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Paradoxical Cyclosporine A Requirements in Pediatric Renal Transplants Receiving High-Dose Steroids

From the Department of Pediatrics, Dalhousie University, IWK Health Centre, Halifax, Nova Scotia (Dr Crocker, Ms McLellan, Dr Goralski, Dr Acott); Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia (Dr Goralski, Dr Renton, Dr Acott); and Queen's University School of Medicine, Kingston, Ontario (Ms Hardy).

The potent immunosuppressant cyclosporine A (CyA) is a mainstay of treatment in the renal transplant population. During episodes of acute allograft rejection, therapy also includes the pulse administration of high-dose steroids such as prednisone or methylprednisolone. Both steroids and CyA are metabolized by the CYP3A4 isoenzyme of the cytochrome P450 catalytic system. On a theoretical basis, high steroid concentrations during a rejection episode could competitively inhibit CyA metabolism, increasing its systemic concentration and decreasing its dose requirements. A database was compiled consisting of pediatric patients who had undergone an acute renal rejection event during the years 1993 to 2003. The severity of rejection events, as well as the CyA and prednisone dosing regimens used during rejection, were assessed using a comprehensive chart analysis. The presence or absence of additional medications that could potentially interact with CyA was also examined. Although some patients responded in the predicted manner, the authors also found that a subgroup of pediatric patients placed on highdose pulse steroid therapy for acute graft rejection required increased amounts of CyA to maintain therapeutic concentrations. The authors recommend monitoring of patients on high-dose steroids for paradoxical CyA requirements intermittently during high-dose steroid treatment to individualize CyA therapy appropriately during renal allograft rejection and thereby maximize efficacy while minimizing potential toxic side effects of CyA such as under-immunosuppression and organ rejection.

Key Words: CyA • corticosteroid • pediatric • kidney • transplantation

Address for reprints: Dr Philip D. Acott, Department of Pediatrics, IWK Health Centre, Halifax, 5850/5980 University Avenue, P.O. Box 3070, Halifax, Nova Scotia, B3J 3G9, Canada.

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