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 ) and allograft (C ) tacrolimus concentrations and tacrolimus dose, haematocrit, genetics, acute nephrotoxicity, rejection status, delayed graft function, and time post-transplant. C and C were quantified in 132 renal transplant recipients together with recipient and donor CYP3A5 (rs776746) and ABCB1 3435 (rs1045642) genotypes.

RESULTS

C ranged from 2.6 to 52.3 ng/mL and C from 33 to 828 pg/mg tissue. Adjusting for dose, recipients who were CYP3A5 expressors had lower C compared to nonexpressors, whilst delayed graft function was associated with higher C . Linear regression showed that the significant predictors of C were C (point-wise P = 7 × 10 ), dose (P = .004) acute nephrotoxicity (P = .002) and an interaction between C and acute tacrolimus nephrotoxicity (P = .0002), with an adjusted r  = 0.35 and no contribution from donor or recipient CYP3A5 or ABCB1 genotype. The association between C and acute nephrotoxicity depended on one very high C (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 were significant predictors of C , and the relationship between C and C appeared to differ in the presence or absence of acute nephrotoxicity.