Objectives: Novel biomarkers indicative of drug-induced
kidney injury (DIKI) in dogs would have significant application in
preclinical drug development. We conducted a feasibility study to identify
genomic expression profiles for monitoring progressive, acute DIKI in dogs.
Materials and Methods: Animals were intramuscularly administered either 0.9%
physiological saline or gentamicin (40 mg/kg/day) for 10 consecutive days
and euthanized on day 11. Serum and urine samples were collected at various
time points and kidney samples were collected at necropsy for biomarker
measurements. Results: Acute gentamicin-induced renal histopathology changes
were localized to the proximal convoluted tubules and characterized as slight-to-marked,
diffuse cortical-medullary tubular epithelial degeneration/necrosis. Serum creatinine
(sCr) and blood urea nitrogen (BUN) elevations suggestive of mild renal
dysfunction were first observed on days 7 to 8. Gentamicin-induced increased urinary kidney
injury molecule-1 (KIM-1) mRNA was observed on day 6 preceding
detectable elevations of sCr and/or BUN. Increased urinary KIM-1 mRNA
correlated with multifocal KIM-1 immunostaining in the corticomedullary tubular
epithelial cells. Microarray analysis revealed changes in additional mRNA
expression products detected in urine and/or kidney that should be further
investigated for use as potential biomarkers for acute gentamicin related
nephrotoxicity in dogs. Conclusion: These findings suggested the utility of
non-invasive urinary genomic parameters for monitoring acute DIKI in dogs.
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