ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: FR-PO771

A Drug-Specific Nephrotoxicity Prediction System Using Kidney Organoids

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Authors

  • Susa, Koichiro, Brigham and Women's Hospital, Boston, United States
  • Tamura, Akitoshi, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Galichon, Pierre, Brigham and Women's Hospital, Boston, United States
  • Gupta, Navin R., Brigham & Women''s Hospital/Massachusetts General Hospital, Brighton, Massachusetts, United States
  • Matsumoto, Takuya, Harvard medical school, Boston, Massachusetts, United States
  • Miyoshi, Tomoya, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Sabbisetti, Venkata, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Bonventre, Joseph V., Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Morizane, Ryuji, Brigham and Women's Hospital, Boston, Massachusetts, United States
Background

Drug-induced nephrotoxicity is increasingly recognized as a serious clinical problem, leading to acute kidney injury (AKI) and chronic kidney disease. Lack of reliable models with physiological function of human kidneys results in the difficulty to predict nephrotoxicity of new drugs in preclinical trials. Here, we demonstrate kidney organoids containing multi-segmented nephron epithelial cells generated from human pluripotent stem cells (hPSCs) as a new technology for pre-clinical nephrotoxicity assessment.

Methods

We generated kidney organoids from hPSCs by a directed differentiation protocol and validated the maturation of organoids using immunostaining and transcriptome analyses. Organoids were treated with various nephrotoxicants which cause injury in a segment-specific manner via specific drug transporters. Injury responses were analyzed by immunostaining, qPCR, and biomarker assays. We also generated reporter organoids to evaluate the toxicity with a real-time biosensor of ATP/ADP ratio in 384-well culture plates.

Results

We confirmed increased expression of drug transporters including OAT1, OAT3, OCT2 and PMAT with matured gene expression profiles in kidney organoids during 5 to 7 weeks of differentiation. Organoids simulated various drug-induced injury such as biomarker upregulation, DNA damages, and morphological changes specifically in the tubules or in the glomeruli by low concentration of nephrotoxicants mediated by these transporters (OATs: tenofovir and aristolochic acid [AA], OCT: cisplatin, PMAT: puromycin aminonucleoside). The injuries induced by tenofovir and AA, or cisplatin were ameliorated by OATs inhibitor probenecid or OCT2 inhibitor cimetidine, respectively. On the other hand, high concentration of these nephrotoxicants resulted in widespread injury to all nephron compartments and interstitial cells. In addition, nephrotoxicants significantly reduced the ATP/ADP ratio within 24 hours of treatment.

Conclusion

Kidney organoids faithfully recapitulate drug-induced AKI by reflecting the toxicity characteristics of the drugs, allowing to distinguish between drug-specific and generalized toxicity responses. The reporter organoids may realize high-throughput and real-time nephrotoxicity screening, providing a new platform to evaluate nephrotoxicity as preclinical trials.

Funding

  • NIDDK Support