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1
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Mohidin B, Marks SD. Acute kidney injury in paediatric kidney transplant recipients. Pediatr Nephrol 2025; 40:2161-2175. [PMID: 39875735 DOI: 10.1007/s00467-025-06655-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 11/21/2024] [Accepted: 12/17/2024] [Indexed: 01/30/2025]
Abstract
Acute kidney injury (AKI) in paediatric kidney transplant recipients is common. Infection including urinary tract infection (UTI) and rejection are the most common causes in children. Surgical complications often cause AKI early post-transplant, whereas BK polyomavirus nephropathy rarely occurs in the first month post-transplant. Understanding kidney physiology helps to appreciate the sensitivity of the allograft to AKI, more so than native kidneys. Although the cause of AKI is often multi-factorial, there may be an underlying process that is treatable. Eliciting the aetiology, in this regard, is of paramount importance. Pre-renal and post-renal causes of allograft dysfunction are important to distinguish from intrinsic kidney disease. Clinical information and examination of fluid balance, urine dipstick testing, blood tests, bladder and kidney transplant ultrasound, and kidney transplant biopsy remain vital assessment tools in narrowing the differential diagnosis. A careful prescribed and recreational drug history is always warranted as many drugs including supplements are nephrotoxic. Additional causes such as allograft rejection, recurrent disease, and calcineurin inhibitor toxicity need to be considered in cases of allograft dysfunction, which would not affect the native kidneys. Early detection and assessment of AKI is crucial in promoting recovery. Significant progress has been made in specific pathologies over the last 20 years, which has improved kidney allograft survival rates considerably. Research into identifying AKI biomarkers to assist early diagnosis, before the serum creatinine rises, is ongoing.
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Affiliation(s)
- Barian Mohidin
- NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London Great Ormond Street Institute of Child Health, London, UK.
| | - Stephen D Marks
- NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London Great Ormond Street Institute of Child Health, London, UK
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
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2
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Zielinski D, Goutaudier V, Sablik M, Divard G, Aubert O, Piedrafita A, Mezine F, Dagobert J, Certain A, Robin B, Gueguen J, Rabant M, Duong van Huyen JP, Sannier A, Randoux-Lebrun C, Maanaoui M, Lionet A, Gibier JB, Gnemmi V, Le Quintrec M, Chauveau B, Vermorel A, Couzi L, Bestard O, Elias M, Louis K, Rosales IA, Smith RN, Kung VL, Anglicheau D, Legendre C, Del Bello A, Huang E, Adam B, Kamar N, Colvin RB, Mengel M, Lefaucheur C, Loupy A. Molecular diagnosis of kidney allograft rejection based on the Banff Human Organ Transplant (B-HOT) gene panel: a multicenter international study. Am J Transplant 2025:S1600-6135(25)00230-8. [PMID: 40345499 DOI: 10.1016/j.ajt.2025.04.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 04/24/2025] [Accepted: 04/29/2025] [Indexed: 05/11/2025]
Abstract
Transcriptomic analysis of kidney biopsies has demonstrated potential to improve diagnosis of allograft rejection. Here, we developed a molecular assessment of antibody-mediated rejection (AMR) and T-cell-mediated rejection (TCMR) based on the Banff-Human-Organ-Transplant (B-HOT) consensus gene panel. Expression assays of formalin-fixed paraffin-embedded kidney biopsies from well-phenotyped cohorts were used to develop prediction models for AMR and TCMR and an automated report of gene expression-based diagnosis. The study population consisted of 950 kidney allograft biopsies from 10 transplantation centers in Europe and North America. The development cohort included 664 renal allograft biopsies split into a training (n=537) and test set (n=127), and two external validation cohorts (n=286). We performed gene selection using regularized regression and developed several different base models based on B-HOT expression data, which were combined into a single ensemble model for each rejection diagnosis. Model performance was assessed in the test set and the two external validation cohorts, showing good discriminative abilities (respective PR-AUC AMR=0.811, 0.891, 0.832 and TCMR=0.736, 0.810, 0.782). We identified challenging biopsies with histology below diagnostic thresholds for which gene expression-based probability can refine rejection diagnosis. This automated molecular diagnostic system shows potential for improving kidney allograft rejection diagnosis in routine practice and clinical trials.
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Affiliation(s)
- Dina Zielinski
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Valentin Goutaudier
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Marta Sablik
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Gillian Divard
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Kidney Transplant Department, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Olivier Aubert
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Alexis Piedrafita
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Department of Nephrology and Organ Transplantation, Toulouse Rangueil University Hospital, Toulouse, France
| | - Fariza Mezine
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Jessy Dagobert
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Anais Certain
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Blaise Robin
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Juliette Gueguen
- Néphrologie-Immunologie Clinique, Hôpital Bretonneau, CHU Tours, Tours, France
| | - Marion Rabant
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Jean-Paul Duong van Huyen
- Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Aurélie Sannier
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Université de Paris, Assistance Publique-Hôpitaux de Paris (AP-HP), Service d'Anatomie et Cytologie Pathologiques, Hôpital Bichat, Paris, France
| | | | - Mehdi Maanaoui
- Department of Nephrology, Service de Néphrologie, CHU de Lille, Hôpital Huriez, 59037, Lille, France; Inserm, CHU Lille, Institut Pasteur Lille, University in Lille, U1190 - EGID, 59000, Lille, France
| | - Arnaud Lionet
- Department of Nephrology, Service de Néphrologie, CHU de Lille, Hôpital Huriez, 59037, Lille, France
| | | | - Viviane Gnemmi
- Department of Pathology, Lille University Hospital, France
| | - Moglie Le Quintrec
- Department of Nephrology, Dialysis and Transplantation, Montpellier University Hospital, France
| | | | - Agathe Vermorel
- Department of Nephrology and Transplantation, Bordeaux University Hospital, France
| | - Lionel Couzi
- Department of Nephrology and Transplantation, Bordeaux University Hospital, France
| | - Oriol Bestard
- Department of Nephrology and Kidney Transplantation, Vall d'Hebrón University Hospital, Barcelona, Spain
| | - Michelle Elias
- Kidney Transplant Department, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Kevin Louis
- Kidney Transplant Department, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Ivy A Rosales
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA
| | - R Neal Smith
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA
| | - Vanderlene L Kung
- Department of Medicine, Division of Nephrology, Comprehensive Transplant Center, Cedars Sinai Medical Center, Los Angeles, CA
| | - Dany Anglicheau
- Department of Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Christophe Legendre
- Department of Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, Toulouse Rangueil University Hospital, Toulouse, France
| | - Edmund Huang
- Department of Medicine, Division of Nephrology, Comprehensive Transplant Center, Cedars Sinai Medical Center, Los Angeles, CA
| | - Benjamin Adam
- Department of Laboratory Medicine and Pathology, ECHA 5-411, University of Alberta, 11405 87 Avenue, Edmonton, Alberta T6G 1C9, Canada
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, Toulouse Rangueil University Hospital, Toulouse, France
| | - Robert B Colvin
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA
| | - Michael Mengel
- Department of Laboratory Medicine and Pathology, ECHA 5-411, University of Alberta, 11405 87 Avenue, Edmonton, Alberta T6G 1C9, Canada
| | - Carmen Lefaucheur
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Kidney Transplant Department, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Alexandre Loupy
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Department of Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
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3
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Vinson AJ, Matas A. Late Allograft Loss and Contemporary Cardiorenal Metabolic Therapies. J Am Soc Nephrol 2025:00001751-990000000-00615. [PMID: 40193211 DOI: 10.1681/asn.0000000726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2025] Open
Abstract
Late kidney allograft loss occurs through one of two mechanisms: ( 1 ) deterioration of kidney function leading to retransplantation or dialysis (death-censored graft loss) and ( 2 ) premature death with a normally functioning transplant (death with graft function)-each accounting for approximately 50% of late kidney graft losses. Late death-censored graft loss typically results from a combination of immune and nonimmune events leading to common nonspecific end points ( e.g ., tubular atrophy, interstitial fibrosis, and glomerulosclerosis). Conversely, leading causes of death with graft function typically include cardiovascular events, malignancy, and infection. With an improved understanding of the multiple mechanism by which late graft dysfunction develops, there is an opportunity to identify patients at greatest risk and institute novel strategies to quell the process. Newer cardiometabolic agents with proven benefit in the general population have not been well-studied in kidney transplant recipients. However, in addition to their potential benefits in reducing cardiovascular, infectious, and malignancy end points (thus minimizing death with graft function risk), many novel agents may have additional anti-inflammatory and/or antifibrotic benefit (minimizing death-censored graft loss risk) in the kidney transplant population. In this review, we summarize existing literature regarding major causes of death-censored graft loss and death with graft function and discuss the potential roles of new cardiorenal metabolic agents including sodium-glucose cotransport 2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists, glucagon-like peptide 1 receptor agonists, and dual endothelin and angiotensin receptor antagonists in the kidney transplant population, including potential mechanisms to improve death with graft function and death-censored graft loss outcomes.
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Affiliation(s)
- Amanda J Vinson
- Division of Nephrology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
- Kidney Research Institute of Nova Scotia
| | - Arthur Matas
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota
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4
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Pinezich MR, O'Neill JD, Guenthart BA, Kim J, Vila OF, Ma SP, Chen YW, Hozain AE, Krishnan A, Fawad M, Cunningham KM, Wobma HM, Van Hassel J, Snoeck HW, Bacchetta M, Vunjak-Novakovic G. Theranostic methodology for ex vivo donor lung rehabilitation. MED 2025:100644. [PMID: 40154476 DOI: 10.1016/j.medj.2025.100644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 10/15/2024] [Accepted: 03/05/2025] [Indexed: 04/01/2025]
Abstract
BACKGROUND About 80% of donor lungs are not utilized for transplantation. Cross-circulation of ex vivo lungs with a support swine enables the rehabilitation of donor lungs that are initially deemed unsuitable for transplantation. Robust therapeutic and diagnostic modalities are needed for ex vivo lung rehabilitation; however, no standardized "theranostic" methodology has been reported. METHODS Ex vivo lungs (n = 23; 17 injured and 6 controls) with multi-focal contusion (n = 6, human), gastric aspiration injury (n = 8, swine), ischemia-reperfusion injury (n = 3, swine), or no injury (n = 6, swine) were used to develop a therapeutic and diagnostic (theranostic) methodology for ex vivo lung rehabilitation during cross-circulation. Airway (bronchoscopic, nebulized), intravascular, and transpleural access enabled sample collection and therapeutic delivery. Diagnostic modalities included non-invasive imaging, functional testing, and molecular assays. Therapeutic modalities included bronchoalveolar lavage, surfactant replacement, recruitment maneuvers, and cell/organoid delivery. Real-time tracking of delivered cells was performed via fluorescence and bioluminescence imaging. FINDINGS Diagnostic assessments revealed tissue-, cell-, and molecular-level insights at global and regional scales of ex vivo lungs during cross-circulation, which informed therapeutic management and interventions to recover donor lungs. Mesenchymal stromal cells and lung organoids were delivered bronchoscopically and transpleurally, tracked non-invasively during cross-circulation, and observed to localize within the parenchyma. CONCLUSIONS Application of a theranostic methodology during cross-circulation enabled real-time ex vivo lung assessment and rehabilitation across a variety of lung injuries to help increase clinical utilization of donor lungs in the future. FUNDING NIH (P41 EB027062, R01HL120046, U01HL134760), CFF (VUNJAK23XX0).
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Affiliation(s)
- Meghan R Pinezich
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - John D O'Neill
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Brandon A Guenthart
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA
| | - Jinho Kim
- Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ, USA
| | - Olaia F Vila
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Stephen P Ma
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Ya-Wen Chen
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Ahmed E Hozain
- Department of Biomedical Engineering, Columbia University, New York, NY, USA; Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Aravind Krishnan
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA
| | - Moeed Fawad
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA
| | | | - Holly M Wobma
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Julie Van Hassel
- Department of Biomedical Engineering, Columbia University, New York, NY, USA; Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Hans-Willem Snoeck
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY USA; Columbia Center for Human Development, Columbia University Irving Medical Center, New York, NY, USA
| | - Matthew Bacchetta
- Departments of Cardiac Surgery and Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Gordana Vunjak-Novakovic
- Department of Biomedical Engineering, Columbia University, New York, NY, USA; Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
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5
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Ramalhete L, Araújo R, Vieira MB, Vigia E, Aires I, Ferreira A, Calado CRC. Integration of FTIR Spectroscopy and Machine Learning for Kidney Allograft Rejection: A Complementary Diagnostic Tool. J Clin Med 2025; 14:846. [PMID: 39941517 PMCID: PMC11818318 DOI: 10.3390/jcm14030846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/21/2025] [Accepted: 01/25/2025] [Indexed: 02/16/2025] Open
Abstract
Background: Kidney transplantation is a life-saving treatment for end-stage kidney disease, but allograft rejection remains a critical challenge, requiring accurate and timely diagnosis. The study aims to evaluate the integration of Fourier Transform Infrared (FTIR) spectroscopy and machine learning algorithms as a minimally invasive method to detect kidney allograft rejection and differentiate between T Cell-Mediated Rejection (TCMR) and Antibody-Mediated Rejection (AMR). Additionally, the goal is to discriminate these rejection types aiming to develop a reliable decision-making support tool. Methods: This retrospective study included 41 kidney transplant recipients and analyzed 81 serum samples matched to corresponding allograft biopsies. FTIR spectroscopy was applied to pre-biopsy serum samples, and Naïve Bayes classification models were developed to distinguish rejection from non-rejection and classify rejection types. Data preprocessing involved, e.g., atmospheric compensation, second derivative, and feature selection using Fast Correlation-Based Filter for spectral regions 600-1900 cm-1 and 2800-3400 cm-1. Model performance was assessed via area under the receiver operating characteristic curve (AUC-ROC), sensitivity, specificity, and accuracy. Results: The Naïve Bayes model achieved an AUC-ROC of 0.945 in classifying rejection versus non-rejection and AUC-ROC of 0.989 in distinguishing TCMR from AMR. Feature selection significantly improved model performance, identifying key spectral wavenumbers associated with rejection mechanisms. This approach demonstrated high sensitivity and specificity for both classification tasks. Conclusions: The integration of FTIR spectroscopy with machine learning may provide a promising, minimally invasive method for early detection and precise classification of kidney allograft rejection. Further validation in larger, more diverse populations is needed to confirm these findings' reliability.
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Affiliation(s)
- Luís Ramalhete
- Blood and Transplantation Center of Lisbon, Instituto Português do Sangue e da Transplantação, Alameda das Linhas de Torres, No. 117, 1769-001 Lisbon, Portugal
- NOVA Medical School, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal; (R.A.)
- iNOVA4Health—Advancing Precision Medicine, RG11: Reno-Vascular Diseases Group, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal
| | - Rúben Araújo
- NOVA Medical School, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal; (R.A.)
| | - Miguel Bigotte Vieira
- NOVA Medical School, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal; (R.A.)
- Nephrology Department, Hospital Curry Cabral, Unidade Local de Saúde São José, 1049-001 Lisbon, Portugal
| | - Emanuel Vigia
- NOVA Medical School, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal; (R.A.)
- Centro Hospitalar Universitário de Lisboa Central, Hepatobiliopancreatic and Transplantation Center—Curry Cabral Hospital, 1069-166 Lisbon, Portugal
| | - Inês Aires
- Nephrology Department, Hospital Curry Cabral, Unidade Local de Saúde São José, 1049-001 Lisbon, Portugal
| | - Aníbal Ferreira
- NOVA Medical School, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal; (R.A.)
- Nephrology Department, Hospital Curry Cabral, Unidade Local de Saúde São José, 1049-001 Lisbon, Portugal
| | - Cecília R. C. Calado
- ISEL—Instituto Superior de Engenharia de Lisboa, Instituto Politécnico de Lisboa, R. Conselheiro Emídio Navarro 1, 1959-007 Lisbon, Portugal;
- Institute for Bioengineering and Biosciences (iBB), The Associate Laboratory Institute for Health and Bioeconomy–i4HB, Instituto Superior Técnico (IST), Universidade de Lisboa (UL), Av. Rovisco Pais, 1049-001 Lisbon, Portugal
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6
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Naimimohasses S, Keshavjee S, Wang B, Brudno M, Sidhu A, Bhat M. Proceedings of the 2024 Transplant AI Symposium. FRONTIERS IN TRANSPLANTATION 2024; 3:1399324. [PMID: 39319335 PMCID: PMC11421390 DOI: 10.3389/frtra.2024.1399324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 07/23/2024] [Indexed: 09/26/2024]
Abstract
With recent advancements in deep learning (DL) techniques, the use of artificial intelligence (AI) has become increasingly prevalent in all fields. Currently valued at 9.01 billion USD, it is a rapidly growing market, projected to increase by 40% per annum. There has been great interest in how AI could transform the practice of medicine, with the potential to improve all healthcare spheres from workflow management, accessibility, and cost efficiency to enhanced diagnostics with improved prognostic accuracy, allowing the practice of precision medicine. The applicability of AI is particularly promising for transplant medicine, in which it can help navigate the complex interplay of a myriad of variables and improve patient care. However, caution must be exercised when developing DL models, ensuring they are trained with large, reliable, and diverse datasets to minimize bias and increase generalizability. There must be transparency in the methodology and extensive validation of the model, including randomized controlled trials to demonstrate performance and cultivate trust among physicians and patients. Furthermore, there is a need to regulate this rapidly evolving field, with updated policies for the governance of AI-based technologies. Taking this in consideration, we summarize the latest transplant AI developments from the Ajmera Transplant Center's inaugural symposium.
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Affiliation(s)
- Sara Naimimohasses
- Division of Gastroenterology, Toronto General Hospital, Toronto, ON, Canada
- Ajmera Transplant Center, University Health Network, Toronto, ON, Canada
| | - Shaf Keshavjee
- Department of Innovation, University Health Network, Toronto, ON, Canada
| | - Bo Wang
- Department of Laboratory Medicine and Pathobiology, The Temerty Centre for AI Research and Education in Medicine, Toronto, ON, Canada
| | - Mike Brudno
- Department of Computer Science, University of Toronto, Toronto, ON, Canada
| | - Aman Sidhu
- Division of Gastroenterology, Toronto General Hospital, Toronto, ON, Canada
- Ajmera Transplant Center, University Health Network, Toronto, ON, Canada
| | - Mamatha Bhat
- Division of Gastroenterology, Toronto General Hospital, Toronto, ON, Canada
- Ajmera Transplant Center, University Health Network, Toronto, ON, Canada
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7
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Zhang R, Trotter PB, McCaffrey J, Fitzroy R, Trivioli G, Stewart BJ, Ferdinand JR, Loudon KW, Riding A, West J, Ferro A, Clatworthy MR. Assessment of biological organ age using molecular pathology in pre-transplant kidney biopsies. Kidney Int 2024; 106:302-316. [PMID: 38692408 DOI: 10.1016/j.kint.2024.03.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 01/21/2024] [Accepted: 03/18/2024] [Indexed: 05/03/2024]
Abstract
Organ shortage is a major challenge in kidney transplantation but the use of older donors, often with co-morbidities, is hampered by inconsistent outcomes. Methods of accurately stratifying marginal donor organs by clinical and histological assessment are lacking. To better understand organ variability, we profiled the transcriptomes of 271 kidneys from deceased donors at retrieval. Following correction for biopsy composition, we assessed molecular pathways that associated with delayed, and sub-optimal one-year graft function. Analysis of cortical biopsies identified an adaptive immune gene-rich module that significantly associated with increasing age and worse outcomes. Cellular deconvolution using human kidney reference single cell transcriptomes confirmed an increase in kidney-specific B and T cell signatures, as well as kidney macrophage, myofibroblast and fibroblast gene sets in this module. Surprisingly, innate immune pathway and neutrophil gene signature enrichment was associated with better outcomes. Thus, our work uncovers cellular molecular features of pathological organ ageing, identifiable at kidney retrieval, with translational potential.
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Affiliation(s)
- Roy Zhang
- Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK
| | - Patrick B Trotter
- Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK
| | - James McCaffrey
- Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK; Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Rory Fitzroy
- Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK
| | - Giorgio Trivioli
- Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK
| | - Benjamin J Stewart
- Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK; Cellular Genetics, Wellcome Sanger Institute, Hinxton, UK
| | - John R Ferdinand
- Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK
| | - Kevin W Loudon
- Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK
| | - Alexandra Riding
- Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK
| | - Jonathan West
- Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK
| | - Ashley Ferro
- Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK
| | - Menna R Clatworthy
- Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK; Cellular Genetics, Wellcome Sanger Institute, Hinxton, UK.
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8
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Giarraputo A, Goutaudier V, Robin B, Angelini A, Sablik M, Aubert O, Rosales IA, Smith RN, Roufosse C, Adam B, Haas M, Colvin RB, Lefaucheur C, Mengel M, Zielinski D, Loupy A. Relevance of the Banff Human Organ Transplant Consensus Gene Panel for Detecting Antibody and T-Cell-Mediated Rejection of Kidney Allografts. Kidney Int Rep 2024; 9:2290-2294. [PMID: 39081730 PMCID: PMC11284421 DOI: 10.1016/j.ekir.2024.04.054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 04/23/2024] [Accepted: 04/25/2024] [Indexed: 08/02/2024] Open
Affiliation(s)
- Alessia Giarraputo
- Université de Paris Cité, INSERM U970, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
- Cardiovascular Pathology, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy
| | - Valentin Goutaudier
- Université de Paris Cité, INSERM U970, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
- Kidney Transplant Department, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Blaise Robin
- Université de Paris Cité, INSERM U970, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Annalisa Angelini
- Cardiovascular Pathology, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy
| | - Marta Sablik
- Université de Paris Cité, INSERM U970, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Olivier Aubert
- Université de Paris Cité, INSERM U970, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
- Kidney Transplant Department, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Ivy A. Rosales
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Rex N. Smith
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Candice Roufosse
- Department of Immunology and Inflammation, Imperial College, Center for Inflammatory Disease, London, UK
| | - Benjamin Adam
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
| | - Mark Haas
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Robert B. Colvin
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Carmen Lefaucheur
- Université de Paris Cité, INSERM U970, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
- Kidney Transplant Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Michael Mengel
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
| | - Dina Zielinski
- Université de Paris Cité, INSERM U970, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Alexandre Loupy
- Université de Paris Cité, INSERM U970, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
- Kidney Transplant Department, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
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9
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Salvadori M, Rosati A, Rosso G. Evolving Biomarkers in Kidney Transplantation. TRANSPLANTOLOGY 2024; 5:116-128. [DOI: 10.3390/transplantology5030012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025] Open
Abstract
Precision medicine is mainly based on reliable and noninvasive biomarkers. The aim of this review was to describe the newest biomarkers in the field of kidney transplantation and kidney rejection, one of the most common and severe complications. The standard tools used to identify acute rejection largely result in errors and have many drawbacks. In recent years, new and reliable biomarkers have been identified. These methods avoid risks, are noninvasive, and are able to detect rejection even in cases in which acute rejection is clinically asymptomatic and not otherwise identifiable, which is a frequent occurrence. In recent years, several biomarkers have been identified. Very recently, new relevant biomarkers with high positive predictive value and low negative predictive value have been identified. These are the donor-derived cell-free DNA found in the recipient, the gene expression profile of the donor found in the recipient, and the urinary cytokines that are modified in the graft tissue. The aim of this study was to identify the most recent findings in the literature on this topic and to describe the utility and possible limitations of such new biomarkers for kidney rejection.
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Affiliation(s)
- Maurizio Salvadori
- Department of Renal Transplantation, Careggi University Hospital, Viale Pieraccini 18, 50139 Florence, Italy
| | - Alberto Rosati
- Division of Nephrology, San Giovanni di Dio Hospital, 50143 Florence, Italy
| | - Giuseppina Rosso
- Division of Nephrology, San Giovanni di Dio Hospital, 50143 Florence, Italy
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10
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Xu Y, Wang Y, Zhang D, Zhang H, Wang Y, Wang W, Hu X. An autophagy-associated diagnostic signature based on peripheral blood for antibody-mediated rejection in renal transplantation. Transpl Immunol 2024; 84:102021. [PMID: 38452984 DOI: 10.1016/j.trim.2024.102021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 03/03/2024] [Accepted: 03/03/2024] [Indexed: 03/09/2024]
Abstract
BACKGROUND Antibody-mediated rejection (ABMR) emerged as a major cause of graft loss in renal transplantation. Needle biopsy is the gold standard for diagnosis of ABMR in renal allografts. Thus, noninvasive diagnosis methods of ABMR with high accuracy are urgently needed to prevent unnecessary biopsies. METHODS We collected peripheral blood transcriptome data from two independent renal transplantation cohorts with patients with ABMR, stable well-functioning transplants (STA), and T-cell mediated rejection (TCMR). Differentially expressed genes (DEGs) were identified by comparing the ABMR group with the STA group. In addition, functional enrichment analysis and gene set enrichment analysis were performed to seek new key underlying mechanisms in ABMR. Subsequently, we utilized a Boruta algorithm and least absolute shrinkage and selection operator logistic algorithm to establish a diagnostic model which was then evaluated and validated in an independent cohort. RESULTS According to functional enrichment analysis, autophagy was found to be the primary upregulated biological process in ABMR. Based on algorithms, three autophagy-associated genes, ubiquitin specific peptidase 33 (USP33), Ras homolog mTORC1 binding (RHEB), and ABL proto-oncogene 2 (ABL2), were selected to establish the diagnostic model in the training cohort. This autophagy-related gene model possessed good diagnostic value in distinguishing ABMR from STA blood samples in the training cohort (AUC = 0.907) and in the validation cohort (AUC = 0.972). In addition, this model also showed good discernibility in distinguishing ABMR from TCMR in the training and validation cohorts (AUCs = 0.908 and 0.833). CONCLUSION We identified and validated an autophagy-associated diagnostic model with high accuracy for renal transplant patients with ABMR. Our study provided a new potential test for the non-invasive diagnosis of ABMR in clinical practice and highlighted the importance of autophagy in ABMR.
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Affiliation(s)
- Yue Xu
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Institute of Urology, Capital Medical University, Beijing 100020, China
| | - Yuxuan Wang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Institute of Urology, Capital Medical University, Beijing 100020, China
| | - Di Zhang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Institute of Urology, Capital Medical University, Beijing 100020, China
| | - Hao Zhang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Institute of Urology, Capital Medical University, Beijing 100020, China
| | - Yicun Wang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Institute of Urology, Capital Medical University, Beijing 100020, China
| | - Wei Wang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Institute of Urology, Capital Medical University, Beijing 100020, China
| | - Xiaopeng Hu
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Institute of Urology, Capital Medical University, Beijing 100020, China.
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11
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Goutaudier V, Sablik M, Racapé M, Rousseau O, Audry B, Kamar N, Raynaud M, Aubert O, Charreau B, Papuchon E, Danger R, Letertre L, Couzi L, Morelon E, Le Quintrec M, Taupin JL, Vicaut E, Legendre C, Le Mai H, Potluri V, Nguyen TVH, Azoury ME, Pinheiro A, Nouadje G, Sonigo P, Anglicheau D, Tieken I, Vogelaar S, Jacquelinet C, Reese P, Gourraud PA, Brouard S, Lefaucheur C, Loupy A. Design, cohort profile and comparison of the KTD-Innov study: a prospective multidimensional biomarker validation study in kidney allograft rejection. Eur J Epidemiol 2024; 39:549-564. [PMID: 38625480 DOI: 10.1007/s10654-024-01112-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 03/04/2024] [Indexed: 04/17/2024]
Abstract
There is an unmet need for robust and clinically validated biomarkers of kidney allograft rejection. Here we present the KTD-Innov study (ClinicalTrials.gov, NCT03582436), an unselected deeply phenotyped cohort of kidney transplant recipients with a holistic approach to validate the clinical utility of precision diagnostic biomarkers. In 2018-2019, we prospectively enrolled consecutive adult patients who received a kidney allograft at seven French centers and followed them for a year. We performed multimodal phenotyping at follow-up visits, by collecting clinical, biological, immunological, and histological parameters, and analyzing a panel of 147 blood, urinary and kidney tissue biomarkers. The primary outcome was allograft rejection, assessed at each visit according to the international Banff 2019 classification. We evaluated the representativeness of participants by comparing them with patients from French, European, and American transplant programs transplanted during the same period. A total of 733 kidney transplant recipients (64.1% male and 35.9% female) were included during the study. The median follow-up after transplantation was 12.3 months (interquartile range, 11.9-13.1 months). The cumulative incidence of rejection was 9.7% at one year post-transplant. We developed a distributed and secured data repository in compliance with the general data protection regulation. We established a multimodal biomarker biobank of 16,736 samples, including 9331 blood, 4425 urinary and 2980 kidney tissue samples, managed and secured in a collaborative network involving 7 clinical centers, 4 analytical platforms and 2 industrial partners. Patients' characteristics, immune profiles and treatments closely resembled those of 41,238 French, European and American kidney transplant recipients. The KTD-Innov study is a unique holistic and multidimensional biomarker validation cohort of kidney transplant recipients representative of the real-world transplant population. Future findings from this cohort are likely to be robust and generalizable.
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Affiliation(s)
- Valentin Goutaudier
- Paris Institute for Transplantation and Organ Regeneration (PITOR), INSERM U970, Université Paris Cité, 56 rue Leblanc, 75015, Paris, France
- Department of Kidney Transplantation, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Marta Sablik
- Paris Institute for Transplantation and Organ Regeneration (PITOR), INSERM U970, Université Paris Cité, 56 rue Leblanc, 75015, Paris, France
| | - Maud Racapé
- Paris Institute for Transplantation and Organ Regeneration (PITOR), INSERM U970, Université Paris Cité, 56 rue Leblanc, 75015, Paris, France
| | - Olivia Rousseau
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
- Pôle Hospitalo-Universitaire 11: Santé Publique, Clinique des Données, INSERM, CIC 1413, Nantes Université, CHU Nantes, 44000, Nantes, France
| | - Benoit Audry
- Agence de la Biomédecine, Saint Denis la Plaine, France
| | - Nassim Kamar
- Department of Nephrology-Dialysis-Transplantation, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Marc Raynaud
- Paris Institute for Transplantation and Organ Regeneration (PITOR), INSERM U970, Université Paris Cité, 56 rue Leblanc, 75015, Paris, France
| | - Olivier Aubert
- Paris Institute for Transplantation and Organ Regeneration (PITOR), INSERM U970, Université Paris Cité, 56 rue Leblanc, 75015, Paris, France
- Department of Kidney Transplantation, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Béatrice Charreau
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
| | - Emmanuelle Papuchon
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
| | - Richard Danger
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
| | - Laurence Letertre
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
| | - Lionel Couzi
- Department of Nephrology, Transplantation, Dialysis and Apheresis, CHU Bordeaux, Bordeaux, France
| | - Emmanuel Morelon
- Department of Transplantation, Edouard Herriot University Hospital, Hospices Civils de Lyon, University Lyon, University of Lyon I, Lyon, France
| | - Moglie Le Quintrec
- Department of Nephrology, Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | - Jean-Luc Taupin
- Immunology and Histocompatibility Laboratory, Medical Biology Department, Saint-Louis Hospital, Paris, France
| | - Eric Vicaut
- Clinical Trial Unit Hospital, Lariboisière Saint-Louis AP-HP, Paris Cité University, Paris, France
| | - Christophe Legendre
- Paris Institute for Transplantation and Organ Regeneration (PITOR), INSERM U970, Université Paris Cité, 56 rue Leblanc, 75015, Paris, France
- Department of Kidney Transplantation, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Hoa Le Mai
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
| | - Vishnu Potluri
- Department of Biostatistics, Epidemiology and Bioinformatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Thi-Van-Ha Nguyen
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
| | | | | | | | | | - Dany Anglicheau
- Department of Kidney Transplantation, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
- Université Paris Cité, Inserm U1151, Necker Enfants-Malades Institute, Paris, France
| | - Ineke Tieken
- Eurotransplant International Foundation, Leiden, the Netherlands
| | - Serge Vogelaar
- Eurotransplant International Foundation, Leiden, the Netherlands
| | | | - Peter Reese
- Department of Biostatistics, Epidemiology and Bioinformatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Pierre-Antoine Gourraud
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
- Pôle Hospitalo-Universitaire 11: Santé Publique, Clinique des Données, INSERM, CIC 1413, Nantes Université, CHU Nantes, 44000, Nantes, France
| | - Sophie Brouard
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
| | - Carmen Lefaucheur
- Paris Institute for Transplantation and Organ Regeneration (PITOR), INSERM U970, Université Paris Cité, 56 rue Leblanc, 75015, Paris, France
- Kidney Transplant Department, Saint-Louis Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Alexandre Loupy
- Paris Institute for Transplantation and Organ Regeneration (PITOR), INSERM U970, Université Paris Cité, 56 rue Leblanc, 75015, Paris, France.
- Department of Kidney Transplantation, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.
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12
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Alexander MP, Zaidi M, Larson N, Mullan A, Pavelko KD, Stegall MD, Bentall A, Wouters BG, McKee T, Taner T. Exploring the single-cell immune landscape of kidney allograft inflammation using imaging mass cytometry. Am J Transplant 2024; 24:549-563. [PMID: 37979921 DOI: 10.1016/j.ajt.2023.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 11/01/2023] [Accepted: 11/11/2023] [Indexed: 11/20/2023]
Abstract
Kidney allograft inflammation, mostly attributed to rejection and infection, is an important cause of graft injury and loss. Standard histopathological assessment of allograft inflammation provides limited insights into biological processes and the immune landscape. Here, using imaging mass cytometry with a panel of 28 validated biomarkers, we explored the single-cell landscape of kidney allograft inflammation in 32 kidney transplant biopsies and 247 high-dimensional histopathology images of various phenotypes of allograft inflammation (antibody-mediated rejection, T cell-mediated rejection, BK nephropathy, and chronic pyelonephritis). Using novel analytical tools, for cell segmentation, we segmented over 900 000 cells and developed a tissue-based classifier using over 3000 manually annotated kidney microstructures (glomeruli, tubules, interstitium, and arteries). Using PhenoGraph, we identified 11 immune and 9 nonimmune clusters and found a high prevalence of memory T cell and macrophage-enriched immune populations across phenotypes. Additionally, we trained a machine learning classifier to identify spatial biomarkers that could discriminate between the different allograft inflammatory phenotypes. Further validation of imaging mass cytometry in larger cohorts and with more biomarkers will likely help interrogate kidney allograft inflammation in more depth than has been possible to date.
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Affiliation(s)
- Mariam P Alexander
- Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota, USA.
| | - Mark Zaidi
- Department of Medical Biophysics, University of Toronto, Canada
| | - Nicholas Larson
- Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Aidan Mullan
- Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Kevin D Pavelko
- Immune Monitoring Core Laboratory, Mayo Clinic, Rochester, Minnesota, USA
| | - Mark D Stegall
- Departments of Surgery and Immunology, Mayo Clinic, Rochester, Minnesota, USA
| | - Andrew Bentall
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Bradly G Wouters
- Department of Medical Biophysics, University of Toronto, Canada; Princess Margaret Cancer Center, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Trevor McKee
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Pathomics Inc., Toronto, Ontario, Canada
| | - Timucin Taner
- Departments of Surgery and Immunology, Mayo Clinic, Rochester, Minnesota, USA
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13
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Santacroce E, D’Angerio M, Ciobanu AL, Masini L, Lo Tartaro D, Coloretti I, Busani S, Rubio I, Meschiari M, Franceschini E, Mussini C, Girardis M, Gibellini L, Cossarizza A, De Biasi S. Advances and Challenges in Sepsis Management: Modern Tools and Future Directions. Cells 2024; 13:439. [PMID: 38474403 PMCID: PMC10931424 DOI: 10.3390/cells13050439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 02/27/2024] [Accepted: 02/29/2024] [Indexed: 03/14/2024] Open
Abstract
Sepsis, a critical condition marked by systemic inflammation, profoundly impacts both innate and adaptive immunity, often resulting in lymphopenia. This immune alteration can spare regulatory T cells (Tregs) but significantly affects other lymphocyte subsets, leading to diminished effector functions, altered cytokine profiles, and metabolic changes. The complexity of sepsis stems not only from its pathophysiology but also from the heterogeneity of patient responses, posing significant challenges in developing universally effective therapies. This review emphasizes the importance of phenotyping in sepsis to enhance patient-specific diagnostic and therapeutic strategies. Phenotyping immune cells, which categorizes patients based on clinical and immunological characteristics, is pivotal for tailoring treatment approaches. Flow cytometry emerges as a crucial tool in this endeavor, offering rapid, low cost and detailed analysis of immune cell populations and their functional states. Indeed, this technology facilitates the understanding of immune dysfunctions in sepsis and contributes to the identification of novel biomarkers. Our review underscores the potential of integrating flow cytometry with omics data, machine learning and clinical observations to refine sepsis management, highlighting the shift towards personalized medicine in critical care. This approach could lead to more precise interventions, improving outcomes in this heterogeneously affected patient population.
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Affiliation(s)
- Elena Santacroce
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy; (E.S.); (M.D.); (A.L.C.); (L.M.); (D.L.T.); (L.G.); (A.C.)
| | - Miriam D’Angerio
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy; (E.S.); (M.D.); (A.L.C.); (L.M.); (D.L.T.); (L.G.); (A.C.)
| | - Alin Liviu Ciobanu
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy; (E.S.); (M.D.); (A.L.C.); (L.M.); (D.L.T.); (L.G.); (A.C.)
| | - Linda Masini
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy; (E.S.); (M.D.); (A.L.C.); (L.M.); (D.L.T.); (L.G.); (A.C.)
| | - Domenico Lo Tartaro
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy; (E.S.); (M.D.); (A.L.C.); (L.M.); (D.L.T.); (L.G.); (A.C.)
| | - Irene Coloretti
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy; (I.C.); (S.B.); (M.M.); (E.F.); (C.M.); (M.G.)
| | - Stefano Busani
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy; (I.C.); (S.B.); (M.M.); (E.F.); (C.M.); (M.G.)
| | - Ignacio Rubio
- Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany;
| | - Marianna Meschiari
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy; (I.C.); (S.B.); (M.M.); (E.F.); (C.M.); (M.G.)
| | - Erica Franceschini
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy; (I.C.); (S.B.); (M.M.); (E.F.); (C.M.); (M.G.)
| | - Cristina Mussini
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy; (I.C.); (S.B.); (M.M.); (E.F.); (C.M.); (M.G.)
| | - Massimo Girardis
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy; (I.C.); (S.B.); (M.M.); (E.F.); (C.M.); (M.G.)
| | - Lara Gibellini
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy; (E.S.); (M.D.); (A.L.C.); (L.M.); (D.L.T.); (L.G.); (A.C.)
| | - Andrea Cossarizza
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy; (E.S.); (M.D.); (A.L.C.); (L.M.); (D.L.T.); (L.G.); (A.C.)
| | - Sara De Biasi
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy; (E.S.); (M.D.); (A.L.C.); (L.M.); (D.L.T.); (L.G.); (A.C.)
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14
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Mubarak M, Raza A, Rashid R, Shakeel S. Evolution of human kidney allograft pathology diagnostics through 30 years of the Banff classification process. World J Transplant 2023; 13:221-238. [PMID: 37746037 PMCID: PMC10514746 DOI: 10.5500/wjt.v13.i5.221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 06/05/2023] [Accepted: 06/12/2023] [Indexed: 09/15/2023] Open
Abstract
The second half of the previous century witnessed a tremendous rise in the number of clinical kidney transplants worldwide. This activity was, however, accompanied by many issues and challenges. An accurate diagnosis and appropriate management of causes of graft dysfunction were and still are, a big challenge. Kidney allograft biopsy played a vital role in addressing the above challenge. However, its interpretation was not standardized for many years until, in 1991, the Banff process was started to fill this void. Thereafter, regular Banff meetings took place every 2 years for the past 30 years. Marked changes have taken place in the interpretation of kidney allograft biopsies, diagnosis, and classification of rejection and other non-rejection pathologies from the original Banff 93 classification. This review attempts to summarize those changes for increasing the awareness and understanding of kidney allograft pathology through the eyes of the Banff process. It will interest the transplant surgeons, physicians, pathologists, and allied professionals associated with the care of kidney transplant patients.
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Affiliation(s)
- Muhammed Mubarak
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Amber Raza
- Department of Nephrology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Rahma Rashid
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Shaheera Shakeel
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
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15
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Beadle J, Papadaki A, Toulza F, Santos E, Willicombe M, McLean A, Peters J, Roufosse C. Application of the Banff Human Organ Transplant Panel to kidney transplant biopsies with features suspicious for antibody-mediated rejection. Kidney Int 2023; 104:526-541. [PMID: 37172690 DOI: 10.1016/j.kint.2023.04.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 03/07/2023] [Accepted: 04/14/2023] [Indexed: 05/15/2023]
Abstract
The Banff Classification for Allograft Pathology includes the use of gene expression in the diagnosis of antibody-mediated rejection (AMR) of kidney transplants, but a predictive set of genes for classifying biopsies with 'incomplete' phenotypes has not yet been studied. Here, we developed and assessed a gene score that, when applied to biopsies with features of AMR, would identify cases with a higher risk of allograft loss. To do this, RNA was extracted from a continuous retrospective cohort of 349 biopsies randomized 2:1 to include 220 biopsies in a discovery cohort and 129 biopsies in a validation cohort. The biopsies were divided into three groups: 31 that fulfilled the 2019 Banff Criteria for active AMR, 50 with histological features of AMR but not meeting the full criteria (Suspicious-AMR), and 269 with no features of active AMR (No-AMR). Gene expression analysis using the 770 gene Banff Human Organ Transplant NanoString panel was carried out with LASSO Regression performed to identify a parsimonious set of genes predictive of AMR. We identified a nine gene score that was highly predictive of active AMR (accuracy 0.92 in the validation cohort) and was strongly correlated with histological features of AMR. In biopsies suspicious for AMR, our gene score was strongly associated with risk of allograft loss and independently associated with allograft loss in multivariable analysis. Thus, we show that a gene expression signature in kidney allograft biopsy samples can help classify biopsies with incomplete AMR phenotypes into groups that correlate strongly with histological features and outcomes.
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Affiliation(s)
- Jack Beadle
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK; Imperial College Renal and Transplant Centre, Imperial College NHS Trust, London, UK.
| | - Artemis Papadaki
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK
| | - Frederic Toulza
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK
| | - Eva Santos
- H&I Laboratory, North West London Pathology, London, UK
| | - Michelle Willicombe
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK; Imperial College Renal and Transplant Centre, Imperial College NHS Trust, London, UK
| | - Adam McLean
- Imperial College Renal and Transplant Centre, Imperial College NHS Trust, London, UK
| | - James Peters
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK
| | - Candice Roufosse
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK; Department of Cellular Pathology, North West London Pathology, London, UK
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16
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van den Broek DAJ, Meziyerh S, Budde K, Lefaucheur C, Cozzi E, Bertrand D, López del Moral C, Dorling A, Emonds MP, Naesens M, de Vries APJ, the ESOT Working Group Subclinical DSA Monitoring. The Clinical Utility of Post-Transplant Monitoring of Donor-Specific Antibodies in Stable Renal Transplant Recipients: A Consensus Report With Guideline Statements for Clinical Practice. Transpl Int 2023; 36:11321. [PMID: 37560072 PMCID: PMC10408721 DOI: 10.3389/ti.2023.11321] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 06/22/2023] [Indexed: 08/11/2023]
Abstract
Solid phase immunoassays improved the detection and determination of the antigen-specificity of donor-specific antibodies (DSA) to human leukocyte antigens (HLA). The widespread use of SPI in kidney transplantation also introduced new clinical dilemmas, such as whether patients should be monitored for DSA pre- or post-transplantation. Pretransplant screening through SPI has become standard practice and DSA are readily determined in case of suspected rejection. However, DSA monitoring in recipients with stable graft function has not been universally established as standard of care. This may be related to uncertainty regarding the clinical utility of DSA monitoring as a screening tool. This consensus report aims to appraise the clinical utility of DSA monitoring in recipients without overt signs of graft dysfunction, using the Wilson & Junger criteria for assessing the validity of a screening practice. To assess the evidence on DSA monitoring, the European Society for Organ Transplantation (ESOT) convened a dedicated workgroup, comprised of experts in transplantation nephrology and immunology, to review relevant literature. Guidelines and statements were developed during a consensus conference by Delphi methodology that took place in person in November 2022 in Prague. The findings and recommendations of the workgroup on subclinical DSA monitoring are presented in this article.
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Affiliation(s)
- Dennis A. J. van den Broek
- Division of Nephrology, Department of Medicine, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands
| | - Soufian Meziyerh
- Division of Nephrology, Department of Medicine, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Carmen Lefaucheur
- Paris Translational Research Center for Organ Transplantation, Kidney Transplant Department, Saint Louis Hospital, Université de Paris Cité, Paris, France
| | - Emanuele Cozzi
- Department of Cardiac, Thoracic and Vascular Sciences and Public Health, Transplant Immunology Unit, Padua University Hospital, Padua, Italy
| | - Dominique Bertrand
- Department of Nephrology, Transplantation and Hemodialysis, Rouen University Hospital, Rouen, France
| | - Covadonga López del Moral
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
- Valdecilla Biomedical Research Institute (IDIVAL), Santander, Spain
| | - Anthony Dorling
- Department of Inflammation Biology, Centre for Nephrology, Urology and Transplantation, School of Immunology & Microbial Sciences, King’s College London, Guy’s Hospital, London, United Kingdom
| | - Marie-Paule Emonds
- Histocompatibility and Immunogenetics Laboratory (HILA), Belgian Red Cross-Flanders, Mechelen, Belgium
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Aiko P. J. de Vries
- Division of Nephrology, Department of Medicine, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands
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Clinical recommendations for posttransplant assessment of anti-HLA (Human Leukocyte Antigen) donor-specific antibodies: A Sensitization in Transplantation: Assessment of Risk consensus document. Am J Transplant 2023; 23:115-132. [PMID: 36695614 DOI: 10.1016/j.ajt.2022.11.013] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/29/2022] [Accepted: 11/04/2022] [Indexed: 01/13/2023]
Abstract
Although anti-HLA (Human Leukocyte Antigen) donor-specific antibodies (DSAs) are commonly measured in clinical practice and their relationship with transplant outcome is well established, clinical recommendations for anti-HLA antibody assessment are sparse. Supported by a careful and critical review of the current literature performed by the Sensitization in Transplantation: Assessment of Risk 2022 working group, this consensus report provides clinical practice recommendations in kidney, heart, lung, and liver transplantation based on expert assessment of quality and strength of evidence. The recommendations address 3 major clinical problems in transplantation and include guidance regarding posttransplant DSA assessment and application to diagnostics, prognostics, and therapeutics: (1) the clinical implications of positive posttransplant DSA detection according to DSA status (ie, preformed or de novo), (2) the relevance of posttransplant DSA assessment for precision diagnosis of antibody-mediated rejection and for treatment management, and (3) the relevance of posttransplant DSA for allograft prognosis and risk stratification. This consensus report also highlights gaps in current knowledge and provides directions for clinical investigations and trials in the future that will further refine the clinical utility of posttransplant DSA assessment, leading to improved transplant management and patient care.
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18
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Unraveling complexity of antibody-mediated rejections, the mandatory way towards an accurate diagnosis and a personalized treatment. Presse Med 2022; 51:104141. [PMID: 36209931 DOI: 10.1016/j.lpm.2022.104141] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 09/29/2022] [Indexed: 11/09/2022] Open
Abstract
Antibody-mediated rejection (ABMR) remains one of the most challenging issues after organ transplantation and particularly after kidney transplantation. Despite many progresses during the last decade, ABMR is still the main cause of kidney graft loss and this all over the post- transplant period. In this review, we describe the recent knowledge about molecular and cellular mechanisms involved in ABMR. We focused our report on the role of the complement pathway in the process of ABMR and we give some insights into the role of inflammatory cells, NK lymphocytes and the role of endothelial cells. We further describe the potential role of non-HLA antibodies, of which the importance has been increasingly emphasized in recent years. Overall, this report could be of interest for all physicians who are working in the field of organ transplantation or who are working in the field of immunology. It gives essential information to understand new diagnosis advances and further therapeutic approaches. Antibody-mediated rejection (ABMR) is the leading cause of graft failure ([1,2]). In contrast to T-cell mediated rejection usually sensitive to steroids, active ABMR remains a therapeutic challenge. ABMR diagnosis relies on the presence of renal injuries and donor-specific antibodies (DSA) (HLA and non HLA antibodies) with sometimes the evidence of interaction between DSA and graft endothelium. Regularly revised during expert conferences, ABMR definition is currently categorized as active or chronic active. [3] The emergence of validated molecular assays targeting a better phenotyping of ABMR and the recent advances regarding the detrimental effect of DSA directed against minor antigens open the way to a better assessment of the heterogeneity of ABMR. In this review, we will address new aspects of ABMR regarding its mechanisms, diagnosis and treatments.
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19
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Rosales IA, Mahowald GK, Tomaszewski K, Hotta K, Iwahara N, Otsuka T, Tsuji T, Takada Y, Acheampong E, Araujo-Medina M, Bruce A, Rios A, Cosimi AB, Elias N, Kawai T, Gilligan H, Safa K, Riella LV, Tolkoff-Rubin NE, Williams WW, Smith RN, Colvin RB. Banff Human Organ Transplant Transcripts Correlate with Renal Allograft Pathology and Outcome: Importance of Capillaritis and Subpathologic Rejection. J Am Soc Nephrol 2022; 33:2306-2319. [PMID: 36450597 PMCID: PMC9731628 DOI: 10.1681/asn.2022040444] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 07/19/2022] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND To seek insights into the pathogenesis of chronic active antibody-mediated rejection (CAMR), we performed mRNA analysis and correlated transcripts with pathologic component scores and graft outcomes. METHODS We utilized the NanoString nCounter platform and the Banff Human Organ Transplant gene panel to quantify transcripts on 326 archived renal allograft biopsy samples. This system allowed correlation of transcripts with Banff pathology scores from the same tissue block and correlation with long-term outcomes. RESULTS The only pathology score that correlated with AMR pathways in CAMR was peritubular capillaritis (ptc). C4d, cg, g, v, i, t, or ci scores did not correlate. DSA-negative CAMR had lower AMR pathway scores than DSA-positive CAMR. Transcript analysis in non-CAMR biopsies yielded evidence of increased risk of later CAMR. Among 108 patients without histologic CAMR, 23 developed overt biopsy-documented CAMR within 5 years and as a group had higher AMR pathway scores (P=3.4 × 10-5). Random forest analysis correlated 3-year graft loss with elevated damage, innate immunity, and macrophage pathway scores in CAMR and TCMR. Graft failure in CAMR was associated with TCMR transcripts but not with AMR transcripts, and graft failure in TCMR was associated with AMR transcripts but not with TCMR transcripts. CONCLUSIONS Peritubular capillary inflammation and DSA are the primary drivers of AMR transcript elevation. Transcripts revealed subpathological evidence of AMR, which often preceded histologic CAMR and subpathological evidence of TCMR that predicted graft loss in CAMR.
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Affiliation(s)
- Ivy A. Rosales
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Grace K. Mahowald
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Kristen Tomaszewski
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Kiyohiko Hotta
- Department of Urology, Hokkaido University Hospital, Hokkaido, Japan
| | - Naoya Iwahara
- Department of Urology, Hokkaido University Hospital, Hokkaido, Japan
| | - Takuya Otsuka
- Department of Surgical Pathology, Hokkaido University Hospital, Hokkaido, Japan
| | - Takahiro Tsuji
- Department of Pathology, Sapporo City General Hospital, Hokkaido, Japan
| | - Yusuke Takada
- Department of Kidney Transplant Surgery, Sapporo City General Hospital, Hokkaido, Japan
| | - Ellen Acheampong
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Milagros Araujo-Medina
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Amy Bruce
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Andrea Rios
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Anthony Benedict Cosimi
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Nahel Elias
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Tatsuo Kawai
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Hannah Gilligan
- Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Kassem Safa
- Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Leonardo V. Riella
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Nina E. Tolkoff-Rubin
- Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Winfred W. Williams
- Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Rex Neal Smith
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Robert B. Colvin
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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20
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Zanza C, Caputo G, Tornatore G, Romenskaya T, Piccioni A, Franceschi F, Artico M, Taurone S, Savioli G, Longhitano Y. Cellular Immuno-Profile in Septic Human Host: A Scoping Review. BIOLOGY 2022; 11:1626. [PMID: 36358327 PMCID: PMC9687154 DOI: 10.3390/biology11111626] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/01/2022] [Accepted: 11/02/2022] [Indexed: 11/09/2022]
Abstract
Innate and adaptive immune system cells play a critical role in the host response to sepsis. Sepsis is a life-threatening disease characterized by apoptosis-induced depletion of immune cells and immunodepression, which contribute to morbidity and mortality. Many alterations in the expression of surface markers of neutrophils and monocytes have been described in septic patients. The aim of this study was to inspect the recently published literature to inform the clinician about the most up-to-date techniques for the study of circulating leukocytes. The impact on cell phenotypes and on the function of leukocytes of extracorporeal and non-blood purification treatments proposed for sepsis were also analyzed. We conducted a systematic review using Pubmed/Medline, Ovid/Willey, the Cochrane Library, the Cochrane Controlled Trials Register, and EMBASE, combining key terms related to immunological function in sepsis and selected the most relevant clinical trials and review articles (excluding case reports) published in the last 50 years. The most important alteration in neutrophils during sepsis is that they activate an anti-apoptotic survival program. In septic monocytes, a reduced characteristic expression of HLA-DR is observed, but their role does not seem to be significantly altered in sepsis. As regards adaptive immunity, sepsis leads to lymphopenia and immunosuppression in patients with septic shock; this process involves all types of T cells (CD4, CD8 and Natural Killer), except for regulatory T cells, which retain their function. Several promising therapies that target the host immune response are currently under evaluation. During the worldwide pandemic caused by SARS-CoV-2, it was useful to study the "cytokine storm" to find additional treatments, such as the oXiris® filter. This therapy can decrease the concentration of inflammatory markers that affect the severity of the disease.
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Affiliation(s)
- Christian Zanza
- Foundation “Ospedale Alba e Bra”, Department of Emergency Medicine, Anesthesia and Critical Care Medicine, Michele and Pietro Ferrero Hospital, 12060 Verduno, Italy
- Department of Emergency Medicine, Policlinico Gemelli-RCCS-Catholic University of Sacred Heart, 00168 Rome, Italy
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio Hospital, 15121 Alessandria, Italy
| | - Giorgia Caputo
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio Hospital, 15121 Alessandria, Italy
| | - Gilda Tornatore
- Department of Anesthesia and Intensive Care Medicine, University of Milan-Bicocca, 20126 Milan, Italy
| | - Tatsiana Romenskaya
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio Hospital, 15121 Alessandria, Italy
| | - Andrea Piccioni
- Department of Emergency Medicine, Policlinico Gemelli-RCCS-Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Francesco Franceschi
- Department of Emergency Medicine, Policlinico Gemelli-RCCS-Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Marco Artico
- Department of Sensory Organs, Policlinico Umberto I, Sapienza University of Rome, 00185 Rome, Italy
| | - Samanta Taurone
- Department of Movement, Human and Health Sciences—Division of Health Sciences, University of Rome “Foro Italico”, 00135 Rome, Italy
| | - Gabriele Savioli
- Department of Emergency Medicine, Polyclinic IRCCS S. Matteo, University of Pavia, 27100 Pavia, Italy
| | - Yaroslava Longhitano
- Foundation “Ospedale Alba e Bra”, Department of Emergency Medicine, Anesthesia and Critical Care Medicine, Michele and Pietro Ferrero Hospital, 12060 Verduno, Italy
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio Hospital, 15121 Alessandria, Italy
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21
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Roufosse C, Becker JU, Rabant M, Seron D, Bellini MI, Böhmig GA, Budde K, Diekmann F, Glotz D, Hilbrands L, Loupy A, Oberbauer R, Pengel L, Schneeberger S, Naesens M. Proposed Definitions of Antibody-Mediated Rejection for Use as a Clinical Trial Endpoint in Kidney Transplantation. Transpl Int 2022; 35:10140. [PMID: 35669973 PMCID: PMC9163810 DOI: 10.3389/ti.2022.10140] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 03/03/2022] [Indexed: 12/15/2022]
Abstract
Antibody-mediated rejection (AMR) is caused by antibodies that recognize donor human leukocyte antigen (HLA) or other targets. As knowledge of AMR pathophysiology has increased, a combination of factors is necessary to confirm the diagnosis and phenotype. However, frequent modifications to the AMR definition have made it difficult to compare data and evaluate associations between AMR and graft outcome. The present paper was developed following a Broad Scientific Advice request from the European Society for Organ Transplantation (ESOT) to the European Medicines Agency (EMA), which explored whether updating guidelines on clinical trial endpoints would encourage innovations in kidney transplantation research. ESOT considers that an AMR diagnosis must be based on a combination of histopathological factors and presence of donor-specific HLA antibodies in the recipient. Evidence for associations between individual features of AMR and impaired graft outcome is noted for microvascular inflammation scores ≥2 and glomerular basement membrane splitting of >10% of the entire tuft in the most severely affected glomerulus. Together, these should form the basis for AMR-related endpoints in clinical trials of kidney transplantation, although modifications and restrictions to the Banff diagnostic definition of AMR are proposed for this purpose. The EMA provided recommendations based on this Broad Scientific Advice request in December 2020; further discussion, and consensus on the restricted definition of the AMR endpoint, is required.
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Affiliation(s)
- Candice Roufosse
- Department of Immunology and Inflammation, Centre for Inflammatory Disease, Imperial College London, London, United Kingdom
| | - Jan Ulrich Becker
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Marion Rabant
- Department of Pathology, Hôpital Necker-Enfants Malades, Paris, France
| | - Daniel Seron
- Department of Nephrology and Kidney Transplantation, Vall d'Hebrón University Hospital, Barcelona, Spain
| | | | - Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Fritz Diekmann
- Department of Nephrology and Kidney Transplantation, Hospital Clinic Barcelona, Barcelona, Spain
| | - Denis Glotz
- Paris Translational Research Center for Organ Transplantation, Hôpital Saint Louis, Paris, France
| | - Luuk Hilbrands
- Department of Nephrology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Alexandre Loupy
- Paris Translational Research Center for Organ Transplantation, Hôpital Necker, Paris, France
| | - Rainer Oberbauer
- Division of Nephrology and Dialysis, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - Liset Pengel
- Centre for Evidence in Transplantation, University of Oxford, Oxford, United Kingdom
| | - Stefan Schneeberger
- Department of General, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
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22
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Van Loon E, Lamarthée B, Barba T, Claes S, Coemans M, de Loor H, Emonds MP, Koshy P, Kuypers D, Proost P, Senev A, Sprangers B, Tinel C, Thaunat O, Van Craenenbroeck AH, Schols D, Naesens M. Circulating Donor-Specific Anti-HLA Antibodies Associate With Immune Activation Independent of Kidney Transplant Histopathological Findings. Front Immunol 2022; 13:818569. [PMID: 35281018 PMCID: PMC8904423 DOI: 10.3389/fimmu.2022.818569] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 01/10/2022] [Indexed: 12/17/2022] Open
Abstract
Despite the critical role of cytokines in allograft rejection, the relation of peripheral blood cytokine profiles to clinical kidney transplant rejection has not been fully elucidated. We assessed 28 cytokines through multiplex assay in 293 blood samples from kidney transplant recipients at time of graft dysfunction. Unsupervised hierarchical clustering identified a subset of patients with increased pro-inflammatory cytokine levels. This patient subset was hallmarked by a high prevalence (75%) of donor-specific anti-human leukocyte antigen antibodies (HLA-DSA) and histological rejection (70%) and had worse graft survival compared to the group with low cytokine levels (HLA-DSA in 1.7% and rejection in 33.7%). Thirty percent of patients with high pro-inflammatory cytokine levels and HLA-DSA did not have histological rejection. Exploring the cellular origin of these cytokines, we found a corresponding expression in endothelial cells, monocytes, and natural killer cells in single-cell RNASeq data from kidney transplant biopsies. Finally, we confirmed secretion of these cytokines in HLA-DSA-mediated cross talk between endothelial cells, NK cells, and monocytes. In conclusion, blood pro-inflammatory cytokines are increased in kidney transplant patients with HLA-DSA, even in the absence of histology of rejection. These observations challenge the concept that histology is the gold standard for identification of ongoing allo-immune activation after transplantation.
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Affiliation(s)
- Elisabet Van Loon
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Baptiste Lamarthée
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Thomas Barba
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital Lyon, Hospices Civils de Lyon, Lyon, France
| | - Sandra Claes
- Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Maarten Coemans
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Leuven Biostatistics and Statistical Bioinformatics Centre, Department of Public Health and Primary Care, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Henriette de Loor
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Marie-Paule Emonds
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Histocompatibility and Immunogenetics Laboratory, Red Cross-Flanders, Mechelen, Belgium
| | - Priyanka Koshy
- Department of Imaging and Pathology, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Dirk Kuypers
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Paul Proost
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Aleksandar Senev
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Histocompatibility and Immunogenetics Laboratory, Red Cross-Flanders, Mechelen, Belgium
| | - Ben Sprangers
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium.,Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Claire Tinel
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Olivier Thaunat
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital Lyon, Hospices Civils de Lyon, Lyon, France
| | - Amaryllis H Van Craenenbroeck
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Dominique Schols
- Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
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23
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Sazpinar O, Gaspert A, Sidler D, Rechsteiner M, Mueller TF. Histologic and Molecular Patterns in Responders and Non-responders With Chronic-Active Antibody-Mediated Rejection in Kidney Transplants. Front Med (Lausanne) 2022; 9:820085. [PMID: 35573002 PMCID: PMC9099145 DOI: 10.3389/fmed.2022.820085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 04/05/2022] [Indexed: 11/13/2022] Open
Abstract
IntroductionThere is no proven therapy for chronic-active antibody-mediated rejection (caABMR), the major cause of late kidney allograft failure. Histological and molecular patterns associated with possible therapy responsiveness are not known.MethodsBased on rigorous selection criteria this single center, retrospective study identified 16 out of 1027 consecutive kidney transplant biopsies taken between 2008 and 2016 with pure, unquestionable caABMR, without other pathologic features. The change in estimated GFR pre- and post-biopsy/treatment were utilized to differentiate subjects into responders and non-responders. Gene sets reflecting active immune processes of caABMR were defined a priori, including endothelial, inflammatory, cellular, interferon gamma (IFNg) and calcineurin inhibitor (CNI) related-genes based on the literature. Transcript measurements were performed in RNA extracted from stored, formalin-fixed, paraffin-embedded (FFPE) samples using NanoString™ technology. Histology and gene expression patterns of responders and non-responders were compared.ResultsA reductionist approach applying very tight criteria to identify caABMR and treatment response excluded the vast majority of clinical ABMR cases. Only 16 out of 139 cases with a written diagnosis of chronic rejection fulfilled the caABMR criteria. Histological associations with therapy response included a lower peritubular capillaritis score (p = 0.028) along with less glomerulitis. In contrast, no single gene discriminated responders from non-responders. Activated genes associated with NK cells and endothelial cells suggested lack of treatment response.ConclusionIn caABMR active microvascular injury, in particular peritubular capillaritis, differentiates treatment responders from non-responders. Transcriptome changes in NK cell and endothelial cell associated genes may further help to identify treatment response. Future prospective studies will be needed which include more subjects, who receive standardized treatment protocols to identify biomarkers for treatment response.Clinical Trial Registration[ClinicalTrials.gov], identifier [NCT03430414].
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Affiliation(s)
- Onur Sazpinar
- Clinic of Nephrology, Department of Medicine, University Hospital Zürich, Zurich, Switzerland
| | - Ariana Gaspert
- Department of Pathology and Molecular Pathology, University Hospital Zürich, Zurich, Switzerland
| | - Daniel Sidler
- Department of Nephrology and Hypertension, University Hospital Bern, Bern, Switzerland
| | - Markus Rechsteiner
- Department of Pathology and Molecular Pathology, University Hospital Zürich, Zurich, Switzerland
| | - Thomas F. Mueller
- Clinic of Nephrology, Department of Medicine, University Hospital Zürich, Zurich, Switzerland
- *Correspondence: Thomas F. Mueller,
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Westphal SG, Mannon RB. Emerging biomarkers in kidney transplantation and challenge of clinical implementation. Curr Opin Organ Transplant 2022; 27:15-21. [PMID: 34939960 DOI: 10.1097/mot.0000000000000941] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
PURPOSE OF REVIEW Despite improvement in short-term outcomes after kidney transplantation, long-term outcomes remain suboptimal. Conventional biomarkers are limited in their ability to reliably identify early immunologic and nonimmunologic injury. Novel biomarkers are needed for noninvasive diagnosis of subclinical injury, prediction of response to treatment, and personalization of the care of kidney transplant recipients. RECENT FINDINGS Recent biotechnological advances have led to the discovery of promising molecular biomarker candidates. However, translating potential biomarkers from bench to clinic is challenging, and many potential biomarkers are abandoned prior to clinical implementation. Despite these challenges, several promising urine, blood, and tissue novel molecular biomarkers have emerged and are approaching incorporation into clinical practice. SUMMARY This article highlights the challenges in adopting biomarker-driven posttransplant management and reviews several promising emerging novel biomarkers that are approaching clinical implementation.
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Affiliation(s)
- Scott G Westphal
- Division of Nephrology, Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
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25
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Gowrishankar S. Banff classification from 1991 to 2019. A significant contribution to our understanding and reporting of allograft renal biopsies. Indian J Nephrol 2022; 32:1-7. [PMID: 35283563 PMCID: PMC8916159 DOI: 10.4103/ijn.ijn_270_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 09/04/2020] [Accepted: 10/09/2020] [Indexed: 11/05/2022] Open
Abstract
The Banff schema of classification of renal allograft biopsies, first proposed at the meeting in Banff, Canada in 1991 has evolved through subsequent meetings held once in two years and is the internationally accepted scheme of classification which is consensual, current, validated and in clinical use. This review traces the evolution of the classification and our understanding of renal transplant pathology, with emphasis on alloimmune reactions. The proceedings of the meetings and the important studies which have shaped the classification are covered.
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Halloran PF, Einecke G, Sikosana MLN, Madill-Thomsen K. The Biology and Molecular Basis of Organ Transplant Rejection. Handb Exp Pharmacol 2022; 272:1-26. [PMID: 35091823 DOI: 10.1007/164_2021_557] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Allograft rejection is defined as tissue injury in a transplanted allogeneic organ produced by the effector mechanisms of the adaptive alloimmune response. Effector T lymphocytes and IgG alloantibodies cause two different types of rejection that can occur either individually or simultaneously: T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). In TCMR, cognate effector T cells infiltrate the graft and orchestrate an interstitial inflammatory response in the kidney interstitium in which effector T cells engage antigen-presenting myeloid cells, activating the T cells, antigen-presenting cells, and macrophages. The result is intense expression of IFNG and IFNG-induced molecules, expression of effector T cell molecules and macrophage molecules and checkpoints, and deterioration of parenchymal function. The diagnostic lesions of TCMR follow, i.e. interstitial inflammation, parenchymal deterioration, and intimal arteritis. In ABMR, HLA IgG alloantibodies produced by plasma cells bind to the donor antigens on graft microcirculation, leading to complement activation, margination, and activation of NK cells and neutrophils and monocytes, and endothelial injury, sometimes with intimal arteritis. TCMR becomes infrequent after 5-10 years post-transplant, probably reflecting adaptive mechanisms such as checkpoints, but ABMR can present even decades post-transplant. Some rejection is triggered by inadequate immunosuppression and non-adherence, challenging the clinician to target effective immunosuppression even decades post-transplant.
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Affiliation(s)
- Philip F Halloran
- Division of Nephrology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
| | - Gunilla Einecke
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Majid L N Sikosana
- Division of Nephrology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
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27
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Yatim KM, Azzi JR. Novel Biomarkers in Kidney Transplantation. Semin Nephrol 2022; 42:2-13. [DOI: 10.1016/j.semnephrol.2022.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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28
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Loupy A, Mengel M, Haas M. 30 years of the International Banff Classification for Allograft Pathology: The Past, Present and Future of Kidney Transplant Diagnostics. Kidney Int 2021; 101:678-691. [DOI: 10.1016/j.kint.2021.11.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/06/2021] [Accepted: 11/05/2021] [Indexed: 10/19/2022]
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Khilnani C, Heeger PS. Two Can Be Better Than One: Improving Noninvasive Diagnostics in Kidney Transplantation. Clin J Am Soc Nephrol 2021; 16:1462-1463. [PMID: 34620644 PMCID: PMC8499010 DOI: 10.2215/cjn.10630821] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Calla Khilnani
- Renal Division, Department of Medicine, Translational Transplant Research Center and Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Peter S. Heeger
- Renal Division, Department of Medicine, Translational Transplant Research Center and Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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30
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Buscher K, Heitplatz B, van Marck V, Song J, Loismann S, Rixen R, Hüchtmann B, Kurian S, Ehinger E, Wolf D, Ley K, Pavenstädt H, Reuter S. Data-Driven Kidney Transplant Phenotyping as a Histology-Independent Framework for Biomarker Discovery. J Am Soc Nephrol 2021; 32:1933-1945. [PMID: 34078665 PMCID: PMC8455252 DOI: 10.1681/asn.2020121685] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 03/15/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND In transplant medicine, clinical decision making largely relies on histology of biopsy specimens. However, histology suffers from low specificity, sensitivity, and reproducibility, leading to suboptimal stratification of patients. We developed a histology-independent immune framework of kidney graft homeostasis and rejection. METHODS We applied tailored RNA deconvolution for leukocyte enumeration and coregulated gene network analysis to published bulk human kidney transplant RNA transcriptomes as input for unsupervised, high-dimensional phenotype clustering. We used framework-based graft survival analysis to identify a biomarker that was subsequently characterized in independent transplant biopsy specimens. RESULTS We found seven immune phenotypes that confirm known rejection types and uncovered novel signatures. The molecular phenotypes allow for improved graft survival analysis compared with histology, and identify a high-risk group in nonrejecting transplants. Two fibrosis-related phenotypes with distinct immune features emerged with reduced graft survival. We identified lysyl oxidase-like 2 (LOXL2)-expressing peritubular CD68+ macrophages as a framework-derived biomarker of impaired allograft function. These cells precede graft fibrosis, as demonstrated in longitudinal biopsy specimens, and may be clinically useful as a biomarker for early fibrogenesis. CONCLUSIONS This study provides a comprehensive, data-driven atlas of human kidney transplant phenotypes and demonstrates its utility to identify novel clinical biomarkers.
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Affiliation(s)
- Konrad Buscher
- Division of General Internal Medicine, Nephrology and Rheumatology, Department of Medicine D, University Hospital of Muenster, Muenster, Germany,Division of Inflammation Biology, La Jolla Institute for Immunology, La Jolla, California
| | - Barbara Heitplatz
- Institute of Pathology, University Hospital Muenster, Muenster, Germany
| | - Veerle van Marck
- Institute of Pathology, University Hospital Muenster, Muenster, Germany
| | - Jian Song
- Institute of Physiological Chemistry and Pathobiochemistry, University of Muenster, Muenster, Germany,Cells-in-Motion Cluster of Excellence, University of Muenster, Muenster, Germany
| | - Sophie Loismann
- Institute of Physiological Chemistry and Pathobiochemistry, University of Muenster, Muenster, Germany,Cells-in-Motion Cluster of Excellence, University of Muenster, Muenster, Germany
| | - Rebecca Rixen
- Division of General Internal Medicine, Nephrology and Rheumatology, Department of Medicine D, University Hospital of Muenster, Muenster, Germany
| | - Birte Hüchtmann
- Division of General Internal Medicine, Nephrology and Rheumatology, Department of Medicine D, University Hospital of Muenster, Muenster, Germany
| | - Sunil Kurian
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California
| | - Erik Ehinger
- Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, California
| | - Dennis Wolf
- Division of Inflammation Biology, La Jolla Institute for Immunology, La Jolla, California,Department of Cardiology and Angiology I, University Heart Center, and Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Klaus Ley
- Division of Inflammation Biology, La Jolla Institute for Immunology, La Jolla, California
| | - Hermann Pavenstädt
- Division of General Internal Medicine, Nephrology and Rheumatology, Department of Medicine D, University Hospital of Muenster, Muenster, Germany
| | - Stefan Reuter
- Division of General Internal Medicine, Nephrology and Rheumatology, Department of Medicine D, University Hospital of Muenster, Muenster, Germany
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Toulza F, Dominy K, Willicombe M, Beadle J, Santos E, Cook HT, Szydlo RM, McLean A, Roufosse C. Diagnostic application of transcripts associated with antibody-mediated rejection in kidney transplant biopsies. Nephrol Dial Transplant 2021; 37:1576-1584. [PMID: 34320215 PMCID: PMC9317169 DOI: 10.1093/ndt/gfab231] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Indexed: 11/22/2022] Open
Abstract
Background The diagnosis of antibody-mediated rejection (AMR) is reached using the Banff Classification for Allograft Pathology, which now includes gene expression analysis. In this study, we investigate the application of ‘increased expression of thoroughly validated gene transcripts/classifiers strongly associated with AMR’ as diagnostic criteria. Method We used quantitative real-time polymerase chain reaction for 10 genes associated with AMR in a retrospective cohort of 297 transplant biopsies, including biopsies that met the full diagnostic criteria for AMR, even without molecular data (AMR, n = 27), biopsies that showed features of AMR, but that would only meet criteria for AMR with increased transcripts [suspicious for AMR (AMRsusp), n = 49] and biopsies that would never meet criteria for AMR (No-AMR, n = 221). Results A 10-gene AMR score trained by a receiver-operating characteristic to identify AMR found 16 cases with a high score among the AMRsusp cases (AMRsusp-high) that had significantly worse graft survival than those with a low score (AMRsusp-low; n = 33). In both univariate and multivariate Cox regression analysis, the AMR 10-gene score was significantly associated with an increased hazard ratio (HR) for graft loss (GL) in the AMRsusp group (HR = 1.109, P = 0.004 and HR = 1.138, P = 0.012, respectively), but not in the whole cohort. Net reclassification index and integrated discrimination improvement analyses demonstrated improved risk classification and superior discrimination, respectively, for GL when considering the gene score in addition to histological and serological data, but only in the AMRsusp group, not the whole cohort. Conclusions This study provides evidence that a gene score strongly associated with AMR helps identify cases at higher risk of GL in biopsies that are suspicious for AMR but do not meet full criteria.
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Affiliation(s)
- Frederic Toulza
- Imperial College, Centre for Inflammatory Disease, Dept Immunology and Inflammation, London, United Kingdom
| | - Kathy Dominy
- Molecular Pathology Laboratory, North West London Pathology, London, United Kingdom
| | - Michelle Willicombe
- Imperial College, Centre for Inflammatory Disease, Dept Immunology and Inflammation, London, United Kingdom.,Imperial College Renal and Transplant Centre, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Jack Beadle
- Imperial College, Centre for Inflammatory Disease, Dept Immunology and Inflammation, London, United Kingdom
| | - Eva Santos
- Histocompatibility and Immunogenetics, North West London Pathology, London, United Kingdom
| | - H Terence Cook
- Imperial College, Centre for Inflammatory Disease, Dept Immunology and Inflammation, London, United Kingdom
| | - Richard M Szydlo
- Imperial College, Medical Statistician, Dept Immunology and Inflammation, London, United Kingdom
| | - Adam McLean
- Imperial College Renal and Transplant Centre, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Candice Roufosse
- Imperial College, Centre for Inflammatory Disease, Dept Immunology and Inflammation, London, United Kingdom
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32
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Impact of Belatacept Conversion on Renal Function, Histology, and Gene Expression in Kidney Transplant Patients With Chronic Active Antibody-mediated Rejection. Transplantation 2021; 105:660-667. [PMID: 32510913 DOI: 10.1097/tp.0000000000003278] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Here, we present our initial experience with a prospective protocol of belatacept conversion in patients with chronic active antibody-mediated rejection (caAMR) and a high degree of chronicity at the time of diagnosis. METHODS We converted 19 patients (mean age, 45 ± 12 y) with biopsy-proven caAMR from tacrolimus to belatacept at a median of 44 months post-kidney transplant. RESULTS At a median of 29 months (interquartile range, 16-46 mo) postconversion, death-censored graft and patient survivals were 89% and 95%, respectively. When compared to a 1:2 propensity-matched control cohort from the INSERM U970 registry maintained on calcineurin inhibitor, the belatacept group had progressive improvement (P = 0.02) in estimated glomerular filtration rate from a mean of 33.9 ± 10 at baseline to 37.8 ± 13 at 6 months and 38.5 ± 12 mL/min/1.73 m2 at 12 months postconversion, as compared to a steady decline noted in the controls (36.2 [baseline] → 33.1 [6 mo] → 32.7 mL/min/1.73 m2 [12 mo] of follow-up). A paired histologic comparison of preconversion and postconversion (performed at median 9.5 mo postconversion) biopsies showed no worsening in microvascular inflammation or chronicity. The paired tissue gene expression analysis showed improved mean total rejection score (0.68 ± 0.26-0.56 ± 0.33; P = 0.02) and a trend toward improved antibody-mediated rejection score (0.64 ± 0.34-0.56 ± 0.39; P = 0.06). CONCLUSIONS Here, we report that in patients diagnosed with caAMR who were not subjected to intensive salvage immunosuppressive therapies, isolated belatacept conversion alone was associated with stabilization in renal function. These results are bolstered by molecular evidence of improved inflammation.
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Reese SR, Wilson NA, Huang Y, Ptak L, Degner KR, Xiang D, Redfield RR, Zhong W, Panzer SE. B-cell Deficiency Attenuates Transplant Glomerulopathy in a Rat Model of Chronic Active Antibody-mediated Rejection. Transplantation 2021; 105:1516-1529. [PMID: 33273321 PMCID: PMC8106694 DOI: 10.1097/tp.0000000000003530] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Transplant glomerulopathy (TG) is a pathological feature of chronic active antibody-mediated rejection (cAMR) and is associated with renal allograft failure. The specific role of B cells in the pathogenesis of TG is unclear. METHODS We used a minor mismatched rat kidney transplant model with B cell-deficient recipients, generated by clustered regularly interspaced short palindromic repeats/Cas9 technology, to investigate the impact of B-cell depletion on the pathogenesis of TG. We hypothesized that B-cell deficiency would prevent TG in the rat kidney transplant model of cAMR. Treatment groups included syngeneic, allogeneic, sensitized allogeneic, and B cell-deficient allogeneic transplant recipients. RESULTS B cell-deficient recipients demonstrated reduced TG lesions, decreased microvascular inflammation, reduced allograft infiltrating macrophages, and reduced interferon gamma transcripts within the allograft. Allograft transcript levels of interferon gamma, monocyte chemoattractant protein-1, and interleukin-1β correlated with numbers of intragraft macrophages. B cell-deficient recipients lacked circulating donor-specific antibodies and had an increased splenic regulatory T-cell population. CONCLUSIONS In this model of cAMR, B-cell depletion attenuated the development of TG with effects on T cell and innate immunity.
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Affiliation(s)
- Shannon R. Reese
- Department of Medicine, Division of Nephrology, University of Wisconsin, Madison, WI, United States
| | - Nancy A. Wilson
- Department of Medicine, Division of Nephrology, University of Wisconsin, Madison, WI, United States
| | - Yabing Huang
- Department of Pathology, Renmin Hospital of Wuhan University, China
| | - Lucille Ptak
- Department of Medicine, Division of Nephrology, University of Wisconsin, Madison, WI, United States
| | - Kenna R. Degner
- Department of Medicine, Division of Nephrology, University of Wisconsin, Madison, WI, United States
| | - Ding Xiang
- Department of Organ Transplantation, Xiangya Hospital, Central South University, China
| | - Robert R. Redfield
- Department of Surgery, Division of Transplant Surgery, University of Wisconsin, Madison, WI, United States
| | - Weixiong Zhong
- Department of Pathology, University of Wisconsin, Madison, WI, United States
| | - Sarah E. Panzer
- Department of Medicine, Division of Nephrology, University of Wisconsin, Madison, WI, United States
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34
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Schinstock CA, Askar M, Bagnasco SM, Batal I, Bow L, Budde K, Campbell P, Carroll R, Clahsen-van Groningen MC, Cooper M, Cornell LD, Cozzi E, Dadhania D, Diekmann F, Hesselink DA, Jackson AM, Kikic Z, Lower F, Naesens M, Roelofs JJ, Sapir-Pichhadze R, Kraus ES. A 2020 Banff Antibody-mediatedInjury Working Group examination of international practices for diagnosing antibody-mediated rejection in kidney transplantation - a cohort study. Transpl Int 2021; 34:488-498. [PMID: 33423340 DOI: 10.1111/tri.13813] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 11/24/2020] [Accepted: 01/02/2021] [Indexed: 12/24/2022]
Abstract
The Banff antibody-mediated rejection (ABMR) classification is vulnerable to misinterpretation, but the reasons are unclear. To better understand this vulnerability, we evaluated how ABMR is diagnosed in practice. To do this, the Banff Antibody-Mediated Injury Workgroup electronically surveyed an international cohort of nephrologists/surgeons (n = 133) and renal pathologists (n = 99). Most providers (97%) responded that they use the Banff ABMR classification at least sometimes, but DSA information is often not readily available. Only 41.1% (55/133) of nephrologists/surgeons and 19.2% (19/99) of pathologists reported that they always have DSA results when the biopsy is available. Additionally, only 19.6% (26/133) of nephrologists/surgeons responded that non-HLA antibody or molecular transcripts are obtained when ABMR histologic features are present but DSA is undetected. Several respondents agreed that histologic features concerning for ABMR in the absence of DSA and/or C4d are not well accounted for in the current classification [31.3% (31/99) pathologists and 37.6% (50/133) nephrologist/surgeons]. The Banff ABMR classification appears widely accepted, but efforts to improve the accessibility of DSA information for the multidisciplinary care team are needed. Further clarity is also needed in Banff ABMR nomenclature to account for the spectrum of ABMR and for histologic features suspicious for ABMR when DSA is absent.
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Affiliation(s)
- Carrie A Schinstock
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA
| | - Medhat Askar
- Baylor University Medical Center, Dallas, TX, USA.,Texas A&M Health Science Center Collect of Medicine, Bryan, TX, USA
| | - Serena M Bagnasco
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ibrahim Batal
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Laurine Bow
- Department of Transplantation Surgery, Yale University School of Medicine, New Haven, CT, USA
| | - Klemens Budde
- Medizinische Klinik mit Schwerpunkt Nephrologie und Internistische Intensivmedizin, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Patricia Campbell
- Department of Medicine and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Robert Carroll
- Transplantation Immunogenetics Service, Australian Red Cross Blood Service Melbourne, Melbourne, Vic., Australia.,University of South Australia, Adelaide, SA, Australia
| | | | - Matthew Cooper
- Medstar Georgetown Transplant Institute, Washington, DC, USA
| | - Lynn D Cornell
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Emanuele Cozzi
- Transplant Immunology Unit, Department of Cardiac, Thoracic and Vascular Sciences, Padua University Hospital, Padua, Italy
| | - Darshana Dadhania
- Department of Medicine, Weill Cornell Medicine - New York Presbyterian Hospital, New York, NY, USA
| | - Fritz Diekmann
- Kidney Transplant Unit, Institut d'Incestigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Barcelona, Spain
| | - Dennis A Hesselink
- Department of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | | | - Zeljko Kikic
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Vienna, Austria
| | - Fritz Lower
- Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY, USA
| | - Maarten Naesens
- Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.,Department of Nephrology, University Hospitals Leuven, Leuven, Belgium
| | - Joris J Roelofs
- Department of Pathology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Ruth Sapir-Pichhadze
- Centre for Outcomes Research & Evaluation Research Institute, McGill University Health Center, Montreal, QC, Canada
| | - Edward S Kraus
- Division of Nephrology/Transplant Nephrology, Johns Hopkins University, Baltimore, MD, USA
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35
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Kim MY, Brennan DC. Therapies for Chronic Allograft Rejection. Front Pharmacol 2021; 12:651222. [PMID: 33935762 PMCID: PMC8082459 DOI: 10.3389/fphar.2021.651222] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/10/2021] [Indexed: 12/14/2022] Open
Abstract
Remarkable advances have been made in the pathophysiology, diagnosis, and treatment of antibody-mediated rejection (ABMR) over the past decades, leading to improved graft outcomes. However, long-term failure is still high and effective treatment for chronic ABMR, an important cause of graft failure, has not yet been identified. Chronic ABMR has a relatively different phenotype from active ABMR and is a slowly progressive disease in which graft injury is mainly caused by de novo donor specific antibodies (DSA). Since most trials of current immunosuppressive therapies for rejection have focused on active ABMR, treatment strategies based on those data might be less effective in chronic ABMR. A better understanding of chronic ABMR may serve as a bridge in establishing treatment strategies to improve graft outcomes. In this in-depth review, we focus on the pathophysiology and characteristics of chronic ABMR along with the newly revised Banff criteria in 2017. In addition, in terms of chronic ABMR, we identify the reasons for the resistance of current immunosuppressive therapies and look at ongoing research that could play a role in setting better treatment strategies in the future. Finally, we review non-invasive biomarkers as tools to monitor for rejection.
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Affiliation(s)
| | - Daniel C. Brennan
- Department of Internal Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States
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The FCGR3A 158 V/V-genotype is associated with decreased survival of renal allografts with chronic active antibody-mediated rejection. Sci Rep 2021; 11:7903. [PMID: 33846428 PMCID: PMC8041758 DOI: 10.1038/s41598-021-86943-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 03/19/2021] [Indexed: 01/24/2023] Open
Abstract
Natural killer (NK) cells express the Fc-gamma receptor CD16 (FCGR3A) and could therefore mediate renal endothelial cell damage in cases of chronic-active antibody mediated rejection (c-aABMR). The V/V-genotype of the FCGR3A 158 F/V polymorphism is associated with increased CD16 expression and cytotoxicity by NK cells. This study evaluated whether this genotype is associated with the diagnosis of c-aABMR and renal allograft loss. The distribution of the FGCR3A 158 F/V-genotypes was not different for c-aABMR cases (N = 133) compared to control kidney transplant recipients (N = 116, P = 0.65). The V-allele was associated with increased median fluorescence intensity (MFI) of CD16 by NK cells (MFI 3.5 × 104 versus 1.3 × 104 for V/V and F/F-genotype, P < 0.001). Increased expression of CD16 correlated with CD16-dependent degranulation of NK cells (R = 0.4; P = 0.02). Moreover, the V/V-genotype was significantly associated with a higher glomerulitis score and an independent risk factor (HR 1.98; P = 0.04) for decreased allograft survival. Death-censored graft survival in c-aABMR cases at 3 years follow-up was 33% for the FCGR3A 158 V/V-genotype versus 62% for the F/F-genotype. In conclusion, the FCGR3A V/V-genotype increases CD16-mediated NK cell cytotoxicity and is associated with a higher glomerulitis score and decreased graft survival in cases with c-aABMR.
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37
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Teixeira AC, Távora F, de Deus e Silva MLF, Prado RMG, de Matos Esmeraldo R, de Sandes-Freitas TV. The immunohistochemical expression of von Willebrand factor, T-cadherin, and Caveolin-1 is increased in kidney allograft biopsies with antibody-mediated injury. Clin Exp Nephrol 2021; 25:305-314. [PMID: 33242156 DOI: 10.1007/s10157-020-01994-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 11/08/2020] [Indexed: 01/01/2023]
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38
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Khachatoorian Y, Khachadourian V, Chang E, Sernas ER, Reed EF, Deng M, Piening BD, Pereira AC, Keating B, Cadeiras M. Noninvasive biomarkers for prediction and diagnosis of heart transplantation rejection. Transplant Rev (Orlando) 2020; 35:100590. [PMID: 33401139 DOI: 10.1016/j.trre.2020.100590] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 11/15/2020] [Accepted: 11/16/2020] [Indexed: 01/12/2023]
Abstract
For most patients with end-stage heart failure, heart transplantation is the treatment of choice. Allograft rejection is one of the major post-transplantation complications affecting graft outcome and survival. Recent advancements in science and technology offer an opportunity to integrate genomic and other omics-based biomarkers into clinical practice, facilitating noninvasive evaluation of allograft for diagnostic and prognostic purposes. Omics, including gene expression profiling (GEP) of blood immune cell components and donor-derived cell-free DNA (dd-cfDNA) are of special interest to researchers. Several studies have investigated levels of dd-cfDNA and miroRNAs in blood as potential markers for early detection of allograft rejection. One of the achievements in the field of transcriptomics is AlloMap, GEP of peripheral blood mononuclear cells (PBMC), which can identify 11 differentially expressed genes and help with detection of moderate and severe acute cellular rejection in stable heart transplant recipients. In recent years, the utilization of GEP of PBMC for identifying differentially expressed genes to diagnose acute antibody-mediated rejection and cardiac allograft vasculopathy has yielded promising results. Advancements in the field of metabolomics and proteomics as well as their potential implications have been further discussed in this paper.
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Affiliation(s)
- Yeraz Khachatoorian
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
| | - Vahe Khachadourian
- Turpanjian School of Public Health, American University of Armenia, Yerevan, Armenia
| | - Eleanor Chang
- Division of Cardiology, David Geffen School of Medicine, Los Angeles, CA, United States of America
| | - Erick R Sernas
- Division of Cardiovascular Medicine, University of California Davis, Davis, CA, United States of America
| | - Elaine F Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, United States of America
| | - Mario Deng
- Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, United States of America
| | - Brian D Piening
- Earle A Chiles Research Institute, Providence Health and Services, Portland, OR, United States of America
| | | | - Brendan Keating
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America
| | - Martin Cadeiras
- Division of Cardiovascular Medicine, University of California Davis, Davis, CA, United States of America
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39
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Kumar D, Yakubu I, Safavi F, Levy M, Moinuddin I, Kimball P, Kamal L, King A, Massey D, Halloran P, Gupta G. Lack of Histological and Molecular Signature Response to Tocilizumab in Kidney Transplants with Chronic Active Antibody Mediated Rejection: A Case Series. KIDNEY360 2020; 1:663-670. [PMID: 35372943 DOI: 10.34067/kid.0000182019] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 04/21/2020] [Indexed: 02/08/2023]
Abstract
Background Traditional therapies for caAbMR have unclear efficacy with significant side effects in recipients of kidney transplants (KTs). A recent single-center case series suggested tocilizumab (TCZ) could stabilize renal function and improve microvascular inflammation. Here we report our findings of the use of TCZ in patients with caAbMR. Methods Ten adult recipients of KTs with biopsy-proven caAbMR were treated with TCZ at 8 mg/kg per month. Patients were monitored for adverse events, and therapy was interrupted in the setting of serious infections. Six patients (60%) underwent post-treatment biopsies. Results Patients (mean age of 43 years) were initiated on TCZ at a median of 36 months post-KT. A majority of patients were black (70%), underwent regrafts (40%), and were sensitized (mean cPRA=41%). Patients received a median of six doses of TCZ (range=3-10). At a median follow-up of 12 months (range=8-24 months), renal function did not show improvement (mean eGFR, 42±18 ml/min per 1.73 m2 to 37±24 ml/min per 1.73 m2; P=0.27). The slope of decline in eGFR remained unchanged (-0.14±0.9 to -0.33±1.1; P=0.25). There was no improvement in mean MVI (g+ptc) (4.8±1.4 to 4.2±2.0; P=0.39) scores or Molecular Microscope Diagnostic System (MMDx) AbMR scores (0.79±0.17 to 0.78±0.26; P=0.86). There was a numeric worsening of chronicity (ci+ct) scores (2.5±0.8 to 3.3±1.7; P=0.38) and MMDx atrophy fibrosis scores (0.36±0.24 to 0.58±0.15; P=0.21). Patient survival was 90%, with one patient death due to complications from a hip infection. Overall death-censored graft survival was 80%, with two graft losses in patients who had recurrent infections requiring hospitalization. Conclusions In this early experience, we report a lack of efficacy and toxicity with the use of TCZ for caAbMR. Prospective clinical trials are needed to clarify the role of IL-6 blockade and the possibility of increased incidence of infections in patients with caAbMR who are treated with TCZ.
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Affiliation(s)
- Dhiren Kumar
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Idris Yakubu
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Frough Safavi
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Marlon Levy
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Irfan Moinuddin
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Pamela Kimball
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Layla Kamal
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Anne King
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Davis Massey
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Philip Halloran
- Alberta Transplant Applied Genomics Center, Edmonton, Alberta, Canada
| | - Gaurav Gupta
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
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40
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Kotla SK, Tanriover B. Recurrent antibody-mediated rejection in renal allograft: physician's dilemma. J Nephrol 2020; 33:661-665. [PMID: 32557204 DOI: 10.1007/s40620-020-00780-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 06/08/2020] [Indexed: 11/29/2022]
Abstract
Antibody-mediated rejection is the primary cause of renal allograft failure, and the molecular mechanistic is relatively less known in comparison to cell-mediated rejection. With the advent of new immunological agents, the short-term graft survival outcomes have improved, but the long-term outcomes are still unchanged. We present a case of 47-year-old with end-stage renal disease due to presumed lupus status post deceased donor renal transplantation. The patient developed recurrent (a total of five) antibody-mediated rejections (donor-specific antibody and C4d staining negative) spanning within a year of transplant despite the standard of care therapies. The present case draws attention to the importance of non-HLA antibodies in antibody-mediated rejection and diagnostic tools we can rely on when the histology is inconclusive and the role of new immunological agents.
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Affiliation(s)
- Suman Krishna Kotla
- Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5939, Harry Hines Blvd, HP5, POB 1, Dallas, TX, 75390-8516, USA.
| | - Bekir Tanriover
- Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5939, Harry Hines Blvd, HP5, POB 1, Dallas, TX, 75390-8516, USA
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41
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Abstract
Early detection of graft injury after kidney transplantation is key to maintaining long-term good graft function. Graft injury could be due to a multitude of factors including ischaemia reperfusion injury, cell or antibody-mediated rejection, progressive interstitial fibrosis and tubular atrophy, infections and toxicity from the immunosuppressive drugs themselves. The current gold standard for assessing renal graft dysfunction is renal biopsy. However, biopsy is usually late when triggered by a change in serum creatinine and of limited utility in diagnosis of early injury when histological changes are equivocal. Therefore, there is a need for timely, objective and non-invasive diagnostic techniques with good early predictive value to determine graft injury and provide precision in titrating immunosuppression. We review potential novel plasma and urine biomarkers that offer sensitive new strategies for early detection and provide major insights into mechanisms of graft injury. This is a rapidly expanding field, but it is likely that a combination of biomarkers will be required to provide adequate sensitivity and specificity for detecting graft injury.
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42
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Kovács G, Devercelli G, Zelei T, Hirji I, Vokó Z, Keown PA. Association between transplant glomerulopathy and graft outcomes following kidney transplantation: A meta-analysis. PLoS One 2020; 15:e0231646. [PMID: 32343692 PMCID: PMC7188300 DOI: 10.1371/journal.pone.0231646] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 03/28/2020] [Indexed: 02/07/2023] Open
Abstract
Transplant glomerulopathy (TG), a morphological lesion associated with confluent mechanisms of endothelial injury of renal allografts, may provide a viable predictor of graft failure. This systematic literature review and meta-analysis were performed according to the PRISMA statement to examine evidence describing the association between TG and graft loss or failure and time to these events. The literature review was conducted using the Scopus, EBSCO, and Cochrane Library search engines. Hazard ratios, median survival times, and 95% confidence intervals (CIs) were estimated to evaluate graft survival in the total population and prespecified subgroups. Meta-regression analysis assessed heterogeneity. Twenty-one publications comprising 6,783 patients were eligible for data extraction and inclusion in the meta-analysis. Studies were highly heterogeneous (I2 = 67.3%). The combined hazard ratio of graft loss or failure from random-effects meta-analysis was 3.11 (95% CI 2.44–3.96) in patients with TG compared with those without. Median graft survival in patients with TG was 3.25 (95% CI 0.94–11.21) years—15 years shorter than in those without TG (18.82 [95% CI 10.03–35.32] years). The effect of time from transplantation to biopsy on graft outcomes did not reach statistical significance (p = 0.116). TG was associated with a threefold increase in the risk of graft loss or failure and a 15-year loss in graft survival, indicating viability as a surrogate measure for both clinical practice and studies designed to prevent or reverse antibody-mediated rejection.
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Affiliation(s)
| | | | - Tamás Zelei
- Syreon Research Institute, Budapest, Hungary
| | - Ishan Hirji
- Shire, a Takeda company, Lexington, Massachusetts, United States of America
| | - Zoltán Vokó
- Syreon Research Institute, Budapest, Hungary
- Center for Health Technology Assessment, Semmelweis University, Budapest, Hungary
| | - Paul A. Keown
- Syreon Corporation, Vancouver, British Columbia, Canada
- University of British Columbia, Vancouver, British Columbia, Canada
- * E-mail:
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43
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Trailin A, Hruba P, Viklicky O. Molecular Assessment of Kidney Allografts: Are We Closer to a Daily Routine? Physiol Res 2020; 69:215-226. [PMID: 32199018 DOI: 10.33549/physiolres.934278] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Kidney allograft pathology assessment has been traditionally based on clinical and histological criteria. Despite improvements in Banff histological classification, the diagnostics in particular cases is problematic reflecting a complex pathogenesis of graft injuries. With the advent of molecular techniques, polymerase-chain reaction, oligo- and microarray technologies allowed to study molecular phenotypes of graft injuries, especially acute and chronic rejections. Moreover, development of the molecular microscope diagnostic system (MMDx) to assess kidney graft biopsies, represents the first clinical application of a microarray-based method in transplantation. Whether MMDx may replace conventional pathology is the subject of ongoing research, however this platform is particularly useful in complex histological findings and may help clinicians to guide the therapy.
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Affiliation(s)
- A Trailin
- Department of Nephrology, Transplant Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
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44
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Jacquemont L, Tilly G, Yap M, Doan-Ngoc TM, Danger R, Guérif P, Delbos F, Martinet B, Giral M, Foucher Y, Brouard S, Degauque N. Terminally Differentiated Effector Memory CD8 + T Cells Identify Kidney Transplant Recipients at High Risk of Graft Failure. J Am Soc Nephrol 2020; 31:876-891. [PMID: 32165419 DOI: 10.1681/asn.2019080847] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 01/16/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Identifying biomarkers to predict kidney transplant failure and to define new therapeutic targets requires more comprehensive understanding of the immune response to chronic allogeneic stimulation. METHODS We investigated the frequency and function of CD8+ T cell subsets-including effector memory (EM) and terminally differentiated EM (TEMRA) CD8+ T cells-in blood samples from 284 kidney transplant recipients recruited 1 year post-transplant and followed for a median of 8.3 years. We also analyzed CD8+ T cell reactivity to donor-specific PBMCs in 24 patients who had received living-donor kidney transplants. RESULTS Increased frequency of circulating TEMRA CD8+ T cells at 1 year post-transplant associated with increased risk of graft failure during follow-up. This association remained after adjustment for a previously reported composite of eight clinical variables, the Kidney Transplant Failure Score. In contrast, increased frequency of EM CD8+ T cells associated with reduced risk of graft failure. A distinct TEMRA CD8+ T cell subpopulation was identified that was characterized by expression of FcγRIIIA (CD16) and by high levels of proinflammatory cytokine secretion and cytotoxic activity. Although donor-specific stimulation induced a similar rapid, early response in EM and TEMRA CD8+ T cells, CD16 engagement resulted in selective activation of TEMRA CD8+ T cells, which mediated antibody-dependent cytotoxicity. CONCLUSIONS At 1 year post-transplant, the composition of memory CD8+ T cell subsets in blood improved prediction of 8-year kidney transplant failure compared with a clinical-variables score alone. A subpopulation of TEMRA CD8+ T cells displays a novel dual mechanism of activation mediated by engagement of the T-cell receptor or of CD16. These findings suggest that TEMRA CD8+ T cells play a pivotal role in humoral and cellular rejection and reveal the potential value of memory CD8+ T cell monitoring for predicting risk of kidney transplant failure.
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Affiliation(s)
- Lola Jacquemont
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France.,CHU Nantes, Université de Nantes, ITUN, Nantes, France
| | - Gaëlle Tilly
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France.,CHU Nantes, Université de Nantes, ITUN, Nantes, France
| | - Michelle Yap
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France.,CHU Nantes, Université de Nantes, ITUN, Nantes, France
| | - Tra-My Doan-Ngoc
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France.,CHU Nantes, Université de Nantes, ITUN, Nantes, France
| | - Richard Danger
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France.,CHU Nantes, Université de Nantes, ITUN, Nantes, France
| | | | | | - Bernard Martinet
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France.,CHU Nantes, Université de Nantes, ITUN, Nantes, France
| | - Magali Giral
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France.,CHU Nantes, Université de Nantes, ITUN, Nantes, France
| | - Yohann Foucher
- INSERM, Université de Nantes, methodS in Patient-centered outcomes and HEalth ResEarch (SPHERE), UMR1246, Nantes, France
| | - Sophie Brouard
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France.,CHU Nantes, Université de Nantes, ITUN, Nantes, France
| | - Nicolas Degauque
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France; .,CHU Nantes, Université de Nantes, ITUN, Nantes, France
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45
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Chong AS. B cells as antigen-presenting cells in transplantation rejection and tolerance. Cell Immunol 2020; 349:104061. [PMID: 32059816 DOI: 10.1016/j.cellimm.2020.104061] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 02/04/2020] [Accepted: 02/06/2020] [Indexed: 12/21/2022]
Abstract
Transplantation of fully allogeneic organs into immunocompetent recipients invariably elicits T cell and B cell responses that lead to the production of donor-specific antibodies (DSA). When immunosuppression is inadequate donor-specific T cell and B cell responses escape, leading to T cell-mediated rejection (TCMR), antibody mediated (ABMR) rejection, or mixed rejection (MR) exhibiting features of both TCMR and ABMR. Current literature suggests that ABMR is a major cause of late graft loss, and that new therapies to curtail the donor-specific humoral response are necessary. The majority of research into B cell responses elicited by allogeneic allografts in both preclinical models and clinical studies, has focused on the function of B cells as antibody-secreting cells and the pathogenic effects of DSA as mediators of ABMR. However, it has long been recognized that the DSA response to allografts is T cell-dependent, and that B cells engage in cognate interactions with T cells that provide "help" and promote B cell differentiation into antibody-secreting cells (ASCs). This review focusses the function of B cells as antigen-presenting cells (APCs) to T cells in lymphoid organs, how they may be critical APCs to T cell in the allograft, and the functional consequences of these interactions.
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Affiliation(s)
- Anita S Chong
- Section of Transplantation, Department of Surgery, University of Chicago, Chicago, IL, United States.
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46
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Abstract
Monitoring allograft function after kidney transplant has routinely relied on the use of nonspecific markers, such as serum creatinine, glomerular filtration rate, proteinuria, and donor-specific antibodies. These traditional markers have low sensitivity and fail to detect subclinical changes. Diagnosis of renal allograft dysfunction still requires an allograft biopsy, as it remains the criterion standard for assessment of graft status. However, renal biopsy is an invasive procedure, and sampling errors may result in misdiagnosis, perhaps causing graft failure. New biomarkers have been developed to monitor allograft function, although many are not yet routinely used. Other shortcomings, such as lack of standardization and high cost, should be solved before their widespread application in the clinic. A recipient's immune status could be monitored by use of urine or blood samples. These include functional cell-based assays and the evaluation of molecular expression at the messenger RNA or protein levels. Molecular technologies, including molecular microscope diagnostic systems, have been recently developed to improve the yield of histologic evaluation of the allograft biopsy. Prospective, interventional trials are required to demonstrate whether these new biomarkers improve patient or transplant outcomes. Implementation of these technologies into standard clinical practice remains challenging until their generalizability, cost, ease of interpretation, and the identification of patients who may benefit from more than standard-of-care surveillance can be determined. These biomarkers could allow immunosuppressive therapy to be individualized for patients.
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Affiliation(s)
- Hassan Argani
- From the Urology and Nephrology Research Center, Shahidbeheshti University of Medical Sciences, Tehran, Iran
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47
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Jeon HJ, Lee JG, Kim K, Jang JY, Han SW, Choi J, Ryu JH, Koo TY, Jeong JC, Lee JW, Ishida H, Park JB, Lee SH, Ahn C, Yang J. Peripheral blood transcriptome analysis and development of classification model for diagnosing antibody-mediated rejection vs accommodation in ABO-incompatible kidney transplant. Am J Transplant 2020; 20:112-124. [PMID: 31373158 DOI: 10.1111/ajt.15553] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 07/02/2019] [Accepted: 07/28/2019] [Indexed: 02/07/2023]
Abstract
The major obstacle to successful ABO blood group-incompatible kidney transplantation (ABOi KT) is antibody-mediated rejection (AMR). This study aimed to investigate transcriptional profiles through RNA sequencing and develop a minimally invasive diagnostic tool for discrimination between accommodation and early acute AMR in ABOi KT. Twenty-eight ABOi KT patients were selected: 18 with accommodation and 10 with acute AMR at the 10th day posttransplant protocol biopsy. Complete transcriptomes of their peripheral blood were analyzed by RNA sequencing. Candidate genes were selected by bioinformatics analysis, validated with quantitative polymerase chain reaction, and used to develop a classification model to diagnose accommodation. A total of 1385 genes were differentially expressed in accommodation compared with in AMR with P-adjusted < .05. Functional annotation and gene set enrichment analysis identified several immune-related and immunometabolic pathways. A 5-gene classification model including COX7A2L, CD69, CD14, CFD, and FOXJ3 was developed by logistic regression analysis. The model was further validated with an independent cohort and discriminated between accommodation and AMR with 92.7% sensitivity, 85.7% specificity, and 91.7% accuracy. Our study suggests that a classification model based on peripheral blood transcriptomics may allow minimally invasive diagnosis of acute AMR vs accommodation and subsequent patient-tailored immunosuppression in ABOi KT.
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Affiliation(s)
- Hee Jung Jeon
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea
| | - Jae-Ghi Lee
- Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Kwangsoo Kim
- Division of Clinical Bioinformatics, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Joon Young Jang
- Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sung Won Han
- School of Industrial Management Engineering, Korea University, Seoul, Republic of Korea
| | - Jinwoo Choi
- School of Industrial Management Engineering, Korea University, Seoul, Republic of Korea
| | - Jung-Hwa Ryu
- Transplantation Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Tai Yeon Koo
- Transplantation Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Jong Cheol Jeong
- Department of Nephrology, Ajou University School of Medicine, Suwon, Gyeonggi-do, Republic of Korea
| | - Jae Wook Lee
- Nephrology Clinic, National Cancer Center, Goyang, Gyeonggi-do, Republic of Korea
| | - Hideki Ishida
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Jae Berm Park
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sang Ho Lee
- Department of Internal Medicine, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Curie Ahn
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jaeseok Yang
- Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.,Transplantation Center, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Surgery, Seoul National University Hospital, Seoul, Republic of Korea
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48
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Wilson NA, Dylewski J, Degner KR, O'Neill MA, Reese SR, Hidalgo LG, Blaine J, Panzer SE. An in vitro model of antibody-mediated injury to glomerular endothelial cells: Upregulation of MHC class II and adhesion molecules. Transpl Immunol 2019; 58:101261. [PMID: 31887408 DOI: 10.1016/j.trim.2019.101261] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 12/24/2019] [Accepted: 12/25/2019] [Indexed: 11/15/2022]
Abstract
Chronic active antibody-mediated rejection is a major cause of allograft failure in kidney transplantation. Microvascular inflammation and transplant glomerulopathy are defining pathologic features of chronic active antibody-mediated rejection and are associated with allograft failure. However, the mechanisms of leukocyte infiltration and glomerular endothelial cell injury remain unclear. We hypothesized MHC class II ligation on glomerular endothelial cells (GEnC) would result in upregulation of adhesion molecules and production of chemoattractants. A model of endothelial cell activation in the presence of antibodies to MHC classes I and II was used to determine the expression of adhesion molecules and chemokines. Murine GEnC were activated with IFNγ, which upregulated gene expression of β2-microglobulin (MHC class I), ICAM1, VCAM1, CCL2, CCL5, and IL-6. IFNγ stimulation of GEnC increased surface expression of MHC class I, MHC class II, ICAM1, and VCAM1. Incubation with antibodies directed at MHC class I or class II did not further enhance adhesion molecule expression. Multispectral imaging flow cytometry and confocal microscopy demonstrated MHC molecules co-localized with the adhesion molecules ICAM1 and VCAM1 on the GEnC surface. GEnC secretion of chemoattractants, CCL2 and CCL5, was increased by IFNγ stimulation. CCL2 production was further enhanced by incubation with sensitized plasma. Endothelial activation induces de novo expression of MHC class II molecules and increases surface expression of MHC class I, ICAM1 and VCAM1, which are all co-localized together. Maintaining the integrity and functionality of the glomerular endothelium is necessary to ensure survival of the allograft. IFNγ stimulation of GEnC propagates an inflammatory response with production of chemokines and co-localization of MHC and adhesion molecules on the GEnC surface, contributing to endothelial cell function as antigen presenting cells and an active player in allograft injury.
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Affiliation(s)
- Nancy A Wilson
- Division of Nephrology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - James Dylewski
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado-Denver, Aurora, CO, USA
| | - Kenna R Degner
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison, Madison, WI, USA
| | - Megan A O'Neill
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison, Madison, WI, USA
| | - Shannon R Reese
- Division of Nephrology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Luis G Hidalgo
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison, Madison, WI, USA
| | - Judith Blaine
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado-Denver, Aurora, CO, USA
| | - Sarah E Panzer
- Division of Nephrology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
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49
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Seifert ME, Gaut JP, Guo B, Jain S, Malone AF, Geraghty F, Manna DD, Yang ES, Yi N, Brennan DC, Mannon RB. WNT pathway signaling is associated with microvascular injury and predicts kidney transplant failure. Am J Transplant 2019; 19:2833-2845. [PMID: 30916889 PMCID: PMC6763350 DOI: 10.1111/ajt.15372] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 03/15/2019] [Accepted: 03/20/2019] [Indexed: 01/25/2023]
Abstract
Microvascular injury is associated with accelerated kidney transplant dysfunction and allograft failure. Molecular pathology can identify new mechanisms of microvascular injury while improving on the diagnostic and prognostic capabilities of traditional histology. We conducted a case-control study of archived kidney biopsy specimens stored up to 10 years with microvascular injury (n = 50) compared with biopsy specimens without histologic injury (n = 45) from patients of similar age, race, and sex. We measured WNT gene expression with a multiplex quantification platform by using digital barcoding, given the importance of WNT reactivation to the response to wounding in the kidney microvasculature and other compartments. Of 210 genes from a commercial WNT panel, 71 were associated with microvascular injury and 79 were associated with allograft failure, with considerable overlap of genes between each set. Molecular pathology identified 46 biopsy specimens with molecular evidence of microvascular injury; 18 (39%) were either C4d negative, donor-specific antibody negative, or had no microvascular injury by histology. The majority of cases with molecular evidence of microvascular injury had poor long-term outcomes. We identified novel WNT pathway genes associated with microvascular injury and allograft failure in residual clinical biopsy specimens obtained up to 10 years earlier. Further mechanistic studies may identify the WNT pathway as a new diagnostic and therapeutic target.
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Affiliation(s)
- Michael E. Seifert
- Department of Pediatrics, University of Alabama School of Medicine, Birmingham, AL
| | - Joseph P. Gaut
- Department of Pathology, Washington University, St. Louis, Missouri
| | - Boyi Guo
- Department of Biostatistics, School of Public Health, University of Alabama, Birmingham, Alabama
| | - Sanjay Jain
- Division of Nephrology, Department of Medicine, Washington University, St. Louis, Missouri
| | - Andrew F. Malone
- Division of Nephrology, Department of Medicine, Washington University, St. Louis, Missouri
| | - Feargal Geraghty
- Division of Nephrology, Department of Medicine, Washington University, St. Louis, Missouri
| | - Deborah Della Manna
- UAB NanoString Laboratory, Department of Radiation Oncology, University of Alabama School of Medicine, Birmingham, Alabama
| | - Eddy S. Yang
- UAB NanoString Laboratory, Department of Radiation Oncology, University of Alabama School of Medicine, Birmingham, Alabama
| | - Nengjun Yi
- Department of Biostatistics, School of Public Health, University of Alabama, Birmingham, Alabama
| | - Daniel C. Brennan
- Division of Nephrology, Department of Medicine, Washington University, St. Louis, Missouri,Comprehensive Transplant Center, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Roslyn B. Mannon
- Department of Medicine, University of Alabama School of Medicine, Birmingham, Alabama,Comprehensive Transplant Institute, University of Alabama School of Medicine, Birmingham, Alabama
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50
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Louis K, Hertig A, Taupin JL, Buob D, Jamme M, Brocheriou I, Luque Y, Jouanneau C, Ouali N, Audouin M, Rondeau E, Xu-Dubois YC. Markers of graft microvascular endothelial injury may identify harmful donor-specific anti-HLA antibodies and predict kidney allograft loss. Am J Transplant 2019; 19:2434-2445. [PMID: 30836425 DOI: 10.1111/ajt.15340] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 01/29/2019] [Accepted: 02/22/2019] [Indexed: 01/25/2023]
Abstract
Graft microvasculature is a major target of donor-specific antibodies (DSA) and endothelial damage is direct evidence of antibody-mediated rejection (ABMR). Using immunohistochemistry, we analyzed the expression of three microvascular endothelial activation markers (fascin, vimentin, and hsp47), suggestive of endothelial-to-mesenchymal transition (EndMT) in 351 graft biopsies from 248 kidney recipients, with concomitant screening of circulating antihuman leukocyte antigen (HLA) DSA at the time of the biopsy. The factors associated with EndMT marker expression were DSA and the presence of microvascular inflammation (MI). EndMT expressing grafts had significantly more allograft loss compared to EndMT negative grafts (P < .0001). The expression of EndMT markers positively correlated with anti-HLA DSA class II mean fluorescence intensity (MFI) levels and especially identified DQ and DR antibodies as being more closely associated with microvascular injury. Moreover, only DSA linked to positive EndMT score affected allograft survival, regardless of DSA MFI levels or presence of C4d deposition. Thus, EndMT markers could represent a clinically relevant tool for early identification of ongoing endothelial injury, harmful DSA, and patients at high risk for allograft failure.
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Affiliation(s)
- Kevin Louis
- Sorbonne University, Inserm UMR_S1155, AP-HP, Hôpital Tenon, F-75020, Paris, France
| | - Alexandre Hertig
- Sorbonne University, Inserm UMR_S1155, AP-HP, Hôpital Tenon, F-75020, Paris, France.,Sorbonne Universités, UPMC Université Paris 06, UMR S 1155, Paris, France
| | - Jean-Luc Taupin
- AP-HP, Hôpital Saint Louis, Laboratoire d'immunologie et d'histocompatibilité, Paris, France
| | - David Buob
- Sorbonne Universités, UPMC Université Paris 06, UMR S 1155, Paris, France.,AP-HP, Hôpital Tenon, Service d'Anatomo-Pathologie, Paris, France
| | - Matthieu Jamme
- Sorbonne University, Inserm UMR_S1155, AP-HP, Hôpital Tenon, F-75020, Paris, France
| | - Isabelle Brocheriou
- Sorbonne Universités, UPMC Université Paris 06, UMR S 1155, Paris, France.,AP-HP, Hôpital Pitié-Salpétrière, Service d'Anatomo-Pathologie, Paris, France
| | - Yosu Luque
- Sorbonne University, Inserm UMR_S1155, AP-HP, Hôpital Tenon, F-75020, Paris, France.,Sorbonne Universités, UPMC Université Paris 06, UMR S 1155, Paris, France
| | - Chantal Jouanneau
- Sorbonne University, Inserm UMR_S1155, AP-HP, Hôpital Tenon, F-75020, Paris, France
| | - Nacera Ouali
- Sorbonne University, Inserm UMR_S1155, AP-HP, Hôpital Tenon, F-75020, Paris, France
| | - Marie Audouin
- APHP, Hôpital Tenon, Service d'urologie, Paris, France
| | - Eric Rondeau
- Sorbonne University, Inserm UMR_S1155, AP-HP, Hôpital Tenon, F-75020, Paris, France.,Sorbonne Universités, UPMC Université Paris 06, UMR S 1155, Paris, France
| | - Yi-Chun Xu-Dubois
- Sorbonne University, Inserm UMR_S1155, AP-HP, Hôpital Tenon, F-75020, Paris, France.,APHP, Hôpital Tenon, Service de Santé publique, Paris, France
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