroids has been shown to improve blood pressure.IS7Conversion from cyclosporine to tacrolimus or mycophenolate may be 157 Hypertension may also respond to dose important in selected patients.70* reduction. Because vasoconstriction is important in the pathophysiology of cyclosporine- and tacrolimus-induced hypertension, calcium channel blocking agents are frequently prescribed first line agents. The dihydropyridine class of calcium channel blockers (nifedipine, isradipine, amlodipine, felodipine, nitrendipine) reduces systemic arterial and renal vasoconstriction.171 Diltiazem, verapamil, and nicardipine are effective vasodilators; however, they can increase cyclosporine and tacrolimus levels. For hypertension refractory to calcium channel blockers, a second agent frequently has to be administered; beta-adrenergic blockers can be useful in this circumstance; however, they are usually not effective as single agents because of the low renin state that develops after tran~p1antation.l~~ Alpha-adrenergic blockers have been used, but orthostatic symptoms can occur. Angiotensin converting enzyme (ACE) inhibitors are effective vasodilators, but they must be used with caution; a fall in GFR and hyperkalemia can follow initiation of therapy. Diuretics may be appropriate for selected patients, but their use has been associated with intravascular volume depletion, azotemia, and hyperuricemia.

Renal Insufficiency

Because patients who receive allografts are living longer, renal insufficiency has become an important cause of morbidity. Long-term therapy with cyclosporine and tacrolimus is associated with renal dysfunction.lg3Fisher et a1 found that 80% of patients treated with cyclosporine had a reduction in renal In patients surviving at least 1 year, 4% function 5 years after tran~plantation.~~ developed severe renal insufficiency and 2% sustained end-stage renal disease (ESRD) requiring dialysis. The median time to onset of ESRD was approximately 5 years. Studies comparing cyclosporine to tacrolimus found that the rate of late nephrotoxocity was similar; however, higher doses of tacrolimus were used in these re~0rts.I~" 148 Interestingly, other studies found that patients receiving tacrolimus had a lower GFR at 12 or 24 months when compared with patients receiving cyclosporine?o,152 Dose reduction of immunosuppressant early after transplantation is usually effective in stabilizing or reversing mild-to-moderate renal dysfunction.8s,152 Herrero et a1 showed that the dose of cyclosporine could be reduced in 10 of 11 patients with moderate renal insufficiency who also received myc~phenolate.~~ Improvements in serum creatinine and creatinine clearance were noted in 9 patients. In another study of 19 patients with azotemia and stable graft function, conversion from cyclosporine to tacrolimus led to a significant improvement in serum creatinine in 13 patients (68%).157 Along with judicious use of immunosuppressants, other nephrotoxic medications and dehydration should be avoided. Aminoglycosides, nonsteroidal anti-

MODERN IMMUNOSUPPRESSION

641

inflammatory drugs, and amphotericin B may worsen renal function in patients who are receiving cyclosporine or tacrolimus. Progression to chronic renal failure or ESRD is usually irre~ersible.~~ pathologic changes suggestive of chronic cyclosporine or tacrolimus toxicity include vascular obliteration, tubular atrophy, interstitial fibrosis, and glomerular 175 Dialysis or renal transplantation may be required for selected patients (see article by Dr. Wilkinsen). Hyperlipidemia

The cause of posttransplant hyperlipidemia is multifactorial including corticosteroids, diuretics and beta blockers use, weight gain, and genetic susceptibility.211The role of cyclosporine and tacrolimus in the pathogenesis of hyperlipidemia remains unclear. Cyclosporine may interfere with bile acid synthesis and cholesterol d e g r a d a t i ~ nor ,~~ may interfere with feedback control of cholesterol synthesis after binding to the low density lipoproteins (LDL) receptor.35 Hypercholesterolemia may be more prevalent in patients receiving cyclosporine (20% to 75%)when compared with patients receiving tacrolimus (0 to 50%).7,19, 66, 75, Differences, however, in corticosteroid requirements between the two groups may account for discrepant results.= Triglyceride levels also show an increase after transplantation, with no significant difference between cyclosporine or tacrolimus.' 19, 66, lO3 The initial approach to hyperlipidemia in the transplant recipient is to control dietary intake of fat and cholesterol. Maintenance of ideal body weight after transplantation is also important. Tapering of steroids has a beneficial effect on cholesterol levels." 25, lS7 3-Hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA)reductase inhibitors are currently first line agents. Imagawa et a1 used pravastatin for 1 year in 98 patients who exhibited stable allograft function and hyperchole~terolemia.~~ No episodes of rhabdomyolysis or hepatotoxicity occurred; however, the medication was discontinued in two patients because of myositis and mild elevation in creatine phosphokinase. Mean pretreatment cholesterol levels were 251 mg / dL for both cyclosporine and tacrolimus patients. After 12 months of treatment, mean cholesterol levels were 224 mg/dL and 208 mg/dL for cyclosporine and tacrolimus patients respectively. Triglyceride levels decreased in a similar fashion; however, there were no significant changes in LDL and high-density lipoprotein (HDL) levels over time in either treatment group. Other HMG-CoA reductase inhibitors (simvastatin and lovastatin) have been shown to be safe in renal and cardiac transplant patients.z3,202 Bile acid sequestrants are now often limited to combination regimens with HMG-CoA reductase inhibitors.la They have not been used extensively in transplant patients because of concern that they may interfere with the absorption of other drugs, such as cyclosporine. Niacin has been used to treat hypertriglyceridemia in patients on cyclosporine, though patients should be followed closely for evidence of rhabdomyolysis or m ~ o s i t i s . ' ~ ~ Steroid Withdrawal

Many posttransplant metabolic complications (diabetes, hyperlipidemia, osteoporosis, hypertension) are related to corticosteroids. In one prospective study, complete prednisone withdrawal 14 days after transplantation in patients receiv-

642

CRONIN et a1

ing mycophenolate mofetil and either cyclosporine or tacrolimus led to a lower incidence of metabolic complication^.^^^ Six months after transplantation, 12% and 30% of patients on tacrolimus-mycophenolate and cyclosporine-mycophenolate respectively developed hypertension, when compared with 64% of patients receiving prednisone and cyclosporine. Hypercholesterolemia and new-onset diabetes were less prevalent in patients undergoing rapid steroid withdrawal. The incidence of acute rejection (46% in the cyclosporine-mycophenolate group and 42% in the tacrolimus-mycophenolate group) was comparable with that of other studies. The investigators concluded that early withdrawal of prednisone was well tolerated by patients and was associated with fewer metabolic complications. Other studies have shown a favorable influence on cholesterol level, hypertension, and diabetes after complete withdrawal of prednisone early after 34 Long-term allograft recipients also appear to benefit?" lS7 tran~plantation?~, One obvious concern with steroid withdrawal is the potential for precipitating rejection. McDiarmid et a1 randomized patients with stable graft function into a steroid withdrawal group (31 patients) and a control group (29 patients)."' Patient transplanted for autoimmune hepatitis and those with a history of biopsy-proven rejection more than 6 months after transplantation were excluded from the study. All patients initially received cyclosporine (trough 120 ng/mL to 180 ng/mL), azathioprine (1 mg/kg/d) and prednisone (5 mg/d). In the steroid withdrawal group, prednisone was reduced by 1 mg every 2 weeks. In 1-year of follow-up, two patients in each group developed mild acute rejection. Chronic rejection did not occur in either group. The investigators concluded that late steroid withdrawal was not associated with an increased risk of rejection. Another report suggested that the incidence of acute and chronic rejection was less in patients receiving cyclosporine and azathioprine when compared with those receiving cyclosporine alone after steroids were withdrawn.le All cases of chronic rejection and most episodes of acute rejection occurred in patients on cyclosporine monotherapy. In another study, prednisone was reduced gradually and stopped at a mean of 3.5 months po~ttransplantation.'~~ After 23 months of follow-up, the rate of acute rejection was 21%; cyclosporine monotherapy was associated with a higher rate of acute rejection when compared with regimens consisting of cyclosporine-azathioprine, tacrolimus monotherapy, or tacrolimus-azathioprine. In summary, steroid withdrawal after transplantation affords the benefit of decreased metabolic complications. Withdrawal of steroids in patients with stable graft function appears to be safe, with no significant increased risk of rejection. A two drug cyclosporine-based regimen or tacrolimus may be preferable to cyclosporine monotherapy after steroid withdrawal. Additional studies should address the role of novel immunosuppressants in steroid withdrawal protocols. PEDIATRIC IMMUNOSUPPRESSION

Initial Immunosuppression

Over the past decade, immunosuppression regiments in pediatrics have also become more varied. Direct comparisons between pediatric patients receiving cyclosporine and tacrolimus have demonstrated similar graft and patient survival, but patients receiving tacrolimus had less acute, chronic, and steroid-resistant rejection.', Although triple therapy is required with cyclosporine, tacrolimus is used in combination with prednisone alone."5, 193, 199 Another advantage of tacrolimus

MODERN IMMUNOSUPPRESSION

643

is steroids can be withdrawn much more rapidly then in cyclosporine-based immunosuppression thereby limiting the complications associated with long115, 199 term steroid In early studies, the rate of adverse events in patients on tacrolimus was higher then those patients taking cyclosporine; however, more recent studies demonstrate a favorable profile.', 78, 16' The incidence of nephrotoxicity and hypertension are similar to those reported with cyclosporine, but the rate of hyperkalemia requiring treatment and the rate of insulin-dependent diabetes is slightly higher then that reported for cyclosporine.', 78, 161 The most worrisome side effect in pediatric patients receiving tacrolimus is on increased incidence of posttransplant lymphoproliferative disease. In cyclosporine-based immunosuplz5, 138 pression the rate is 4% and the rate on tacrolimus is 6% to 13%.78, Neoral is a microemulsified form of cyclosporine. Compared with Sandimmune, Neoral has better absorption and bioa~ailability.~~ Sandimmune is poorly absorbed after liver transplantation because bile flow is diminished; therefore, in the early postoperative period and when patients have graft dysfunction with cholestasis the cyclosporine needs to be given intravenously.lB Infants with smaller bowel length have poorer Sandimmune absorption.z12Neoral gives the advantage of being given orally regardless of bile flow. In studies comparing the two drugs directly, smaller doses of Neoral were required to attain the same peak and trough levels of cyclosporine. The increased exposure to cyclosporine offered by Neoral had the potential to reduce rejection rates.33,43 In studies comparing pediatric patients taking Sandimmune and Neoral directly there was no significant difference in the rates of rejection, or of graft or patient survival.102 The results in adult studies are mixed.62 lz3 As many as 70% to 74% of pediatric patients on tacrolimus can be maintained on single drug therapy 1 year after trans~lant.~~, '15 Because cyclosporine is a less potent immunosuppressant drug, most patients are maintained on double immunosuppression with steroid use long-term. Recently in a study of long-term pediatric liver transplant survivors (>18 months) receiving cyclosporine, 28 of 37 patients were considered eligible for monotherapy and 25 were able to be maintained on single drug therapy." A similar study with both adult and pediatric patients demonstrated steroids could be withdrawn safely in long-term survivors maintained on cyclosporine and azathiaprine."' These patients had improvement in their lipid profiles."' Potential withdrawal of all immunosuppressive drugs has been the focus of two studies. The University of Pittsburgh's on-going study has 95 patients enrolled in a drug withdrawal program.lo7Nineteen YO of patients are drug free and an additional 39% are still being weaned off their medication. Twenty-nine % of patients were restarted on immunosuppression because of biopsy-proven or presumed rejection, and 13% have withdrawn from the study, including two for recurrent autoimmune disease.lo7In a King's College study 18 patients were enrolled in a rapid drug withdrawal study?6Five patients (28%) were completely taken off drugs. The remaining 13 had biochemical dysfunction, with biopsies demonstrating rejection in 4 and various histologic abnormalities in the remaining patients. Once immunosuppressive drugs were reintroduced, nine patients had normalization of their liver function and were able to wean their immunosuppression below baseline levels. Unfortunately, the major potential benefit of decreasing serious side effects such as hypertension and renal impairment have yet to be demonstrated in these studies.'07 In both studies the risk of rejection and other histologic changes were significant?6,Io7 It has been suggested that demonstration of microchimerism derived from the donor may be associated with graft tolerance.181There

644

CRONIN et a1

was no consistent demonstration of microchimerism in patients who tolerated immunosuppression withdrawal and several studies have demonstrated late rejection episodes despite the presence of microchimerism?6,47, Iz4 Current Pediatric Immunosuppression

Over the past five years, SPLIT (study of pediatric liver transplantation) has begun collecting data about practices in pediatric liver transplant centers. The summary of this data allows insight into current practices across the United States. Most recently data was published on 404 pediatric transplant patients.65At initial transplant 50% of patients were placed on cyclosporine-based immunosuppression. Most patients (42% of all patients) were on cyclosporine, steroids, and azathiaprine. Forty-four percent of patients received tacrolimus, most commonly in combination with steroids alone (29%). An additional 2.5% received steroids alone or in combination with antibody induction or azathiaprine. Ten percent of patients received antibody induction therapy. Over 12 month follow-up the percentage of patients being treated with tacrolimus increased to 43.1% at day 30, 46.8% at 6 months, and 49.2% at 12 months. At 12 months, 28.3% of patients were being treated with triple immunosuppression, with combinations of cyclosporine or tacrolimus with steroids and azathiaprine or mycophenolate. There were 44.9% of patients being treated with double therapy of cyclosporine or tacrolimus with steroids. There were 20.3% on single therapy, most (13.9%)on tacrolimus. Posttransplant LymphoproliferativeDisease (PTLD)

The use of increasingly potent immunosuppressives has been associated with an increased rate of Epstein-Barr virus (EBV) associated PTLD, especially in pediatric patients.I7,78, 12*, 138 During the early 1980s when cyclosporine was the primary immunosuppressant, the incidence of PTLD in pediatric patients was approximately 4%.Iq5With the introduction of tacrolimus the incidence of 78, lz5,138 In patients with resistant rejection PTLD has increased to 6% to 13%.17* requiring the use of OKT3 and conversion from cyclosporine to tacrolimus, and incidence as high as 27% has been dem~nstrated.'~~ The role of EBV in PTLD is well established.n Cyclosporine, tacrolimus and OKT3 all act via suppression of cytotoxic T cells. This suppression inhibits the host's immune surveillance against EBV. The risk of developing PTLD is much greater in a primary EBV infection and this places pediatric patients at high risk because they are likely to be seronegative for EBV before transplant. Also, they are likely to receive a graft from and EBV-positive donor leading to a primary EBV infection. Posttransplant lymphoproliferative disease should be suspected in any pediatric patient with fever of unknown origin, lymphadenopathy, unexplained graft dysfunction, gastrointestinal bleeding or perforation, or upper airway obstmction.17,138 The disease is frequently found in the liver graft, gastrointestinal tract, and abdominal or peripheral lymph n o d e ~ . ' ~The , ' ~ ~histology ranges from welllocalized polyclonal proliferation of lymphocytes to malignant lymph~ma.'~, n,13* The disease has been classified into three clinical entities: mononucleosis-type syndrome, lymphoproliferation, and malignant lymphoma.72 The treatment of PTLD includes decreasing immunosuppression and initiat-

MODERN IMMUNOSUPPRESSION

645

ing antiviral therapy. In the late 1980s and early 1990s patients who failed to respond to decreased immunosuppression were treated with interferon but there was no statistically significant improvement in survival in treated patients so interferon is no longer used.17,112, 138 Today, patients who fail to respond to decreased immunosuppression and antiviral therapy are given chemotherapy. In addition, patients who present with malignant lymphoma are treated with conventional lymphoma ~hernotherapy.'~, 138 Despite the increased incidence PTLD, several interventions have led to a decrease in the morbidity and m~rtality.'~,'~~ First, the ability to monitor EBV viral load through EBV-PCR has improved. Immunosuppression can be lowered when there is evidence of increased viral load (200 genome copies/ lo5 peripheral blood lymphocytes) before appearance of PTLD symptoms. Second, the recognition of the high risk in pediatrics has led to prophylaxis against EBV infection. Several regimens are used, including giving intravenous ganciclovir for 14 days postoperatively followed by oral antivirals for 90 days posttransplant or intravenous ganciclovir for 100 days.112Prophylaxis is used in h g h risk patients, defined as patients seronegative for EBV receiving grafts from a seropositive donor, or all pediatric patients depending on the center.112Finally, there is evidence the currently used antiviral ganciclovir may be more effective then antivirals previously used.11o Treatment of PTLD by reduction of immunosuppression led to a high incidence of chronic rejection in patients who survived PTLD.13*Because patients responding to treatment for PTLD decrease their EBV viral load, the ability to monitor viral load makes it possible to make an informed decision when it is appropriate to reinstate immunosuppression.63Although some patients show evidence of increasing viral load once immunosuppression is restarted, most patients did not have recurrence of PTLD.I7,63 In summary, the current treatment of PTLD includes prophylaxis at the time of transplant, decreasing or stopping immunosuppression and initiation of antiviral therapy in patients with polymerase chain reaction (PCR)or clinical evidence of PTLD, and judicial reintroduction of immunosuppression in patients who have cleared their PTLD and begin to have rejection. References 1. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. The US.Multicenter FK506 Liver Study Group [see comments]. N Engl J Med 331:1110, 1994 2. Abouljoud MS, Levy MF, Klintmalm GB: Hyperlipidemia after liver transplantation: Long-term results of the FK506/ cyclosporine a US multicenter trial. Transplant Proc 271121, 1995 3. Abramowicz D, De Pauw L, Le Moine A, et al: Prevention of OKT3 nephrotoxicity after kidney transplantation. Kidney Int 53(suppl):S39, 1996 4. Allison AC, Eugui E M Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil. Immunol Rev 136:5, 1993 5. Allison AC, Kowalski WJ, Muller CD, et al: Mechanisms of action of mycophenolic acid. Ann NY Acad Sci 696:63, 1993 6. Andoh TF, Burdmann EA, Lindsley J, et al: Functional and structural characteristics of experimental FK 506 nephrotoxicity. Clin Exp Pharmacol Physiol22:646, 1995 7. Atillasoy E, Gurkan A, Mor E, et al: Cholesterol levels long term after liver transplant. Transplant Proc 30:2049, 1998 8. Balan V, Abu-Elmagd K, Demetris AJ: Autoimmune liver diseases: recurrence after liver transplantation. Surg Clin North Am 79:147, 1999 9. Berard JL, Velez RL, Freeman RB, et al: A review of interleukin-2 receptor antagonists in solid organ transplantation. Pharmacotherapy 19:1127, 1999

646

CRONIN et a1

10. Bierer BE, Mattila PS, Standaert RF, et al: Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. Proc Natl Acad Sci U S A 879231, 1990 11. Birnbaum AH, Benkov KJ, Pittman NS, et al: Recurrence of autoimmune hepatitis in children after liver transplantation. J Pediat Gastroenterol Nutr 25:20, 1997 12. Bonnefoy-Berard N, Flacher M, Revillard JP: Antiproliferative effect of antilymphocyte globulins on B cells and B- cell lines. Blood 79:2164, 1992 13. Bonnefoy-Berard N, Revillard JP: Mechanisms of immunosuppression induced by antithymocyte globulins and OKT3. J Heart Lung Transplant 15:435, 1996 14. Bonnefoy-Berard N, Verrier 8, Vincent C, et al: Inhibition of CD25 (IL-2R alpha) expression and T-cell proliferation by polyclonal anti-thymocyte globulins. Immunology 7761, 1992 15. Brennan DC, Flavin K, Lowell JA, et al: A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients [published erratum appears in Transplantation 1999 May 27;671386]. Transplantation 671011, 1999 16. Buysmann S, Bemelman FJ, Schellekens PT, et al: Activation and increased expression of adhesion molecules on peripheral blood lymphocytes is a mechanism for the immediate lymphocytopenia after administration of OKT3. Blood 87404, 1996 17. Cacciarelli TV, Green M, Jaffe R, et a1 Management of posttransplant lymphoproliferative disease in pediatric liver transplant recipients receiving primary tacrolimus (FK506) therapy. Transplantation 66:1047, 1998 18. Calne RY, Rolles K, White DJ, et al: Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet 2:1033, 1979 19. Canzanello VJ, Schwartz L, Taler SJ, et al: Evolution of cardiovascular risk after liver transplantation: a comparison of cyclosporine A and tacrolimus (FK506).Liver Transpl Surg 33, 1997 20. Canzanello VJ, Textor SC, Taler SJ, et al: Late hypertension after liver transplantation: a comparison of cyclosporine and tacrolimus (FK506). Liver Transplant Surg 4:328, 1998 21. Canzanello VJ, Textor SC, Taler SJ, et al: Renal sodium handling with cyclosporin A and FK506 after orthotopic liver transplantation. J Am SOCNephrol 5:1910, 1995 22. Capone I'M, Cohen ME: Seizures and cerebritis associated with administration of OKT3. Pediatr Neurol 7299, 1991 23. Castelao AM, Grino JM, Andres E, et al: HMGCoA reductase inhibitors lovastatin and simvastatin in the treatment of hypercholesterolemia after renal transplantation. Transplant Proc 25:1043, 1993 24. Chan CK, Head G A Relative importance of central imidazoline receptors for the antihypertensive effects of moxonidine and rilmenidine. J Hypertens 14855, 1996 25. Charco R, Cantarell C, Vargas V, et al: Serum cholesterol changes in long-term survivors of liver transplantation: a comparison between cyclosporine and tacrolimus therapy. Liver Transplant Surg 5:204, 1999 26. Christians U, Sewing KF: Cyclosporin metabolism in transplant patients. Pharmacol Ther 57291, 1993 27. Chung J, Kuo CJ, Crabtree GR, et al: Rapamycin-FKBP specifically blocks growthdependent activation of and signaling by the 70 kd S6 protein kinases. Cell 69:1227, 1992 28. Ciancio G, Siquijor AP, Burke GW, et al: Post-transplant lymphoproliferative disease in kidney transplant patients in the new immunosuppressive era. Clin Transplant 11:243, 1997 29. Colonna JOd, Goldstein LI, Brems JJ, et al: A prospective study on the use of monoclonal anti-T3-cell antibody (OKT3) to treat steroid-resistant liver transplant rejection. Arch Surg 1221120, 1987 30. Cooper DK, Novitzky D, Davis L, et al: Does central nervous system toxicity occur in transplant patients with hypercholesterolemia receiving cyclosporine? J Heart Transplant 8:221, 1989 31. Cosimi AB, Cho SI, Delmonico FL, et al: A randomized clinical trial comparing OKT3

MODERN IMMUNOSUPPRESSION

32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44.

45. 46. 47. 48. 49. 50. 51. 52. 53.

54.

647

and steroids for treatment of hepatic allograft rejection. Transplant Proc 19(1 Pt 3):2431, 1987 Costanzo-Nordin MR Cardiopulmonary effects of OKT3: determinants of hypotension, pulmonary edema, and cardiac dysfunction. Transplant Proc 25:21, 1993 DAgostino D, Gimenez M, Yamaguchi B, et al: Conversion and pharmacokinetic studies of a microemulsion formulation of cyclosporine in pediatric liver transplant patients. Transplantation 62:1068, 1996 De Carlis L, Belli LS, Rondinara GF, et al: Early steroid withdrawal in liver transplant patients: final report of a prospective randomized trial. Transplant Proc 29:539, 1997 deGroen P: Cyclosporine, low density lipoprotein, and cholesterol. Mayo Clinic Proc 63:1012, 1988 Devlin J, Doherty D, Thomson L, et al: Defining the outcome of immunosuppression withdrawal after liver transplantation. Hepatology 27926, 1998 Devlin J, Williams R Transplantation for filminant hepatic failure: comparing tacrolimus versus cyclosporine for immunosuppression and the outcome in elective transplants. Transplantation 62:1251, 1996 Dietze 0, Vogel W, Margreiter R Primary biliary cirrhosis (PBC) after liver transplantation. Transplant Proc 22:1501, 1990 Dmitrewski J, Hubscher SG, Mayer AD, et al: Recurrence of primary biliary cirrhosis in the liver allograft: the effect of immunosuppression. J Hepatol24253, 1996 Doyle HR, Morelli F, McMichael J, et al: Hepatic retransplantation: an analysis of risk factors associated with outcome. Transplantation 61:1499, 1996 Drachenberg CB, Klassen DK, Weir MR, et al: Islet cell damage associated with tacrolimus and cyclosporine: morphological features in pancreas allograft biopsies and clinical correlation. Transplantation 68:396, 1999 Dumont FJ, Staruch MJ, Koprak SL, et al: Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin. J Immunol 144:251, 1990 DUM SP, Cooney GF, Kulinsky A, et al: Absorption characteristics of a microemulsion formulation of cyclosporine in de novo pediatric liver transplant recipients. Transplantation 601438, 1995 DUM SP, Falkenstein K, Lawrence JP, et al: Monotherapy with cyclosporine for chronic immunosuppression in pediatric liver transplant recipients. Transplantation 57544, 1994 Eckhoff DE, McGuire BM, Frenette LR, et al: Tacrolimus (FK506) and mycophenolate mofetil combination therapy versus tacrolimus in adult liver transplantation. Transplantation 65:180, 1998 Ekberg H, Backman L, Tufveson G, et al: Zenapax (daclizumab) reduces the incidence of acute rejection episodes and improves patient survival following renal transplantation. No 14874 and No 14393 Zenapax Study Groups. Transplant Proc 31:267, 1999 Elwood ET, Larsen CP, Maurer DH, et al: Microchimerism and rejection in clinical transplantation [see comments]. Lancet 349:1358, 1997 Esquivel CO, Fung JJ, Markus B, et al: OKT3 in the reversal of acute hepatic allograft rejection. Transplant Proc 19(1 Pt 3):2443, 1987 Ferron GM, Mishina EV, Zimmerman JJ, et al: Population pharmacokinetics of sirolimus in kidney transplant patients. Clin Pharmacol Ther 61:416, 1997 Fisher NC, Nightingale PG, Gunson BK, et al: Chronic renal failure following liver transplantation. Transplantation 66:59, 1998 Fisher RA, Ham JM, Marcos A, et al: A prospective randomized trial of mycophenolate mofetil with neoral or tacrolimus after orthotopic liver transplantation. Transplantation 66:1616, 1998 Freeman D, Grant D, Levy G, et al: Pharmacokinetics of a new oral formulation of cyclosporine in liver transplant recipients. Ther Drug Monit 17213, 1995 Fryer JP, Fortier MY, Metrakos P, et al: Central pontine myelinolysis and cyclosporine neurotoxicity following liver transplantation. Transplantation 61:658, 1996 Fung J, Abu-Elmagd K, Jain A, et al: A randomised trial of primary liver transplantation under immunosuppression with FK506 vs cyclosporine. Transplant Proc 23:29772983, 1991

648

CRONIN et a1

55. Fung JJ, Todo S, Jain A, et al: Conversion from cyclosporine to FK 506 in liver allograft recipients with cyclosporine-related complications. Transplant Proc 226,1990 56. Fung JJ, Todo S, Tzakis A, et al: Conversion of liver allograft recipients from cyclosporine to FK 506-based immunosuppression: benefits and pitfalls. Transplant Proc 23(1 Pt 1):14, 1991 57. Gaber AO, First MR, Tesi RJ, et al: Results of the double-blind, randomized, multicenter, phase 111 clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation. Transplantation 6629, 1998 58. Gomez R, Moreno E, Colina F, et al: Steroid withdrawal is safe and beneficial in stable cyclosporine-treated liver transplant patients. J Hepatol28:150, 1998 59. Gordon RD, Tzakis AG, Iwatsuki S, et al: Experience with Orthoclone OKT3 monoclonal antibody in liver transplantation. Am J Kidney Dis 11:141, 1988 60. Goss JA, Shackleton CR, Farmer DG, et al: Orthotopic liver transplantation for primary sclerosing cholangitis: A 12-year single center experience. Ann Surg 225:472, 1997 61. Gothel SF, Marahiel M A Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts. Cell Mol Life Sci 55:423, 1999 62. Grant D, Rochon J, Levy G: Comparison of the long-term tolerability, pharmacodynamics, and safety of Sandimmune and Neoral in liver transplant recipients. Ontario Liver Transplant Study Group. Transplant Proc 282232, 1996 63. Green M, Cacciarelli W, Mazariegos GV, et al: Serial measurement of Epstein-Barr viral load in peripheral blood in pediatric liver transplant recipients during treatment for posttransplant lymphoproliferative disease. Transplantation 66:1641, 1998 64. Groth CG, Backman L, Morales JM, et a1 Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group [see comments]. Transplantation 671036, 1999 65. Group SR Studies of Pediatric Liver Transplantation (SPLIT) Annual Report: EMMES, 1999 66. Guckelberg 0, Langrehr JM, Bechstein WO, et al: Does the choice of primary immunosuppression influence the prevalence of cardiovascular risk factors after liver transplantation? Transplant Proc 233173, 1996 67. Hauters l?, de Hemptinne B, Carlier M, et al: Long-term analysis of glomerular filtration rate and hypertension in adult liver transplant recipients treated with cyclosporine A. Transplant Proc 23:1458, 1991 68. Hayashi M, Keeffe EB, Krams SM, et al: Allograft rejection after liver transplantation for autoimmune liver diseases. Liver Transplant Surg 4208, 1998 69. Hebert MF, Ascher NL, Lake JR, et al: Four-year follow-up of mycophenolate mofetil for graft rescue in liver allograft recipients. Transplantation 67707, 1999 70. Herrero JI, Quiroga J, Sangro 8, et al: Conversion of liver transplant recipients on cyclosporine with renal impairment to mycophenolate mofetil. Liver Transplant Surg 5:414, 1999 71. Hirano Y, Fujihira S, Ohara K, et al: Morphological and functional changes of islets of Langerhans in FK506- treated rats. Transplantation 53:889, 1992 72. Ho M, Jaffe R, Miller G, et al: The frequency of Epstein-Barr virus infection and associated lymphoproliferative syndrome after transplantation and its manifestations in children. Transplantation 45:719, 1988 73. Ho S, Clipstone N, Timmermann L, et al: The mechanism of action of cyclosporin A and FK506. Clin Immunol Immunopathol80(3 Pt 2):S40,1996 74. Hubscher SG, Elias E, Buckels JAC, et al: Primary biliary cirrhosis: histological evidence of disease recurrence after liver transplantation. J Hepatol 18:173, 1993 75. Imagawa DK, Dawson S, Holt CD, et al: Hyperlipidemia after liver transplantation. Transplantation 62934, 1996 76. Jain A, Brody D, Hamad I, et al: Conversion to neoral for neurotoxicity after primary adult liver transplantation under tacrolimus [in process citation]. Transplantation 69:172, 2000 77. Jain A, Reyes J, Kashyap R, et al: Liver transplantation under tacrolimus in infants,

MODERN IMMUNOSUPPRESSION

649

children, adults, and seniors: long-term results, survival, and adverse events in 1000 consecutive patients. Transplant Proc 30:1403, 1998 78. Jain A, Reyes J, Kashyap R, et al: What have we learned about primary liver transplantation under tacrolimus immunosuppression? Long-term follow-up of the first 1000 patients. Ann Surg 230:441, 1999 79. Jeyarajah DR, Netto GJ, Lee SP, et al: Recurrent primary sclerosing cholangitis after orthotopic liver transplantation. Transplantation 661300, 1998 80. Jindal RM, Popescu I, Emre S, et al: Serum lipid changes in liver transplant recipients in a prospective trial of cyclosporine versus FK506. Transplantation 571395, 1994 81. Johnson MR, Mullen GM, OSullivan EJ, et al: Risk/benefit ratio of perioperative OKT3 in cardiac transplantation. Am J Cardiol 74261, 1994 82. Jonas S, Bechstein WO, Tullius SG, et al: Indications for tacrolimus anti-rejection therapy in liver allograft recipients. Transpl Int 9 Suppl 1 9 6 4 , 1996 83. Kahan BD, Julian BA, Pescovitz MD, et al: Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in Caucasian recipients of mismatched primary renal allografts: a phase I1 trial. Rapamune Study Group. Transplantation 68:1526, 1999 84. Kahan BD, Podbielski J, Napoli KL, et al: Immunosuppressive effects and safety of a sirolimus/ cyclosporine combination regimen for renal transplantation. Transplantation 661040, 1998 85. Kahan BD, Rajagopalan PR, Hall M: Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric antiinterleukin-2-receptor monoclonal antibody. United Stated Simulect Renal Study Group. Transplantation 67276, 1999 86. Kahan BD, Wong RL, Carter C, et al: A phase I study of a 4-week course of SDZRAD (RAD) quiescent cyclosporine-prednisone-treatedrenal transplant recipients. Transplantation 68:1100, 1999 87. Kato T, Ruiz P, DeFaria W, et al: Mycophenolate mofetil rescue therapy in patients with chronic hepatic allograft rejection. Transplant Proc 31:396, 1999 88. Keown PA Molecular and clinical therapeutics of cyclosporine in transplantation. In Ginns LC, Cosimi AB, Morris PJ (eds): Transplantation. Malden, MA, Blackwell Science, 1999, p 101 89. Klintmalm GB, Goldstein R, Gonwa T, et al: Prognostic factors for successful conversion from cyclosporine to FK 506-based immunosuppressive therapy for refractory rejection after liver transplantation. US Multicenter FK 506 Liver Study Group. Transplant Proc 25(1 Pt 1):641, 1993 90. Klintmalm GB, Goldstein R, Gonwa T, et al: Use of Prograf (FK 506) as rescue therapy for refractory rejection after liver transplantation. US Multicenter FK 506 Liver Study Group. Transplant Proc 25(1 Pt 1):679, 1993 91. Klupp J, Glanemann M, Bechstein WO, et al: Mycophenolate mofetil in combination with tacrolimus versus Neoral after liver transplantation. Transplant Proc 31(12):1113, 1999 92. Kovarik I. Breidenbach T, Gerbeau C. et al: Disuosition and immunodvnamics of basiliximab in liver allograft recipients: Clin Pharmacol Ther 64:66, 1998 ’ 93. Kovarik JM, Rawlings E, Sweny P, et al: Pharmacokinetics and immunodynamics of chimeric IL-2 receptor monoclonal antibody SDZ CHI 621 in renal allograft recipients. Transpl Int 9 Suppl 1:S32, 1996 94. Kumar N, Wall WJ, Grant DR, et al: Liver retransplantation. Transplant Proc 31:541, 1999 95. Kuo CJ, Chung J, Fiorentino DF, et al: Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature 358(6381):70, 1992 96. Lampen A, Christians U, Gonschior AK, et a1 Metabolism of the macrolide immunosuppressant, tacrolimus, by the pig gut mucosa in the Ussing chamber. Br J Phannacol 1171730, 1996 97. Lampen A, Christians U, Guengerich FP, et al: Metabolism of the immunosuppressant tacrolimus in the small intestine: cytochrome P450, drug interactions, and interindividual variability. Drug Metab Dispos 23:1315, 1995

650

CRONIN et a1

98. Lee CW, Logan JL, Zukoski CF: Cardiovascular collapse following orthoclone OKT3 administration: a case report. Am J Kidney Dis 1773, 1991 99. Lee YM, Kaplan M M Primary biliary cirrhosis. In Friedman LS, Keefe EB (eds): Handbook of Liver Disease. Edinburgh, Churchill Livingstone, 1998, p 197 100. Lin JC, Smith MC, Pagano JS: Prolonged inhibitory effect of 9-(1,3-dihydroxy-2propoxymethyl) guanine against replication of Epstein-Barr virus. J Virol 50:50, 1984 101. Liu J: FK506 and cyclosporin, molecular probes for studying intracellular signal transduction [published erratum appears in Immunol Today 14:399, Aug 19931. Immunol Today 14290, 1993 102. Loss GE, Jr, Brady L, Grewal HE', et al: Cyclosporine versus cyclosporine microemulsion in pediatric liver transplant recipients. Transplant Proc 301435, 1998 103. Loss M, Winkler M, Schneider A, et al: M u e n c e of long-term cyclosporine or FK506 therapy on glucose and lipid metabolism in stable liver graft recipients. Transplant Proc 27:1136, 1995 104. Luo H, Chen H, Daloze P, et al: Inhibition of in vitro immunoglobulin production by rapamycin. Transplantation 53:1071, 1992 105. Markmann JF, Gornbein J, Markowitz JS, et al: A simple model to estimate survival after retransplantation of the liver. Transplantation 67422, 1999 106. Mattila PS, Ullman KS, Fiering S, et al: The actions of cyclosporin A and FK506 suggest a novel step in the activation of T lymphocytes. EMBOJ 9:4425, 1990 107. Mazariegos GV, Reyes J, Marino IR, et al: Weaning of immunosuppression in liver transplant recipients. Transplantation 63243, 1997 108. McAlister V, Gao Z, Pltekian K, et al: Sirolimus-tacrolimus combination immunosuppression. Lancet 355(9201), 2000 109. McDiarmid SV, Colonna JOd, Shaked A, et al: A comparison of renal function in cyclosporine- and FK-506-treated patients after primary orthotopic liver transplantation. Transplantation 56:847, 1993 110. McDiarmid SV, Colonna JO 11, Shaked A, et al: Differences in oral FK506 dose requirements between adult and pediatric liver transplant patients. Transplantation 55:1328, 1993 111. McDiarmid SV, Farmer DA, Goldstein LI, et al: A randomized prospective trial of steroid withdrawal after liver transplantation. Transplantation 60:1443, 1995 112. McDiarmid SV, Jordan S, Lee GS, et al: Prevention and preemptive therapy of postransplant lymphoproliferative disease in pediatric liver recipients. Transplantation 66:1604, 1998 113. McDiarmid SV, Klintmalm GB, Busuttil RW. FK506 conversion for intractable rejection of the liver allograft. Transpl Int 6305, 1993 114. McDiarmid SV, Millis MJ, Terasaki PI, et al: OKT3 prophylaxis in liver transplantation. Dig Dis Sci 361418, 1991 115. McKee M, Mattei P, Schwarz K, et al: Steroid withdrawal in tacrolimus (FK506)treated pediatric liver transplant recipients. J Pediatr Surg 32973, 1997 116. Mignat C: Clinically significant drug interactions with new immunosuppressive agents. Drug Saf 16267, 1997 117. Milkiewicz P, Hubscher SG, Skiba G, et al: Recurrence of autoimmune hepatitis after liver transplantation. Transplantation 68253, 1999 118. Millis JM, Bruce DS, Newell KA, et al: Treatment of steroid-resistant rejection with tacrolimus prior to OKT3 in liver transplant recipients. Transplant Proc 28:1014, 1996 119. Millis JM, Cronin DC, Newell KA, et al: Successful use of tacrolimus for initial rejection episodes after liver transplantation. Transplant Proc 30:1407, 1998 120. Millis JM, Cronin DC, Newell KA, et al: Tacrolimus treatment of steroid-resisthnt rejection provides economic advantages compared with OKT3 therapy. Transplant Proc 29:1549, 1997 121. Millis JM, McDiarmid SV, Hiatt JR, et al: Randomized prospective trial of OKT3 for early prophylaxis of rejection after liver transplantation. Transplantation 4782, 1989 122. Millis JM, Woodle ES, Piper JB, et al: Tacrolimus for primary treatment of steroidresistant hepatic allograft rejection. Transplantation 61:1365, 1996 123. Mirza DF, Gunson BK, Soonawalla Z, et al: Reduced acute rejection after liver

MODERN IMMUNOSUPPRESSION

651

transplantation with Neoral-based triple immunosuppression [letter]. Lancet 349:701, 1997 124. Molleston JP, Alevy YG, SivaSai KS, et al: Evidence that pediatric liver transplant recipients may undergo late rejection episodes in spite of donor-specific microchimerism. Transplantation 61:656, 1996 125. Morgan G, Superina RA: Lymphoproliferative disease after pediatric liver transplantation. J Pediatr Surg 29:1192, 1994 126. Morice WG, Brunn GJ, Wiederrecht G, et al: Rapamycin-induced inhibition of p34cdc2 kinase activation is associated with Gl/S-phase growth arrest in T lymphocytes. J Biol Chem 268:3734, 1993 GJ, et al: Rapamycin inhibition of interleukin-2127. Morice WG, Wiederrecht G, B ~ M dependent p33cdk2 and p34cdc2 kinase activation in T lymphocytes. J Biol Chem 268:22737, 1993 128. Mueller AR, Platz KP, Bechstein WO, et al: Neurotoxicity after orthotopic liver transplantation: A comparison between cyclosporine and FK506. Transplantation 58:155, 1994 129. Mueller EA, Kovarik Jh4,van Bree JB, et al: Improved dose linearity of cyclosporine pharmacokinetics from a microemulsion formulation. Pharm Res 11:301, 1994 130. Mulloy LL, Wright F, Hall ML, et al: Simulect (basiliximab) reduces acute cellular rejection in renal allografts from cadaveric and living donors. Transplant Proc 31:1210, 1999 131. Nammi S, Roberts JF, Emond JC, et al: Liver transplantation for sclerosing cholangitis. Hepatology 22:451, 1995 132. Nashan B, Moore R, Arnlot P, et al: Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft reapients. CHIB 201 International Study Group [published erratum appears in Lancet 1997 Nov 15;350(9089):1484]. Lancet 350(9086):1193, 1997 133. Neuberger J, Portman B, Calne R, et al: Recurrence of autoimmune chronic active hepatitis following orthotopic liver grafting. Transplantation 37363, 1984 134. Neuberger J, Portmann B, Macdougall BRD, et al: Recurrence of primary biliary cirrhosis after liver transplantation. N Engl J Med 306:1, 1982 135. Neuhaus P, Bechstein WO, Blumhardt G, et al: Comparison of quadruple immunosuppression after liver transplantation with ATG or IL-2 receptor antibody. Transplantation 553320, 1993 136. Neuhaus P, Blumhardt G, Bechstein WO, et al: Comparison of FK506- and cyclosporine-based immunosuppression in primary orthotopic liver transplantation. Transplantation 59:31, 1995 137. New monoclonal antibodies to prevent transplant rejection. Med Lett Drugs Ther 40:93, 1998 138. Newel1 KA, Alonso EM, Whitington PF, et al: Posttransplant lymphoproliferative disease in pediatric liver transplantation. Interplay between primary Epstein-Barr virus infection and immunosuppression. Transplantation 62:370, 1996 139. OGorman MA, Fivush B, Wise B, et al: Proximal renal tubular acidosis secondary to FK506 in pediatric liver transplant patients. Clin Transplant 9:312, 1995 140. OGrady JG, Forbes A, Rolles K, et al: An analysis of cyclosporin efficacy and toxicity after liver transplantation. Transplantation 45:575, 1988 141. Onrust SV, Wiseman LR. Basiliximab. Drugs 57207, 1999 142. Otto MG, Mayer AD, Clavien PA, et al: Randomized trial of cyclosporine microemulsion (neoral) versus conventional cyclosporine in liver transplantation: MILTON study. Multicentre International Study in Liver Transplantation of Neoral [published erratum appears in Transplantation 671386, 1999 May 271. Transplantation 66:1632, 1998 143. Padbury RTA, Gunson BK, Dousset B, et al: Steroid withdrawal from long-term immunosuppression in liver allograft recipients. Transplantation 55:789, 1993 144. Papatheodoridis GV, OBeime J, Mistry P, et al: Mycophenolate mofetil monotherapy in stable liver transplant patients with cyclosporine-induced renal impairment: A preliminary report. Transplantation 68:155, 1999

652

CRONIN et a1

145. Parlevliet KJ, Bemelman FJ, Yong SL, et al: Toxicity of OKT3 increases with dosage: A controlled study in renal transplant recipients. Transpl Int 8:141, 1995 146. Pichlmayr R, Winkler M, Neuhaus P, et al: Three-year follow-up of the European Multicenter Tacrolimus (FK506) Liver Study. Transplant Proc 29:2499, 1997 147. Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. European Mycophenolate Mofetil Cooperative Study Group [see comments]. Lancet 345(8961):1321, 1995 148. Platz KP, Mueller AR, Blumhardt G, et a1 Nephrotoxicity following orthotopic liver transplantation: a comparison between cyclosporine and FK506. Transplantation 58:170, 1994 149. Platz KP, Mueller AR, Willimski C, et al: Indication for mycophenolate mofetil therapy in hepatitis C patients undergoing liver transplantation. Transplant Proc 30:2232,1998 150. Platz KP, Mueller AR, Zytowski M, et al: Management of acute steroid-resistant rejection after liver transplantation. World J Surg 20:1052, 1996 151. Polson RJ, Portmann 8,Neuberger J, et al: Evidence for disease recurrence after liver transplantation for primary biliary cirrhosis. Gastroenterology 97715, 1989 152. Porayko MK, Textor SC, Krom RAF, et al: Nephrotoxic effects of primary immunosuppression with FK-506 and cyclosporine regimens after liver transplantation. Mayo Clin Proc 69:105, 1994 153. Portela D, Pate1 R, Larson-Keller JJ, et al: OKT3 treatment for allograft rejection is a risk factor for cytomegalovirus disease in liver transplantation. J Infect Dis 171:1014, 1995 154. Porter GA, Bennett WM, Sheps SG: Cyclosporine-associatedhypertension. Arch Intern Med 150:280, 1990 155. Poston RS, Billingham M, Hoyt EG, et al: Rapamycin reverses chronic graft vascular disease in a novel cardiac allograft model. Circulation 100:67, 1999 156. Prados E, Cuervas-Mons V, De La Mata M, et al: Outcome of autoimmune hepatitis after liver transplantation. Transplantation 66:1645, 1998 157. Pratschke J, Neuhaus R, Tullius SG, et al: Treatment of cyclosporine-related adverse effects by conversion to tacrolimus after liver transplantation. Transplantation 64938, 1997 158. Ramirez CB, Sebayel MI, Kizilisik T Early steroid withdrawal after liver transplantation. Transplant Proc 30:3182, 1998 159. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. European FK506 Multicentre Liver Study Group [see comments]. Lancet 344(8920):423, 1994 160. Ratziu V, Samuel D, Sebagh M, et al: Long-term follow-up after liver transplantation for autoimmune hepatitis: evidence of recurrence of primary disease. J Hepatol 30:131, 1999 161. Reding R, Wallemacq PE, Lamy ME, et al: Conversion from cyclosporine to FK506 for salvage of immunocompromised pediatric liver allografts. Efficacy, toxicity, and dose regimen in 23 children. Transplantation 5793, 1994 162. Ringe B, Braun F, Lorf T, et al: Tacrolimus and mycophenolate mofetil in clinical liver transplantation: experience with a steroid-sparing concept. Transplant Proc 30:1415, 1998 163. Rodino MA, Schachter N, Shane E: Endocrine and metabolic considerations of organ transplantation. In Ginns LC, Cosimi AB, Morris PJ (eds): Transplantation. Malden, MA, Blackwell Science, 1999, p 672 164. Rosen HR, Schackleton CR, Higa L, et al: Use of OKT3 is associated with early and severe recurrence of hepatitis C after liver transplantation [see comments]. Am J Gastroenterol 923453, 1997 165. Rowe PA, Rocker GM, Morgan AG, et al: OKT3 and pulmonary capillary permeability. Br Med J (Clin Res Ed) 295(6606):1099, 1987 166. Sanchez-Urdazpal L, Czaja AJ, Van Hoek B, et al: Prognostic features and role of liver transplantation in severe corticosteroid-treated autoimmune chronic active hepatitis. Hepatology 15:215, 1992 167. Sattler M, Guengerich FP, Yun CH, et al: Cytochrome P-450 3A enzymes are responsi-

MODERN IMMUNOSUPPRESSION

653

ble for biotransfonnation of FK506 and rapamycin in man and rat. Drug Metab Dispos 20:753, 1992 168. Sebagh MI Farges Q, Kalil A, et al: Sclerosing cholangitis following human orthotopic liver transplantation. Am J Surg Pathol 19531, 1995 169. Sehgal SN: Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem 31:335, 1998 170. Seifeldin RA, Lawrence KR, Rahamtulla AF, et al: Generalized seizures associated with the use of muromonab-CD3 in two patients after kidney transplantation. Ann Pharmacother 31:586, 1997 171. Semigran MJ: Cardiovascular considerations of organ transplantation. In Ginns LC, Cosimi AB, Morris PJ (eds): Transplantation. Malden, MA, Blackwell Science, 1999, p 651 172. Sempoux C, Horsmans Y, Lerut J, et al: Acute lobular hepatitis as the first manifestation of recurrent autoimmune hepatitis after orthotopic liver transplantation. Liver 17311, 1997 173. Sgro C: Side-effects of a monoclonal antibody, muromonab CDB/orthoclone OKT3: bibliographic review. Toxicology 10523, 1995 174. Sher LS, Cosenza CA, Michel J, et a1 Efficacy of tacrolimus as rescue therapy for chronic rejection in orthotopic liver transplantation: a report of the US. Multicenter Liver Study Group. Transplantation 64:258, 1997 175. Shihab FS, Bennett WM, Tanner AM, et al: Mechanism of fibrosis in experimental tacrolimus nephrotoxicity. Transplantation 643829, 1997 176. Sievers TM, Rossi SJ, Ghobrial RM, et al: Mycophenolate mofetil. Pharmacotherapy 17:1178, 1997 177. Slapak GI, Saxena R, Portmann B, et al: Graft and systemic disease in long-term survivors of liver transplantation. Hepatology 25:195, 1997 178. Sollinger Hw.Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. US. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 60:225, 1995 179. Solomon H, Gonwa TA, Mor E, et al: OKT3 rescue for steroid-resistant rejection in adult liver transplantation. Transplantation 55:87, 1993 180. Spieker C, Zidek W, Barenbrock M, et a1 Cardiovascular side effects after renal allograft rejection therapy with Orthoclone: prevention with nitrendipine. J Cardiovasc Pharmacol 18 Suppl 1579, 1991 181. Starzl TE, Demetris AJ, Murase N, et al: Cell migration, himerism, and graft acceptance [see comments]. Lancet 339(8809):1579, 1992 182. Starzl TE, Groth CG, Brettschneider L, et al: Orthotopic homotransplantation of the human liver. Ann Surg 168:392, 1968 183. Starzl TE, Klintmalm GB, Porter KA, et al: Liver transplantation with use of cyclosporin a and prednisone. N Engl J Med 305266, 1981 184. Starzl TE, Porter KA, Mazzaferro V, et al: Hepatotrophic effects of FK506 in dogs. Transplantation 51:67, 1991 185. Starzl TE, Todo S, Fung J, et al: FK 506 for liver, kidney, and pancreas transplantation. Lancet 2(8670):1000, 1989 186. Stegall MD, Everson G, Schroter G, et al: Metabolic complications after liver transplantation. Diabetes, hypercholesterolemia, hypertension, and obesity. Transplantation 60:1057, 1995 187. Stegall MD, Everson GT, Schroter G, et al: Prednisone withdrawal late after adult liver transplantation reduces diabetes, hypertension, and hypercholesterolemia without causing graft loss. Hepatology 25373, 1997 188. Stegall MD, Wachs ME, Everson G, et al: Prednisone withdrawal 14 days after liver transplantation with mycophenolate: a prospective trial of cyclosporine and tacrolimus. Transplantation 64:1755, 1997 189. Takaya S, Bronsther 0, Todo S, et al: Retransplantation of liver: a comparison of FK506- and cyclosporine-treated patients. Transplant Proc 23:3026, 1991 190. Tamura K, Fujimura T, Tsutsumi T, et al: Transcriptional inhibition of insulin by

654

CRONIN et a1

FK506 and possible involvement of FK506 binding protein-12 in pancreatic beta-cell. Transplantation 59:1606, 1995 191. Tchervenkov J, Flemming C, Guttmann RD, et al: Use of thymoglobulin induction therapy in the prevention of acute graft rejection episodes following liver transplantation. Transplant Proc 29138 1997 192. Tejani A, Butt KM, Khawar MR, et al: Cyclosporine experience in renal transplantation in children. Mt Sinai J Med 54467, 1987 193. The US Multicenter FK506 Liver Study Group. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression in liver transplantation. N Engl J Med 331:1110, 1994 194. Thyagarajan GK, Cobanoglu A, Johnston W: FK506-induced fulminant leukoencephalopathy after single-lung transplantation. Ann Thorac Surg 64:1461, 1997 195. Tocci MJ, Matkovich DA, Collier DA, et al: The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. J Immunol 143:718, 1989 196. Torocsik HV, Curless RG, Post J, et al: FK506-induced leukoencephalopathy in children with organ transplants. Neurology 52:1497, 1999 197. Trepanier DJ, Gallant H, Legatt DE et al: Rapamycin: distribution, pharmacokinetics and therapeutic range investigations: an update. Clin Biochem 31:345, 1998 198. Trouillot TE, Shrestha R, Kam I, et al: Successful withdrawal of prednisone after adult liver transplantation for autoimmune hepatitis. Liver Transplant Surg 5:375, 1999 199. Tzakis AG, Fung JJ, Todo S, et al: Use of FK 506 in pediatric patients. Transplant Proc 23:924, 1991 200. Van de Stadt J, Gelin M, Bourgeois N, et a1 Liver transplantation for fulminant and subacute viral hepatic failure in adults. Transplant Proc 221505, 1990 201. van Hoek B, Wiesner RH, Ludwig J, et a1 Recurrence of ductopenic rejection in liver allografts after retransplantation for vanishing bile duct syndrome. Transplant Proc 231242, 1991 202. Vanhaecke 1, Van Cleemuut I, Van Lierde TV, et al: Safetv and efficacv of low dose simvastin in cardiac transplant recipients treated with cyclosporine. Transplantation 5842, 1994 203. Venkataramanan R, Jain A, Warty VS, et al: Pharmacokinetics of FK 506 in transplant patients. Transplant Proc 232736, 1991 204. Venkataramanan R, Jain A, Warty VW, et al: Pharmacokinetics of FK 506 following oral administration: a comparison of FK 506 and cyclosporine. Transplant Proc 23:931, 1991 205. Vilella-Bach M, Nuzzi P, Fang Y, et al: The FKBP12-rapamycin-bindingdomain is required for FKBP12-rapamycin-associatedprotein kinase activity and G1 progression. J Biol Chem 274:4266, 1999 206. Vincenti F, Lantz M, Bimbaum J, et al: A phase I trial of humanized anti-interleukin 2 receptor antibody in renal transplantation. Transplantation 63:33, 1997 207. Waldmann TA, OShea J: The use of antibodies against the IL-2 receptor in transplantation. Curr Opin Immunol 10:507, 1998 208. Wall WJ, Ghent CN, Roy A, et al: Use of OKT3 monoclonal antibody as induction therapy for control of rejection in liver transplantation. Dig Dis Sci 40:52, 1995 209. Wall WJ: Use of antilymphocyte induction therapy in liver transplantation. Liver Transpl Surg 54(suppl 1):S64, 1999 210. Watson CJ, Friend PJ, Jamieson NV, et a1 Sirolimus: a potent new immunosuppressant for liver transplantation. Transplantation 67505, 1999 211. Weisner RH, Martin P, Stribling R Post-transplant care/medical complications. In Norman DJ, Suki WN (eds): Primer on Transplantation. Thorofare, NJ, American Society of Transplant Physicians, 1998, p 343 212. Whitington PF, Emond JC, Whitington SH, et al: Small-bowel length and the dose of cyclosporine in children after liver transplantation. N Engl J Med 322:733, 1990 213. Wiederrecht G, Lam E, Hung S, et al: The mechanism of action of FK-506 and cyclosporin A. Ann NY Acad Sci 696:9,1993 214. Wiesner RH: A long-term comparison of tacrolimus (FK506) versus cyclosporine in liver transplantation: a report of the United States FK506 Study Group. Transplantation 66:493, 1998 v

I

_I

I

.

MODERN IMMUNOSUPPRESSION

655

215. Wilde MI, Goa KL: Muromonab CD3: a reappraisal of its pharmacology and use as prophylaxis of solid organ transplant rejection. Drugs 515365, 1996 216. Wong PYN, Portmann B, OGrady JG, et a1 Recurrence of primary biliary cirrhosis after liver transplantation following FK506-based immunosuppression. J Hepatol 17284, 1993 217. Woodle ES, Bruce DS, Josephson M, et al: FK 506 therapy for refractory renal allograft rejection: lessons from liver transplantation. Clin Transplant 10:323, 1996 218. Wright HL, Bou-Abboud CF, Hassanein T, et al: Disease recurrence and rejection following transplantation for autoimmune chronic active liver disease. Transplantation 53:136, 1992 219. Yatscoff R, LeGatt D, Keenan R, et al: Blood distribution of rapamycin. Transplantation 56:1202, 1993 220. Zimmerman JJ, Ferron GM, Lim HK, et al: The effect of a high-fat meal on the oral bioavailability of the immunosuppressant sirolimus (rapamycin). J Clin Pharmacol 39:1155, 1999

Address reprint requests to J. Michael Millis, MD Section of Transplantation Surgery Department of Surgery University of Chicago 5841 South Maryland Avenue MC 5027 Chicago, IL 60637