LATE INTRA-PATIENT TACROLIMUS VARIABILITY PREDICTS DE NOVO DONOR-SPECIFIC ANTIBODY AND GRAFT LOSS

Abstract

Introduction: Intra-patient variability (IPV) of tacrolimus level has been associated with poor outcomes after kidney transplantation. However, these findings were limited mainly to measurements early after transplantation, and little is known about the effects of late IPV. We evaluated whether late IPV of tacrolimus level is associated with de novo donor-specific antibody (dnDSA) development and graft failure in a cohort of 703 transplant recipients. Methods: We analyzed the late IPV on the basis of trough levels for two years before dnDSA monitoring, and grouped patients into low IPV (n=411; coefficient of variation [CV]≤ 30%) and high IPV groups (n=292; CV> 30%). Monitoring of dnDSA was performed at a median 70 months (IQR 36-104) post-transplant. Results: During the follow-up, 206 developed dnDSA and 36 lost their graft excluding death. A total of 104 patients (35.6%) with high IPV and 102 (24.8%) with low IPV developed dnDSA (P=0.002). Mean tacrolimus trough levels of two groups were not significantly different (4.6 ± 1.3 for low IPV vs. 4.7 ± 1.3 for high IPV, P=0.714). High IPV (OR, 1.62; 95% CI, 1.16 to 2.28; P=0.005) and DR mismatches (OR, 2.25; 95% CI, 1.16 to 3.06; P<0.001) were the independent risk factors for dnDSA development. As compared to the low IPV group, high death-censored graft loss was observed in the high IPV group (P<0.001). Conclusion: High IPV of tacrolimus in late phases of transplantation was significantly associated with dnDSA development and graft loss. Late IPV of tacrolimus may serve as a useful tool for long-term post-transplant management.