Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Erasmus MC Transplant Institute, Rotterdam, the Netherlands.
Ther Drug Monit. 2022 Oct 1;44(5):625-632. doi: 10.1097/FTD.0000000000000982.
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.
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.
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.
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.
细胞内他克莫司浓度在周围血单个核细胞（PBMC）（TAC[PBMC]）中被提议比全血浓度更好地代表其活性浓度。由于他克莫司作用于 T 淋巴细胞和其他白细胞，包括单核细胞，我们研究了肾移植后 T 淋巴细胞（TAC[CD3]）和 CD14+单核细胞（TAC[CD14]）中他克莫司浓度与急性排斥反应的关系。
在这项病例对照研究的总共 61 个样本中，28 个样本是在活检证实的急性排斥反应时获得的（排斥组），33 个样本是在无排斥反应时获得的（对照组）。从冷冻保存的（回顾性）和新鲜获得的（前瞻性）样本中收集 PBMC。从 PBMC 中分离 CD3+T 淋巴细胞和 CD14+单核细胞，并测量其细胞内他克莫司浓度。
他克莫司全血和细胞内浓度之间的相关性很差。TAC[CD3]明显低于 TAC[CD14]（中位数 12.8 与 81.6 pg/百万细胞；P<0.001）。TAC[PBMC]（48.5 与 44.4 pg/百万细胞；P=0.82）、TAC[CD3]（13.4 与 12.5 pg/百万细胞；P=0.28）和 TAC[CD14]（90.0 与 72.8 pg/百万细胞；P=0.27）在排斥组和对照组之间无差异。然而，新鲜分离的 PBMC 显示 TAC[PBMC]明显高于冷冻保存样本的 PBMC。对新鲜分离细胞细胞内他克莫司浓度的亚组分析显示，排斥者和非排斥者之间无差异。
在有和无排斥反应的患者之间，TAC[CD3]和 TAC[CD14]的差异不能被证明。然而，由于观察到新鲜和冷冻保存细胞之间 TAC[PBMC]的差异，需要进一步优化细胞分离过程。这些结果需要在一项有更多患者的研究中得到证实。
