Abstract: TH-PO0190
Molecular and Soluble Biomarker Profiles of Immune Checkpoint Inhibitor-Induced Nephrotoxicity in a Humanized Immune System Mouse Model
Session Information
- Onconephrology: Anticancer Therapies, PTLD, Paraneoplastic Diseases, and More
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Onconephrology
- 1700 Onconephrology
Authors
- Asby, Sarah C., University of Colorado Anschutz Medical Campus Skaggs School of Pharmacy and Pharmaceutical Sciences, Denver, Colorado, United States
- Wen, Xia, Rutgers The State University of New Jersey, Piscataway, New Jersey, United States
- Goedken, Michael J., Rutgers The State University of New Jersey, Piscataway, New Jersey, United States
- Lanis, Jordi, University of Colorado Cancer Center, Aurora, Colorado, United States
- Kostka-Newman, Zander C., University of Colorado Cancer Center, Aurora, Colorado, United States
- Thompson, Lauren E., University of Colorado Anschutz Medical Campus Skaggs School of Pharmacy and Pharmaceutical Sciences, Denver, Colorado, United States
- Pelanda, Roberta, University of Colorado Cancer Center, Aurora, Colorado, United States
- Lang, Julie, University of Colorado Cancer Center, Aurora, Colorado, United States
- Aleksunes, Lauren, Rutgers The State University of New Jersey, Piscataway, New Jersey, United States
- Joy, Melanie S., University of Colorado Anschutz Medical Campus Skaggs School of Pharmacy and Pharmaceutical Sciences, Denver, Colorado, United States
Background
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target receptors on immune cells to activate antitumor responses. Overactivation of immune responses can also trigger immune related adverse effects (irAEs) in numerous organs including the kidney. While it is estimated that at least 5% of patients receiving ICIs develop AKI, the incidence of other phenotypes and subclinical forms of injury are unknown. This study interrogated the expression of protein biomarkers and genetic pathways driving kidney injury in humanized immune system (HIS)-BRGS mice treated with ICIs.
Methods
HIS-BRGS and non-humanized BRGS mice bearing MDA-MB-231 tumors were treated weekly for 4 wks with PBS or a combination of nivolumab and ipilimumab (10-20mg/kg, ip). Human cytokines and chemokines, and soluble kidney injury biomarkers (KIM1, IP10/CXCL10, renin, β2-microglobulin, VEGF, TIMP1, EGF, NGAL, osteopontin, and clusterin) were measured in plasma and kidney homogenates using multiplex ELISAs. mRNA expression of enriched genes was quantified in total kidney RNA using qPCR with human primers.
Results
ICI treatment in HIS-BRGS mice resulted in increased renal concentrations of several human cytokines, chemokines, and soluble receptors (Fig 1A). Increased renal concentrations of serine proteases granzyme A and B (400% & 200% respectively) and NGFb were found in ICI treated HIS-BRGS mice (Fig 1A), as well as increased expression of several lymphocyte related genes (Fig 1B). Significant correlations were observed between renal vasculitis and nephritis and PD1, MIF, and NGFb levels (p<0.05). ICI treatment did not significantly change emerging kidney injury biomarkers concentrations including KIM1 and NGAL.
Conclusion
These findings reveal a mechanistic link between ICI therapy and kidney immune activation, implicating proteomic and genetic changes in the pathogenesis of kidney irAEs and identifying potentially relevant biomarkers for detection and intervention in patients receiving ICIs.
Funding
- Other NIH Support