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Serum N-glycan profiling can predict biopsy-proven graft rejection after living kidney transplantation

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Abstract

Background

To evaluate whether serum N-glycan profile can be used as a diagnostic marker of graft rejection after living-donor kidney transplants (KT).

Methods

We retrospectively examined 174 KT recipients at five medical centers. N-Glycan levels were analyzed in postoperative serum samples using glycoblotting combined with mass spectrometry. We developed an integrated score to predict graft rejection based on a combination of age, gender, immunological risk factors, and serum N-glycan levels at post-KT day D1 and D7. Rejection-free survival rates stratified by the sum of integrated scores (D1 + D7) were evaluated using Kaplan–Meier curves.

Results

Of 174, 52 showed graft rejection (Rejection-pos. group) and 122 recipients did not show graft rejection (Rejection-neg. group). The integrated scores were significantly higher in the Rejection-pos. group than those of the Rejection-neg. group. Area-under-curve (AUC) value of integrated scores at post-KT D1, and D7 were 0.84 and 0.84, respectively. The sum of integrated scores (D1 + D7) ≥ 0.50 identified graft rejection with 81% sensitivity and 80% specificity; with an AUC value of 0.87. Recipients with higher sum of integrated scores (D1 + D7 ≥ 0.5) had significantly shorter rejection-free survival than those with lower scores.

Conclusion

Evaluation of serum N-glycosylation profiles can identify recipients who are prone to rejection.

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Acknowledgements

The authors are grateful to Takahiro Yoneyama, Satomi Sakamoto, Yukie Nishizawa, Itsuto Hamano, Naoki Fujita, Takuma Narita, and Yuki Fujita for their invaluable help with sample collection and patient data management.

Funding

This work was supported by a Grant-in-Aid for Scientific Research (Nos. 15H02563, 17K11119, and 19H05556) from the Japan Society for the Promotion of Science, and Japanese Society for Clinical Renal Transplant grant-in-aid for multicenter clinical research Grant 2014.

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Authors and Affiliations

  1. Department of Urology, Hirosaki University Graduate School of Medicine, 5 Zaifu-chou, Hirosaki, 036-8562, Japan

    Osamu Soma, Shingo Hatakeyama, Yuki Tobisawa, Daisuke Noro, Yuichiro Suzuki & Chikara Ohyama

  2. Department of Advanced Transplant and Regenerative Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

    Tohru Yoneyama & Chikara Ohyama

  3. Department of Urology, Akita University Graduate School of Medicine, Akita, Japan

    Mitsuru Saito & Shigeru Satoh

  4. Department of Urology, St. Marianna University School of Medicine, Kawasaki, Japan

    Hideo Sasaki

  5. Frontier Research Centre for Advanced Material and Life Science, Graduate School of Life Science, Hokkaido University, Sapporo, Japan

    Masakazu Tanaka & Shin-Ichiro Nishimura

  6. Department of Kidney Transplant Surgery, Sapporo City General Hospital, Sapporo, Japan

    Hiroshi Harada

  7. Department of Urology, Tokyo Woman’s Medical University, Tokyo, Japan

    Hideki Ishida & Kazunari Tanabe

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  1. Osamu Soma
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Corresponding author

Correspondence to Shingo Hatakeyama.

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Human and animal rights

This study was performed in accordance with the ethical standards of the Declaration of Helsinki and was approved by the Ethics Committee of the Hirosaki University Graduate School of Medicine (approval number: 2014–195).

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10157_2019_1820_MOESM1_ESM.pdf

Supplementary file1 (PDF 1808 kb) Figure S1. Schematic representation of the 35 types of N-glycans identified by N-glycomics. Putative structures of the N-glycans are represented using monosaccharide symbols. Yellow circles, galactose (Gal); green circles, mannose (Man); blue squares, N-acetylglucosamine (GlcNAc); red triangles, fucose (Fuc); and purple diamonds, N-acetylneuraminic acid (sialic acid).Figure S2. Representative MALDI-TOF mass spectra. Representative MALDI-TOF mass spectra (m/z range of 1250 to 4000) of benzyloxyamine (BOA)-labeled N-glycans derived from the serum of patients in kidney transplantation at day 1 and 7 were shown. A mass spectrum of serum N-glycans from a patient who did not develop any adverse events (A). A mass spectrum of serum N-glycans from a patient who developed ABMR (B). A mass spectrum of serum N-glycans from a patient who developed TCMR (C), A mass spectrum of serum N-glycans from a patient who developed ABMR and TCMR (D). Figure S3. The AUC for immunological risks and pure N-glycan score.The AUC for ABOi-KT, preformed DSA status, rituximab use, and the sum of immunological risks (ABOi-KT, preformed DSA positive, plus rituximab use) were 0.59 (A; P = 0.055), 0.54 (B; P = 0.373), 0.59 (C; P = 0.078), and 0.62 (D; P = 0.012), respectively. When we compared the pure N-glycan score (without age, sex, ABO compatibility, rituximab administration, and presence of DSA) and integrated score using ROC curve, there was no significant difference in the AUC value between the pure N-glycan score and integrated score in D1 (E; AUC 0.84 vs. 0.84, respectively, P = 0.609), D7 (F; AUC 0.83 vs 0.84, respectively, P = 0.564), and D1+D7 (G; AUC 0.87 vs 0.87, respectively, P = 0.551).

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Soma, O., Hatakeyama, S., Yoneyama, T. et al. Serum N-glycan profiling can predict biopsy-proven graft rejection after living kidney transplantation. Clin Exp Nephrol 24, 174–184 (2020). https://doi.org/10.1007/s10157-019-01820-8

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