Improved pulse wave velocity and renal function in individualized calcineurin-inhibitor treatment by immunomonitoring: the randomized controlled Calcineurin Inhibitor-Sparing (CIS) Trial
To compare the monitoring of cyclosporine A (CsA) using nuclear factor of activiated T-cells -regulated gene expression (NFAT-RE), versus standard CsA trough level (C0) monitoring.
Participants were randomly assigned to either standard monitoring (CsA dose adjusted to target a C0 of 80–150 μg/L), or NFAT-RE (CsA adjusted to target a residual NFAT-RE of 15–30%).
55 renal allograft recipients from a deceased or living donor ≥6 months prior to study entry, aged ≥18 years with stable renal allograft function, and receiving CsA microemulsion, mycophenolic acid with or without low-dose steroids.
The primary outcome measured was the change in arterial stiffness, assessed by pulse wave velocity. Secondary outcomes included peripheral and central blood pressure, cardiac augmentation index, biopsy-proven acute rejection, graft loss or death, renal function, safety and tolerability.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
This small but interesting RCT investigates the use of immune monitoring using NFAT-regulated gene expression (NFAT-RE) in stable kidney transplant recipients. All patients received cyclosporine and MMF with/without steroids, and control patients were monitored using standard trough cyclosporine levels. The authors demonstrate a significant improvement in pulse-wave velocity and GFR with NFAT-RE monitoring, with no obvious excess in adverse events or rejection. The small size of this study means that further evidence would be required to demonstrate safety in terms of rejection and graft survival. It appears, however, that NFAT-RE monitoring may allow minimisation of cyclosporine dose safely in these
stable, low risk recipients. It is worth noting that trough cyclosporine levels in the standard monitoring arm increased over the 12-month study period, with a corresponding fall in GFR, which does raise the risk of treatment bias in a non-blinded study such as this.
Professor Ron Shapiro, Kidney/Pancreas Transplantation, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mt. Sinai, USA.
Conflicts of interest:
This is an extremely interesting trial of utilizing immunologic monitoring to manage immunosuppression in stable renal transplant recipients. Patients were randomized either to routine PK monitoring (i.e. peak and trough levels) or NFAT-regulated gene expression. Patients randomized to NFAT-regulated gene expression had reduced cardiovascular risk, as assessed by pulse wave velocity, fewer infections, and better renal function than the control group. This is a very important trial. Most immunosuppression is, at some level, an educated guess about what patients should be receiving, based on a composite of clinical and laboratory factors, but without any real immunologic monitoring
data. This trial utilized immunologic monitoring to titrate immunosuppressive drug dosing. Even with a very small number of patients, the authors were able to demonstrate a benefit of immunologic monitoring. The study utilized an immunosuppressive agent, cyclosporine that is used in a very small minority of transplant recipients. This work should be repeated by other centers, with larger numbers of patients, utilizing tacrolimus-based immunosuppression. If the findings from this initial experience are replicated, this could lead to a sea change in how patients are managed after transplantation.
BACKGROUND A new immune monitoring tool which assesses the expression of nuclear factor of activated T-cells (NFAT)-regulated genes measures the functional effects of cyclosporine A. This is the first prospective randomized controlled study to compare standard pharmacokinetic monitoring by cyclosporine trough levels to NFAT-regulated gene expression (NFAT-RE). METHODS Expression of the NFAT-regulated genes was determined by qRT-PCR at cyclosporine trough and peak level. Cardiovascular risk was assessed by change of pulse wave velocity from baseline to month 6. Clinical follow-up was 12 months. RESULTS In total, 55 stable kidney allograft recipients were enrolled. Mean baseline residual NFAT-regulated gene expression was 13.1 +/- 9.1 %. Patients in the NFAT-RE group showed a significant decline in pulse wave velocity from baseline to month 6 versus the standard group (-1.7 +/- 2.0 vs. 0.4 +/- 1.4 m/s, p<0.001). Infections occurred more often in the standard group compared to the immune monitoring group. No opportunistic infections occurred with NFAT-RE monitoring. At 12 months' follow-up, renal function was significantly better with NFAT-RE versus standard monitoring (Nankivell GFR 68.5 +/- 17.4 vs. 57.2 +/- 19.0 ml/min, p=0.009). CONCLUSIONS NFAT-RE as translational immune monitoring tool proved efficacious and safe in individualizing cyclosporine therapy, with the opportunity to reduce the cardiovascular risk and improve long-term renal allograft function.