Background: Monitoring the intracellular concentration of immunosuppressive agents can be promising to improve and individualize clinical practice in patients receiving transplantation. However, this issue remains unresolved in kidney transplant recipients.

Methods: Both whole blood and intracellular concentrations of tacrolimus (WB-TAC and IC-TAC, respectively) were simultaneously measured in 215 kidney recipients with stable graft function using LC-MS/MS. The tacrolimus ratio was defined as WB-TAC/IC-TAC. Furthermore, the genetic polymorphisms of ATP-binding cassette subfamily B member 1 (ABCB1), such as rs1128503, rs2032582, and rs1045642, were examined. Flow cytometry was used to determine the proportion of T cells producing interferon gamma according to the IC-TAC levels.

Results: The levels of WB-TAC, IC-TAC, and tacrolimus ratio were 4.6 ± 1.8 ng/mL, 43.3 ± 30.2 pg/10⁶ cells, and 125.9 ± 48.5, respectively. The correlation coefficient (r) between WB-TAC and IC-TAC was 0.676 (P < 0.001).Genetic polymorphisms of ABCB1 were not associated with IC-TAC or the tacrolimus ratio. Among baseline covariates, the duration of transplantation was the strongest predictor of IC-TAC and the tacrolimus ratio: patients who had a long period since transplantation had lower IC-TAC and higher tacrolimus ratio. Among the other covariates, patients with deceased donor and a history of delayed graft function had a higher tacrolimus ratio than their counterparts. After stimulation with PMA and ionomycin, the proportion of T cells producing interferon gamma was higher in the patients with a lower IC-TAC level than the counterpart group.

Conclusions: This is the first study to identify the factors associated with the IC-TAC in kidney transplant recipients. The present results will be helpful in monitoring and predicting IC-TAC or the tacrolimus ratio in this subset.

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