Early immunosuppression protocols

The immediate post-transplant immunosuppression protocol has a profound impact on the incidence of acute rejection and subsequent graft survival. There is a delicate balance between the desired goal of preventing acute rejection and minimizing side-effects from over-immunosuppression. Complications due to over-immunosuppression are serious and can impact graft as well as patient survival. They include opportunistic infections, malignancies, and organ toxicity, particularly nephrotoxicity from cyclosporine A or tacrolimus (FK 506). Most American transplant immunosuppression protocols are variations of quadruple drug induction therapy. In addition to corticosteroids in a tapering dose, cyclosporine A is introduced after a few days, overlapping with antithymocyte globulin or the monoclonal antibody OKT-3, until therapeutic cyclosporine A blood concentration is achieved. The introduction of cyclosporine A is delayed to allow the kidney to recover from the ischemic event. The fourth component of the protocol is azathioprine or, more recently, mycophenolate mofetil (RS 61443 CellCept®, Upjohn, Valhalla, NY).

An example of a quadruple induction protocol is given in Fig 1. The specifics of this protocol include 375 mg of methylprednisolone given perioperatively in three doses, followed by prednisone, tapering the dose to 30 mg daily by day 8. Verapamil is given to protect the kidney from ischemia and cyclosporine-induced vasospasm, and also to increase blood cyclosporine A levels. The old formulation of cyclosporine A (Sandimmune®) has been replaced by a microemulsion formulation (Neoral®, Sandoz Pharmaceuticals, Hanover, NJ) with more consistent uniform absorption characteristics. Cyclosporine A therapy is initiated when serum creatinine is half the preoperative level or below 3.0 mg/dl. Recently, ketoconazole 50 mg daily has also been given with the first dose of cyclosporine A so that therapeutic cyclosporine A blood levels are obtained more rapidly. When cyclosporine A blood levels have reached 300 ng/ml for two consecutive days, antithymocyte globulin and ketoconazole are discontinued and subsequent cyclosporine A is administered at maintenance levels of at least 300 ng/ml for 16 weeks. In cases of delayed function, the introduction of cyclosporine A is delayed and antithymocyte globulin is continued for up to 14 days.

Fig. 1 The early post-transplant immunosuppression protocol currenty used in the Transplant Program at the State University of New York at Buffalo: ATG, antithymocyte globulin; CsA, cyclosporine A; SR, slow release formulation. Perioperatively, methylprednisolone 125 mg is given intravenously, followed by prednisone tapering to 30 mg daily by day 8. Antithymocyte globulin 15 mg/kg, diluted in 500 ml 5 per cent glucose or 0.9 per cent saline, is started within 6 h of surgery and infused over 4 to 6 h daily, overlapping with cyclosporine A (Neoral®) starting at 8 mg/kg orally. When cyclosporine blood levels have exceeded 300 ng/ml for two consecutive days, antithymocyte globulin is stopped. Mycophenolate mofetil (CellCept®) 1 g twice daily is started when the patient can take oral medication, usually within 24 to 48 h. Verapamil is started with 120-mg slow-release formulation as pre-medication; 10 mg verapamil is injected intra-arterially during/after the perfusion and given chronically in a dose of 120 mg twice daily.

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