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Toxicologic Pathology
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Articles

Discovery of Metabolomics Biomarkers for Early Detection of Nephrotoxicity

Kurt J. Boudonck1, Matthew W. Mitchell1, László Német2, Lilla Keresztes3, Abraham Nyska4, Doron Shinar5 and Moti Rosenstock5

1 Metabolon Inc., Durham, North Carolina, USA
2 Huntingdon Life Sciences, Alconbury, Huntingdon, Cambridgeshire, UK
3 AuriCoop Institute of Drug Research Ltd., Pálya u.2, Hungary
4 Sackler School of Medicine, Tel Aviv University, Timrat, Israel
5 Teva Pharmaceutical Industries Ltd., Nonclinical Development Department, Teva Innovative Ventures, Netanya, Israel

Correspondence: Kurt J. Boudonck, Metabolon Inc., 800 Capitola Drive, Suite 1, Durham, NC 27713, USA; e-mail:kboudonck{at}metabolon.com.

Drug-induced nephrotoxicity is a major concern, since many pharmacological compounds are filtered through the kidneys for excretion into urine. To discover biochemical biomarkers useful for early identification of nephrotoxicity, metabolomic experiments were performed on Sprague-Dawley Crl:CD (SD) rats treated with the nephrotoxins gentamicin, cisplatin, or tobramycin. Using a combination of gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS), a global, nontargeted metabolomics analysis was performed on urine and kidney samples collected after one, five, and twenty-eight dosing days. Increases in polyamines and amino acids were observed in urine from drug-treated rats after a single dose, and prior to observable histological kidney damage and conventional clinical chemistry indications of nephrotoxicity. Thus, these metabolites are potential biomarkers for the early detection of drug-induced nephrotoxicity. Upon prolonged dosing, nephrotoxin-induced changes included a progressive loss of amino acids in urine, concomitant with a decrease in amino acids and nucleosides in kidney tissue. A nephrotoxicity prediction model, based on the levels of branched-chain amino acids in urine, distinguished nephrotoxin-treated samples from vehicle-control samples, with 100%, 93%, and 70% accuracy at day 28, day 5, and day 1, respectively. Thus, this panel of biomarkers may provide a noninvasive method to detect kidney injury long before the onset of histopathological kidney damage.

Key Words: metabolomics • nephrotoxicity • biomarkers • kidney • nephrotoxin • MS

Abbreviations: BUN, blood urea nitrogen • GC, gas chromatography • LC, liquid chromatography • MS, mass spectrometry

Toxicologic Pathology, Vol. 37, No. 3, 280-292 (2009)
DOI: 10.1177/0192623309332992
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