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

Jun Zeng^#^{1

2}, Ming Ma^#^{1

2

3}, Ze Tao^#^{3

4

5}, Zhengsheng Rao^#⁶, Chaomeng Wu^#⁷, Saifu Yin^#^{1

2}, Xiaojuan Jiang^#⁷, Guo Chen⁷, Zhiling Wang⁶, Dan Huang^{8

9}, Mengli Zhu¹⁰, Ling Liu⁶, Wenqian Huo⁶, Hao Yang^{3

4

5}, Hui Guo¹¹, Gang Chen¹¹, Feng Li^{9

12}, Chengyu Zheng¹³, Dajiu Huang¹³, Peter Rahfeld^{14

15}, Jayachandran N Kizhakkedathu^{16

17

18}, Stephen G Withers^{19

20

21}, Xiaofeng Lu^{22

23

24}, Keqin Zhang²⁵, Tao Lin^{26

27}, Turun Song^{28

29}

Affiliations

¹ Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
² Kidney Transplantation Center, West China Hospital, Sichuan University, Chengdu, China.
³ Transplant Center and NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, China.
⁴ Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
⁵ Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application, West China Hospital, Sichuan University, Chengdu, China.
⁶ Center of Urology and Nephrology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
⁷ Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.
⁸ Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.
⁹ Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu, China.
¹⁰ Core Facilities of West China Hospital, Chengdu, China.
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.
¹² Med+X Center for Manufacturing, West China Hospital, Sichuan University, Chengdu, China.
¹³ China Telecom Corporation Sichuan Branch, Chengdu, China.
¹⁴ Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁵ Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁶ Department of Pathology and Laboratory Medicine, Life Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁷ Centre for Blood Research, Life Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁸ School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁹ Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada. withers@chem.ubc.ca.
²⁰ Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada. withers@chem.ubc.ca.
²¹ Department of Biochemistry, Life Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada. withers@chem.ubc.ca.
²² Transplant Center and NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, China. xiaofenglu@scu.edu.cn.
²³ Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. xiaofenglu@scu.edu.cn.
²⁴ Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application, West China Hospital, Sichuan University, Chengdu, China. xiaofenglu@scu.edu.cn.
²⁵ Center of Urology and Nephrology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. zhkq2000@sina.com.
²⁶ Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China. dr_taolin@163.com.
²⁷ Kidney Transplantation Center, West China Hospital, Sichuan University, Chengdu, China. dr_taolin@163.com.
²⁸ Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China. songturun1986@scu.edu.cn.
²⁹ Kidney Transplantation Center, West China Hospital, Sichuan University, Chengdu, China. songturun1986@scu.edu.cn.

^# Contributed equally.

PMID: 41044341
DOI: 10.1038/s41551-025-01513-6

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

Jun Zeng et al. Nat Biomed Eng. 2025.

. 2025 Oct 3.

doi: 10.1038/s41551-025-01513-6. Online ahead of print.

Authors

Affiliations

¹ Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
² Kidney Transplantation Center, West China Hospital, Sichuan University, Chengdu, China.
³ Transplant Center and NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, China.
⁴ Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
⁵ Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application, West China Hospital, Sichuan University, Chengdu, China.
⁶ Center of Urology and Nephrology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
⁷ Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.
⁸ Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.
⁹ Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu, China.
¹⁰ Core Facilities of West China Hospital, Chengdu, China.
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.
¹² Med+X Center for Manufacturing, West China Hospital, Sichuan University, Chengdu, China.
¹³ China Telecom Corporation Sichuan Branch, Chengdu, China.
¹⁴ Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁵ Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁶ Department of Pathology and Laboratory Medicine, Life Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁷ Centre for Blood Research, Life Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁸ School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁹ Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada. withers@chem.ubc.ca.
²⁰ Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada. withers@chem.ubc.ca.
²¹ Department of Biochemistry, Life Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada. withers@chem.ubc.ca.
²² Transplant Center and NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, China. xiaofenglu@scu.edu.cn.
²³ Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. xiaofenglu@scu.edu.cn.
²⁴ Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application, West China Hospital, Sichuan University, Chengdu, China. xiaofenglu@scu.edu.cn.
²⁵ Center of Urology and Nephrology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. zhkq2000@sina.com.
²⁶ Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China. dr_taolin@163.com.
²⁷ Kidney Transplantation Center, West China Hospital, Sichuan University, Chengdu, China. dr_taolin@163.com.
²⁸ Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China. songturun1986@scu.edu.cn.
²⁹ Kidney Transplantation Center, West China Hospital, Sichuan University, Chengdu, China. songturun1986@scu.edu.cn.

^# Contributed equally.

PMID: 41044341
DOI: 10.1038/s41551-025-01513-6

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.

PubMed Disclaimer

Conflict of interest statement

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.

References

1. Tonelli, M. et al. Systematic review: kidney transplantation compared with dialysis in clinically relevant outcomes. Am. J. Transplant. 11, 2093–2109 (2011). - PubMed
1. Lentine, K. L. et al. OPTN/SRTR 2021 annual data report: kidney. Am. J. Transplant. 23, S21–S120 (2023). - PubMed - PMC
1. Glander, P. et al. The ‘blood group O problem’ in kidney transplantation—time to change? Nephrol. Dial. Transplant. 25, 1998–2004 (2010). - PubMed
1. Heidt, S., Witvliet, M. D., Haasnoot, G. W. & Claas, F. H. The 25th anniversary of the Eurotransplant Acceptable Mismatch program for highly sensitized patients. Transpl. Immunol. 33, 51–57 (2015). - PubMed
1. Holscher, C. M. et al. Kidney exchange match rates in a large multicenter clearinghouse. Am. J. Transplant. 18, 1510–1517 (2018). - PubMed - PMC

LinkOut - more resources

Full Text Sources
- Nature Publishing Group

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

LinkOut - more resources

Full Text Sources