Transplant recipients generally require lifelong treatment with immunosuppressive medication to prevent rejection of the graft by their immune system. Inhibitors of the enzyme calcineurin,... Show moreTransplant recipients generally require lifelong treatment with immunosuppressive medication to prevent rejection of the graft by their immune system. Inhibitors of the enzyme calcineurin, including cyclosporin A and tacrolimus, constitute a very potent class of immunosuppressants that has revolutionized transplant medicine. However, their reputation has been showing cracks due to the severe side-effects associated with long-term use of these drugs, including an explosively increased risk of developing skin cancer. The pathophysiological mechanism of this phenomenon is not known, although a number of hypotheses have been put forward. In this dissertation, we show that oxidative stress, mainly derived from exposure to UVA radiation, may locally augment the effects of the calcineurin inhibitors; we propose that overly strong suppression of calcineurin activity may result in malignancy formation due to disruption of tumor-suppressive signaling pathways or disturbed immunosurveillance in skin. Show less
Over the last decades, restoration of renal function by renal allograft transplantation has evolved into the preferred treatment option for patients with end stage renal disease. The introduction... Show moreOver the last decades, restoration of renal function by renal allograft transplantation has evolved into the preferred treatment option for patients with end stage renal disease. The introduction of the calcineurin inhibitors (CNI) cyclosporine and tacrolimus have significantly contributed to this success. Adverse drug effects, together with the large inter-individual variation in pharmacokinetics of both drugs necessitates therapeutic drug monitoring (TDM). Nowadays, TDM is routinely performed by drug concentration measurement in blood. Unfortunately, the incidence of acute allograft rejection episodes is still 10-20% within first year after transplantation. A strategy to improve clinical immunesuppresion early after transplantation is improved monitoring. Next to advanced pharmacokinetic monitoring, such as estimated AUC monitoring, the development of pharmacodynamic markers could theoretically contribute to improve CNI therapy. Pharmacodynamic monitoring strategies, however, are still in an experimental phase and have not proven clinical benefit yet. They carry the theoretical advantage of monitoring the true effectiveness of immunosuppressive therapy. This led us to investigate pharmacodynamic monitoring as potential tool to guide drug dosing. We choose calcineurin activity as pharmacodynamic marker for monitoring and in this thesis, the analytical aspects, fundamental characteristics and insights in clinical usefulness of calcineurin activity measurement as a pharmacodynamic marker for CNI were investigated. Show less
