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Results of a multicenter prospective clinical study in Japan for evaluating efficacy and safety of desensitization protocol based on rituximab in ABO-incompatible kidney transplantation

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Abstract

Background

Deceased organ donations are rare in Japan, with most kidney transplants performed from a limited number of living donors. Researchers have thus developed highly successful ABO-incompatible transplantation procedures, emphasizing preoperative desensitization and postoperative immunosuppression. A recent open-label, single-arm, multicenter clinical study prospectively examined the efficacy and safety of rituximab/mycophenolate mofetil desensitization in ABO-incompatible kidney transplantation without splenectomy.

Methods

Mycophenolate mofetil and low dose steroid were started 28 days pretransplant, followed by two doses of rituximab 375 mg/m2 at day −14 and day −1, and postoperative immunosuppression with tacrolimus or ciclosporin and basiliximab. The primary endpoint was the non-occurrence rate of acute antibody-mediated rejection. Patient survival and graft survival were monitored for 1 year posttransplant.

Results

Eighteen patients received rituximab and underwent ABO-incompatible kidney transplantation. CD19-positive peripheral B cell count decreased rapidly after the first rituximab infusion and recovered gradually after week 36. The desensitization protocol was tolerable, and most rituximab-related infusion reactions were mild. No anti-A/B antibody-mediated rejection occurred with this series. One patient developed anti-HLA antibody-mediated rejection (Banff 07 type II) on day 2, which was successfully managed. Patient and graft survival were both 100 % after 1 year.

Conclusion

Our desensitization protocol was confirmed to be clinically effective and with acceptable toxicities for ABO-I-KTx (University Hospital Medical Information Network Registration Number: UMIN000006635).

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Acknowledgments

The authors thank the patients and their families, the investigators and other physicians, and the nurses and laboratory technicians in the institutions participating in this multicenter trial. We are also grateful to Dr. Shinichi Nishi (Kobe University Graduate School of Medicine, Hyogo, Japan) and Dr. Hideki Ohdan (Hiroshima University, Hiroshima, Japan) for their critical review of the clinical data as members of the Independent Data and Safety Monitoring Committee, and to Yutaka Yamaguchi (Yamaguchi Pathology Laboratory, Chiba, Japan) and Asami Takeda (Nagoya Daini Red Cross Hospital, Aichi, Japan) for their histopathological review as members of the Central Pathology Review Committee.

Author information

Authors and Affiliations

  1. Niigata Organ Transplant Foundation, Niigata, Japan

    Kota Takahashi

  2. Division of Urology, Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan

    Kazuhide Saito

  3. Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan

    Shiro Takahara

  4. Department of Surgery, Tokyo Women’s Medical University, Tokyo, Japan

    Shohei Fuchinoue

  5. Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Tochigi, Japan

    Takashi Yagisawa

  6. Department of Nephrology, Toho University, Tokyo, Japan

    Atsushi Aikawa

  7. Transplant Surgery, Nagoya Daini Red Cross Hospital, Aichi, Japan

    Yoshihiko Watarai

  8. Department of Organ Transplant and General Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Norio Yoshimura

  9. Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan

    Kazunari Tanabe

  10. Department of Nephrology, Masuko Memorial Hospital, Aichi, Japan

    Kunio Morozumi

  11. Department of Digestive and Transplantation Surgery, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan

    Motohide Shimazu

  12. 1-23-3 Kitaotsuka, Toshima-ku, Tokyo, 170-0004, Japan

    Kota Takahashi

Authors
  1. Kota Takahashi
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  2. Kazuhide Saito
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  3. Shiro Takahara
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  4. Shohei Fuchinoue
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  5. Takashi Yagisawa
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  6. Atsushi Aikawa
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  7. Yoshihiko Watarai
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  8. Norio Yoshimura
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  9. Kazunari Tanabe
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  10. Kunio Morozumi
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  11. Motohide Shimazu
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Consortia

The IDEC-C2B8 ABO-I KTx Study Group

Corresponding author

Correspondence to Kota Takahashi.

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Funding sources

This multicenter, prospective clinical study was sponsored by Zenyaku Kogyo, Tokyo, Japan. This study was initiated to satisfy the development requirements from the Japan Transplant Recipients Organization and a request from the Ministry of Health, Labour and Welfare under the system for resolution of unapproved drugs and off-label drug use. The study protocol was based on long-term survey results from the Japanese ABO Incompatible Transplantation Committee. The rationale for the desensitization protocol and immunosuppression was based on research supported by a Grant-in-Aid for Scientific Research No. (A)24249078 by the Japan Society for the Promotion of Science, the Ministry of Education, Culture, Sports, Science and Technology 2012–2014 (Corresponding Researcher: Kota Takahashi).

Conflict of interest

Honoraria: Kota Takahashi (Zenyaku Kogyo), Kazunari Tanabe (Chugai) and Kunio Morozumi (Novartis). Research Funding: Takashi Yagisawa (Astellas, Chugai and Novartis) and Kazunari Tanabe (Astellas). Subsidies or Donations: Kazunari Tanabe (Chugai). Travel fees, gifts, and others: Kota Takahashi (Zenyaku Kogyo) and Kazuhide Saito (Astellas, Chugai, Novartis and Zenyaku Kogyo).

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee at which the studies were conducted (IRB Approval Number at Niigata University: CH23-012) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Takahashi, K., Saito, K., Takahara, S. et al. Results of a multicenter prospective clinical study in Japan for evaluating efficacy and safety of desensitization protocol based on rituximab in ABO-incompatible kidney transplantation. Clin Exp Nephrol 21, 705–713 (2017). https://doi.org/10.1007/s10157-016-1321-5

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  • DOI: https://doi.org/10.1007/s10157-016-1321-5

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