Association Between the Intracellular Tacrolimus Concentration in CD3+ T Lymphocytes and CD14+ Monocytes and Acute Kidney Transplant Rejection

Abstract

Background:

Intracellular tacrolimus concentration in peripheral blood mononuclear cells (PBMCs) (TAC _[PBMC]) has been proposed to better represent its active concentration than its whole blood concentration. As tacrolimus acts on T lymphocytes and other white blood cells, including monocytes, we investigated the association of tacrolimus concentration in CD3 ⁺ T lymphocytes (TAC _[CD3]) and CD14 ⁺ monocytes (TAC _[CD14]) with acute rejection after kidney transplantation.

Methods:

From a total of 61 samples in this case–control study, 28 samples were obtained during biopsy-proven acute rejection (rejection group), and 33 samples were obtained in the absence of rejection (control group). PBMCs were collected from both cryopreserved (retrospectively) and freshly obtained (prospectively) samples. CD3 ⁺ T lymphocytes and CD14 ⁺ monocytes were isolated from PBMCs, and their intracellular tacrolimus concentrations were measured.

Results:

The correlation between tacrolimus whole-blood and intracellular concentrations was poor. TAC _[CD3] was significantly lower than TAC _[CD14] (median 12.8 versus 81.6 pg/million cells; P < 0.001). No difference in TAC _[PBMC] (48.5 versus 44.4 pg/million cells; P = 0.82), TAC _[CD3] (13.4 versus 12.5 pg/million cells; P = 0.28), and TAC _[CD14] (90.0 versus 72.8 pg/million cells; P = 0.27) was found between the rejection and control groups. However, freshly isolated PBMCs showed significantly higher TAC _[PBMC] than PBMCs from cryopreserved samples. Subgroup analysis of intracellular tacrolimus concentrations from freshly isolated cells did not show a difference between rejectors and nonrejectors.

Conclusions:

Differences in TAC _[CD3] and TAC _[CD14] between patients with and without rejection could not be demonstrated. However, further optimization of the cell isolation process is required because a difference in TAC _[PBMC] between fresh and cryopreserved cells was observed. These results need to be confirmed in a study with a larger number of patients.