Liver Transplantation in Adults: Overview of Immunosuppression

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Official reprint from UpToDate®

www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
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
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2023. | 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".)
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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
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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].
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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.
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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
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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
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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
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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
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● 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.
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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
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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].
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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".)
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● 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].
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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
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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].
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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
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(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
3/29/23, 7:58 PM 4586
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.)
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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
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● 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.
Use of UpToDate is subject to the Terms of Use.
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Topic 4586 Version 37.0
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GRAPHICS
The three signals of T cell activation
Signal I: Antigen presentation by APC to the T cell receptor.
Signal II: Costimulation - binding of additional APC ligands to specific T cell

receptors.
Signal III: Newly synthesized IL-2 and growth factors feed back on T cell membrane
receptors, causing clonal expansion of newly activated T cells.
Reproduced with permission from: Vierling, JM. Clinical Use of Immunosuppressive Drugs to Control the
Immune Response. In: Liver Immunology: Principles and Practice, Gershwin, ME, Vierling, JM, Manns,
MP (Eds), Humana Press, Totowa 2007. Copyright ©2007 Springer-Verlag.
Graphic 54486 Version 2.0
3/29/23, 7:58 PM 4586
Overview of T cell activation and proliferation showing the site of

action of available and experimental immunomodulatory agents
Reproduced with permission from: Vierling, JM. Clinical Use of Immunosuppressive Drugs to Control the
Immune Response. In: Liver Immunology: Principles and Practice, Gershwin, ME, Vierling, JM, Manns, MP (Eds),
Humana Press, Totowa 2007. Copyright ©2007 Springer-Verlag.
3/29/23, 7:58 PM 4586
Examples of common drug interactions of immunosuppressants used in

solid-organ transplant: Cyclosporine, tacrolimus, sirolimus, and everolimus
Approach to management in
Common types of
Examples of interacting drugs the absence of appropriate
drug interactions
noninteracting alternatives
Coadministration of Amiodarone Closely monitor

drugs that inhibit ART-boosting agents (eg, immunosuppressant
CYP3A metabolism ritonavir, cobicistat) concentrations and signs of
and/or P-gp efflux toxicity (eg, tremors and
Azole antifungals (eg,
can increase headaches).
fluconazole, posaconazole,
immunosuppressant Substantial, including preemptive,
voriconazole)
serum dose reduction of
HIV protease inhibitors (eg,
concentrations, immunosuppressant drug may be
atazanavir, nelfinavir, saquinavir)
leading to significant needed (eg, on average, only 25%
toxicities. Macrolide antibiotics
of the standard dose of
Non-dihydropyridine calcium
cyclosporine is required if
channel blockers
administered concomitantly with
Ombitasvir-paritaprevir-ritonavir
HIV protease inhibitors).
with or without dasabuvir (an
Some combinations are
HCV, direct-acting antiviral
considered contraindicated
regimen)
according to product labeling;
Grapefruit juice refer to appropriate topic reviews
for detail.
Lists of CYP3A and P-gp
inhibitors are provided as
separate tables within UpToDate.
Coadministration of Antiseizure medications, enzyme Closely monitor

drugs that induce inducing (eg, carbamazepine, immunosuppressant serum
CYP3A metabolism fosphenytoin, phenobarbital, concentrations and signs of organ
and/or P-gp efflux phenytoin, primidone) rejection.
pumping can Enzalutamide Significant immunosuppressant
decrease dose increases may be needed.
Nafcillin
immunosuppressant
Rifamycins (eg, rifabutin, Enzyme induction can require up
serum
rifampin, rifapentine) to 2 weeks to achieve maximum
concentrations,
St. John's wort effect and persists for up to 2
increasing the risk of
weeks after discontinuation of the
organ rejection.
interacting medication. Clinically
significant effects can occur
within hours to days of starting a
CYP inducer.
3/29/23, 7:58 PM 4586
Lists of CYP3A and P-gp inducers

are provided as separate tables
within UpToDate.
Coadministration of Aminoglycosides Concomitant administration of

nephrotoxic drugs Amphotericin B cyclosporine and tacrolimus with
with cyclosporine or other potentially nephrotoxic
Colchicine
tacrolimus can cause drugs should be avoided.
Nonsteroidal anti-inflammatory
additive or Suggested dose adjustments for
drugs (NSAIDs)
synergistic kidney use with colchicine are available
injury. in the Lexicomp monograph
included within UpToDate.
Coadministration of ACE inhibitors/ARBs Closely monitor serum potassium

drugs that increase Amiloride levels.
serum potassium
Spironolactone
with cyclosporine or
Triamterene
tacrolimus may cause
severe Trimethoprim, trimethoprim-
sulfamethoxazole (cotrimoxazole)
hyperkalemia.
Coadministration of Cyclosporine Separate administration of

cyclosporine with sirolimus from cyclosporine by 4
sirolimus can hours; give sirolimus at a
increase sirolimus consistent time with respect to
concentrations. cyclosporine.
Closely monitor
immunosuppressant serum
concentrations.
Coadministration of Atorvastatin Pravastatin and fluvastatin are

statin drugs with Lovastatin preferred due to decreased
cyclosporine can interactions.
Pitavastatin
increase statin Tacrolimus may be preferred over
Rosuvastatin
levels and risk of cyclosporine in patients receiving
myotoxicity. Simvastatin
statin therapy.
Cyclosporine and simvastatin
should not be used together.
Some combinations are
considered contraindicated or
statin daily dose limits are
recommended in the product
labeling; refer to the Lexicomp
monographs included within
UpToDate for detailed
information.
3/29/23, 7:58 PM 4586
Important note: The interactions listed in this table illustrate some of the common types of
interactions with immunosuppressive drugs; this is not a complete list, and many other
significant drug interactions can occur.
Cyclosporine, tacrolimus, sirolimus, and everolimus are highly dependent upon CYP3A
metabolism for clearance and are also substrates of P-gp drug efflux pump. Some interactions
can lead to subtherapeutic or dangerously toxic levels of immunosuppressant concentrations.
When appropriate noninteracting alternatives are readily available, consider modifying treatment
to avoid combined use with potent metabolic inhibitors/inducers or agents known to have
additive toxicities with immunosuppressants.
Drug therapy should be managed by transplant specialists with expertise in therapeutic drug
monitoring, and doses should be adjusted based upon measurement of immunosuppressant
concentrations, particularly whenever drug therapy is altered. If there are any concerns about
the safety of a given medication or supplement, they should be discussed with the patient's
transplant center prior to initiation.
CYP: cytochrome P450 metabolism; P-gp: P-glycoprotein drug efflux pump; ART: HIV antiretroviral
therapy; HIV: human immunodeficiency virus; HCV: hepatitis C virus; ACE: angiotensin-converting
enzyme; ARB: angiotensin II receptor blocker.
Prepared with data from Lexicomp Online. Copyright © 1978-2023 Lexicomp, Inc. All Rights Reserved.
3/29/23, 7:58 PM 4586
Dosing equivalents for common steroid compounds
Steroid compound Dose equivalent, mg
Hydrocortisone 20
Prednisolone 5
Prednisone 5
Methylprednisolone 4
3/29/23, 7:58 PM 4586
Steroid protocol, Baylor College of Medicine Liver Transplant Unit
Induction (prior to transplant) Solu-Medrol® (IV) 40 mg
Anhepatic phase Solu-Cortef® (IV) 1 g
Post-op day 1 Solu-Medrol® (IV) 200 mg
Post-op day 6 Prednisone (oral) 20 mg
3/29/23, 7:58 PM 4586
Summary of immunosuppression dosing, formulations, and monitoring
Drug Frequency Formulations Monitoring
Prednisone Daily Tablets, suspension, Blood pressure, glucose, lipids

parenteral by substitution
Azathioprine Daily Tablets, suspension, CBC, liver tests, pancreas toxicity

parenteral
Mycophenolate Twice daily Tablets, suspension CBC, abdominal symptoms

mofetil
Myocphenolate Twice daily Tablets CBC, abdominal symptoms

sodium
Cyclosporine Twice daily Capsules, suspension, Drug level, creatinine, lipids, K(+),
parenteral Mg(2+), CNS toxicity
Tacrolimus Twice daily Capsules, suspension, Drug level, creatinine, glucose,

parenteral lipids, K(+), Mg(2+), CNS toxicity
Sirolimus Daily Tablets, suspension CBC, drug level, lipids
Everolimus Daily Tablets CBC, drug level, lipids
CBC: complete blood count; CNS: central nervous system.
3/29/23, 7:58 PM 4586
Survival plot showing freedom from primary endpoint

(combined treatment failure, retransplantation, or death)
following liver transplantation
* Includes 1 patient lost to follow-up.
• Includes 2 patients lost to follow-up.
Reproduced with permission from: O'Grady, JG, et al. Tacrolimus versus microemulsified
ciclosporin in liver transplantation: the TMC randomised controlled trial. Lancet 2002; 360:1119.
Copyright ©2002 Elsevier.
3/29/23, 7:58 PM 4586
Relative risk of complication using tacrolimus versus cyclosporine after

liver transplantation
Parameter - tacrolimus versus cyclosporine RR 95% CI
One-year mortality 0.85 0.73-0.99
One-year graft loss 0.73 0.61-0.86
Acute rejection 0.81 0.75-0.88
Steroid-resistant rejection 0.54 0.47-0.74
Likely to change to another agent 0.57 0.49-0.66
De novo diabetes mellitus 1.38 1.01-1.86
Data from: McAlister, VC, Haddad, E, Renouf, E, et al. Cyclosporine versus tacrolimus as primary immunosuppressant after
liver transplantation: a meta-analysis. Am J Transplant 2006; 6:1578.
3/29/23, 7:58 PM 4586
Contributor Disclosures
John M Vierling, MD, FACP Equity Ownership/Stock Options: Athenex, Inc [Oncology Therapeutics].
Grant/Research/Clinical Trial Support: Allergan [NASH]; Enanta [NASH]; Gilead [PBC, PSC, NASH]; Intercept
[PBC, NASH]; Lilly [PBC]; Novartis [PBC, AIH, NASH, OLT]; Pliant [PSC]; Taiwan J [AIH]. Consultant/Advisory
Boards: Arena [AIH, PBC, PSC]; Blade [PSC, NASH]; Enanta [NASH]; Gilead [PBC, PSC]; Intercept [PBC,
NASH]; Kezar [AIH]; Lilly [PBC]; Moderna [AIH, AILDs]; Novartis [PBC, AIH, NASH, OLT]; Perspectum [Liver
Multiplex imaging, MRCP-Plus imaging]; Selecta [PBC, AIH, PSC]; Taiwan J [AIH]. Speaker's Bureau: Chronic
Liver Disease Foundation [CME only]. Other Financial Interest: Athenex Inc – Biopharmaceutical company
developing novel oncology therapies, including CAR-NKT and CAR-T cell technologies [Member, Board of
Directors]. All of the relevant financial relationships listed have been mitigated. Robert S Brown, Jr, MD,
MPH Grant/Research/Clinical Trial Support: AbbVie [Hepatitis C]; DURECT [Alcoholic hepatitis]; Enanta
[Nonalcoholic fatty liver disease]; Genfit [Nonalcoholic fatty liver disease]; Gilead [Hepatitis C]; Intercept
[Nonalcoholic fatty liver disease]; Mallinckrodt [Hepatorenal, Hepatitis C]; Mirum [Pruritus, cholestasis];
Salix [Encephalopathy, hepatorenal, Hepatitis C, nonalcoholic fatty liver disease]. Consultant/Advisory
Boards: AbbVie [Hepatitis B, hepatitis C, primary biliary cholangitis, cirrhosis]; Ambys [Hepatocyte
transplantation]; Antios [Hepatitis B]; Gilead [Hepatitis B, hepatitis C, hepatitis D]; Intercept [NASH,
primary biliary cholangitis, cirrhosis]; Mallinckrodt [Hepatorenal syndrome]; Mirum [Pruritus, cholestasis];
Salix [Hepatic encephalopathy]. All of the relevant financial relationships listed have been
mitigated. Kristen M Robson, MD, MBA, FACG No relevant financial relationship(s) with ineligible
companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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Liver transplantation in adults: Overview of

IMMUNOBIOLOGY OF ACUTE REJECTION

Organ rejection is a multistep process that includes alloantigen recognition, lymphocyte

Signal I: Alloantigen recognition — Alloantigen recognition requires presentation of a foreign

Signal II: Lymphocyte activation (costimulation) — T-cell activation requires costimulation, a

Inflammation — T-cell proliferation is associated with cell-mediated cytotoxicity and secretion

Approach to therapy — Glucocorticoids suppress antibody and complement binding,

Four steroid formulations are used commonly in transplantation: hydrocortisone, prednisone,

A possible alternative to traditional glucocorticoids is budesonide. Budesonide is a

Management of HCV infection in liver transplant candidates and recipients is discussed

Cyclosporine — Cyclosporine, a peptide derived from the fungus Cylindrocarpon lucidum, is a

Cyclosporine was initially formulated as Sandimmune, a corn oil-based preparation with

Cyclosporine can be administered intravenously, although it is usually given orally as a tablet or

Tacrolimus — In an update on liver transplantation in 1988, the University of Pittsburgh group

Tacrolimus (Prograf) is a macrolide compound originally isolated from Streptomyces

transplant using a composite primary endpoint of death, retransplantation, or "treatment

A number of strategies, including switching to mammalian (mechanistic) target of rapamycin

Tacrolimus is superior in terms of preventing acute rejection, steroid-resistant rejection, graft

The concept is that significant immunosuppression is needed in the immediate post-transplant

INHIBITORS OF MAMMALIAN (MECHANISTIC) TARGET OF RAPAMYCIN

Sirolimus — Sirolimus (Rapamune), a macrolide antibiotic produced by Streptomyces

Sirolimus may be especially useful as a substitute in cases of CNI-intolerance (primarily renal

Everolimus — Because prolonged use of calcineurin inhibitors (CNI), such as tacrolimus, is

● In an open-label trial, liver transplantation recipients received standard

INHIBITORS OF PURINE AND PYRIMIDINE SYNTHESIS

Mycophenolate mofetil and mycophenolate sodium — MPA is produced by several species of

MPA inhibits inosine monophosphate dehydrogenase (IMPDH), preventing the formation of

● In a prospective open-label study, 19 patients at the University of Washington were

Azathioprine — Azathioprine is a prodrug of 6-mercaptopurine, which is further metabolized

Polyclonal antibodies — Antithymocyte globulin (ATG, thymoglobulin) and antilymphocyte

Polyclonal antibodies have been used for induction of immunosuppression or treatment of

Basiliximab — Basiliximab (Simulect) and daclizumab (Zenapax) are humanized monoclonal

Few controlled trials have compared contemporary immunosuppressive regimens involving

Efalizumab — This is a humanized monoclonal antibody against leukocyte function-associated

Alemtuzumab — Alemtuzumab is a humanized monoclonal, complement-fixing, anti-CD52

IMMUNOSUPPRESSION MANAGEMENT IN PATIENTS UNDERGOING NON-

In patients receiving glucocorticoids, additional perioperative glucocorticoid coverage should

Discontinuing immunosuppression was examined in a study of 24 patients without active viral

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

● Organ rejection is a multistep process that includes alloantigen recognition, lymphocyte

● Tacrolimus remains the mainstay of immunosuppression in many centers. (See

Use of UpToDate is subject to the Terms of Use.

29. Stracciari A, Guarino M. Neuropsychiatric complications of liver transplantation. Metab

43. Liu Z, Chen Y, Tao R, et al. Tacrolimus-based versus cyclosporine-based

57. Kneteman NM, Oberholzer J, Al Saghier M, et al. Sirolimus-based immunosuppression for

72. Gurk-Turner C, Manitpisitkul W, Cooper M. A comprehensive review of everolimus clinical

99. Boillot O, Mayer DA, Boudjema K, et al. Corticosteroid-free immunosuppression with

The three signals of T cell activation

Signal I: Antigen presentation by APC to the T cell receptor.

Signal II: Costimulation - binding of additional APC ligands to specific T cell

Graphic 54486 Version 2.0

Overview of T cell activation and proliferation showing the site of

Graphic 60525 Version 1.0

Examples of common drug interactions of immunosuppressants used in

Coadministration of Amiodarone Closely monitor

Coadministration of Antiseizure medications, enzyme Closely monitor