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.
Induction AgentsInduction 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 a. 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). The most commonly used antibody induction agent (18% of LT procedures) is basiliximab, a chimeric monoclonal antibody against the a chain of heterotrimeric IL-2 receptor (CD25). A recent meta-analysis 7 found that patients who received an IL-2 receptor a, 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 CD224, 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.
Maintenance AgentsCNIs: Cyclosporine and Tacrolimus. The introduction of cyclosporine in 1982 revolutionized the field of LT. Cyclosporine has now been largely supplanted by tacrolimus.
10Long-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...
