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Yan Zhang, Yu Yang, Xianduo Li, Dongdong Chen, Guanbao Tang, Tongyi Men
Chronic T cell mediated rejection (TCMR), which is characterized by infiltration of the interstitium by T cells and macrophages, still remains a major barrier to the long-term survival of kidney transplantation. Our recent report indicated that thalidomide can attenuate graft arteriosclerosis in an aortic transplant model. In this study, we investigated the effect of thalidomide on chronic TCMR in a rat model of kidney transplantation. Fischer or Lewis kidney allografts were transplanted into Lewis recipient rats...
March 12, 2019: International Immunopharmacology
Jeff Reeve, Georg A Böhmig, Farsad Eskandary, Gunilla Einecke, Gaurav Gupta, Katelynn Madill-Thomsen, Martina Mackova, Philip F Halloran
We previously reported a system for assessing rejection in kidney transplant biopsies using microarray-based gene expression data, the Molecular Microscope® Diagnostic System (MMDx). The present study was designed to optimize the accuracy and stability of MMDx diagnoses by replacing single machine learning classifiers with ensembles of diverse classifier methods. We also examined the use of automated report sign-outs and the agreement between multiple human interpreters of the molecular results. Ensembles generated diagnoses that were both more accurate than the best individual classifiers, and nearly as stable as the best, consistent with expectations from the machine learning literature...
March 13, 2019: American Journal of Transplantation
You Zou, Wei Zhang, Hong Hao Zhou, Rong Liu
AIM: To analyse long noncoding RNAs (lncRNA) in kidney transplant biopsies. METHODS: Using a data mining approach, we constructed expression profiles in kidney transplant cohorts (n = 1105) from Gene Expression Omnibus. Integrative analysis of the lncRNAs with acute rejection (AR), T-cell-mediated acute rejection (TCMR) and graft loss were performed. RESULTS: Six lncRNAs were identified as are associated with AR in the training and validating datasets, and with a risk score was generated with 3-lncRNAs that were predictive of graft loss (AUC = 0...
February 26, 2019: Biomarkers in Medicine
David N Rush, Ian W Gibson
The standardization of renal allograft pathology began in 1991 at the first Banff Conference held in Banff, Alberta, Canada. The first task of transplant pathologists, clinicians and surgeons was to establish diagnostic criteria for T cell-mediated rejection (TCMR). The histological threshold for this diagnosis was arbitrarily set at "i2t2": a mononuclear interstitial cell infiltrate present in at least 25% of normal parenchyma, and >4 mononuclear cells within the tubular basement membrane of non atrophic tubules...
February 19, 2019: Transplantation
Kieran M Halloran, Michael D Parkes, Jessica Chang, Irina L Timofte, Gregory I Snell, Glen P Westall, Ramsey Hachem, Daniel Kreisel, Elbert Trulock, Antoine Roux, Stephen Juvet, Shaf Keshavjee, Peter Jaksch, Walter Klepetko, Philip F Halloran
BACKGROUND: Improved understanding of lung transplant disease states is essential because failure rates are high, often due to chronic lung allograft dysfunction. However, histologic assessment of lung transplant transbronchial biopsies (TBBs) is difficult and often uninterpretable even with 10 pieces. METHODS: We prospectively studied whether microarray assessment of single TBB pieces could identify disease states and reduce the amount of tissue required for diagnosis...
February 6, 2019: Journal of Heart and Lung Transplantation
Yu Ho Lee, Se-Yun Kim, Haena Moon, Jung-Woo Seo, Dong-Jin Kim, Seon Hwa Park, Yang-Gyun Kim, Ju-Young Moon, Jin Sug Kim, Kyung-Hwan Jeong, Sung-Jig Lim, Chan-Duck Kim, Jae Berm Park, Byung Ha Chung, Yeong Hoon Kim, Jaeseok Yang, Hyung-In Yang, Kyoung Soo Kim, Sang-Ho Lee
Endocan is a water-soluble proteoglycan exclusively secreted by vascular endothelium. Endocan levels may be elevated in kidney transplant recipients experiencing antibody-mediated rejection (ABMR), which is characterized by vascular inflammation in transplanted kidney. We evaluated the clinical relevance of endocan as markers of microvascular inflammation in patients who underwent kidney transplantation. Plasma and urinary endocan levels were measured in 203 kidney transplant recipients and were compared across different etiologies of allograft dysfunction and various pathologic scores...
February 12, 2019: Scientific Reports
Yassine Bouatou, Denis Viglietti, Daniele Pievani, Kevin Louis, Jean-Paul Duong Van Huyen, Marion Rabant, Olivier Aubert, Jean-Luc Taupin, Denis Glotz, Christophe Legendre, Alexandre Loupy, Carmen Lefaucheur
The recent recognition of complex and chronic phenotypes of T cell-mediated rejection (TCMR) has fostered the need to better evaluate the response of acute TCMR - a condition previously considered to lack relevant consequences for allograft survival - to the standard of care. In a prospective cohort of kidney recipients (n=256) with biopsy-proven acute TCMR receiving corticosteroids, we investigated clinical, histological and immunological phenotypes at the time of acute TCMR diagnosis and 3 months posttreatment...
February 12, 2019: American Journal of Transplantation
William Hoffman, Rajil Mehta, Dana R Jorgensen, Puneet Sood, Parmjeet Randhawa, Christine M Wu, Chetan Puttarajappa, Nirav A Shah, Amit D Tevar, Sundaram Hariharan
BACKGROUND: We investigated the effect of Clinical and Subclinical T Cell Mediated Rejection (C-TCMR and SC-TCMR) on allograft histology, function and progression. METHODS: Adult kidney recipients with 2 protocol biopsies were divided into: No-TCMR (No-TCMR) on biopsies (n=104), SC-TCMR (n=56), and C-TCMR (n=32) in at least 1 biopsy. Chronicity (ci+ct+cg+cv) scores, renal function, and the burden of renal disease measured by AUC (serum creatinine mg*month/dl) were compared...
February 4, 2019: Transplantation
Nicholas L Robbins, Matthew J Wordsworth, Bijaya K Parida, Bruce Kaplan, Vijay S Gorantla, Col Erik K Weitzel, Warren C Breidenbach
BACKGROUND: From 1996 to 2000 Diefenbeck et al. carried out 6 knee vascularized composite allotransplants(VCA). The VCAs were composed of bone, soft tissue, and the femoral vascular pedicle (25-40 cm total length). All rejected between 14 to 56 months. The failures were attributed to chronic rejection (CR). In 2008 the Louisville team lost their fourth patient's hand transplant at 8 months. During the rejection workup the senior surgeon's intra-operative findings noted a thickened arterial pedicle attributed to intimal hyperplasia (IH) with significant fibrotic perivascular tissue and a near 'no flow phenomenon'...
December 28, 2018: Plastic and Reconstructive Surgery
Caroline C Jadlowiec, Paige E Morgan, Nehra K Avinash, Matthew A Hathcock, Walter K Kremers, Julie K Heimbach, Russell H Wiesner, Timucin Taner
T-cell mediated rejection (TCMR) is common after liver transplantation (LT), and is often thought to have minimum impact on outcomes. Because alloimmune response changes over time, we investigated the role of the timing of TCMR on patient and allograft survival, and examined the risk factors for early and late TCMR. 787 consecutive LT recipients with protocol liver biopsies were reviewed, with an 8.6 year follow-up. The incidence of early TCMR (≤6 weeks post-LT) was 33%, with NASH patients having the lowest incidence...
January 7, 2019: Liver Transplantation
Claire Leibler, Marie Matignon, Anissa Moktefi, Chloé Samson, Anissa Zarour, Stéphanie Malard, Emmanuelle Boutin, Caroline Pilon, Laurent Salomon, Pierre-André Natella, Antoine Durrbach, Thomas Robert, Florence Canoui-Poitrine, Philippe Grimbert
The benefit of belatacept on antibody-mediated rejection (ABMR) incidence after kidney transplantation with preformed DSA has never been assessed. Between 2014 and 2016, we conducted a multicenter prospective clinical trial, including N=49 patients, to determine kidney allograft outcome in recipients with preformed DSA (maximal mean fluorescence intensity (MFImax) 500-3000) treated with belatacept (BELACOR trial). Immunosuppressive strategy included antithymocyte globulin, belatacept, mycophenolate mofetil and steroids...
December 23, 2018: American Journal of Transplantation
Brian J Nankivell, Nidhi Agrawal, Ankit Sharma, Anne Taverniti, Chow H P'Ng, Meena Shingde, Germaine Wong, Jeremy R Chapman
The pathological diagnosis of borderline rejection (BL-R) denotes possible T cell-mediated rejection (TCMR), but its clinical significance is uncertain. This single-center, cross-sectional cohort study compared the functional and histological outcomes of consecutive BL-R diagnoses (n = 146) against normal controls (n = 826) and acute TCMR (n = 55) from 551 renal transplant recipients. BL-R was associated with the following: contemporaneous renal dysfunction, acute tubular necrosis, and chronic tubular atrophy (P < ...
November 30, 2018: American Journal of Transplantation
Philip F Halloran, Arthur Matas, Bertram L Kasiske, Katelynn Madill-Thomsen, Martina Mackova, Konrad S Famulski
In kidney transplant biopsies, inflammation in areas of atrophy-fibrosis (i-IFTA) is associated with increased risk of failure, presumably because inflammation is evoked by recent parenchymal injury from rejection or other insults, but some cases also have rejection. The present study explored the frequency of rejection in i-IFTA, by histology Banff 2015 and microarray-based molecular diagnostic system (MMDx). In unselected indication biopsies (108 i-IFTA, 73 uninflamed IFTA (i0-IFTA), and 53 no IFTA), i-IFTA biopsies were later, more scarred, and had more antibody-mediated rejection (ABMR) by histology (28%) and MMDx (45%)...
November 12, 2018: American Journal of Transplantation
Saleh Yazdani, Jasper Callemeyn, Stéphane Gazut, Evelyne Lerut, Henriette de Loor, Max Wevers, Line Heylen, Carole Saison, Alice Koenig, Olivier Thaunat, Lieven Thorrez, Dirk Kuypers, Ben Sprangers, Laure-Hélène Noël, Leentje Van Lommel, Frans Schuit, Marie Essig, Wilfried Gwinner, Dany Anglicheau, Pierre Marquet, Maarten Naesens
Despite partial elucidation of the pathophysiology of antibody-mediated rejection (ABMR) after kidney transplantation, it remains largely unclear which of the involved immune cell types determine disease activity and outcome. We used microarray transcriptomic data from a case-control study (n=95) to identify genes that are differentially expressed in ABMR. Given the co-occurrence of ABMR and T-cell-mediated rejection (TCMR), we built a bioinformatics pipeline to distinguish ABMR-specific mRNA markers. Differential expression of 503 unique genes was identified in ABMR, with significant enrichment of natural killer (NK) cell pathways...
January 2019: Kidney International
Mareen Matz, Frederik Heinrich, Qiang Zhang, Christine Lorkowski, Evelyn Seelow, Kaiyin Wu, Nils Lachmann, Richard Kwasi Addo, Pawel Durek, Mir-Farzin Mashreghi, Klemens Budde
CONTEXT: Antibody-mediated rejection (ABMR) after kidney transplantation (KTx) remains the crucial obstacle to successful long-term graft function. The identification of gene signatures involved in ABMR could grant the basis for better prevention and treatment strategies. OBJECTIVE: The identification of gene signatures in whole blood cells specific for ABMR after kidney transplantation. MATERIAL AND METHODS: Total RNA from blood cells of 16 kidney transplanted patients with ABMR, stable graft function (SGF) and with T-cell mediated rejection (TCMR) was isolated...
October 20, 2018: Clinical Transplantation
Philip F Halloran, Jeff Reeve, Arezu Z Aliabadi, Martin Cadeiras, Marisa G Crespo-Leiro, Mario Deng, Eugene C Depasquale, Johannes Goekler, Xavier Jouven, Daniel H Kim, Jon Kobashigawa, Alexandre Loupy, Peter Macdonald, Luciano Potena, Andreas Zuckermann, Michael D Parkes
BACKGROUND: Because injury is universal in organ transplantation, heart transplant endomyocardial biopsies present an opportunity to explore response to injury in heart parenchyma. Histology has limited ability to assess injury, potentially confusing it with rejection, whereas molecular changes have potential to distinguish injury from rejection. Building on previous studies of transcripts associated with T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), we explored transcripts reflecting injury...
October 18, 2018: JCI Insight
Cornelius C Thaiss, Tetsu Oura, Hajime Sasaki, Abbas Dehnadi, Masatoshi Matsunami, Ivy A Rosales, Benedict A Cosimi, Tatsuo Kawai
BACKGROUND: Although induction of durable mixed chimerism is required for murine skin allograft tolerance, renal allograft tolerance has been achieved after induction of only transient mixed chimerism in nonhuman primates (NHPs) and humans. To better define the level/duration of chimerism required for stable renal allograft tolerance, we retrospectively analyzed these parameters and compared them with transplant outcomes in NHP combined kidney and bone marrow transplant (CKBMT) recipients...
October 8, 2018: Transplantation
Peng Liu, George Tseng, Zijie Wang, B S Yuchen Huang, Parmjeet Randhawa
Molecular diagnosis is being increasingly used into transplant pathology to render more objective and quantitative determinations that also provide mechanistic and prognostic insights. This study performed RNA-Seq on biopsies from kidneys with stable function (STA) and biopsies with classical findings of T-cell mediated rejection (TCMR). Machine learning tools were used to develop prediction models for distinguishing TCMR and STA samples using the top genes identified by DSeq2. The prediction models were tested on 703 biopsies with Affymetrix chip gene expression profiles available in the public domain...
October 5, 2018: Human Pathology
Steffen Bobka, Nadja Ebert, Eloed Koertvely, Johannes Jacobi, Michael Wiesener, Maike Büttner-Herold, Kerstin Amann, Christoph Daniel
BACKGROUND/AIMS: Complement activation is important in post-transplantation renal injury, but data on its role as predictor of transplant outcome/complications when assessed in donor kidneys are lacking. METHODS: In human renal transplant biopsies with delayed graft function (DGF, n=12), antibody mediated rejection (ABMR, n=8), T-cell mediated rejection (TCMR, n=11), 1 year protocol biopsies (control, n=10) and corresponding zero-biopsies we performed immunohistochemical analyses of 6 complement factors using FFPE sections and correlated the findings with kidney function, as assessed by serum creatinine, and morphological changes including interstitial fibrosis and tubular atrophy (IF/TA)...
2018: Kidney & Blood Pressure Research
Jeong-Hoon Lim, Chan-Hyeong Lee, Kyu Yeun Kim, Hee-Yeon Jung, Ji-Young Choi, Jang-Hee Cho, Sun-Hee Park, Yong-Lim Kim, Moon-Chang Baek, Jae Berm Park, Young-Hoon Kim, Byung Ha Chung, Sang-Ho Lee, Chan-Duck Kim
BACKGROUND: Acute rejection is hazardous to graft survival in kidney transplant recipients (KTRs). We aimed to identify novel biomarkers for early diagnosis of acute T cell-mediated rejection (TCMR) in urinary exosomes of KTRs. METHODS: Among 458 graft biopsies enrolled in a cross-sectional multicenter study, 22 patients with stable graft function (STA) who had not shown pathologic abnormality and 25 patients who diagnosed biopsy-proven TCMR were analyzed. We performed proteomic analysis using nano-ultra performance liquid chromatography-tandem mass spectrometry (nano-UPLC-MS/MS) to identify candidate biomarkers for early TCMR diagnosis on urinary exosomes...
2018: PloS One
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