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 a t 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 we re compared among patients having mean cyclosporine f(U) (Csfu) that were l ow (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 r espect to the total number of biopsies performed in the first 3 months afte r transplant was significantly higher in the L-Csfu group than the other gr oups (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-d ays) 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. intermedia te-high). The mean (95% confidence interval) of time interval between the f irst 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 gr oup compared with the others (4.0+/-1.7 episodes for L-Csfu vs. 2.9+/-1.1 f or 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 hi gh group required treatment with total lymphoid irradiation (P<0.02). Conclusions. This finding suggests that patients with lower levels of cyclo sporine f(U) are more prone to cardiac rejection and that the level of cycl osporine fraction unbound may be clinically important for determination of response to cyclosporine therapy.