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

Abstract

-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.

Kidney Injury Monitoring in Tobramycin-Treated Rhesus Monkeys: Supplementing Urinary Kidney Biomarkers With Kidney Biopsy Gene Expression Profiling

“…The upregulation of KIM-1 expression in both cortex and medulla sections of kidney in the monkey is consistent with KIM-1 expression in the proximal tubules of the cortex and the S3 segment of proximal tubules in the outer medulla in the rat 19 and the medullary tubule epithelium of the monkey. 21…”

“…The upregulation of KIM-1 expression in both cortex and medulla sections of kidney in the monkey is consistent with KIM-1 expression in the proximal tubules of the cortex and the S3 segment of proximal tubules in the outer medulla in the rat 19 and the medullary tubule epithelium of the monkey. 21 CLU is a glycoprotein involved in various biological processes such as binding and trafficking of necrotic tissue debris 22,23 and is transcriptionally upregulated in both proximal and distal tubules upon kidney injury. 1 OPN is a glycophosphoprotein with presence in the loop of Henle and distal tubules and it is also upregulated upon kidney injury.…”

Nephrotoxicity and fungal resistance associated with Amphotericin B

“…Although NGAL has been considered a reliable marker of AKI, studies are necessary to confirm its use in clinical practice and define adequate cut-offs for different populations and clinical situations 47,48 .…”