The Development and Use of New Methods and Strategies for the Monitoring of Nephrotoxicity and the Study of Renal Physiology: Proteomics- and Metabonomics-based Studies

Abstract

A Key for avoiding the negative effects of immunosuppressant caused nephropathy after transplantation is early detection. This study shows a set of biomarkers, which could serve for the early detection of nephrotoxicity. Systematic development of a new model enables for the evaluation of drug induced nephrotoxicity and could be used for the development of new drugs in an early phase. We found indicators for the drug induced formation of reactive oxygen species, which could be causing the toxicity. The NMR-based model correlated with the 8-isoprostaglandin-F2aplha levels and the glomerular filtration rates showing the trend in toxicity:control<sirolimus<=tacrolimus<Sirl. Tac.<cyclosporine<Sirl. cylosporine. The combination of calcineurin inhibitors with sirolimus shows synergistic toxicity and that the combination of tacrolimus with sirolimus is favorable compared to cyclosporine with sirolimus.Investigations on changes caused by hyperosmotic stress in inner medullary collecting duct cells showed the importance of sorbitol and the polyol pathway as the most important mechanism in an environment of 900 mOsm/KgH2O media tonicity