The effects of HLA mismatching and immunosuppressive therapy on early rejection outcome in pediatric heart transplant recipients

Background: Although HLA-DR antigen mismatching between heart transplant re cipients and donors has been associated with increased early allograft reje ction in adult patients treated with cyclosporine, little information exist s in the pediatric age group. In this study we examined retrospectively the effects of HLA mismatching and immunosuppression choice, cyclosporine vers us tacrolimus on early rejection outcome in pediatric heart transplant reci pients. Methods: Between 1992 and 1997, 38 patients (ages 10 days to 18 years) unde rwent 40 heart transplantations. All recipients were typed prospectively an d donors retrospectively by use of serologic microcytotoxicity testing for HLA-A and HLA-B antigens and by a polymerase chain reaction technique for H LA-DR antigens. All heart transplant recipients received induction immunosu ppression with methylprednisolone and maintenance prednisone, and 38 receiv ed OKT3. The first 25 heart transplant recipients received cyclosporine and azathioprine, and the last 15 were given tacrolimus. Clinical courses, HLA mismatching, and biopsy results for the first year after heart transplanta tion were reviewed and compared between treatment groups. Results: Mean age, donor/recipient weight ratios, and biopsies/patient were similar between treatment groups. Five deaths occurred among cyclosporine- treated patients and none among tacrolimus-treated patients during the stud y period. HLA mismatching was similar between groups, with 94% of patients having 1 or 2 HLA-A mismatches and 96% having I or 2 HLA-B and -DR mismatch es. Both International Society for Heart and Lung Transplantation grade 2 a nd grade 3 or 4 rejections were significantly increased in biopsies from cy closporine-treated patients (P <.05). Significantly increased grade 3 or 4 rejection was present in patients treated with cyclosporine who had two DR mismatches versus those with one DR mismatch (3.0 +/- 1.6 vs 1.4 +/- 0.8; P <.05); no statistical significance between patients treated with tacrolimu s with 1 vs 2 DR mismatches was noted. Patients treated with tacrolimus who had 2 DR mismatches had fewer grade 3 or 4 rejection episodes/patient than either patients treated with cyclosporine who had one DR mismatch (0.6 +/- 0.4 vs 1.4 +/- 0.8, P =.03) or those treated with cyclosporine who had two DR mismatches (0.6 +/- 0.4 vs 3.0 +/- 1.6, P =.01). Grade 3 or 4 rejection episodes/patient were not affected by HLA-A or B mismatching, and grade 2 rejection was not affected by mismatching at any of the loci. Conclusion: Although mismatching of HLA-A and -B antigens did not affect fr equency of early cellular rejection, the presence of 2 HLA-DR loci mismatch es increased the risk of high-grade rejection in pediatric heart transplant recipients treated with cyclosporine. The potent effects of tacrolimus-bas ed immunosuppression mitigated the impact of HLA-DR mismatching, because pa tients treated with tacrolimus who had 2 DR mismatches had less rejection t han even patients treated with cyclosporine who had one DR mismatch and see med to be at no greater risk for rejection than patients treated with tacro limus who had 1 DR mismatch.