| Summary: | Karyomegalic interstitial nephritis (KIN) is a genetic kidney disease caused by mutations in the FANCD2/FANCI-Associated Nuclease 1 (<i>FAN1</i>) gene on 15q13.3, which results in karyomegaly and fibrosis of kidney cells through the incomplete repair of DNA damage. The aim of this study was to explore the possibility of using a human induced pluripotent stem cell (hiPSC)-derived kidney organoid system for modeling <i>FAN1</i>-deficient kidney disease, also known as KIN. We generated kidney organoids using WTC-11 (wild-type) hiPSCs and <i>FAN1</i>-mutant hiPSCs which include KIN patient-derived hiPSCs and <i>FAN1</i>-edited hiPSCs (WTC-11 <sup>FAN1+/−</sup>), created using the CRISPR/Cas9 system in WTC-11-hiPSCs. Kidney organoids from each group were treated with 20 nM of mitomycin C (MMC) for 24 or 48 h, and the expression levels of Ki67 and H2A histone family member X (H2A.X) were analyzed to detect DNA damage and assess the viability of cells within the kidney organoids. Both WTC-11-hiPSCs and <i>FAN1</i>-mutant hiPSCs were successfully differentiated into kidney organoids without structural deformities. MMC treatment for 48 h significantly increased the expression of DNA damage markers, while cell viability in both <i>FAN1</i>-mutant kidney organoids was decreased. However, these findings were observed in WTC-11-kidney organoids. These results suggest that <i>FAN1</i>-mutant kidney organoids can recapitulate the phenotype of <i>FAN1</i>-deficient kidney disease.
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