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
