Acute biomarker panel changes associated with amphotericin B nephrotoxicity in female Sprague-Dawley rats

Abstract

-To date, eight next-generation urinary protein kidney safety biomarkers have been qualified to enable monitoring for subclinical drug-induced kidney injury (DIKI) in rat preclinical studies; however, most DIKI biomarker studies have included only male rats. The objective of this study was to assess the utility of novel DIKI biomarkers, including but not limited to urinary total protein, albumin, cystatin C and osteopontin in female Sprague-Dawley rats (8/group) that received repeated intravenous injections of amphotericin B (AmpB, 3 mg/kg/day) or vehicle for 10 consecutive days. Serial serum/urine samples were collected on study day (D)4, D8, and D11. Surviving animals were necropsied on D11. The AmpB-induced kidney histopathology findings were characterized by cortical and medullary tubular alterations, interstitial inflammation, intratubular granular and inflammatory cell casts, acute pelvic inflammation and tubular mineralization. Significant elevations in urinary clusterin on D4, D8 and D11 (3.5 fold, 2.2 fold and 3.3 fold respectively) were observed (versus concurrent controls) following repeated injections of AmpB. In addition, significantly elevated (fold changes) in biomarkers, neutrophil gelatinase-associated lipocalin (14.6 fold), albumin (13.5 fold), cystatin C (13.5 fold), total protein (3.5 fold), kidney injury molecule 1 (3.0 fold) and osteopontin (2.3 fold) were detected in urine as early as D4. These findings demonstrate the value of early elevations in nephron-specific DIKI biomarkers for detecting subclinical AmpB nephrotoxicity in female Sprague-Dawley rats. These findings are anticipated to provide the basis for inclusion of female rats on a case-by-case basis in preclinical toxicology studies designed to detect DIKI.

Nephrotoxicity and fungal resistance associated with Amphotericin B

“…In contrast, another study found no relevant alteration in the levels of Cys C, even when Saúde Meio Ambient. v. 10, p. 141-157, 2021 ISSNe 2316-347X histopathological analysis confirmed the occurrence of AKI, after the intravenous administration of AB for 10 days 46 .…”

Nephrotoxicity and fungal resistance associated with Amphotericin B

“…In contrast, another study found no relevant alteration in the levels of Cys C, even when Saúde Meio Ambient. v. 10, p. 45-62, 2021 ISSNe 2316-347X histopathological analysis confirmed the occurrence of AKI, after the intravenous administration of AB for 10 days 46 .…”

Brief Overview: Assessment of Compound-induced Acute Kidney Injury Using Animal Models, Biomarkers, and In Vitro Platforms

“…Until 2008, the eight fully qualified urinary protein DIKI biomarkers had not been systematically investigated in AmpB-treated rats (Thukral et al 2005). Hence, McDuffie et al (2016) demonstrated the value of early elevations in Ur CLU, Ur NGAL, Ur ALB, Ur CYS C, Ur TP, Ur KIM-1, and Ur OPN for detecting subclinical AmpB nephrotoxicity in female SD rats, thereby providing the basis for inclusion of female rats on a case-by-case basis in nonclinical toxicology studies designed to investigate DIKI. Besides expected AmpB binding to tubular epithelial cells and subsequent swelling and lysis/increased tubular permeability and tubular dysfunction, the nature of DIKI in female SD rats remains unclear.…”