Yu Ho Lee1,2, Yuki Sato1,3, Mitsuru Saito4, Shingo Fukuma5, Masaya Saito6, Shigenori Yamamoto1,3, Atsushi Komatsuda6, Nobuhiro Fujiyama7, Shigeru Satoh7, Sang-Ho Lee8, Peter Boor9,10,11, Tomonori Habuchi4, Jürgen Floege9, Motoko Yanagita12,13. 1. Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 2. Division of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea. 3. Medical Innovation Center TMK Project, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 4. Department of Urology, Graduate School of Medicine, Akita University, Akita, Japan. 5. Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 6. Department of Hematology, Nephrology, and Rheumatology, Graduate School of Medicine, Akita University, Akita, Japan. 7. Center for Kidney Disease and Transplantation, Akita University Hospital, Akita, Japan. 8. Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, Republic of Korea. 9. Division of Nephrology, RWTH University of Aachen, Germany, Aachen, Germany. 10. Electron Microscopy Facility, RWTH University of Aachen, Aachen, Germany. 11. Institute of Pathology, RWTH University of Aachen, Germany, Aachen, Germany. 12. Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan motoy@kuhp.kyoto-u.ac.jp. 13. Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan.
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.
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.
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