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Enzyme-converted O kidneys allow ABO-incompatible transplantation without hyperacute rejection in a human decedent model

Nature Biomedical Engineering (2025)Cite this article

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Abstract

ABO-incompatible kidney transplantation is widely used to meet the escalating need for organs. Current recipient-centric desensitization protocols involving antibody depletion through plasmapheresis increase the risk of infections, perioperative bleeding events and costs. Here we present a donor-centric desensitization protocol, converting type-A kidneys into enzyme-converted O kidneys during hypothermic perfusion to remove the A antigen from the kidneys. An ex vivo model resulted in no antibody-mediated injury. Encouraged by this, an enzyme-converted O kidney was transplanted into a type-O brain-dead recipient with a high titre of anti-A antibody, and no hyperacute rejection was observed. The graft was well tolerated with no evidence of antibody-mediated rejection for 2 days. Antibody-mediated lesions and complement deposition were found starting 3 days post-transplant, coinciding with A-antigen regeneration, and later higher Banff scores, suggesting an immune-mediated response. Single-cell sequencing confirms the elevated expression of accommodation-related genes, suggesting the potential for longer-term tolerance. This study provides a donor-centric organ engineering strategy and has the potential to broaden the reach of ABO-incompatible kidney transplantation, improving the fairness of and access to organ allocation.

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Fig. 1: Study conception and scheme.
Fig. 2: Enzymes removed A-Ag from type-A1 RBCs and aorta in KD-40 solution at 4 °C.
Fig. 3: Enzymes removed A-Ag from human type-A1 kidneys by HMP and avoided antibody-mediated injury in the ABOi kidney transplant model.
Fig. 4: The ECO kidney was successfully transplanted into a type-O brain-dead recipient, avoiding hyperacute rejection.
Fig. 5: Gross view and kidney histopathology of ECO allograft after transplantation.
Fig. 6: Immunofluorescence staining of blood group antigens and immunological change in ECO allograft at different timepoints.
Fig. 7: The single-cell landscape of the ECO kidney before transplantation and POD 7.

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Data availability

The main data supporting the results in this study are available within the article and its Supplementary Information. Raw data have been deposited to the National Center for Biotechnology Information (NCBI) under BioProject numberPRJNA1303224. The raw and analysed datasets generated during the study are available for research purposes from the corresponding authors on reasonable request. Code related to data analysis in this study is available via GitHub at https://github.com/Yuuuushan/ABOcode (ref. 51). Source data are provided with this paper.

Change history

  • 24 October 2025

    In the version of Supplementary Information initially published alongside this article, due to a figure preparation error, the Supplementary Fig. 12e, Ctrl panel was an accidental duplicate of the Supplementary Fig. 11e, 7 h panel. Supplementary Fig. 12 has now been updated in the Supplementary Information.

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Acknowledgements

We gratefully thank L. Li, F. Chen, C. Bao and Y. Deng from the Institute of Clinical Pathology, West China Hospital, Sichuan University, for their assistance with histological staining. We appreciate T. Zhu and Q. Tan from Nephrology and Urology Ward, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, for the collection of samples for this study. The study was supported by the Natural Science Foundation of China (grant number 82370753), the Natural Science Foundation of Sichuan Province (grant number 2024NSFSC1502), the Key Research Funding for Sichuan Province (grant numbers 2021YFS0118 and 2022NSFSC0712), the Kidney Transplant Early Warning and Intelligent Follow-up System/Phase I R&D project (grant number 312230522), the Clinical Novel Technique Funding of West China Hospital, Sichuan University (grant number 2020-113,10230) and the Nursing Development Funding (grant number HXHL21010).

Author information

Author notes

  1. These authors contributed equally: Jun Zeng, Ming Ma, Ze Tao, Zhengsheng Rao, Chaomeng Wu, Saifu Yin, Xiaojuan Jiang.

Authors and Affiliations

  1. Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China

    Jun Zeng, Ming Ma, Saifu Yin, Tao Lin & Turun Song

  2. Kidney Transplantation Center, West China Hospital, Sichuan University, Chengdu, China

    Jun Zeng, Ming Ma, Saifu Yin, Tao Lin & Turun Song

  3. Transplant Center and NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, China

    Ming Ma, Ze Tao, Hao Yang & Xiaofeng Lu

  4. Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China

    Ze Tao, Hao Yang & Xiaofeng Lu

  5. Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application, West China Hospital, Sichuan University, Chengdu, China

    Ze Tao, Hao Yang & Xiaofeng Lu

  6. Center of Urology and Nephrology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Zhengsheng Rao, Zhiling Wang, Ling Liu, Wenqian Huo & Keqin Zhang

  7. Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China

    Chaomeng Wu, Xiaojuan Jiang & Guo Chen

  8. Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China

    Dan Huang

  9. Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu, China

    Dan Huang & Feng Li

  10. Core Facilities of West China Hospital, Chengdu, China

    Mengli Zhu

  11. Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China

    Hui Guo & Gang Chen

  12. Med+X Center for Manufacturing, West China Hospital, Sichuan University, Chengdu, China

    Feng Li

  13. China Telecom Corporation Sichuan Branch, Chengdu, China

    Chengyu Zheng & Dajiu Huang

  14. Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada

    Peter Rahfeld & Stephen G. Withers

  15. Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada

    Peter Rahfeld & Stephen G. Withers

  16. Department of Pathology and Laboratory Medicine, Life Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada

    Jayachandran N. Kizhakkedathu

  17. Centre for Blood Research, Life Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada

    Jayachandran N. Kizhakkedathu

  18. School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada

    Jayachandran N. Kizhakkedathu

  19. Department of Biochemistry, Life Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada

    Stephen G. Withers

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  1. Jun Zeng
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  3. Ze Tao
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Contributions

J.Z., M.M. and T.S. designed the study. J.Z., M.M., Z.T. and Z.R. performed the experiments. C.W., S.Y., X.J. and Z.W. contributed to data acquisition. Guo Chen, Dan Huang, M.Z., L.L. and W.H. developed the data analysis. Z.T., H.Y. and X.L. expressed the enzymes in the study. H.G., Gang Chen, F.L., C.Z. and Dajiu Huang performed the data interpretation. J.Z. and M.M. provided the first draft of the paper. P.R. and J.N.K. reviewed and edited the paper. J.N.K., S.G.W., X.L., K.Z., T.L. and T.S. participated in the conception and experimental design. T.L., S.G.W. and T.S. supervised the project and edited the paper.

Corresponding authors

Correspondence to Stephen G. Withers, Xiaofeng Lu, Keqin Zhang, Tao Lin or Turun Song.

Ethics declarations

Competing interests

P.R., J.N.K. and S.G.W. are founders of Avivo Biomedical Inc., which is commercializing the enzymes described. P.R., J.N.K. and S.G.W. are inventors on patent application (PCT number WO2020034043A1) submitted by the University of British Columbia. The other authors declare no competing interests.

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Peer review information

Nature Biomedical Engineering thanks Hyongbum Kim, Thomas Wekerle and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary figures.

Reporting Summary

Supplementary Video 1

These videos showed that the kidney turned pink after circulation establishment and produced urine from allograft after 2 h.

Supplementary Video 2

These videos showed that the kidney turned pink after circulation establishment and produced urine from allograft after 2 h.

Supplementary Video 3

These videos showed the Doppler ultrasonography of the allograft from POD 4 to POD 6, during which the blood supply of the kidney was good.

Supplementary Video 4

These videos showed the Doppler ultrasonography of the allograft from POD 4 to POD 6, during which the blood supply of the kidney was good.

Supplementary Video 5

These videos showed the Doppler ultrasonography of the allograft from POD 4 to POD 6, during which the blood supply of the kidney was good.

Supplementary Video 6

These videos showed the biopsy process of the allograft from POD 4 to POD 6, during which blood was sprayed at the biopsy point, indicating that the blood supply of the transplanted kidney was good at this time.

Supplementary Video 7

These videos showed the biopsy process of the allograft from POD 4 to POD 6, during which blood was sprayed at the biopsy point, indicating that the blood supply of the transplanted kidney was good at this time.

Supplementary Video 8

These videos showed the biopsy process of the allograft from POD 4 to POD 6, during which blood was sprayed at the biopsy point, indicating that the blood supply of the transplanted kidney was good at this time.

Supplementary Data 1

Source data for supplementary figures.

Source data

Source Data Figs. 2–4, 6 and 7

Statistical source data for Figs. 2–4, 6 and 7.

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Zeng, J., Ma, M., Tao, Z. et al. Enzyme-converted O kidneys allow ABO-incompatible transplantation without hyperacute rejection in a human decedent model. Nat. Biomed. Eng (2025). https://doi.org/10.1038/s41551-025-01513-6

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