Unbound cyclosporine and allograft rejection after heart transplantation

Background. To determine the impact of cyclosporine plasma protein binding on organ rejection after cardiac transplantation, the incidence of cardiac rejection episodes was compared among patients who had differing levels of cyclosporine plasma fraction unbound (f(U)), Methods. Forty-six consecutive cardiac transplant recipients were sampled at 1, 3, 6, and 12 months after transplantation, and cyclosporine plasma f(U) was determined, using a specially developed equilibrium dialysis method. At the completion of the study, incidences of cardiac rejection episodes were compared among patients having mean cyclosporine f(U) (Csfu) that were low (L-Csfu; mean +/- SD, 1.33+/-0.10%, n=15), intermediate (I-Csfu; 1.60+/-0.07%, n=16), and high (H-Csfu; 1.99+/-0.30%, n=15), Results. Percentage of endomyocardial biopsies (grade 3a, 3b, and 4) with respect to the total number of biopsies performed in the first 3 months after transplant was significantly higher in the L-Csfu group than the other groups (40.9% in L-Csfu vs. 28.5% for I-Csfu and 32.1% for H-Csfu groups, P=0.02). The linearized rate of rejection (episodes of rejection/100 patient-days) in the first month after transplant was 6.5+/-1.7 for L-Csfu, 3.5+/-0.8 for I-Csfu and 4.3+/-0.9 for the H-Csfu group (P<0.05, low vs. intermediate-high). The mean (95% confidence interval) of time interval between the first and second episodes of rejections was 10.7 (5.6-16.0) days for L-Csfu, 18.0 (8.6 -29.0) days for the I-Csfu, and 26.0 (15.1-36.9) days for the H-Csfu group (P<0.01). The total number of rejections requiring treatment per patient in the first 3 months after transplant was higher in the L-Csfu group compared with the others (4.0+/-1.7 episodes for L-Csfu vs. 2.9+/-1.1 for I-Csfu and 3.2+/-1.2 episodes for H-Csfu; P<0.05). Four patients in the low group, one patient in the intermediate group, and no patients in the high group required treatment with total lymphoid irradiation (P<0.02). Conclusions. This finding suggests that patients with lower levels of cyclosporine f(U) are more prone to cardiac rejection and that the level of cyclosporine fraction unbound may be clinically important for determination of response to cyclosporine therapy.