Nuclear Factor of Activated T-Cells Post-Renal Transplant.
1Translational Pharmacology Research Center, School of Pharmacy, Buffalo
2Biostatistics, School of Public Health, Buffalo
3Flow Cytometry Laboratory, Roswell Park Cancer Institute, Buffalo
4Medicine, School of Medicine, University at Buffalo, Buffalo.
Meeting: 2016 American Transplant Congress
Abstract number: D235
Keywords: FK506, Kidney transplantation, Pharmacokinetics, T helper cells
Session Information
Session Name: Poster Session D: Poster Session II: Kidney Complications-Other
Session Type: Poster Session
Date: Tuesday, June 14, 2016
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Halls C&D
Background: Nuclear Factor of Activated T-cells (NFAT1) is a transcription factor regulating the expression of key targets involved with cellular immune function. Calcineurin is a phosphatase that regulates the nuclear translocation necessary for NFAT activation and targeted by calcineurin inhibitors such as tacrolimus (TAC) for immunosuppression in renal transplant recipients (RTR). TAC doses are individualized using therapeutic drug monitoring (TDM) of extracellular troughs due to PK variability. We assessed nuclear NFAT1 localization as a pharmacodynamic (PD) marker with TAC PK.
Methods:We enrolled 47 (25 males; 22 females) stable RTR > 6 months post-transplant receiving TAC and mycophenolic acid. NFAT activation was measured at TAC trough (0 hour) and 4 hour after drug (post-peak) in CD4 and CD8 lymphocytes. Baseline nuclear localization of NFAT (unstimulated) and localization following ex-vivo exposure to PMA/Ionomycin (stimulated) generating an Rd value was assessed by flow cytometry based image analysis. Concurrent steady-state 12-hour PK studies determined lean body weight (LBW) adjusted TAC clearance(CL) and dose-adjusted area under the concentration time curve 0-12hrs(AUC0-12).
Results: Female RTR had higher nuclear NFAT translocation in CD4 and CD8 cells when adjusted for race(*) with more rapid TAC CL and higher doses. No association of NFAT Rd translocation to TAC troughs or CL were found with a trend noted with AUC0-12/Dose (P=0.08).
| Mean(SD) | Males | Females | P Values |
| eGFR[ml/min/1.73m2] | 56.4(17.9) | 46.3(13.2) | 0.034 |
| TAC Dose[mg] | 2.8(1.3) | 3.4(1.9) | NS |
| TAC Dose[mg/weight] | 0.03(0.02) | 0.04(0.02) | 0.023 |
| TAC Trough[ng/ml] | 6.74(1.47) | 6.74(1.47) | NS |
| Tac CL/LBW | 0.36(0.18) | 0.58(0.32) | 0.003 |
| NFAT Rd CD4+[0hr] | 0.46(0.55) | 0.72(0.57) | 0.088* |
| NFAT Rd CD4+[4hr] | 0.36(0.58) | 0.73(0.64) | 0.041* |
| NFAT Rd CD8+[0hr] | 0.79(0.65) | 1.04(0.61) | 0.182* |
| NFAT Rd CD8+[4hr] | 0.69(0.59) | 1.04(0.67) | 0.052 |
Conclusion: These data suggest a gender difference in NFAT nuclear translocation in CD4 and CD8 cells and may be reflective of intracellular tacrolimus concentrations. Extracellular tacrolimus troughs alone may not adequately guide TDM of TAC immunosuppression.
CITATION INFORMATION: Tornatore K, Attwood K, McGuire O, O'Loughlin K, Venuto R, Minderman H. Nuclear Factor of Activated T-Cells Post-Renal Transplant. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:
Tornatore K, Attwood K, McGuire O, O'Loughlin K, Venuto R, Minderman H. Nuclear Factor of Activated T-Cells Post-Renal Transplant. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/nuclear-factor-of-activated-t-cells-post-renal-transplant/. Accessed November 22, 2024.« Back to 2016 American Transplant Congress