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Updated: Dec 26, 2025
Acute Kidney Injury Model Induced by Cisplatin in Adult Zebrafish
Published on: May 15, 2021
Evaluation of cisplatin-induced injury in human kidney organoids
Jenny L M Digby1, Thitinee Vanichapol1, Aneta Przepiorski1
1Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
Abstract:
Acute kidney injury (AKI) remains a major global healthcare problem, and there is a need to develop human-based models to study AKI in vitro. Toward this goal, we have characterized induced pluripotent stem cell-derived human kidney organoids and their response to cisplatin, a chemotherapeutic drug that induces AKI and preferentially damages the proximal tubule. We found that a single treatment with 50 µM cisplatin induces hepatitis A virus cellular receptor 1 (HAVCR1) and C-X-C motif chemokine ligand 8 (CXCL8) expression, DNA damage (γH2AX), and cell death in the organoids but greatly impairs organoid viability. DNA damage was not specific to the proximal tubule but also affected the distal tubule and interstitial cell populations. This lack of specificity correlated with low expression of proximal tubule-specific SLC22A2/organic cation transporter 2 (OCT2) for cisplatin. To improve viability, we developed a repeated low-dose regimen of 4 × 5 µM cisplatin over 7 days and found this caused less toxicity while still inducing a robust injury response that included secretion of known AKI biomarkers and inflammatory cytokines. This work validates the use of human kidney organoids to model aspects of cisplatin-induced injury, with the potential to identify new AKI biomarkers and develop better therapies.
Insights
Human kidney organoids model acute kidney injury (AKI) from cisplatin. A new low-dose regimen reduces toxicity while still detecting AKI biomarkers and inflammatory cytokines.
Area of Science:
- Nephrology
- Stem Cell Biology
- Toxicology
Background:
- Acute kidney injury (AKI) is a significant global health concern.
- Developing human-based in vitro models is crucial for studying AKI.
- Cisplatin is a chemotherapeutic agent known to induce AKI, primarily affecting proximal tubules.
Purpose of the Study:
- To characterize the response of human induced pluripotent stem cell-derived kidney organoids to cisplatin.
- To evaluate the potential of these organoids as a model for cisplatin-induced AKI.
- To develop and test a modified cisplatin dosing regimen to improve organoid viability while maintaining a robust injury response.
Main Methods:
- Human kidney organoids were treated with cisplatin (50 µM single dose).
- Organoids were analyzed for gene expression (HAVCR1, CXCL8), DNA damage (γH2AX), and cell death.
- A repeated low-dose regimen (4 × 5 µM over 7 days) was developed and tested.
- AKI biomarkers and inflammatory cytokines secreted by organoids were measured.
Main Results:
- A single 50 µM cisplatin dose induced significant organoid injury, including gene expression changes, DNA damage, and cell death, impairing viability.
- DNA damage was observed in proximal tubules, distal tubules, and interstitial cells, suggesting a lack of specificity.
- The low expression of cisplatin transporter OCT2 in proximal tubules may explain the non-specific damage.
- The repeated low-dose cisplatin regimen showed reduced toxicity but still elicited a robust AKI response, including biomarker and cytokine secretion.
Conclusions:
- Human kidney organoids effectively model key aspects of cisplatin-induced AKI.
- The developed low-dose regimen offers a more viable approach for studying AKI in vitro.
- These organoids hold potential for identifying novel AKI biomarkers and therapeutic strategies.
