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Clinical Research
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Advanced Tertiary Lymphoid Tissues in Protocol Biopsies are Associated with Progressive Graft Dysfunction in Kidney Transplant Recipients

Yu Ho Lee, Yuki Sato, Mitsuru Saito, Shingo Fukuma, Masaya Saito, Shigenori Yamamoto, Atsushi Komatsuda, Nobuhiro Fujiyama, Shigeru Satoh, Sang-Ho Lee, Peter Boor, Tomonori Habuchi, Jürgen Floege and Motoko Yanagita
JASN January 2022, 33 (1) 186-200; DOI: https://doi.org/10.1681/ASN.2021050715
Yu Ho Lee
1Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
2Division of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
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Yuki Sato
1Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
3Medical Innovation Center TMK Project, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Mitsuru Saito
4Department of Urology, Graduate School of Medicine, Akita University, Akita, Japan
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Shingo Fukuma
5Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Masaya Saito
6Department of Hematology, Nephrology, and Rheumatology, Graduate School of Medicine, Akita University, Akita, Japan
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Shigenori Yamamoto
1Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
3Medical Innovation Center TMK Project, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Atsushi Komatsuda
6Department of Hematology, Nephrology, and Rheumatology, Graduate School of Medicine, Akita University, Akita, Japan
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Nobuhiro Fujiyama
7Center for Kidney Disease and Transplantation, Akita University Hospital, Akita, Japan
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Shigeru Satoh
7Center for Kidney Disease and Transplantation, Akita University Hospital, Akita, Japan
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Sang-Ho Lee
8Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, Republic of Korea
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Peter Boor
10Division of Nephrology, RWTH University of Aachen, Germany, Aachen, Germany
11Electron Microscopy Facility, RWTH University of Aachen, Aachen, Germany
9Institute of Pathology, RWTH University of Aachen, Germany, Aachen, Germany
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Tomonori Habuchi
4Department of Urology, Graduate School of Medicine, Akita University, Akita, Japan
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Jürgen Floege
10Division of Nephrology, RWTH University of Aachen, Germany, Aachen, Germany
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Motoko Yanagita
1Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
12Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan
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Significance Statement

Tertiary lymphoid tissues (TLTs) are frequently found in transplanted kidneys, but their prevalence and clinical significance remain uncertain. Serial protocol kidney transplant biopsies without signs of rejection were collected and TLTs staged according to the presence of proliferating lymphocytes and follicular dendritic cells. TLTs rapidly developed within 1 month after kidney transplantation in approximately half of the 214 patients. Advanced TLTs, defined as the presence of follicular dendritic cells, were associated with progressive decline in graft function independent of interstitial inflammation score. These findings suggest advanced TLTs are strongly associated with late graft dysfunction, even in the absence of rejection.

Abstract

Background Tertiary lymphoid tissues (TLTs) are ectopic lymphoid tissues found in chronically inflamed organs. Although studies have documented TLT formation in transplanted kidneys, the clinical relevance of these TLTs remains controversial. We examined the effects of TLTs on future graft function using our histologic TLT maturity stages and the association between TLTs and Banff pathologic scores. We also analyzed the risk factors for the development of TLTs.

Methods Serial protocol biopsy samples (0 hour, 1, 6, and 12 months) without rejection were retrospectively analyzed from 214 patients who underwent living donor kidney transplantation. TLTs were defined as lymphocyte aggregates with signs of proliferation and their stages were determined by the absence (stage I) or presence (stage II) of follicular dendritic cells.

Results Only 4% of patients exhibited TLTs at the 0-hour biopsy. Prevalence increased to almost 50% at the 1-month biopsy, and then slightly further for 12 months. The proportion of advanced stage II TLTs increased gradually, reaching 19% at the 12-month biopsy. Presence of stage II TLTs was associated with higher risk of renal function decline after transplantation compared with patients with no TLT or stage I TLTs. Stage II TLTs were associated with more severe tubulitis and interstitial fibrosis/tubular atrophy at 12 months and predicted poorer graft function independently from the degree of interstitial inflammation. Pretransplantation rituximab treatment dramatically attenuated the development of stage II TLTs.

Conclusions TLTs are commonly found in clinically stable transplanted kidneys. Advanced stage II TLTs are associated with progressive graft dysfunction, independent of interstitial inflammation.

  • kidney transplantation
  • renal biopsy
  • transplant outcomes
  • renal pathology
  • biopsy
  • lymphoid tissue
  • Copyright © 2022 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 33 (1)
Journal of the American Society of Nephrology
Vol. 33, Issue 1
January 2022
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Advanced Tertiary Lymphoid Tissues in Protocol Biopsies are Associated with Progressive Graft Dysfunction in Kidney Transplant Recipients
Yu Ho Lee, Yuki Sato, Mitsuru Saito, Shingo Fukuma, Masaya Saito, Shigenori Yamamoto, Atsushi Komatsuda, Nobuhiro Fujiyama, Shigeru Satoh, Sang-Ho Lee, Peter Boor, Tomonori Habuchi, Jürgen Floege, Motoko Yanagita
JASN Jan 2022, 33 (1) 186-200; DOI: 10.1681/ASN.2021050715

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Advanced Tertiary Lymphoid Tissues in Protocol Biopsies are Associated with Progressive Graft Dysfunction in Kidney Transplant Recipients
Yu Ho Lee, Yuki Sato, Mitsuru Saito, Shingo Fukuma, Masaya Saito, Shigenori Yamamoto, Atsushi Komatsuda, Nobuhiro Fujiyama, Shigeru Satoh, Sang-Ho Lee, Peter Boor, Tomonori Habuchi, Jürgen Floege, Motoko Yanagita
JASN Jan 2022, 33 (1) 186-200; DOI: 10.1681/ASN.2021050715
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Keywords

  • kidney transplantation
  • renal biopsy
  • transplant outcomes
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  • lymphoid tissue

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