Noninvasive graft monitoring using donor-derived cell-free DNA in Japanese liver transplantation

Hiroki Kanamori; Yohei Yamada; Yoko Ito; Koji Shirosaki; Satoko Yamagishi; Yutaro Maeda; Yumi Kudo; Tomoshige Umeyama; Nobuhiro Takahashi; Mototoshi Kato; Yasushi Hasegawa; Kentaro Matsubara; Masahiro Shinoda; Hideaki Obara; Rie Irie; Hanako Tsujikawa; Hajime Okita; Phuong Thanh Nguyen; Kenichi Saigo; Shigeki Mitsunaga; Ituro Inoue; Yuko Kitagawa; Tatsuo Kuroda

doi:10.1111/hepr.13978

Noninvasive graft monitoring using donor-derived cell-free DNA in Japanese liver transplantation

Hepatol Res. 2024 Mar;54(3):300-314. doi: 10.1111/hepr.13978. Epub 2023 Nov 1.

Authors

Hiroki Kanamori¹, Yohei Yamada¹, Yoko Ito¹, Koji Shirosaki¹, Satoko Yamagishi¹, Yutaro Maeda¹, Yumi Kudo¹, Tomoshige Umeyama², Nobuhiro Takahashi¹, Mototoshi Kato¹, Yasushi Hasegawa³, Kentaro Matsubara³, Masahiro Shinoda⁴, Hideaki Obara³, Rie Irie⁵, Hanako Tsujikawa⁶, Hajime Okita⁶, Phuong Thanh Nguyen⁷, Kenichi Saigo⁸, Shigeki Mitsunaga⁷, Ituro Inoue⁷, Yuko Kitagawa³, Tatsuo Kuroda^{1

9}

Affiliations

¹ Department of Pediatric Surgery, Keio University School of Medicine, Tokyo, Japan.
² Department of Pediatric Surgery, St Luke's International Hospital, Tokyo, Japan.
³ Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
⁴ Digestive Diseases Center, International University of Health and Welfare School of Medicine, Mita Hospital, Tokyo, Japan.
⁵ Department of Diagnostic Pathology, Nippon Koukan Hospital, Kawasaki, Japan.
⁶ Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo, Japan.
⁷ Human Genetics Laboratory, National Institute of Genetics, Mishima, Japan.
⁸ Department of Transplantation Surgery, Japan Community Health Care Organization, Chiba Hospital, Chiba, Japan.
⁹ Kanagawa Children's Medical Center, Kanagawa, Japan.

PMID: 37850337
DOI: 10.1111/hepr.13978

Abstract

Aim: To evaluate the use of donor-derived cell-free DNA (dd-cfDNA) in diagnosing graft injuries in Japanese liver transplantation (LTx), including family-related living donors.

Methods: A total of 321 samples from 10 newly operated LTx recipients were collected to monitor the early dynamics of dd-cfDNA levels after LTx. Fifty-five samples from 55 recipients were collected during protocol biopsies (PB), whereas 36 samples from 27 recipients were collected during event biopsies, consisting of 11 biopsy-proven acute rejection (AR), 20 acute dysfunctions without rejection (ADWR), and 5 chronic rejections. The levels of dd-cfDNA were quantified using a next-generation sequencer based on single nucleotide polymorphisms.

Results: The dd-cfDNA levels were elevated significantly after LTx, followed by a rapid decline to the baseline in patients without graft injury within 30 days post-LTx. The dd-cfDNA levels were significantly higher in the 11 samples obtained during AR than those obtained during PB (p < 0.0001), which decreased promptly after treatment. The receiver operator characteristic curve analysis of diagnostic ability yielded areas under the curve of 0.975 and 0.897 for AR (rejection activity index [RAI] ≥3) versus PB and versus non-AR (ADWR + PB). The dd-cfDNA levels during AR were elevated earlier and correlated more strongly with the RAI (r = 0.740) than aspartate aminotransferase/alanine aminotransferase. The dd-cfDNA levels were neither associated with graft fibrosis based on histology nor the status of donor-specific antibodies in PB samples.

Conclusions: Donor-derived cell-free DNA serves as a sensitive biomarker for detecting graft injuries in LTx. Further large-scale cohort studies are warranted to optimize its use in differentiating various post-LTx etiologies.

Keywords: biomarker; clinical research; donor-derived cell-free DNA; graft injury; liver transplantation; next generation sequencer.

Abstract

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