Monitoring of gene expression in tacrolimus‐treated de novo renal allograft recipients facilitates individualized immunosuppression: Results of the IMAGEN study

Abstract

Calcineurin inhibitors (CNI) have a small therapeutic window, and drug monitoring is required. Pharmacokinetic monitoring does not correlate sufficiently with clinical outcome. Therefore, the expression of nuclear factor of activated T cells (NFAT)-regulated genes in the peripheral blood has been suggested as a potentially useful immune monitoring tool to optimize CNI therapy. NFAT-regulated gene expression (RGE) was evaluated in renal allograft recipients as predictive biomarker to detect patients at risk of acute rejection or infections.Methods: NFAT-RGE (interleukin-2, interferon-γ, granular-macrophage colonystimulating factor) was evaluated by quantitative real-time polymerase chain reaction in whole blood samples at day 7, day 14, month 1, 3, and 6 after transplantation in 64 de novo renal allograft recipients from 3 European centres. Immunosuppression consisted of tacrolimus (Tac), mycophenolic acid, and corticosteroids.Results: Tac concentrations (C0 and C1.5) correlated inversely with NFAT-RGE (P < .01). NFAT-RGE showed a high interindividual variability (1-61%). Patients with high residual gene expression (NFAT-RGE ≥30%) were at the increased risk of acute rejection in the following months (35 vs. 5%, P = .02), whereas patients with low residual gene expression (NFAT-RGE <30%) showed a higher incidence of viral complications, especially cytomegalovirus and BK virus replication (52.5 vs.10%, P = .01).Conclusions: NFAT-RGE was confirmed as a potential noninvasive early predictive biomarker in the immediate post-transplant period to detect patients at risk of acute rejection and infectious complications in Tac-treated renal allograft recipients.Monitoring of NFAT-RGE may provide additional useful information for physicians to achieve individualized Tac treatment.The authors confirm that Claudia Sommerer is the principal investigator for this paper and that she had direct clinical responsibility for patients.

Pharmacodynamic Monitoring of Ciclosporin and Tacrolimus: Insights From Nuclear Factor of Activated T-Cell–Regulated Gene Expression in Healthy Volunteers

“…Thus, it seems that further mechanisms (independent of NFAT-RGE) would not be required as an explanation for the apparent discrepancy between similar or even better clinical efficacy of tacrolimus-based regimens 23,24 and considerably higher RGE tmax values (ie, apparently less suppression) in patients using tacrolimus. 6,9,[12][13][14]16,22 Intriguingly, the relative 12-hour NFAT-RGE associated with typical ciclosporin trough concentrations of 100 mcg/L would equally be expected with tacrolimus trough concentrations of around 9 mcg/L. Thus, one would expect average trough concentrations achieved in the ELITE-Symphony trial (100 mcg/L and 7 mcg/L in the low-dose ciclosporin and tacrolimus groups, respectively) to be associated with similar relative 12-hour NFAT-RGEs.…”

“…Thus, it seems that further mechanisms (independent of NFAT-RGE) would not be required as an explanation for the apparent discrepancy between similar or even better clinical efficacy of tacrolimus-based regimens 23,24 and considerably higher RGE tmax values (ie, apparently less suppression) in patients using tacrolimus. 6,9,12–14,16,22…”

“…7,21 Patients on tacrolimus exhibit considerably higher RGE tmax values (ie, less suppression of NFAT-RGE) and higher cutoff values (RGE tmax cutoff approximately 30%), separating patients with higher or lower organ rejection or infection risks, compared with patients on ciclosporin (RGE tmax cutoff approximately 15%). 6,9,[12][13][14]16,22 This apparent discrepancy remains unexplained, limits interpretation of individual RGE tmax values, and may seem surprising because of the similar or even better clinical efficacy of tacrolimus-based regimens in patients with renal transplants. 23,24 Although additional effect mechanisms other than calcineurin inhibition might be suspected in the case of tacrolimus, conclusive evidence for such additional effects is lacking.…”

“…[8][9][10][11] The current application of the NFAT-RGE method is largely based on relative changes in NFAT-RGE 2 hours (ciclosporin) or 1.5 hours (tacrolimus) after oral drug administration, that is, residual NFAT-RGE at the times where maximum concentrations are expected (RGE tmax ). Indeed, RGE tmax has been related to various clinical end points, including the risk of organ rejection, [11][12][13][14][15][16] infection, 9,[11][12][13][16][17][18] cancer, 9,19 and gingival hyperplasia. 20 RGE tmax has been used to guide CNI dosing in kidney transplant patients during clinical trials.…”