Abstract
BackgroundAdequate monitoring tools are required to optimise the immunosuppressive therapy of an individual patient. Particularly, in calcineurin inhibitors, as critical dose drugs with a narrow therapeutic range, the optimal monitoring strategies are discussed in terms of safety and efficacy. Nevertheless, no pharmacokinetic monitoring markers reflect the biological activity of the drug. A new quantitative analysis of gene expression was employed to directly measure the functional effects of calcineurin inhibition: the transcriptional activities of the nuclear factor of activated T-cell (NFAT)-regulated genes in the peripheral blood.Methods/DesignThe CIS study is a randomised prospective controlled trial, comparing a ciclosporin A (CsA)-based immunosuppressive regimen monitored by CsA trough levels to a CsA-based immunosuppressive regimen monitored by residual NFAT-regulated gene expression. Pulse wave velocity as an accepted surrogate marker of the cardiovascular risk is assessed in both study groups. Our hypothesis is that an individualised CsA therapy monitored by residual NFAT-regulated gene expression results in a significantly lower cardiovascular risk compared to CsA therapy monitored by CsA trough levels.DiscussionThere is a lack of evidence in individualising standard immunosuppression in renal allograft recipients. The CIS study will consider the feasibility of individualised ciclosporin A immunosuppression by pharmacodynamic monitoring and evaluate the opportunity to reduce cardiovascular risk while maintaining sufficient immunosuppression.Trial registrationEudraCT identifier 2011-003547-21, registration date 18 July 2011https://www.clinicaltrialsregister.eu
Highlights
Adequate monitoring tools are required to optimise the immunosuppressive therapy of an individual patient
There is a lack of evidence in individualising standard immunosuppression in renal allograft recipients
The Calcineurin Inhibitor-Sparing (CIS) study will consider the feasibility of individualised ciclosporin A immunosuppression by pharmacodynamic monitoring and evaluate the opportunity to reduce cardiovascular risk while maintaining sufficient immunosuppression
Summary
Adequate monitoring tools are required to optimise the immunosuppressive therapy of an individual patient. In calcineurin inhibitors, as critical dose drugs with a narrow therapeutic range, the optimal monitoring strategies are discussed in terms of safety and efficacy. Current challenges for individualised immunosuppression Calcineurin inhibitors (CNI) represent the most widely used immunosuppressive agents in kidney transplantation. More than 80% of all renal allograft recipients are on CNI therapy [1]. The current one-year survival rate of a renal allograft exceeds 90% [2]. The overall renal allograft survival has not improved as expected, indicating a shift of graft failure from early acute rejection to side effects of long-term immunosuppression and chronic rejection. Death with a functioning graft is an important aspect in the long-term follow-up after successful renal transplantation. Cardiovascular (CV) disease is the leading cause of death in kidney transplant recipients (KTRs), with a 3.5% to 5% annual risk of fatal or non-fatal CV events, much higher than in the general population despite adjustment for traditional risk factors [3,4]
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