Kidney Effects of Immune Checkpoint Inhibitors on a Humanized Chimeric Mouse Model

Background: The widespread use of immune checkpoint inhibitors (ICIs) has raised concerns about immune related adverse events, in the kidney acute interstitial nephritis (AIN) is the most common presentation. Although the exact mechanism is unclear, previous studies have shown upregulation of IFN-γ and TNF-α pathways. This study investigates the renal effects of ICIs, with or without co-administration of TNF-α and IFN-γ, using a humanized chimeric mouse model. Methods: Humanized PD-1/PD-L1 mice were divided into three groups and treated for up to 8 weeks: Control N=10 (Saline), ICI-Only N=12 (Pembrolizumab + anti-CTLA-4), and ICI-Cyt N=12 (ICIs + TNF-α & IFN-γ). Terminal plasma creatinine, BUN, and urine protein/creatinine ratio were assessed. Kidney tissue was analyzed with H&E and immunofluorescence (CD4+, CD8+). Plasma cytokines were measured using a Luminex assay. Single-cell RNA sequencing was used to characterize cell populations. Results: ICI-Only and ICI-Cyt groups exhibited higher plasma creatinine and BUN levels respectively compared to controls. At tissue level, the nephritis group had higher BUN levels than controls (Table 1). ICI-Only and ICI-Cyt groups showed increased CD4+ cell infiltration (Fig. 1a-b) and elevated plasma IL-6, MCP-1, and TNF-α levels (Fig. 2a-c). ICI-Nephritis and ICI-NonNephritis groups had higher MCP-1 and TNF-α levels than controls (Fig. 2e-f). Single-cell analysis revealed 12 cell clusters; T_NK, endothelial, and macrophage clusters were more abundant in ICI groups (Fig. 3, Table 2). Conclusion: In a Hu-PD1/PDL1 immunocompetent mouse model, ICIs alone or combined with a cytokine background successfully induces interstitial mononuclear cell infiltration and early renal function disarrangements. Funding: Private Foundation Support