Pharmacodynamic monitoring of nuclear factor of activated T cell-regulated gene expression in liver allograft recipients on immunosuppressive therapy with calcineurin inhibitors in the course of time and correlation with acute rejection episodes--a prospective study.
BACKGROUND
Due to considerable pharmacokinetic (PK) variability, immunosuppression with calcineurin inhibitors (CNIs) remains challenging. The objective of this study was to assess a pharmacodynamic (PD) approach of monitoring nuclear factor of activated T cell (NFAT)-regulated gene expression in the course of time and in correlation with rejection episodes.


METHODS
22 de novo liver allograft recipients were observed for a period of up to 12 months and the residual gene expression (RGE) of NFAT-regulated genes was monitored prospectively and correlated to acute rejection episodes.


RESULTS
There was a significant increase in RGEs between the time points 4-7 months and 1 month (25±7 µg/l vs. 9±5 µg/l, p≤0.0001) and 8-12 months and 1 month (50±8 µg/l vs. 10±7 µg/l, p=0.002) in the cyclosporine A (CsA) group, whereas in the tacrolimus (Tac) group a significant increase in RGEs appeared at the time point 8-12 months first. Acute rejection episodes occurred in 4 patients within 1 month after transplantation. These patients demonstrated a higher RGE of all NFAT-regulated genes compared to the other patients (CsA-treated patients: 39±0% vs. 11±5%, p=0.0001, Tac-treated patients: 48±12% vs. 18±10%, p=0.0082).


CONCLUSIONS
RGE of all NFAT-regulated genes show a relation between acute rejection episodes in the early post transplant period. Thus, this PD method has the potential to aid therapeutic drug monitoring.
Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.
Niels
N
Steinebrunner
Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.
Catharina
C
Sandig
Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany.
Claudia
C
Sommerer
Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany.
Ulf
U
Hinz
Department of Immunology, University of Heidelberg, Heidelberg, Germany.
Thomas
T
Giese
Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.
Wolfgang
W
Stremmel
Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.
Alexandra
A
Zahn
D000208:Acute Disease; D000328:Adult; D000368:Aged; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D016031:Liver Transplantation; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000235:genetics* / Q000276:immunology; D011446:Prospective Studies; D013601:T-Lymphocytes / Q000276:immunology; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014184:Transplantation, Homologous
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D016572:Cyclosporine; D016559:Tacrolimus