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 (α‑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 α‑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 α‑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.
Discovery Sciences, Preclinical Development & Safety, Janssen Research & Development, LLC, USA.
J Eric
JE
McDuffie
Jing Ying
JY
Ma
Yunhai
Y
Zhang
Frederic S
FS
Almy
Xiaoyun
X
Wu
Ke
K
Li
Manisha
M
Sonee
Ryan
R
Meng
Michele
M
Rizzolio
Sandra S
SS
Snook
D000510:Alpha-Globulins / Q000378:metabolism; D000666:Amphotericin B / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D000890:Anti-Infective Agents / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D000072596:Hepatitis A Virus Cellular Receptor 1 / Q000378:metabolism; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000071068:Lipocalin-2 / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D053495:Osteopontin / Q000378:metabolism
D000510:Alpha-Globulins; D000890:Anti-Infective Agents; D015415:Biomarkers; D000072596:Hepatitis A Virus Cellular Receptor 1; D000071068:Lipocalin-2; C016001:alpha-1-microglobulin; D053495:Osteopontin; D000666:Amphotericin B