THE TREATMENT OF INTRACTABLE REJECTION WITH TACROLIMUS (FK506) IN PEDIATRIC LIVER-TRANSPLANT RECIPIENTS

We report our experience in 17 pediatric orthotopic liver transplant ( OLT) patients converted from cyclosporine (CsA) to FK506 for intractab le acute and chronic rejection. FK506 was initiated orally at a dose o f 0.3 mg/kg/day in most patients; the dose was then adjusted to achiev e serum levels of 0.5-1.5 ng/ml. Azathioprine was discontinued and low -dose prednisone maintained. The median time between liver transplanta tion and FK506 conversion was 41 months. Patients have been treated fo r an average of 14.8 +/- 9.6 months. Six patients were converted for a cute rejection and 11 for chronic rejection, i,e., vanishing bile duct syndrome (VBDS). After FK506 conversion, the actual patient and graft survival was 88% and 82%, respectively, in the group as a whole. Two patients died, one of chronic active hepatitis C and the other of lymp homa. Three patients, all with VBDS, did not respond to FK506 and ther efore required retransplantation. The serum bilirubin is currently nor mal in 14 patients and the serum transaminases < 100 IU/ml in 12. The mean bilirubin pre-FK506 of patients successfully converted to FK506 w as 4.2 mg/dl compared to 11.8 mg/dl in patients who failed conversion. Major complications included nephrotoxicity, neurotoxicity, and lymph oma. The mean glomerular filtration rate (GFR) of 97 +/- 29 mls/min/1. 73m(2) prior to FK506 conversion dropped to 51 +/- 20 mls/min/1.73m(2) (p = 0.0001) after a mean of 13.6 months of FK506 therapy. Three pati ents have developed B-cell lymphomas; two of them responded to decreas ed immunosuppression and one died. We conclude that intractable liver graft rejection in children is most successfully reversed if FK506 is instituted before cholestasis becomes pronounced. The high cumulative doses of immunosuppression needed to control intractable rejection pla ces these patients at special risk for developing lymphomas.