Immunolocalization of novel corticomedullary tubule injury markers in Cynomolgus monkeys treated with amphotericin B.

Amphotericin B (AmpB) nephrotoxicity was used to assess the utility of drug-induced kidney injury (DIKI) biomarkers in an exploratory study in male cynomolgus monkeys. All animals had quantifiable levels of AmpB in plasma on days 1 and 4. There were no clinical signs of AmpB-induced toxicity in this study. The gold standard method used to confirm AmpB-induced DIKI was anatomic pathology which revealed microscopic lesions with varying grades of severity. Immunolocalization of alpha-1 microglobulin (alpha-1M), kidney injury molecule 1 (KIM-1), osteopontin (OPN) and neutrophil gelatinase-associated lipocalin (NGAL) proteins was evaluated in formalin-fixed, paraffin-embedded monkey kidney tissue sections. AmpB related immunoreactivities were identified in distinct nephron segments of treated monkeys including alpha-1M in damaged proximal tubule epithelium, KIM-1 in damaged medullary tubule epithelium, OPN mostly in the infiltrating cells of cortical tubule interstitium, and NGAL in the granular and cellular cast in dilatated cortical tubules. Variations in alpha-1M, KIM-1, OPN and NGAL immunolocalization appear as promising DIKI protein biomarkers when monitoring for AmpB-induced corticomedullary tubule injury in male cynomolgus monkeys.