Survival of both allograft and patient is made possible through immunosuppression following transplantation. Graft rejection is controlled through an immunosuppressant regimen. Standard therapy generally involves a combination of corticosteroids, a calcineurin inhibitor (cyclosporine or tacrolimus), and an antiproliferative agent. At the time of transplant, induction is achieved with high-dose corticosteroids and antithymocyte globulin or monoclonal antibody, followed by the addition of azathioprine and cyclosporine. Newer agents sometimes used in induction include tacrolimus (which, like cyclosporine, inhibits T-cell proliferation) and mycophenolate (a less selective inhibitor similar to azathioprine). [14]
Long-term immunosuppression usually is maintained with cyclosporine, azathioprine, and prednisone. Tacrolimus appears to be superior to cyclosporine in liver transplantation and is being used in many centers. Standard regimens often change during the course of a liver transplant recipient's life.
Studies have shown that dual therapy with steroids and a calcineurin inhibitor are just as efficacious as triple therapy while decreasing serious side effects such as bone marrow suppression. In addition, steroid withdrawal has been shown to be relatively safe in liver transplant recipients, and this has been done in some centers. If steroids are successfully tapered within the first few months of the transplant, there will likely be only minimal increased episodes of acute rejection without any increase in graft loss. Consequently, patients may be weaned down to monotherapy with a calcineurin inhibitor from a previous triple-therapy regimen.
Cyclosporine
Cyclosporine (cyclosporine A) is a cyclic polypeptide immunosuppressant derived from the fungus Beauvaria nivea. Cyclosporine achieves its effects through reversible inhibition of immunocompetent lymphocytes in the G0 and G1 phases of cell division. T-helper cells are the primary targets of the drug, although T-suppressor cells may be affected. Cyclosporine also works by inhibiting calcineurin and thereby impairing interleukin 2 (IL-2) transduction. Since IL-2 is crucial to the recruitment and activation of T-helper cells and is one of the major determinants of the magnitude of the immune response to a donor allograft, blocking its production profoundly influences the rejection process.
Elimination is primarily biliary, with some excretion into the urine. Cyclosporine is dosed according to blood levels and renal function. The dose is highly individualized because of variable absorption, elimination, and effect on renal function. The drug is initiated at 1-2 mg/kg/day in two divided doses and advanced as tolerated, but the maintenance dosage ranges widely, from 1-10 mg/kg/day.
Such target dosing levels are developed by various centers primarily on the basis of experience, given that no clear correlation has been seen between level and immunosuppressive activity. Generally, the 2-hour postdose level is measured and is believed to reflect immunosuppression better than the trough level does.
Cyclosporine toxicity
The principal toxic effect of cyclosporine is nephrotoxicity due to intrarenal vasoconstriction. Nephrotoxicity from cyclosporine occurs in 40-70% of patients and is manifested acutely by elevations in blood urea nitrogen (BUN) and creatinine levels. Whereas acute nephrotoxicity is usually reversible with reductions in dosage, chronic nephrotoxicity is not. This irreversible form is associated with histologic changes in the kidney that may ultimately necessitate renal support through dialysis or retransplantation. Other toxic effects include hyperkalemia, hypertension, venous thrombosis, tremor, headache, paresthesia, gout, gingival hyperplasia, and hepatotoxicity.
Tacrolimus
Tacrolimus is a macrolide antibiotic produced by Streptomyces tsukubaensis. It has immunosuppressant activity similar to that of cyclosporine. Tacrolimus also inhibits calcineurin, which, in turn, results in decreased IL-2 production. Once again, T-cell recruitment and activation is dampened. The drug may produce this effect by binding to intracellular FK 506 proteins and is as much as 100 times more potent than cyclosporine in inhibiting IL-2 synthesis.
Tacrolimus, like cyclosporine, also suppresses humoral immunity through inhibition of B-cell activation by blocking IL-2 production. It is metabolized in the liver via the cytochrome P-450 system. Tacrolimus is approved for use in liver, renal, heart, bone marrow, and other transplantations, and the usual oral dosage in liver transplant recipients is 0.1-0.15 mg/kg/day. Dosing is also based on measuring blood levels, and target levels vary among institutions.
Tacrolimus toxicity
Toxicity is slightly different from that of cyclosporine. Although it has the same degree of nephrotoxicity as cyclosporine, studies have shown a lower incidence of hypertension and hyperlipidemia. However, a higher rate of diabetes and neurotoxicity has been seen.
In general, tacrolimus and cyclosporine are fairly similar in terms of graft and patient survival. However, rates of graft rejection are lower and the need for steroids is less when tacrolimus is used.
When used as part of telaprevir-based triple-drug therapy for posttransplantation HCV recurrence, daily low-dose tacrolimus appears to be a safe and effective immunosuppressive regimen. [15]
Sirolimus
Sirolimus is structurally related to tacrolimus, forming a complex with FK506 binding protein. However, it does not inhibit calcineurin as cyclosporine and tacrolimus do. The mechanism is not clear, but it appears to work by inhibiting IL-2 transduction and inducing the cell to arrest at the G1 to S phase of the cell cycle. Interestingly, sirolimus appears to have antitumorigenic effects through inhibition of angiogenesis. Studies are currently under way investigating this property.
It generally takes 3-5 days for serum levels of sirolimus to equilibrate, and often the sample must be sent out to specialized laboratories that are equipped to perform such studies.
Sirolimus toxicity
The main adverse effects include bone marrow suppression (thrombocytopenia, anemia, leukopenia), hyperlipidemia, peripheral edema, and poor wound healing. Sirolimus alone does not appear to cause significant nephrotoxicity.
Azathioprine
Azathioprine is an imidazolyl derivative of 6-mercaptopurine. The drug inhibits nucleic acid synthesis, suppressing cell-mediated hypersensitivity and altering antibody production. This results in inhibition of T-cell activation, reduction of antibody production, and a decrease in the number of circulating monocytes and granulocytes. It is effective in preventing rejection but does not have a large effect on an immune response already activated.
Azathioprine is metabolized in the liver and erythrocytes. Renal function has minor effects on levels. The drug causes a dose-dependent decrease in leukocyte and platelet counts via bone marrow suppression. It is typically dosed according to white blood cell (WBC) and platelet counts, with an initial dosage of 3-5 mg/kg/day. The maintenance dosage usually is lower, at 1-3 mg/kg/day.
Azathioprine toxicity
Development of severe renal dysfunction warrants closer monitoring with possible reduction in dosage. However, monitoring of blood levels is generally not required. The major toxic effects are neutropenia and thrombocytopenia. Less common adverse effects include nausea, vomiting, pancreatitis, hepatotoxicity, and development of cancer.
Everolimus
Everolimusis an mTOR kinase inhibitor that inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes. It is indicated for prophylaxis of allograft rejection in adult liver transplant recipients in combination with reduced doses of tacrolimus and with corticosteroids. The use of mTOR inhibitors provides a calcineurin inhibitor-sparing regimen to avoid impaired renal function associated with tacrolimus or cyclosporine.
Everolimus toxicity
Use of everolimus for liver transplant rejection is not initiated until at least 30 days post liver transplant. Hepatic artery thrombosis has been reported with mTOR inhibitors when they are used within the first 30 days post transplantation.
Mycophenolate
Mycophenolate or mycophenolate with its morpholino ester (MMF) is an antibiotic isolated from Penicillium species that has immunosuppressant properties. Its mechanism of action is similar to that of azathioprine, but it does not cause as much bone marrow suppression. It works by selectively inhibiting purine synthesis, and thus, it is a potent inhibitor of B-cell and T-cell proliferation.
At present, mycophenolate's major role is in treating acute rejection; however, the drug is finding an increasing role in maintenance immunosuppression. It is currently approved in renal transplantation but is increasingly being used in liver and heart transplantation. Mycophenolate is metabolized in the liver to its active form (ie, mycophenolic acid), is subsequently gluconurated in the liver to an inactive form, and is then excreted renally. The oral dosage is 2-4 g/day, with reductions in the face of renal failure. Monitoring of blood levels is generally not required.
Mycophenolate toxicity
The major toxic effect is neutropenia, but this appears to be less pronounced than with azathioprine. Other less common adverse effects include gastrointestinal symptoms.
Corticosteroids
Nearly all patients receive corticosteroids following transplantation. Corticosteroids are nonspecific anti-inflammatory agents working primarily to inhibit cytokine gene transcription. By doing so, steroids prevent the recruitment and activation of T cells. Typically initiated as methylprednisolone, the drug is switched to oral prednisone (~1 mg/kg) once oral intake is adequate and then is tapered. Acute rejection episodes are treated with higher doses followed by retapering.
Corticosteroids adverse effects
The use of steroids is associated with many adverse effects, including hypertension, cushingoid appearance, personality changes, weight gain, dyslipidemia, osteoporosis, hyperglycemia, diabetes, cataracts, and increased risk of infection.
