Monitoring Of NFAT-Regulated Gene Expression in the Peripheral Blood of Allograft Recipients: A Novel Perspective Towards Individual Optimized Drug Doses of Cyclosporine A.

Monitoring Of NFAT-Regulated Gene Expression in the Peripheral Blood of Allograft Recipients: A Novel Perspective Towards Individual Optimized Drug Doses of Cyclosporine A. Transplantation 2004; 77: 339. T. Giese, M. Zeier, P. Schemmer, W. Uhi, M. Schoels, T. Dengler, M. Buechler, S. Meuer New Approaches To Individualizing Cyclosporine Dose Therapeutic drug monitoring of cyclosporine (CsA) microemulsion is progressively evolving from trough blood-level concentration (C0) to C2 (blood concentration 2 hours after the morning dose). This is supported by clinical research in recipients of solid-organ transplants. We have reported in long-term heart and liver transplant patients that C2 provides a superior correlation with the area-under-the-curve (AUC) compared with C0 (1,2). The excellent correlation between C2 and the AUC was confirmed also in novo liver and renal-transplant patients (3,4). A balance between high and low exposure to CsA as assessed by C2 is of utmost importance to reduce the risk of acute rejection while minimizing nephrotoxicity. Studies in de novo renal- and liver-transplant patients have emphasized the importance of achieving a predetermined C2 range within the first few days after surgery to reduce the incidence of acute rejection (5,6). Moreover, C2 monitoring resulted in a lower incidence of moderate-severe acute rejection compared with C0 in de novo liver-transplant recipients (6). A prospective multicenter study aiming at determining an appropriate C2 range is ongoing in de novo heart-transplant patients. The implementation of C2 monitoring in long-term heart- and liver-transplant patients has resulted in a significant clinical benefit compared with C0 monitoring (2,7). Basic research studies confirmed that the effect of CsA microemulsion is better reflected at C2 compared with C0. Batiuk et al. (8) demonstrated that CsA maximal concentration (Cmax, approximately at 2 hours after the morning dose of CsA microemulsion) is associated with the maximal inhibition of calcineurin. Sindhi et al. (9) showed a significant decreased expression of interleukin (IL)-2) in lymphocytes at C2. On clinical grounds, we demonstrated that, in long-term liver-transplant patients, a similar inhibition of calcineurin may be achieved with two different C2 ranges (300–600 ng/mL and 700–1,000 ng/mL) as well as with a conventional C0 range (100–200 ng/mL). However, renal function was better preserved in patients exposed to the lower C2 range, without increasing the risk of acute rejection (2). The refinement of CsA therapeutic drug monitoring with C2 is an area of ongoing research. In this issue of Transplantation, Giese et al. studied the expression of the nuclear factor of activated T-cells (NFAT)-regulated genes including IL-2, interferon (INF)-γ, and granulocyte-monocyte colony stimulating factor (GM-CSF) in peripheral blood from long-term renal, heart-, and liver-transplant patients treated with CsA microemulsion. The authors used a quantitative real-time (RT) polymerase chain reaction (PCR) technique and correlated the results with CsA pharmacokinetics. Patients were studied at a regular follow-up visit to the outpatient clinic. Patients were at different stages after transplantation, namely, 8 to 201 months after renal transplant, 3 to 155 months after heart transplant, and 2 to 15 years after liver transplantation. Renal- and heart-transplant patients were on CsA, corticosteroids, and either azathioprine or mycophenolate mofetil. Liver-transplant patients were on CsA monotherapy. Patents with acute or chronic infections were excluded. The mean creatinine clearance was 70 mL/min in renal-transplant patients. A history of biopsy-proven acute rejection was observed in 12% of the patients within the first year postrenal transplantation, whereas 20% of the patients experienced histologic evidence of nephrotoxicity secondary to CsA. Heart- and liver-transplant patients were clinically stable. However, there was no mention of their renal-function status. An important finding of this study was that the expression of NFAT-regulated genes in peripheral blood correlated well with CsA C2 rather than with CsA C0 level. A good correlation was observed between the AUC (calculated with C0 and C2) and the inhibition of the gene expression of IL-2, INF-γ, and GM-CSF. The expression of NFAT-regulated genes significantly decreased at 2 hours, with a rapid recovery at 6 and 10 hours after the morning dose of CsA. These results were achieved with a mean CsA C2 close to 1,000 ng/mL, which is in the high range for maintenance transplant patients, especially those with heart or liver transplants. The RT-PCR technique for the quantification of NFAT-regulated genes has a short turn around. As stated by the Giese et al., this technique could complement routine therapeutic drug monitoring with CsA C2 levels to better assess functional immunosuppression in individual cases. Prospective studies in de novo and long-term solid-organ transplant patients treated with CsA should evaluate the cost-effectiveness and the clinical impact of the use of RT-PCR technique for the quantification of NFAT-regulated genes. This strategy may help define the appropriate dosage of CsA in individual cases, such as patients at high risk of acute rejection and those with recurrent acute rejection episodes. It may also be useful to confirm the safest lower C2 range in patients with CsA-induced nephrotoxicity. This is of particular importance in non–renal-transplant patients in whom the incidence of chronic renal failure and end-stage renal disease is becoming a significant problem (10). After the earlier studies on the effect of CsA on calcineurin inhibition and on the expression of IL-2 in lymphocytes, this study adds further evidence that therapeutic drug monitoring of CsA with C2 levels provides a reliable assessment of the pharmacodynamic effect of CsA in solid-organ transplant patients.

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