Abstract: TH-PO058
Bardoxolone Methyl Demonstrates Mitigation of Cisplatin-Induced Kidney Injury in a Mouse Model with Cancer
Session Information
- AKI: Epidemiology, Risk Factors, and Prevention - 1
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 101 AKI: Epidemiology, Risk Factors, and Prevention
Authors
- Asby, Sarah C., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Thompson, Lauren E., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Lucia, M. Scott, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Aleksunes, Lauren, Rutgers The State University of New Jersey, New Brunswick, New Jersey, United States
- Edelstein, Charles L., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Joy, Melanie S., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
Background
Acute kidney injury (AKI) occurs in approximately one-third of patients treated with the chemotherapeutic drug cisplatin. Multiple low-to-moderate doses of cisplatin in tumor-bearing mice recapitulates cisplatin-induced AKI in cancer patients and can be used to test potential mitigation strategies. Bardoxolone methyl (BARD) is an attractive mitigation therapeutic due to its ability to enhance anti-oxidative responses through activation of the Nrf2 transcription factor and potential anti-tumorigenic effects.
Methods
C57BL/6J mice (8-10 wk) were injected with CMT167 murine lung carcinoma cells (50,000) in the right flank and allowed to engraft for 7 days. Then, cisplatin (10-15 mg/kg) or vehicle (saline) were administered IP once weekly for 4 wks. Likewise, BARD (10 mg/kg) or vehicle (34.5% PEG-300, 30% DMSO, 30% saline, 5% propylene glycol, and 0.5% Tween-80) were injected IP 5x/wk per week. Body weight, tumor size, and survival were assessed weekly for 4 wks and urine and blood were also collected. Kidney injury was quantified by urinary kidney injury molecule-1 (KIM-1), serum creatinine (SCr) and assessment of renal histopathology.
Results
Co-treatment with BARD significantly enhanced survival of cisplatin-treated mice with cancer (p=0.01). Cisplatin treatment, with or without BARD, significantly reduced tumor growth compared to vehicle-treated mice (p<0.05). BARD did not demonstrate any significant anti-tumorigenic properties as a single agent. BARD protected the mice from cisplatin-induced kidney injury, as measured by urinary KIM-1 levels (p<0.01). BARD also mitigated the loss of kidney function caused by cisplatin, as measured by SCr (p<0.01). All Veh/CIS treated mice demonstrated tubular injury after just two doses of cisplatin and had significantly higher tubular injury scores (scores 1 or 2) than Veh/Veh and BARD/Veh mice (scores 0; p<0.05). Approximately 30% of BARD/CIS mice had no apparent tubular injury after receiving the 4 cisplatin doses, although not statistically different from Veh/CIS-treated mice.
Conclusion
Overall, the results of this study demonstrate the potential utility of using acute BARD administration during cisplatin treatment to reduce drug-induced AKI.
Funding
- Other NIH Support