Recipients of liver transplantation (LT) generally require lifelong immunosuppression, albeit somewhat less than other organ transplant recipients. Acute cellular rejection, which is most commonly seen within the first year after LT, can have a minimal impact on long-term liver function and allograft survival. Approximately 7.4% and 17.5% of patients experience an episode of acute rejection within 3 and 12 months of LT, respectively.1 However, immunosuppressant side effects affect LT recipients as much as, if not more than, other solid organ transplant recipients. In particular, calcineurin inhibitors (CNIs) carry a cumulative incidence of chronic renal failure of 18% 5 years after LT.2 The management of the healthy LT recipient has been reviewed recently in an AASLD practice guideline.3
Induction immunosuppression is typically defined as the initial regimen used in the first 30 days when alloreactivity is at its peak. Antibody induction at the time of LT is used in a minority of patients (in contrast to recipients of most other solid organ transplants), although the rate is rising. Instead, the typical initial regimen includes corticosteroids and the CNI tacrolimus, often with mycophenolate as an antiproliferative agent (Table 1).4, 5 Corticosteroids block T cell activation through inhibition of cytokine production, suppression of prostaglandins and leukotrienes, and inhibition of interleukin-1 (IL-1) and tumor necrosis factor α.6 A bolus of intravenous methylprednisolone is most commonly given at the time of LT, and corticosteroids are often tapered off within 1 year because of frequent and often severe side effects (Table 2).
|mTOR inhibitors (%)||0.6||6.6||4.0||2.2||3.3|
|Cardiovascular||Sodium and fluid retention, hypertension|
|Gastrointestinal||Pancreatitis with high-dose steroids, peptic ulcer|
|Neuro-psychiatric||Psychosis, altered mood states, headaches, pseudotumor|
|Ophthalmic||Posterior subcapsular cataracts, increased intra-ocular pressure, glaucoma, exophthalmos|
|Musculo-skeletal (MS)||Osteoporosis, vertebral and femoral fractures, aseptic necrosis of femoral head, myopathy, muscle weakness|
|Endocrine||Diabetes mellitus/glucose intolerance, Cushingoid facies, hyperlipidemia, growth retardation, menstrual irregularities, suppression of pituitary-adrenal axis stimulation of appetite|
|Skin||Acne, increased bruising, impaired wound healing|
|Infectious||Increased risk of infections (including fungal infections)|
The most commonly used antibody induction agent (18% of LT procedures) is basiliximab, a chimeric monoclonal antibody against the α chain of heterotrimeric IL-2 receptor (CD25). A recent meta-analysis7 found that patients who received an IL-2 receptor α, in addition to reduced or delayed CNIs, had lower rates of acute rejection, improved renal function, and a lower incidence of diabetes. Basiliximab is usually well tolerated, although side effects, including fever, cytopenias, headache, hypertension, and, rarely, hypersensitivity reactions, may occur.8 Thymoglobulin, a polyclonal rabbit anti-thymocyte globulin with antibodies to CD2−4, CD8, CD28, and T cell receptor, leads to T cell apoptosis, and its use as an induction agent has risen from 1% to 12% over the past 10 years. It is also used for the treatment of severe acute rejection and steroid-resistant rejection. In an interim analysis of a phase 2 randomized control trial (RCT), high-dose thymoglobulin with delayed tacrolimus initiation appeared to improve the estimated glomerular filtration rate without increasing rates of acute rejection in comparison with standard tacrolimus introduction without thymoglobulin.9 Side effects include fever, rash, anemia, thrombocytopenia, serum sickness, and nephritis.
CNIs: Cyclosporine and Tacrolimus
The introduction of cyclosporine in 1982 revolutionized the field of LT. Cyclosporine has now been largely supplanted by tacrolimus.10 Long-term graft and patient survival rates approaching 90% have been made possible by CNI use. Cyclosporine binds the intracellular receptor cyclophilin, whereas tacrolimus binds FK-binding protein. These complexes then inhibit calcineurin, which is responsible for dephosphorylating several transcription factors, such as nuclear factor of activated T cells. These factors are essential for the efficient transcription of multiple cytokines, including IL-2, to ultimately inhibit T cell activity. CNI toxicities include renal dysfunction, hypertension, and neurotoxicities such as headaches, seizures, and tremors. Hyperglycemia and alopecia are more commonly seen with tacrolimus, whereas hyperlipidemia, hirsutism, and gingival hyperplasia have a higher incidence with cyclosporine. CNI dose reduction after the first 3 to 6 months after LT can minimize these side effects. CNIs are metabolized by cytochrome P450 3A4, and drugs that affect this metabolic pathway can greatly affect drug levels (Table 3). Regular monitoring is necessary, and tacrolimus can be adequately monitored with 12-hour trough levels.
|Antifungals (azoles, caspofungin)||Anticonvulsants/mood stabilizers (carbamazepine, phenytoin)|
|Antibiotics (chloramphenicol, clarithromycin, erythromycin)||Antibiotics (rifabutin, rifampin)|
|Non-dihydropyridine calcium channel blockers (diltiazem, verapamil)||Barbiturates (phenobarbital)|
|Human immunodeficiency virus protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir)||Human immunodeficiency virus nonnucleoside reverse transcriptase inhibitors (efavirenz, nevirapine)|
|Hepatitis C virus protease inhibitors (boceprevir, telaprevir)||St. John's wort|
|Grapefruit, pomegranate, pomelo, starfruit|
Antiproliferative Agents: Azathioprine, Mycophenolate, and the Mammalian Target of Rapamycin (mTOR) Inhibitors Sirolimus and Everolimus
Azathioprine was a mainstay of immunosuppression until the introduction of cyclosporine. Having been largely replaced by mycophenolate, it is now used in less than 2% of all LT recipients. Mycophenolate is available in two forms: mycophenolate mofetil (MMF; CellCept) and enteric-coated mycophenolate sodium (MPA; Myfortic). It functions by inhibiting inosine monophosphate dehydrogenase, which is an essential enzyme for purine synthesis. Because lymphocytes lack salvage pathway enzymes, mycophenolate is an effective T and B cell inhibitor. The initial dosing is typically 1000 to 1500 mg twice daily for MMF and 360 to 720 mg twice daily for MPA. The most common side effects are hematological (leukopenia, thrombocytopenia, and occasional anemia) and gastrointestinal (nausea, vomiting, and diarrhea). Mycophenolate is not associated with nephrotoxicity. Long-term immunosuppression with mycophenolate plus corticosteroids after complete CNI withdrawal improves renal function but has a significant risk of graft rejection.11 However, a recent multicenter, prospective RCT found that a combination of mycophenolate with low-dose tacrolimus led to lower rates of acute rejection, renal dysfunction, hypertension, and diabetes in comparison with standard-dose tacrolimus without mycophenolate.12
Sirolimus and its derivative everolimus bind the same intracellular receptor as tacrolimus (FK-binding protein) but instead inhibit mTOR, which is a large kinase responsible for downstream signaling of multiple growth factor receptors. mTOR inhibition blocks cell cycle progression at the G1-to-S phase and causes inhibition of B and T cell proliferation. The half-life of sirolimus is approximately 60 hours, whereas everolimus has a more rapid time to the steady state (half-life = 30 hours) and greater relative bioavailability. Both are cleared through the same cytochrome P450 pathway as the CNIs, and they have similar drug-drug interactions (Table 3). Side effects include proteinuria, mouth ulcers, and a dose-dependent increase in serum lipids. Because wound healing is also affected, their initiation should be delayed for 4 to 6 weeks after major surgical procedures. Finally, there is a black-box warning for hepatic artery thrombosis in fresh post-LT patients on sirolimus, although this has not been seen in subsequent studies or reported in patients on everolimus.
CNI-associated nephrotoxicity has prompted investigations into the conversion of CNIs to mTOR inhibitors. In June 2009, the Food and Drug Administration issued an alert based on an unpublished study that found increased mortality in stable LT patients switched from a CNI to sirolimus. A retrospective analysis showed no renal benefit for patients with chronic kidney disease who were switched from a CNI to sirolimus.13 A recent large RCT found that the complete conversion of CNIs to everolimus increased rates of rejection. However, everolimus with reduced tacrolimus improved renal function without increased acute rejection in comparison with standard-dose tacrolimus monotherapy.14 Therefore, mTOR inhibitors remain adjuncts to CNI-based regimens, particularly in patients with renal insufficiency. mTOR inhibitors also have antiproliferative activity and may have additional benefits for patients who have undergone transplantation for hepatocellular carcinoma. Although retrospective studies have suggested improved posttransplant survival,15 this has yet to be demonstrated in prospective trials.
There are several newer agents whose role in the prevention of acute rejection has yet to be determined. Belatacept is a fusion protein that binds CD80/86 and thus blocks signal 2 (Fig. 1). A multicenter, prospective, phase 2 clinical trial in LT recipients17 showed marked improvement in the estimated glomerular filtration rate but overall increases in deaths, graft loss, and acute rejection at 1 year with belatacept versus tacrolimus/MMF. In kidney transplantation, belatacept does appear to increase the risk for posttransplant lymphoproliferative disorder, especially in the central nervous system, and it should not be used in Epstein-Barr virus−naive patients.18 Sotrastaurin blocks early T cell activation via the inhibition of protein kinase C. A phase 2 study in LT recipients is currently ongoing although it is worth pointing out that further development of sotrastaurin for the prevention of acute rejection in kidney transplant recipients has been halted following a higher incidence of efficacy failure at 12 months when compared with cyclosporine in a phase II study in which all subjects also received basiliximab, everolimus and prednisone.19
The liver is thought to be an immunologically privileged organ with a lower incidence of rejection (despite less immunosuppression) in comparison with other solid organ transplants. Postulated mechanisms for this increased tolerance include its sheer size and antigen load as well as the relatively low costimulatory molecule expression of liver-derived dendritic cells. In addition, the large number of concurrently transplanted hematolymphopoietic precursor and stem cells may lead to donor leukocyte microchimerism.20
Therefore, the complete withdrawal of immunosuppression in adult LT patients has been studied in several nonrandomized trials with a success rate of approximately 20% to 25%.21 Weaning in the remaining patients typically results in rejection and the reinstatement of immunosuppression. In a small prospective pilot trial, 60% of pediatric recipients of parental living donor LT were able to have immunosuppression completely withdrawn.22 Preliminary results from a multicenter, prospective RCT found that among 66 adults on tacrolimus monotherapy 1 to 2 years after LT, 65% and 30% had successful dose reductions to 50% and 25% of the baseline, respectively.23 Unfortunately, no studies have established a diagnostic tool for identifying patients who could have their immunosuppression completely withdrawn without suffering histological damage, although monitoring for the development of donor-specific antibodies during withdrawal appears promising.