Tacrolimus dose, blood concentrations and acute nephrotoxicity, but not CYP3A5/ABCB1 genetics, are associated with allograft tacrolimus concentrations in renal transplant recipients

Aims Long-term use of the immunosuppressant tacrolimus is limited by nephrotoxicity. Following renal transplantation, the risk of nephrotoxicity may be determined more by allograft than by blood tacrolimus concentrations, and thus may be affected by donor CYP3A5 and ABCB1 genetics. Little is known regarding factors that determine tacrolimus intrarenal exposure. Methods This study investigated the relationship between trough blood (C-0Blood) and allograft (C-Graft) tacrolimus concentrations and tacrolimus dose, haematocrit, genetics, acute nephrotoxicity, rejection status, delayed graft function, and time post-transplant. C-0Blood and C-Graft were quantified in 132 renal transplant recipients together with recipient and donor CYP3A5 (rs776746) and ABCB1 3435 (rs1045642) genotypes. Results C-0Blood ranged from 2.6 to 52.3 ng/mL and C-Graft from 33 to 828 pg/mg tissue. Adjusting for dose, recipients who were CYP3A5 expressors had lower C-0Blood compared to nonexpressors, whilst delayed graft function was associated with higher C-0Blood. Linear regression showed that the significant predictors of C-Graft were C-0Blood (point-wise P = 7 x 10(-10)), dose (P = .004) acute nephrotoxicity (P = .002) and an interaction between C-0Blood and acute tacrolimus nephrotoxicity (P = .0002), with an adjusted r(2) = 0.35 and no contribution from donor or recipient CYP3A5 or ABCB1 genotype. The association between C-Graft and acute nephrotoxicity depended on one very high C-Graft (828 pg/mg tissue). Conclusions Recipient and donor CYP3A5 and ABCB1 3435C>T genotypes are not determinants of allograft tacrolimus exposure in kidney transplant recipients. However, tacrolimus dose and C-0Blood were significant predictors of C-Graft, and the relationship between C-0Blood and C-Graft appeared to differ in the presence or absence of acute nephrotoxicity.