Optimal blood levels of (extended-release) tacrolimus in living donor kidney transplantation to prevent de novo donor-specific antibody production: A retrospective cohort study

Abstract

Chronic antibody-mediated rejection, caused by de novo donor-specific antibody (dnDSA) production, results in poor graft survival. To prevent dnDSA production, optimal blood levels of immunosuppressive drugs in living donor kidney transplant recipients were determined. A total of 772 recipients underwent living donor kidney transplantation between January 2008 and December 2017. Graft survival and risk factors for dnDSA production were investigated in 647 recipients. Optimal blood levels of tacrolimus (TAC) and extended-release TAC (TACER) were measured in recipients receiving steroids and mycophenolate mofetil, combined with TAC (n = 53) or TACER (n = 135). Receiver operating characteristic (ROC) curve analysis and comparisons between dnDSA-negative and dnDSA-positive recipients were carried out. The Kaplan-Meier method revealed significantly poor graft survival in dnDSA-positive recipients (P < 0.001). Cox regression models indicated calcineurin inhibitor withdrawal as a significant risk for dnDSA production (P < 0.001; hazard ratio 6.637; 95% confidence interval 2.667-6.517). Average trough levels of TAC and TACER in dnDSA-negative recipients were significantly higher than those in dnDSA-positive recipients (4.88 vs 3.69 ng TAC/ml, P = 0.023, and 4.60 vs 3.85 ng TACER/ml, P = 0.001). ROC curve analysis indicated 4.325 and 3.990 ng/ml as the best trough levels under TAC- and TACER-based regimens, respectively, to prevent dnDSA production (areas under the curve: 0.788 and 0.813, respectively). Maintenance of the trough levels of TAC > 4.325 ng/ml and TACER > 3.990 ng/ml may prevent dnDSA production.

Keywords: De novo donor-specific antibody; Extended-release tacrolimus; Living donor kidney transplantation; Tacrolimus; Trough level.