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Toxicodynamic Therapeutic Drug Monitoring of Immunosuppressants: Promises, Reality, and Challenges

Christians, Uwe MD, PhD*†; Schmitz, Volker MD; Schöning, Wenzel MD†‡; Bendrick-Peart, Jamie MSc*†; Klawitter, Jelena PhD; Haschke, Manuel MD§; Klawitter, Jost PhD*†

doi: 10.1097/FTD.0b013e31816b9063
Proceedings Paper

Although current immunosuppressive protocols have dramatically decreased acute rejection episodes, there has been less progress in terms of long-term graft survival after kidney transplantation over the last 2 decades. The key to reducing the damage to a transplanted organ as caused by chronic processes is early detection. Modern screening technologies in the fields of genetics, genomics, protein profiling (proteomics), and biochemical profiling (metabolomics) have opened new opportunities for the development of sensitive and specific diagnostic tools. Metabolic profiling appears to be a promising strategy because changes in the cell biochemistry are ultimately responsible for the histologic and pathophysiologic changes of the transplanted kidney and are most likely already detectable before histologic and pathophysiologic changes occur. Using truly no-targeted screening technologies as clinical diagnostic tools is not yet feasible, mostly because of the complexity of the data generated and the lack of algorithms to convert this information into clinically applicable information. A realistic and powerful targeted approach is the development of combinatorial biomarkers. These are biomarker patterns that typically consist of five or more individual parameters. Combined biomarker patterns confer significantly more information than a single measurement and, thus, can be expected to have better specificity and sensitivity. A series of studies in rats and healthy individuals evaluating the effects of immunosuppressants on urine metabolite patterns showed that immunosuppressant-induced changes of metabolite patterns in urine were associated with a combination of changes in glomerular filtration, changes in secretion/absorption by tubulus cells, and changes in kidney cell metabolism. These studies suggested that a combination of biomarkers that can be used for toxicodynamic therapeutic drug monitoring of immunosuppressants should include urine metabolites that constitute valid surrogate markers of these kidney functions.

From the *Eurofins/Medinet, Aurora, CO; †Clinical Research and Development, Department of Anesthesiology, University of Colorado at Denver and Health Sciences Center, Aurora, CO; and ‡Department of General, Visceral and Transplantation Surgery, Charité, Campus Virchow, Berlin, Germany; and §Clinical Pharmacology and Toxicology, University Hospital Basel, Switzerland.

Received for publication November 11, 2007; accepted January 27, 2008.

This work was supported in part by the United States National Institutes of Health, grants R01 DK065094 and P30 DK048520 Mass Spectrometry Core.

Reprints: Dr. Uwe Christians, MD, PhD, Eurofins/Medinet 12635 Montview Boulevard, Suite 214, Aurora, CO 80045 (e-mail: uwe.christians@eurofinsmedinet.com).

© 2008 Lippincott Williams & Wilkins, Inc.