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Liver transplantation in adults: Overview of immunosuppression

Liver transplantation in adults: Overview of immunosuppression
Author:
John M Vierling, MD, FACP
Section Editor:
Robert S Brown, Jr, MD, MPH
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Literature review current through: Dec 2022. | This topic last updated: Sep 24, 2021.

INTRODUCTION — In 1994, the US Multicenter FK506 Liver Study Group published a paper comparing cyclosporine and tacrolimus for immunosuppression after liver transplantation [1]. The study was a landmark in the evolution of liver transplantation. First, the introduction stated that rejection remained an important cause of graft loss and death. Second, the paper reported that survival with cyclosporine and tacrolimus was similar but that tacrolimus was associated with fewer episodes of steroid-resistant rejection. Third, it reported that tacrolimus was associated with excess adverse events, including nephrotoxicity and neurotoxicity.

Liver transplantation has evolved substantially since that publication, and we have addressed many of the issues outlined in the 1994 study. Acute rejection is usually easy to manage, and we now try to balance the risk of rejection with the risk of drug toxicity. Our focus has shifted to avoiding the long-term complications of immunosuppression and recurrent liver disease. Tacrolimus has become first-line immunosuppression in most liver transplant programs, and a number of supplemental drugs allow us to customize immunosuppression.

This topic will provide an overview of the drugs used for immunosuppression following liver transplantation. The diagnosis and treatment of acute T-cell mediated (cellular) rejection are discussed elsewhere. (See "Liver transplantation in adults: Clinical manifestations and diagnosis of acute T-cell mediated (cellular) rejection of the liver allograft" and "Liver transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection of the liver allograft".)

IMMUNOBIOLOGY OF ACUTE REJECTION — Organ rejection is a multistep process that includes alloantigen recognition, lymphocyte activation, clonal expansion, and graft inflammation (figure 1 and figure 2).

Signal I: Alloantigen recognition — Alloantigen recognition requires presentation of a foreign alloantigen along with a host major histocompatibility complex (MHC) molecule. Presentation is done by an antigen-presenting cell (APC). The antigen, bound to an MHC molecule, binds to the T-cell receptor. This is the first of three signals that are required for T-cell maturation and can be aborted by antilymphocyte antibodies. (See 'Antibody therapy' below.)

Signal II: Lymphocyte activation (costimulation) — T-cell activation requires costimulation, a process in which a number of ligands on the APC bind to a variety of T-cell receptors, including CD28, CD154, CD2, CD11a, and CD54. The T-cell receptor complex is internalized and binds to immunophilin. Immunophilin stimulates calcineurin, which activates nuclear factor of T-cell activation (NFAT) by removing pyrophosphate. The activated NFAT then translocates to the nucleus where it drives interleukin (IL)-2 transcription. Two immunophilin targets, cyclophilin and FK-binding protein, are targets of cyclosporine and tacrolimus, respectively. Both agents block calcineurin and are known collectively as calcineurin inhibitors. (See 'Tacrolimus' below and 'Cyclosporine' below.)

Signal III: Clonal expansion — Newly synthesized IL-2 is secreted by T cells and binds to IL-2 receptors (IL-2R) on the cell surface in an autocrine fashion, stimulating a burst of cell proliferation. Basiliximab and daclizumab, both monoclonal antibodies against the IL-2 receptor, block this signal. Sirolimus, which binds to the downstream mechanistic target of rapamycin (mTOR), also acts at this step. Finally, the proliferation burst can be inhibited at the level of DNA synthesis by azathioprine and mycophenolate mofetil. (See 'Basiliximab' below and 'Sirolimus' below and 'Inhibitors of purine and pyrimidine synthesis' below.)

Inflammation — T-cell proliferation is associated with cell-mediated cytotoxicity and secretion of cytokines, chemokines, and adhesion molecules. The secreted mediators recruit additional inflammatory cells to the graft. The result is an inflammatory milieu with additional toxic and vasoactive mediators. Control of this step is possible with glucocorticoids and antilymphocyte antibodies. (See 'Glucocorticoids' below and 'Antibody therapy' below.)

DRUG INTERACTIONS — A major issue with the immunosuppressive agents used for liver transplant recipients (particularly calcineurin inhibitors and mechanistic target of rapamycin inhibitors) is their extensive metabolism by CYP3A4. This creates the potential for drug-drug interactions that may produce toxicity or dangerously low levels of immunosuppressive agents, leading to an increased risk of rejection. As examples, antifungal agents, some antibiotics, and many of the drugs used in the treatment of HIV inhibit CYP3A4. (See "Kidney transplantation in adults: Kidney transplantation in patients with HIV".)

A knowledge of the common interfering compounds is essential and drug levels must be monitored closely when these compounds are used (table 1).

GLUCOCORTICOIDS

Approach to therapy — Glucocorticoids suppress antibody and complement binding, upregulate interleukin (IL)-10 expression, and downregulate IL-2, IL-6, and interferon-gamma synthesis by T cells [2-4]. They have traditionally been the cornerstone of immunosuppression, and they remain the first line of initial therapy and treatment of acute allograft rejection in many centers. (See "Liver transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection of the liver allograft".)

Four steroid formulations are used commonly in transplantation: hydrocortisone, prednisone, prednisolone, and methylprednisolone. These drugs have different relative potencies (table 2). Steroid use varies among transplant centers, and there is no agreement on an ideal protocol. The protocol at Baylor College of Medicine is shown in the table (table 3). Another common regimen is a 1 gram bolus of methylprednisolone during the anhepatic phase, followed by 20 mg/day intravenously. Once the patient is able to take oral medications, he/she is switched to prednisone 20 mg/day. Tapering to zero is usually achieved over three to six months, although some centers leave patients on 5 mg/day indefinitely.

Steroids are associated with a number of side effects including diabetes, fluid retention, hypertension, emotional lability, hyperlipidemia, cosmetic changes (acne, buffalo hump, etc), poor wound healing, susceptibility to infection, visual changes, cataracts, and osteopenia, and they may cause adrenal suppression that may persist up to the time of weaning [5].

In addition to the side effects, steroid therapy increases hepatitis C virus (HCV) replication. The basis of this increase is controversial. Steroids may drive replication directly, and/or they may permit more effective replication through immunosuppression. In vitro studies using a replicon system (which avoids the effect of the immune system) have yielded conflicting results [6,7]. The controversy about steroid avoidance and tapering in HCV-infected patients is discussed below, but it is mostly of historical interest with the availability of potent direct acting antiviral agents. (See 'Patients with HCV infection' below.)

Given the problems with glucocorticoids, many centers try to wean from steroids as early as possible. This must be done cautiously since rapid steroid withdrawal can precipitate a flare of an underlying condition (eg, autoimmune hepatitis, inflammatory bowel disease, or hepatitis) or an episode of rejection. A meta-analysis looked at 16 randomized trials that compared postoperative glucocorticoid avoidance or withdrawal with glucocorticoid-containing immunosuppression [8]. There were no differences detected in mortality, graft loss, or infection rates when postoperative glucocorticoid avoidance or withdrawal was compared with glucocorticoid-containing immunosuppression. However, acute rejection and glucocorticoid-resistant rejection were more common with glucocorticoid avoidance or withdrawal (relative risk [RR] 1.33, 95% CI 1.08 to 1.64, and RR 2.14, 95% CI 1.13 to 4.02, respectively). Diabetes mellitus and hypertension occurred less often with glucocorticoid avoidance or withdrawal (RR 0.81, 95% CI 0.66 to 0.99 and RR 0.76, 95% CI 0.65 to 0.90, respectively). However, all of the studies included in the analysis were at high risk of bias.

A possible alternative to traditional glucocorticoids is budesonide. Budesonide is a glucocorticoid with reduced systemic effects because of high first-pass hepatic metabolism. Budesonide is used commonly to treat inflammatory bowel disease and has proven effective in the management of autoimmune hepatitis [9]. Its use in liver transplantation is attractive because of the high frequency of post-transplant diabetes, especially in patients transplanted for hepatitis C virus. One study reported three post-orthotopic liver transplant (OLT) patients treated with budesonide with apparent success [10]. In a single-center study including 20 post-OLT patients and 20 matched controls who were treated with glucocorticoids for 12 weeks in addition to calcineurin inhibitors and mycophenolate mofetil, budesonide was associated with lower infection rates compared with prednisone (30 versus 0 percent); however, rates of acute cellular rejection and new onset diabetes were not significantly different between the groups [11]. Further studies using budesonide for immunosuppressive therapy are needed to validate these findings.

Patients with HCV infection — A great deal of literature had been devoted to optimizing immunosuppression for patients who were transplanted for HCV-related liver disease [12-22]. However, the availability of safe and effective HCV therapy with direct-acting antivirals has revolutionized the approach to HCV management in liver transplant candidates and recipients. Many patients are successfully treated for HCV infection before liver transplantation. Management of HCV infection in liver transplant candidates and recipients is discussed separately. (See "Hepatitis C virus infection in liver transplant candidates and recipients".)

CALCINEURIN INHIBITORS — The early challenges to successful liver transplantation included surgical technique, organ preservation, and immunosuppression. As surgical technique improved, the need for better immunosuppression became more obvious. A report published in 1980 described one-year survival of only 26 percent [23]. The introduction of the calcineurin inhibitor (CNI) cyclosporine A the following year marked a turning point in liver transplantation [24,25].

Cyclosporine — Cyclosporine, a peptide derived from the fungus Cylindrocarpon lucidum, is a potent immunosuppressive agent [26]. It inhibits T-cell activation by binding intracellular cyclophilin, thus reducing calcineurin activation. Without calcineurin, the nuclear factor of activated T cells (NFAT) does not translocate to the nucleus, and interleukin (IL)-2 production (along with a number of other genes) is shut down. The result is a markedly diminished T-cell response to class I and class II antigens, and a significant reduction in the rejection cascade.

The impact of cyclosporine was illustrated in an early report in which one- and five-year survival rates with "conventional" immunosuppression (azathioprine plus prednisone) were 33 and 20 percent, respectively, while the survival rates with cyclosporine plus prednisone were 70 and 63 percent, respectively [27]. Cyclosporine subsequently became first-line therapy, and the first 1000 cases done at the University of Pittsburgh were described in a report in 1988 [28].

Cyclosporine was initially formulated as Sandimmune, a corn oil-based preparation with inconsistent absorption, especially in the absence of bile flow. Accurate dosing was difficult, and serum drug levels varied with meals. In addition, any change in bile flow (eg, with rejection episodes or biliary complications) caused a change in cyclosporine absorption. This is clearly a problem after liver transplantation, so the nonaqueous, microemulsified version (Neoral) has become the preferred formulation.

Cyclosporine can be administered intravenously, although it is usually given orally as a tablet or an oral suspension (table 4). The intravenous dose is approximately 30 percent of the oral dose because of improved bioavailability, and because it is given as a continuous infusion. All of the comments below regarding oral administration are based on the Neoral formulation of cyclosporine.

After oral administration, cyclosporine is variably absorbed in the jejunum and enters the lymphatic system. Peak blood levels are achieved in two to four hours, and the drug is widely distributed with highest concentrations in adipose, pancreatic, adrenal, renal, and hepatic tissues. The average half-life is 15 hours but ranges widely (10 to 40 hours). Cyclosporine is cleared in the bile after extensive metabolism in the liver by CYP3A4. The metabolites have little immunosuppressive activity. CYP3A4 activity (and, therefore, blood cyclosporine levels) depends upon genetic and environmental factors including gene polymorphisms, graft function, hepatitis C virus (HCV) replication, and certain foods and drugs (table 1).

Cyclosporine levels should be monitored frequently in the peritransplant period (typically daily), with decreasing frequency as graft function stabilizes and rejection becomes less of a threat. Patients who are stable can be monitored monthly, but levels should be checked more frequently if they develop an acute illness or start taking a potentially interfering drug. Several drugs commonly affect CNI levels. The goal therapeutic level of cyclosporine is usually 200 to 250 ng/mL in the first three months after transplantation, but is typically tapered to 80 to 120 ng/mL by 12 months.

Cyclosporine levels should be monitored closely, and patients should be monitored for renal toxicity, hypertension, hyperkalemia, and hypomagnesemia. Potassium-sparing diuretics and potentially nephrotoxic drugs should be avoided if possible. Neurologic toxicity may include altered mental status, polyneuropathy, dysarthria, myoclonus, seizures, hallucinations, and cortical blindness [29]. Other common problems include hyperlipidemia, gingival hyperplasia, and hirsutism. (See "Pharmacology of cyclosporine and tacrolimus".)

Tacrolimus — In an update on liver transplantation in 1988, the University of Pittsburgh group reported that phase 1 trials of FK506 (tacrolimus) had recently begun [30]. A year later, the same group described use of FK506 as salvage therapy in patients who had failed cyclosporine [31]. Within approximately five years, tacrolimus would overtake cyclosporine as the mainstay in liver transplantation.

Tacrolimus (Prograf) is a macrolide compound originally isolated from Streptomyces tsukubaensis. It inhibits IL-2 and interferon-gamma production and is 100 times more potent than cyclosporine. Oral bioavailability is variable (5 to 67 percent), and an oral dose of 0.15 mg/kg results in a peak concentration of 0.4 to 3.7 ng/mL. Like cyclosporine, tacrolimus is metabolized in the liver via CYP3A4 and is not removed by dialysis.

Cyclosporine versus tacrolimus — By the mid-1990s, most centers agreed that tacrolimus was associated with superior graft and patient survival. A criticism of the early studies was their use of oil-based cyclosporine, raising the question of bioavailability versus efficacy. A landmark study greatly influenced thinking on the subject [32]. The authors compared the efficacy of tacrolimus versus microemulsified cyclosporine in 606 patients undergoing first orthotopic liver transplant using a composite primary endpoint of death, retransplantation, or "treatment failure for immunological reasons (TFIR)." The study was an open-label, randomized design, and all patients received concomitant prednisolone and azathioprine. TFIR was defined as biopsy-proven rejection requiring a change from protocol immunosuppression including more than one cycle of increased steroid or any increased immunosuppression, including antilymphocyte preparation or investigational drug. The justification for using TFIR as an endpoint was to avoid the distorting effect of tacrolimus rescue in patients who were failing cyclosporine therapy. The groups were well matched for diagnosis, age, gender, blood group, cold ischemia time, and intraoperative blood use.

Both treatment regimens were effective, but tacrolimus was superior with regard to the composite endpoint and for patient and graft survival (figure 3). In addition, more patients in the tacrolimus group survived without an episode of significant rejection.

The results of the study were updated with a two-year extension of the randomization protocol [33]. Tacrolimus remained superior for the composite endpoint (RR 0.79; 95% CI 0.60-0.95), although the individual endpoints of freedom from death or retransplantation were no longer statistically significant. Significantly more patients randomized to tacrolimus were alive with their original graft and on their assigned medication compared with the cyclosporine group (62 versus 42 percent). Six patients were switched from tacrolimus to cyclosporine, while 17 were switched from cyclosporine to tacrolimus (five for graft rejection not meeting endpoint criteria).

Multiple subsequent studies have been performed; the superiority of tacrolimus over cyclosporine was confirmed in a meta-analysis of 16 randomized clinical trials [34,35]. Tacrolimus was superior when analyzed for survival, graft loss, acute rejection, and steroid-resistant rejection in the first year (table 5). The incidence of lymphoproliferative disease was similar for the two groups, and de novo diabetes mellitus was more common in the tacrolimus group. More patients stopped cyclosporine than tacrolimus. The authors estimated that treating 100 patients with tacrolimus versus cyclosporine would avoid rejection, steroid-resistant rejection, graft loss, and death in nine, seven, five, and two patients, respectively, but that four additional patients would develop diabetes.

Tacrolimus dosing — Tacrolimus dosing should be individualized. We usually start with a low dose (0.5 to 1 mg every 12 hours) on postoperative day 1, and aim for a level of 7 to 10 ng/mL by the end of the first week. We use lower dosing, often with the addition of an auxiliary agent like mycophenolate mofetil (MMF) or a monoclonal antibody in patients with preoperative renal impairment. It is important to attain adequate tacrolimus levels quickly. In a study of 493 liver transplantation recipients who were treated with tacrolimus as their primary immunosuppression, patients with trough tacrolimus levels >7 ng/mL at the time of a protocol liver biopsy (mean 6 days after transplantation) had lower rates of moderate or severe rejection compared with those who had lower levels (24 versus 41 percent) [36]. In addition, patients with mean levels between 7 and 10 ng/mL within 15 days after liver transplantation had lower rates of graft loss during follow-up compared with patients who had trough levels <7 ng/mL or 10 to 15 ng/mL (relative risks of 2.32 and 2.17, respectively). These findings suggest that in the early post-transplantation period, a tacrolimus level between 7 and 10 ng/mL is associated with improved outcomes. However, it must be kept in mind that because the study was not a randomized trial, it is at risk for bias and confounding.

A level of 6 ng/mL is usually satisfactory after six months, and maintenance at a level of 4 to 6 ng/mL is common beyond one year. We aim for higher levels in patients who are transplanted for autoimmune liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis. Patients transplanted for alcohol-associated liver disease or hemochromatosis usually tolerate low levels of CNIs after their initial recovery. With improved survival, our goal is to use as little immunosuppression as possible to minimize the known long-term complications of these drugs, including renal insufficiency and post-transplant lymphoproliferative disorders (PTLD).

Calcineurin inhibitors and renal failure — CNI-induced renal failure is a serious problem after orthotopic liver transplant (OLT) [37]. The problem has been exacerbated by the switch to a MELD-based organ allocation system, which is weighted towards higher serum creatinine. (See "Model for End-stage Liver Disease (MELD)".)

A number of strategies, including switching to mammalian (mechanistic) target of rapamycin (mTOR) inhibitors or using alternative supplemental immunosuppressive agents, have been tried. A retrospective analysis of patients who received either dual therapy with a CNI and a steroid (n = 3884) or triple therapy with a CNI, steroid, and MMF (n = 4946 patients) found that triple therapy was associated with a 6 percent lower adjusted risk of progressive renal disease as well as lower risk of death [38]. Progressive renal disease was defined as a 25 percent decline in estimated glomerular filtration rate (eGFR) based on the Modification of Diet in Renal Disease (MDRD) study formula. The authors hypothesized that MMF improved renal function by lowering CNI dosing and via a direct nephroprotective effect.

A prospective, multicenter trial compared standard dose tacrolimus to low dose and delayed tacrolimus with the primary endpoint of a change in eGFR (Cockroft-Gault formula) at 52 weeks [39]. Patients were divided into three groups:

Group A (n = 183): standard-dose tacrolimus (target trough >10 ng/mL) and steroids

Group B (n = 70): MMF 2 g/day, low-dose tacrolimus (target trough 8 ng/mL), and steroids

Group C (n = 172): daclizumab induction, MMF, reduced-dose tacrolimus delayed until the fifth day post-transplant, and steroids

The eGFR decreased by 23.6, 21.2, and 13.6 mL/min in groups A, B, and C, respectively (A versus C, p = 0.012; A versus B, p = 0.199).

Hemodialysis was required more frequently in group A compared with group C (10 versus 4 percent). Biopsy-proven acute rejection rates were 28, 29, and 19 percent, respectively. Patient and graft survival were similar among the groups. This study suggests that the kidney is particularly vulnerable to injury in the immediate post-OLT period. Delayed CNI dosing reduced, but did not eliminate, renal injury.

Patients with HCV infection — The availability of highly effective antiviral agents (DAAs) has greatly simplified post-OLT HCV therapy. Antiviral agents may interfere with drug metabolism because of effects on CYP3A4 and/or P-glycoprotein (gp) [40-45]. In addition, the rate of calcineurin inhibitor clearance may increase with a declining viral load. For these reasons, calcineurin inhibitor levels should be monitored closely after starting DAAs. (See "Hepatitis C virus infection in liver transplant candidates and recipients", section on 'Interactions with immunosuppressive agents'.)

Drug interactions can also be checked through the Lexicomp drug interactions program included with UpToDate.

Summary on the role of calcineurin inhibitors — Cyclosporine and tacrolimus are potent immunosuppressive agents. Their availability has allowed us to shift our focus from acute cellular rejection and short-term post-transplant survival to long-term management of complications. They have similar adverse effects including nephrotoxicity, neurotoxicity, and electrolyte abnormalities, and both can be monitored with drug levels.

Tacrolimus is superior in terms of preventing acute rejection, steroid-resistant rejection, graft loss, and postoperative death. These findings have made tacrolimus first line therapy in most liver transplant centers despite its higher association with post-transplant diabetes mellitus. Diabetes is a significant concern since it will probably contribute to the progressive renal failure that may be seen in long-term survivors.

The concept is that significant immunosuppression is needed in the immediate post-transplant period. Beyond this period, the complications of excessive immunosuppression outweigh the ever decreasing risk of organ rejection. With careful monitoring, low doses of immunosuppression are usually well tolerated.

INHIBITORS OF MAMMALIAN (MECHANISTIC) TARGET OF RAPAMYCIN (MTOR)

Sirolimus — Sirolimus (Rapamune), a macrolide antibiotic produced by Streptomyces hygroscopicus, is a potent immunosuppressive agent approved by the US Food and Drug Administration (FDA) for renal transplantation in 1999 [46]. It is structurally similar to tacrolimus and binds the same target (FK-binding protein) but does not inhibit calcineurin. Instead, it blocks the transduction signal from the IL-2 receptor, thus inhibiting T- and B-cell proliferation. Its advantage over the calcineurin inhibitors (CNIs) is its freedom from nephrotoxicity and neurotoxicity. However, side effects of sirolimus have relegated it to the status of an important second-line drug. (See 'Side effects' below.)

The effectiveness of sirolimus was illustrated in an early report of its use in 15 patients undergoing liver transplantation [47]. Sirolimus was used as a single agent or as part of dual (sirolimus and cyclosporine) or triple therapy (sirolimus, cyclosporine, and prednisolone). Rejection was seen more commonly with monotherapy, rarely with dual therapy, and not at all with triple therapy. In addition, all patients were on sirolimus monotherapy by three months. Only 3 of the 15 patients discontinued sirolimus: one for hyperlipidemia, one for taste perversion, and one for Pneumocystis pneumonia.

Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus, the two drugs act synergistically, rather than competitively, to prevent rejection. This led to speculation that a low-dose combination strategy might reduce the incidence of tacrolimus-associated problems. In a study of 56 patients on this combination, patient and graft survival at 23 months were 93 and 91 percent, respectively [48]. One case of hepatic artery thrombosis was observed in this series.

Sirolimus may be especially useful as a substitute in cases of CNI-intolerance (primarily renal failure and neurotoxicity) [49-51]. However, its benefits in renal failure remain unsettled. While retrospective analyses did not show improved renal function in patients switched to sirolimus [52-54], a small randomized controlled trial showed improvement [51]. In the randomized trial, transplant recipients with underlying renal disease were switched to sirolimus at least six months after liver transplant. The glomerular filtration rate improved within three months. However, long-term outcomes were not reported, and two patients in the sirolimus arm developed acute rejection.

A retrospective analysis showed no benefit for renal function when patients with chronic renal insufficiency were switched from CNIs to sirolimus [54]. This study suggests that renal dysfunction from CNIs becomes irreversible at some point, and highlights the importance of CNI optimization. Similarly, another study showed that early conversion (less than 90 days) to sirolimus was associated with improved renal function, while late conversion was of limited benefit [55].

A systematic review that included 11 studies found a small (3.4 mL/min), nonsignificant increase in glomerular filtration rate after one year of sirolimus use in patients who received sirolimus as primary immunosuppression due to renal insufficiency or who were switched to sirolimus from another regimen due to nephrotoxicity [56]. However, sirolimus use was associated with higher rates of infection, rash, ulcers, and discontinuation of therapy. Sirolimus was not associated with an increased risk of graft failure or death, though the data reporting for these outcomes were incomplete.

Larger trials with longer follow-up are needed to settle the issue and to determine whether the potential improvement in renal function outweighs a possible increased risk of rejection.

Sirolimus has also been proposed as a better choice for patients with hepatocellular carcinoma because of its antiproliferative activity [57-59]. This benefit has yet to be proven in prospective trials. Finally, although not supported by publications, many transplant centers find that sirolimus is inadequate as monotherapy and routinely add a second agent when switching from a CNI for any reason.

Side effects — Side effects of sirolimus reported in the postoperative period include hepatic artery thrombosis, delayed wound healing, and incisional hernias, while chronic use has been associated with hyperlipidemia, bone marrow suppression, mouth ulcers, skin rashes, albuminuria, and pneumonia. These risks are difficult to quantify because the incidence (and even the presence) of side effects varies widely by report. In 2008, the FDA updated the labeling of sirolimus to include a boxed warning stating that the use of sirolimus was associated with excess mortality, graft loss, and hepatic artery thrombosis following liver transplantation, and that its use de novo in liver transplantation recipients was not recommended [60].

As an example, one report showed that sirolimus was more likely to cause hyperlipidemia when administered with cyclosporine than with tacrolimus (30 versus 6 percent for hypercholesterolemia, 33 versus 3 percent for hypertriglyceridemia) [61]. Similar results in another retrospective trial suggested that the combination of sirolimus with tacrolimus is associated with minimal elevation of triglycerides [62]. These contrast with a study that reported a 49 percent incidence of hyperlipidemia in patients switched from a CNI to sirolimus monotherapy [63].

Another retrospective study compared 170 patients treated with sirolimus as initial therapy compared with 180 historic controls [64]. No significant differences in wound complications (12 versus 14 percent) or hepatic artery complications (5 versus 8 percent) were seen [64]. Finally, a large retrospective study found complications that included edema, dermatitis, oral ulcers, joint pains, pleural effusions, hepatic artery thrombosis (two patients), and one wound dehiscence [65]. The results reported in the above studies have not been validated in prospective studies.

An open-label randomized trial found that patients who were switched from a CNI to sirolimus had increased rates of acute rejection but similar mortality at 12 months [66].

Everolimus — Because prolonged use of calcineurin inhibitors (CNI), such as tacrolimus, is associated with renal disease, everolimus (EVR) has been studied as an alternative for long term immunosuppression. The FDA recommends that both mTORs, everolimus and sirolimus, not be used earlier than 30 days after liver transplantation because of an increased risk of hepatic artery thrombosis in the early post-transplantation period [67]. (See 'Sirolimus' above.).

The initial immunosuppressive regimen after transplantation and optimal timing of withdrawal of CNI is not clear [68]. Three trials of post-transplant regimens including EVR compared with standard CNI therapy have generally shown benefit in renal function parameters for the EVR groups but its efficacy compared with standard CNI therapy needs further study [68-70]. (See 'Calcineurin inhibitors and renal failure' above.)

In a trial of 188 liver transplant recipients, all of whom initially received basiliximab induction therapy and enteric coated mycophenolate sodium (with or without steroids), renal function was better after 24 weeks in patients receiving EVR and tacrolimus (EVR+TAC) while tapering tacrolimus (TAC) with discontinuation by week 16, compared with patients receiving continuous TAC (mean eGFR 95.8 versus 76.0 mL/min) [68]. Rates of treatment failure (defined as biopsy-proven acute rejection, graft loss or death) at 24 weeks were not significantly different between the EVR+TAC and the TAC groups.

In a trial of 303 liver transplant recipients with GFR >50 mL/min who received basiliximab induction therapy followed by CNI (with or without steroids) for four weeks post-transplantation and who then continued CNI or were converted to EVR, the mean calculated GFR (Cockroft-Gault) at 11 months showed no difference between regimens (-2.9 mL/min in favor of EVR, 95% CI [-10.65 to 4.81]) [69]. The difference in GFR was significant if the Modification of Diet in Renal Disease formula was used (-7.8 mL/min in favor of EVR; 95% CI: -14.366 to -1.191). Rates of mortality and biopsy-proven acute rejection were similar in both groups. (See "Assessment of kidney function", section on 'Assessment of GFR'.)

In an open-label trial, liver transplantation recipients received standard immunosuppression with steroids and TAC for 30±5 days and were then randomly assigned 1:1:1 to one of three groups: EVR, everolimus with reduced dose tacrolimus (EVR+TAC), or standard dose tacrolimus (TAC) [70]. Because a high rate of acute rejection was observed in the tacrolimus elimination arm, recruitment to this group was suspended. Patients after this point were assigned to receive EVR+TAC or TAC. The final study included 719 patients. The primary endpoint, which was the treatment failure rate (ie, treated biopsy-proven acute rejection, graft loss, or death at 12 months after transplantation), occurred in 45 of 231 (19.5 percent) EVR recipients, in 15 of 245 (6.5 percent) EVR+TAC recipients, and in 23 of 243 (9.5 percent) TAC recipients. The change in adjusted GFR from randomization to month 12 was superior in the EVR+TAC group compared with TAC alone, with a difference of 8.5 mL/min (97.5% CI 3.7-13.3).

Everolimus is the hydroxyethyl derivative of sirolimus. The mechanism of action of EVR is via inhibition of mammalian target of rapamycin (mTOR), similar to sirolimus [71]. Everolimus is rapidly absorbed and reaches a peak concentration within one to two hours if given on an empty stomach [72]. Fatty foods retard absorption. It has higher oral availability and lower plasma binding than sirolimus and a mean elimination half-life of 30±11 hours. A starting dose of 0.75 mg twice daily with a target trough level of 3 to 8 ng/mL is standard [73]. Metabolism is via CYP3A4, 3A5, and 2C8, and interactions with azoles, macrolides, antiepileptic agents, antiviral agents, and grapefruit juice are known. The clearance of everolimus is about 20 percent higher in Black patients.

Side effects — Side effects of everolimus seem to be dose related and are similar to those seen for sirolimus, [72] and may include anemia, peripheral edema, elevations in serum creatinine when used with full dose CNIs, diarrhea, nausea, urinary tract infections, and hyperlipidemia. Mouth ulcers were not seen in heart and kidney transplantation trials, but they were reported in the liver transplantation trials.

INHIBITORS OF PURINE AND PYRIMIDINE SYNTHESIS — The major antimetabolite drugs are prodrugs of mycophenolic acid (MPA), a purine synthesis inhibitor, and azathioprine.

The original drugs in this class, cyclophosphamide (Cytoxan) and azathioprine (Imuran), are rarely used in transplantation in the United States, although a multicenter study suggested that azathioprine is used routinely in the United Kingdom [19]. While mycophenolate mofetil (MMF) has become more popular than the other agents, clear evidence of superiority is lacking [74]. Azathioprine is sometimes substituted for MMF in women who are pregnant or of childbearing age due to increased safety experience with it in pregnancy. MMF is pregnancy class D.

Mycophenolate mofetil and mycophenolate sodium — MPA is produced by several species of the fungus Penicillium. MPA is poorly absorbed, but two orally available prodrugs are available in the United States: the 2-morpholinoethyl ester, mycophenolate mofetil (MMF, CellCept), and mycophenolate sodium (Myfortic). Both drugs are converted to MPA and eliminated predominantly via glucuronidation and urinary excretion [75].

MPA inhibits inosine monophosphate dehydrogenase (IMPDH), preventing the formation of guanosine monophosphate (GMP). Cells depleted of GMP cannot synthesize guanine triphosphate (GTP) or deoxy guanine triphosphate (d-GTP) and therefore cannot replicate. Most mammalian cells are able to maintain GMP levels through the purine salvage pathway. However, lymphocytes lack a key enzyme of the guanine salvage pathway (hypoxanthine-guanine phosphoribosyltransferase), and cannot overcome the MPA-induced block. As a result, MPA selectively inhibits the proliferation of both B and T lymphocytes [75].

Reports on the use of MMF in liver transplantation began to appear in the late 1990s [76-78]. MMF does not cause neurotoxicity or nephrotoxicity, and is widely used as a calcineurin inhibitor (CNI)- or steroid-sparing agent. The most common side effects are bone marrow suppression and gastrointestinal complaints, including abdominal pain, ileus, nausea, vomiting, and oral ulceration. These symptoms are usually dose-related and improve with temporary or permanent dose reduction. Usual dosing is 1 g twice daily. Patients may tolerate the drug better if it is initially dosed at 500 mg twice daily or 500 mg four times daily. Myfortic (mycophenolate sodium) is formulated as 360 mg tablets and is typically given as two tablets (720 mg) orally every 12 hours. Food may interfere with absorption of the drugs, so they should be taken one hour before or two hours after meals.

The role of MMF is similar to that of sirolimus in that it is used to reduce or discontinue CNI dosing in order to treat side effects. Studies suggest MMF monotherapy may be effective in certain situations long after liver transplantation:

A randomized trial assigned 150 patients who had received a liver transplantation and were maintained on a CNI to either continued therapy with a CNI or to MMF monotherapy [79]. The mean time between liver transplantation and study enrollment was 4.9 years for patients assigned to continued CNI therapy, and 5.7 years for those assigned to MMF. After five years of follow-up, there were no significant differences between those who continued on a CNI and those who were switched to MMF with regard to chronic rejection or patient survival (0 versus 0 percent and 94 versus 90 percent, respectively). There was a trend toward lower acute rejection rates in the CNI group (3 versus 11 percent, p = 0.055). All patients with acute rejection were successfully treated with steroid-pulse therapy. Among patients with renal insufficiency, renal function improved in those switched to MMF. There were no significant differences between the groups with regard to malignancy rates or to adverse cardiovascular, gastrointestinal, or neurologic events.

In a prospective open-label study, 19 patients at the University of Washington were switched from azathioprine to MMF with cyclosporine, which was then tapered [80]. After five years, seven patients remained off cyclosporine, and six patients were on MMF monotherapy. Serum creatinine in the seven patients off cyclosporine decreased significantly (from 2.2 to 1.9 mg/dL), while creatinine clearance increased significantly (from 38 to 47 mL/min). Control of arterial hypertension also improved. MMF appeared to be well tolerated, although six patients required dose reductions.

The added immunosuppression of MMF may also allow for the early discontinuation or avoidance of steroids [81].

Azathioprine — Azathioprine is a prodrug of 6-mercaptopurine, which is further metabolized into 6-thioguanine (6-TG) nucleotides that inhibit purine synthesis. By preventing the de novo synthesis of purines, and thus interfering with RNA and DNA synthesis, azathioprine inhibits the replication of T and B cells. Azathioprine is typically given at a dose of 1.5 to 2.0 mg/kg daily, up to a maximum dose of 200 mg daily [82]. Assessing thiopurine methyltransferase metabolite (TPMT) enzyme activity and measuring levels of 6-TG can help optimize dosing of azathioprine. (See "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease".)

Side effects of azathioprine include bone marrow suppression, nausea, vomiting, pancreatitis, hepatotoxicity, and neoplasia. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects'.)

ANTIBODY THERAPY — Because T and B cells express specific antigens on their cell surfaces, antibodies to these markers can be used to deplete populations of cells. The initial concept of lymphoid depletion by thoracic duct fistula [83] gave way to the more elegant method of antithymocyte globulin preparations, now refined to include humanized antibodies and monoclonal antibodies against specific cell surface proteins such as the interleukin (IL)-2 receptor [84].

These agents are not used routinely in liver transplantation, but have an important role in treating steroid-resistant rejection and as calcineurin inhibitor (CNI)-sparing agents in the immediate post-transplant period. Antibody therapy may also permit steroid free immunosuppression regimens if needed. We generally use antibody preparations in the rare case of steroid-resistant rejection and in situations where we wish to minimize CNI dosing, such as in patients with pretransplant renal failure. (See "Liver transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection of the liver allograft", section on 'Therapy for nonresponders'.)

Polyclonal antibodies — Antithymocyte globulin (ATG, thymoglobulin) and antilymphocyte globulin (ALG) are prepared by immunizing animals against mixed populations of thymocytes. The resulting preparations have antibodies to multiple T-cell antigens including CD2, CD3, CD4, and CD8. They are administered via a central line and result in profound lymphopenia by complement-mediated cell lysis and uptake of opsonized cells. Repopulation occurs within 3 to 10 days.

Polyclonal antibodies have been used for induction of immunosuppression or treatment of steroid-resistant rejection [15,85-87]. A review of the Scientific Registry of Transplant Recipient (SRTR) data between 1993 and 2003 showed that antibodies were used commonly in kidney, kidney/pancreas, and intestinal transplants, but uncommonly (<20 percent) in liver transplantation [88]. The authors also noted a shift from muromonab-CD3 and horse ATG to rabbit ATG and anti-IL-2 receptor antagonists.

In addition, a large series examined the efficacy of rabbit ATG following liver transplantation [87]. The series included 500 patients who received a single dose of solumedrol followed by ATG induction. Patients also received mycophenolate mofetil and tacrolimus or sirolimus. The tacrolimus or sirolimus was weaned after three months. After one year, patient and graft survival rates were 93 and 90 percent, respectively. Rejection occurred in 114 patients (23 percent) and 33 patients required glucocorticoids (7 percent).

Complications with these agents include fever, chills, rash, anemia, thrombocytopenia, serum sickness, and nephritis. Although our personal preference is to use monoclonal antibodies when necessary, some reports suggest that polyclonal antibodies are still in use in pediatric and adult patients undergoing liver transplantation [89,90].

Monoclonal antibodies

Basiliximab — Basiliximab (Simulect) and daclizumab (Zenapax) are humanized monoclonal antibodies against the IL-2 receptor. Blockade of the IL-2 receptor prevents T-cell proliferation. The chimeric structure makes both preparations less immunogenic than muromonab-CD3 (OKT3, no longer available), and they have longer half-lives and are better tolerated. Basiliximab, for example, has an elimination half-life of 4.1±2.1 days, and complete saturation of interleukin-2 receptor alpha-chain was maintained as long as serum concentrations exceeded 0.1 microgram/mL [91]. The mean duration of receptor saturation was 23 +/- 7 days after transplantation (range of 13 to 41 days). The half-life may be decreased by the presence of bleeding or ascites.

Similar efficacy has been demonstrated with daclizumab dosed at 2 mg/kg on post-orthotopic liver transplant (OLT) days 1 and 3, and 1 mg/kg on day 8 [92]. CD25 suppression was confirmed through day 30, and maximal effects were noted with a daclizumab concentration of at least 5 micrograms/mL. Similarly, a nonrandomized study of daclizumab 2 mg/kg before engraftment and 1 mg/kg on day 5 post-OLT resulted in a much lower rejection rate in the first six months (18 versus 40 percent), marked improvement in renal function, and no increase in cytomegalovirus (CMV) or infectious complications when compared with a control group treated with standard immunosuppression [93].

However, daclizumab was removed from the market in 2018 due to safety concerns following several reports of inflammatory encephalitis and meningoencephalitis [94,95].

Antibodies can be used to reduce CNI use in patients with pre-OLT renal disease [96] or to minimize steroid use [22,97]. In one report with median follow-up of 22 months, basiliximab controlled steroid-resistant rejection after OLT in five out of seven children [98].

Few controlled trials have compared contemporary immunosuppressive regimens involving these agents. One randomized multicenter study compared tacrolimus plus steroids (T+S; 347 patients) to a steroid-free tacrolimus plus daclizumab group (T+D; 351 patients) [99]. The incidence of biopsy-confirmed glucocorticoid-resistant acute rejection was higher in the T+S group (6 versus 3 percent), although graft and patient survival were comparable. The overall adverse event profiles were similar, but the incidences of diabetes mellitus (15 versus 6 percent) and CMV infection (12 versus 5 percent) were significantly higher in the T+S group. Mean cholesterol levels increased by 16 percent in the T+S group, but were unchanged in the T+D group.

INVESTIGATIONAL AGENTS

Belatacept (LEA29Y) — Belatacept is a high affinity fusion protein that binds CD80/86 on antigen-presenting cells (APCs). This prevents binding of CD80/86 to CD28 on the T cell (signal II in Figure 1) (figure 1), and blocks the costimulatory pathway [100]. The drug is given as a monthly infusion and may permit immunosuppression without nephrotoxicity. Several reports confirm its effectiveness in renal transplantation [101-103], but an increased rate of post-transplant lymphoproliferative disorder (especially involving the central nervous system [104]) has confined its use to Epstein-Barr virus-positive recipients. We are unaware of belatacept use in liver transplantation.

Efalizumab — This is a humanized monoclonal antibody against leukocyte function-associated antigen-1 (LFA-1; CD11a). LFA-1 plays multiple roles in rejection, including cell migration, cell adhesion, and stabilization of the APC-T-cell complex. An open-label trial of efalizumab with lower doses of standard immunosuppression suggested that the drug was effective, but associated with an 11 percent incidence of PTLD [101]. The role of this potent compound in liver transplantation has yet to be determined.

A few other agents, including alefacept and a Janus tyrosine kinase 3 inhibitor, are in early testing in renal transplantation [105].

Alemtuzumab — Alemtuzumab is a humanized monoclonal, complement-fixing, anti-CD52 antibody. CD52 is expressed on the surface of B lymphocytes, T lymphocytes, macrophages, monocytes, and eosinophils. Through complement activation, alemtuzumab leads to profound lymphocyte depletion. It is approved by the US Food and Drug Administration for the treatment of chronic B-cell lymphocytic leukemia, but it has also been used for immunosuppression following solid organ transplantation. In liver transplantation, alemtuzumab has been proposed as a method to decrease steroid and calcineurin inhibitor use [16]. However, concern about profound immunosuppression with attendant infectious complications and PTLD have reduced enthusiasm for alemtuzumab [106-108], although one review supports further studies [109].

IMMUNOSUPPRESSION MANAGEMENT IN PATIENTS UNDERGOING NON-TRANSPLANT SURGERY — Patients should continue to take their immunosuppressive medication around the time of surgery, although the route of administration may need to be changed if the patient cannot tolerate oral medication. Intravenous administration of calcineurin inhibitors (CNIs) is associated with a higher risk of nephrotoxicity and should be avoided if possible. In addition, clinicians should be careful to check for potential drug interactions with medications used around the time of surgery (eg, antimicrobials or antifungals). The patient's transplant hepatologist should be consulted prior to making any changes to the immunosuppression regimen. (See 'Drug interactions' above.)

In patients receiving glucocorticoids, additional perioperative glucocorticoid coverage should be considered for patients likely to have suppression of their hypothalamic-pituitary-adrenal axis (eg, those on long-term, higher dose glucocorticoids). Stress dose steroids are rarely necessary.

STOPPING IMMUNOSUPPRESSION — Some patients will develop immunologic tolerance following liver transplantation and may be able to stop taking immunosuppressants [110]. However, because of the risk of graft rejection and because it is not yet clear which patients are good candidates for stopping immunosuppression, additional studies are needed before recommending attempts at stopping immunosuppression. We have seen a number of fatal rejections in patients who stopped immunosuppression without medical supervision, including patients many years post-orthotopic liver transplant. We therefore never recommend stopping all immunosuppression.

Discontinuing immunosuppression was examined in a study of 24 patients without active viral hepatitis or autoimmune disease who had side effects from immunosuppression or who were at high risk for developing de novo malignancy [111]. The patients underwent gradual reduction of their immunosuppression. Patients who had normal liver function tests following withdrawal of immunosuppression were considered to be tolerant. After a median of 14 months, 15 patients (63 percent) were tolerant. The remaining nine patients could not have their immunosuppression completely withdrawn because of abnormal liver tests. In these patients, immunosuppression was increased with normalization of liver function in seven patients. The remaining two patients underwent liver biopsy. One had mild chronic rejection, and one had acute rejection that was treated with glucocorticoids. A longer median interval between transplantation and inclusion in the study was associated with tolerance (156 months for patients who developed immunotolerance versus 71 months for those who did not).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Liver transplantation".)

SUMMARY AND RECOMMENDATIONS

Organ rejection is a multistep process that includes alloantigen recognition, lymphocyte activation, clonal expansion, and graft inflammation. (See 'Immunobiology of acute rejection' above.)

Tacrolimus remains the mainstay of immunosuppression in many centers. (See 'Tacrolimus' above.)

For patients with pretransplant renal failure in whom we wish to minimize the use of calcineurin inhibitors (CNI), we generally use antibody preparations in the immediate post-transplant period along with delayed calcineurin inhibitors. (See 'Antibody therapy' above and 'Calcineurin inhibitors' above.)

Slowly worsening renal disease in the late post-orthotopic liver transplant period can be managed by reducing the CNI dose, with the addition of MMF, or by switching to sirolimus or everolimus. (See 'Inhibitors of mammalian (mechanistic) target of rapamycin (mTOR)' above.)

Some patients will develop immunologic tolerance following liver transplantation and may be able to stop taking immunosuppressants. However, because of the risk of irreversible graft rejection, and because we have no tools to assess which patients are good candidates for stopping immunosuppression, we never recommend complete cessation of immunosuppression. (See 'Stopping immunosuppression' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Norman Sussman, MD, who contributed to an earlier version of this topic review.

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Topic 4586 Version 37.0

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