Immunomonitoring of stable renal transplantation patients

Kidney transplantation is a successful treatment option for patients with end-stage renal disease. To prevent allograft rejection, renal transplant patients need long-term immunosuppressive therapy with tacrolimus, mycophenolate mofetil (MMF) and prednisolone. The disadvantages of this maintenance treatment regimen, however, is the large intra- and interpatient variability in clinical outcome, especially for tacrolimus. Too little exposure leads to a risk of acute rejection and formation of donor-specific antibodies, while too much exposure leads to an increased risk of infection and nephrotoxicity.
To minimize adverse effects and improve effectiveness of the current treatment regimen, therapeutic drug monitoring (TDM) is routinely
performed. For tacrolimus, the most common method of TDM is measuring pre-dose trough concentration (C0) in whole blood. These
trough concentrations, however, are highly variable and the correlation with clinical outcome is still debatable. TDM is not standardly
performed for MMF and prednisolone treatment, and therapy is usually not individualized. To improve dosing strategies and minimize adverse effects, the current TDM should be optimized. For that reason, we have developed several whole blood-based PD readout measures for the quantification of immunosuppression. These readout measures (PHA-induced cytokine production, T cell proliferation and T cell activation marker expression) were previously tested in healthy volunteers and have shown to be suitable for quantification of the immunosuppressive effect of a single dose of tacrolimus, cyclosporine A and mycophenolic acid. Besides the high variability and small therapeutic window of tacrolimus, the patient’s age also affects clinical outcome. Elderly transplantation patients are generally prescribed lower doses of tacrolimus, while the dose-normalized C0 concentrations are higher than in the younger patients. Moreover, aging causes the number of effector lymphocytes to decrease, which result in a reduced immune response to the transplanted organ. These age-related changes are one of the reasons that elderly transplant recipients are more likely to suffer from side effects of over-immunosuppression, such as diabetes and de novo malignancies. To investigate if the relationship between drug concentration and cellular PD measures is different in older patients, both young (<40 years) and elderly (>60 years) kidney transplantation patients will be included in this study.

To improve dosing strategies and minimize adverse effects, the current TDM should be optimized. We advocate that PD-based instead of PK-based therapeutic drug monitoring, by using clinically relevant immune tests to quantify the immunosuppressive state of the individual patient, may improve the clinical outcome. For that reason, we have developed several whole blood-based PD readout measures for the quantification of immunosuppression. These readout measures (PHA-induced cytokine production, T cell proliferation and T cell activation marker expression) were previously tested in healthy volunteers and have shown to be suitable for quantification of the immunosuppressive effect of a single dose of tacrolimus, cyclosporine A and mycophenolic acid. In the current clinical study we aim to evaluate if the selected PD readout measures are also suitable for immunomonitoring of renal transplantation patients receiving long-term triple immunosuppressive therapy.

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