Calcineurin inhibitors are crucial in the prevention of acute rejection in the first year after renal transplantation. Unfortunately, these drugs (ciclosporin A, tacrolimus) are characterized by... Show moreCalcineurin inhibitors are crucial in the prevention of acute rejection in the first year after renal transplantation. Unfortunately, these drugs (ciclosporin A, tacrolimus) are characterized by serious clinical toxicity and between patient variability in their effect. Therefore, the dose of these drugs should be individualized in order to reach a balance between rejection and toxicity. This thesis aimed to describe the variability between and within patients using mathematical models and subsequently to explain this variability. Genetic and non-genetic factors were used to explain variability and several factors were identified (polymorphism in metabolism enzyme CYP3A5, body weight, concomitant prednisolone dose). For this purpose drug concentrations in blood are measured as a concentration biomarker. Furthermore, another biomarker the activity ot the target enzyme calcineurin was determined in leukocytes, but was found to be more variable within patients than between patients. This response biomarker was not found to be clinically useful to individualize the drug dosage. Finally, pharmacological determinants for subclinical acute rejection at 6 months were determined in patients treated with ciclosporin. Although ciclosporin exposure and several genetic variants were not found to relate, a previous acute rejection period and a kidney from a deceased donor increased the risk of rejection 5-fold. Show less
After successful renal transplantation a gradual decline of renal function can be detected about 40 % of the transplant recipients. The histological substrate for this condition is chronic... Show moreAfter successful renal transplantation a gradual decline of renal function can be detected about 40 % of the transplant recipients. The histological substrate for this condition is chronic allograft nephropathy (CAN). Nephrotoxicity of immunosuppressive drugs and rejection mechanisms, due to insufficient immunosuppression, are known to play a central role in this process. In this thesis we focus on the improvement of drug monitoring of calcineurin-inhibitors, to prevent structural damage imposed by rejection mechanisms or drug-related nephrotoxicity. With the use of a population based, pharmacokinetic computer program, we developed a simple model to estimate the systemic exposure of cyclosporine and tacrolimus and we prospectively tested the model in a cohort of patients, to detect pharmacokinetic changes over time and to define optimal monitoring intervals. The model was used to guide drug dosing for 126 renal transplant recipients, included in a trial to compare the early development of CAN in patients randomized to either Cyclosporine- or Tacrolimus-based immunosuppresion. As primary read-out for this trial we obtained surveillance biopsies at 6 and 12 months, in which interstitial fibrosis was evaluated by quantitative digital analysis of Sirius red staining. Finally, we investigated the clinical relevance of the presence of subclinical rejection in these biopsies. Show less
