J. Eric McDuffie, Manisha Sonee, Jing Ma, Frederic Almy, Xuejun Liu, David La and Sandra Snook
The feasibility of proteinbiomarkers in the prediction of subclinical doxorubicin nephrotoxicity was evaluated in male Sprague-Dawley rats during a 2-week study with once‑weekly dosing. Doxorubicin (5, 7.5, and 10 mg/kg/ dose) or 0.9% Saline was intravenously administered on days 1 and 8. Urine and serum were collected at various time points. Surviving animals were euthanized on day 14, and tissues were collected for microscopic examination. Severe clinical signs were observed in the 7.5 and 10 mg/kg/dose groups. Biomarker data are not reported for these groups because the objective of this study was to evaluate biomarkers at doses not associated with clinical signs. In the 5 mg/kg group, increased serum concentrations of urea nitrogen were observed on day 14 with concurrent renal histopathology findings which were primarily characterized as slight renal glomerular and tubular injury with mild multi-focal intratubular hyaline casts consistent with protein leakage from damaged glomeruli. Of the various urinary protein biomarkers examined, increased urinary concentrations of albumin was observed on day 7 and increased total protein, albumin and lipocalin‑2 were observed on day 14. Taken together, these findings showed that urinary albumin was more sensitive and selective than urinary total protein, lipocalin-2, kidney injury molecule 1 and/or osteopontin in the prediction of progressive doxorubicin‑induced glomerular toxicity with secondary renal tubular toxicity in male Sprague‑Dawley rats.
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