Ciclosporin A tapering monitored by NFAT-regulated gene expression: a new concept of individual immunosuppression.
BACKGROUND
The impact of long-term immunosuppression in renal transplant recipients with respect to safety and efficacy remains undetermined. Pharmacodynamic monitoring of the relative reduction of T-cell-specific gene expression in renal transplant recipients treated with cyclosporine A (CsA) was applied in this study.


METHODS
During the study, 20 stable renal transplant recipients with tapered CsA dose and 20 patients with stable CsA dose (matched for age, gender, CsA dose, time after transplantation) were compared for a median period of 18 months (range 6-44). CsA dose was tapered in two stages of 15% each, and the expression of the nuclear factor of activated T cells (NFAT)-regulated genes was determined by reverse-transcription polymerase chain reaction method at CsA trough level and 2 hr after oral uptake.


RESULTS
The initial residual gene expression at 2 hr after CsA intake increased from 6.31% (range 1.30-16.6) to 21.3% (range 6.58-31.8) in patients with CsA dosage reduction. In one patient, the residual gene expression increased more than 40% and resulted in a reversible Banff 1A rejection episode. Blood pressure was significantly lower after CsA dosage reduction (P<0.05). In the pair-matched control group NFAT-regulated gene expression was comparable before and after the follow-up period (7.45% [range 0.21-18.3] vs. 5.87% [range 0.66-13.2]; P=NS). Estimated glomerular filtration rate was significantly worse in the control group (P<0.05).


CONCLUSIONS
Our observation suggests that the measurement of the relative gene expression in CsA-treated patients is a promising tool to monitor the CsA dosage reduction in long-term renal transplant patients. An increase in residual expression of NFAT-regulated gene expression may result in an acute rejection episode.
Sommerer
Claudia
C
Department of Nephrology, University Hospital, University of Heidelberg, Heidelberg, Germany. Claudia.Sommerer@med.uni-heidelberg.de
Giese
Thomas
T
Schmidt
Jan
J
Meuer
Stefan
S
Zeier
Martin
M
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016030:Kidney Transplantation / Q000276:immunology*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*
D015415:Biomarkers; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D016572:Cyclosporine