Boudonck, K J, et al., Discovery of Metabolomics Biomarkers for Early Detection of Nephrotoxicity. Toxicol Pathol, 2009. 37(3): 280-92.
Metabolon results led to:
- ~ 40 metabolites out of 657 detected were used for predictive modeling of nephrotoxicity
- While traditional assays for nephrotoxicity (creatinine, BUN) and histopath were all negative at day 1 and 5, a panel of 3 metabolites could predict nephrotoxicity with high accuracy on these days
Key metabolomic observations:
- Amioaciduria and glycosuria were leading indicators of impending histopathological changes
- Several polyamines (cadaverine, putrescine, agmatine, and spermidine) were increased as early as day 1 (single dose) in the animals that progressed to histopath
Approximately 30% of new drug candidates fail in clinical trials due to toxicity. The kidney is one of the primary sites of drug toxicity and therefore sensitive and specific markers of nephrotoxicity are a continued need. To discover biochemical biomarkers useful for early identification of nephrotoxicity, metabolomics was performed on rats dosed with several nephrotoxins. The dosing was designed to induce moderate histpathology and some clinical chemistry at 28 days of dosing and none at days 1 and 5. Many metabolites appeared to offer predictive potential (amino acids, sugars and polyamines) suggesting leading glycosuria, aminoaciduria. Indeed, a subset of 3 metabolites could predict with 100%, 93%, and 70% accuracy at day 28, day 5, and day 1, respectively. Thus, the results indicate that metabolites are a highly sensitive leading indicator for organ toxicity and that this same approach should be applied for all modes of drug-induced organ toxicity.