Immunosuppression

The challenge when choosing an immunosuppressive regimen for a child is to balance the need to prevent rejection against the infectious complications of these therapeutic agents.

Cyclosporine, a calcineurin inhibitor introduced in the mid-1980s, is a potent lymphocyte-specific immunosuppressive. Neoral, a new oral formulation, has better intestinal absorption than the previous compounds even in the setting of poor bile flow. Monitoring of cyclosporine levels helps to avoid toxicity and ensures a therapeutic range. Most agree that a cyclosporine whole blood trough level of 200 to 300 ng/mL measured by high-performance liquid chromatography or its equivalent represents the therapeutic range. Monitoring peak cyclosporine levels at 2 hours after the dose (C2 levels) may be a more effective way to ensure adequate immunosuppression and limit toxicity. Acute nephrotoxicity correlates with high cyclosporine levels, especially in the early posttransplantation period. Gingival hyperplasia and hirsutism are common side effects.

Tacrolimus is a more potent calcineurin inhibitor than cyclosporine, which allows children treated with it to be less steroid dependent. Like cyclosporine, tacrolimus is primarily metabolized in the liver and appears to use similar degradative pathways mediated by the cytochrome P-450 system. Blood levels should be monitored with a goal range of 10 to 12 ng/mL in the immediate posttransplantation period. Some of the side effects are anorexia, chronic GI symptoms, hypertension, tremors, hyperglycemia, chronic renal tubular damage, and the predisposition to posttransplantation lymphoproliferative disease (PTLD).

Most regimens also include corticosteroids, azathioprine, or mycophenolic acid and sometimes OKT3 (muromonab-CD3). Methylprednisone is started at a dose of 2 mg/kg/d, with a taper to 0.3 mg/kg/d at 1 month after transplantation. By 18 months, steroids are weaned to an alternate-day schedule to permit normal growth.

OKT3 is a murine monoclonal antibody directed against the CD3 complex receptor common to all T cells that is given for short courses of 10 to 14 days before initiation of the immunosuppressive regimen at some transplant centers. It is also used to treat steroid-resistant acute rejection.

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