An Ex Vivo Patient-Derived Tumor-Bearing Human Kidney Model Recapitulates Drug Toxicity and Metabolic Distribution

Renal metabolic behavior constitutes a critical evaluation parameter during drug development, toxicity assessment, and biodistribution. However, the inherent biological architecture of existing animal and cell-based models fails to recapitulate the authentic metabolic processes and spatial distribution patterns of drugs in the human kidney at a macroscopic level. Therefore, developing a standardized human-derived kidney model was necessary. In this work, the ex vivo tumor-bearing kidney (ETK) model was established using kidneys from 50 clinically diagnosed patients after the radical surgery. The standardized ETK model included the following: (a) selected according to the proportion of preserved normal tissue, vascular status suitable for ETK perfusion, and overall structural integrity of the kidneys; (b) surgical preparation exposed the renal pelvis and enabled catheterization of the renal artery and ureter; (c) perfused with hypothermic (4 to 10 °C) saline at a flow rate of 70 ml/min within perfusion system; and (d) ETK detection efficiency and drug biodistribution were assessed using biological sample indicators. Results showed that ETK maintained intact glomerular and tubular microstructures throughout perfusion and produced stable urine output with preserved filtration capacity. When treated with different kinds of nephrotoxic agents (cisplatin, gentamicin, and cephalosporins), the ETK model reproduced drug-specific injury patterns and exhibited biochemical changes and histological features that were consistent with real clinical observations. In drug-distribution analysis, indocyanine green (ICG) showed a negative fluorescence tumor contrast and enriched fluorescence in the normal kidney in the ETK model, which were consistent with real clinical observations, whereas mouse orthotopic renal cancer models showed positive ICG tumor accumulation, indicating species-dependent differences in renal drug distribution. Overall, the ETK model provided a structurally preserved and functionally responsive human-derived renal system for investigating renal drug metabolism, nephrotoxicity, tumor imaging, and drug-delivery strategies.