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1. Antibody Mediated Rejection and T-cell Mediated Rejection Molecular Signatures Using Next-Generation Sequencing in Kidney Transplant Biopsies

Author

Esteban Cortes Garcia, Alessia Giarraputo, Maud Racapé, Valentin Goutaudier, Cindy Ursule-Dufait, Pierre de la Grange, Lucie Adoux, Marc Raynaud, Clément Couderau, Fariza Mezine, Jessie Dagobert, Oriol Bestard, Francesc Moreso, Jean Villard, Fabian Halleck, Magali Giral, Sophie Brouard, Richard Danger, Pierre-Antoine Gourraud, Marion Rabant, Lionel Couzi, Moglie Le Quintrec, Nassim Kamar, Emmanuel Morelon, François Vrtovsnik, Jean-Luc Taupin, Renaud Snanoudj, Christophe Legendre, Dany Anglicheau, Klemens Budde, Carmen Lefaucheur, Alexandre Loupy, and Olivier Aubert

Subjects
next generation sequencing, RNA-seq experiment, kidney biopsies, molecular signature, allograft rejection, kidney transplantation, Specialties of internal medicine, RC581-951
Abstract

Recently, interest in transcriptomic assessment of kidney biopsies has been growing. This study investigates the use of NGS to identify gene expression changes and analyse the pathways involved in rejection. An Illumina bulk RNA sequencing on the polyadenylated RNA of 770 kidney biopsies was conducted. Differentially-expressed genes (DEGs) were determined for AMR and TCMR using DESeq2. Genes were segregated according to their previous descriptions in known panels (microarray or the Banff Human Organ Transplant (B-HOT) panel) to obtain NGS-specific genes. Pathway enrichment analysis was performed using the Reactome and Kyoto Encyclopaedia of Genes and Genomes (KEGG) public repositories. The differential gene expression using NGS analysis identified 6,141 and 8,478 transcripts associated with AMR and TCMR. While most of the genes identified were included in the microarray and the B-HOT panels, NGS analysis identified 603 (9.8%) and 1,186 (14%) new specific genes. Pathways analysis showed that the B-HOT panel was associated with the main immunological processes involved during AMR and TCMR. The microarrays specifically integrated metabolic functions and cell cycle progression processes. Novel NGS-specific based transcripts associated with AMR and TCMR were discovered, which might represent a novel source of targets for drug designing and repurposing.

Published
2024
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2. Impact of the COVID-19 pandemic on publication dynamics and non-COVID-19 research production

Author

Marc Raynaud, Valentin Goutaudier, Kevin Louis, Solaf Al-Awadhi, Quentin Dubourg, Agathe Truchot, Romain Brousse, Nouredine Saleh, Alessia Giarraputo, Charlotte Debiais, Zeynep Demir, Anaïs Certain, Francine Tacafred, Esteban Cortes-Garcia, Safia Yanes, Jessy Dagobert, Sofia Naser, Blaise Robin, Élodie Bailly, Xavier Jouven, Peter P. Reese, and Alexandre Loupy

Subjects
COVID-19, Meta-research, Publications, High-impact journals, Medicine (General), R5-920
Abstract

Abstract Background The COVID-19 pandemic has severely affected health systems and medical research worldwide but its impact on the global publication dynamics and non-COVID-19 research has not been measured. We hypothesized that the COVID-19 pandemic may have impacted the scientific production of non-COVID-19 research. Methods We conducted a comprehensive meta-research on studies (original articles, research letters and case reports) published between 01/01/2019 and 01/01/2021 in 10 high-impact medical and infectious disease journals (New England Journal of Medicine, Lancet, Journal of the American Medical Association, Nature Medicine, British Medical Journal, Annals of Internal Medicine, Lancet Global Health, Lancet Public Health, Lancet Infectious Disease and Clinical Infectious Disease). For each publication, we recorded publication date, publication type, number of authors, whether the publication was related to COVID-19, whether the publication was based on a case series, and the number of patients included in the study if the publication was based on a case report or a case series. We estimated the publication dynamics with a locally estimated scatterplot smoothing method. A Natural Language Processing algorithm was designed to calculate the number of authors for each publication. We simulated the number of non-COVID-19 studies that could have been published during the pandemic by extrapolating the publication dynamics of 2019 to 2020, and comparing the expected number to the observed number of studies. Results Among the 22,525 studies assessed, 6319 met the inclusion criteria, of which 1022 (16.2%) were related to COVID-19 research. A dramatic increase in the number of publications in general journals was observed from February to April 2020 from a weekly median number of publications of 4.0 (IQR: 2.8–5.5) to 19.5 (IQR: 15.8–24.8) (p

Published
2021
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3. COVID-19-related medical research: a meta-research and critical appraisal

Author

Marc Raynaud, Huanxi Zhang, Kevin Louis, Valentin Goutaudier, Jiali Wang, Quentin Dubourg, Yongcheng Wei, Zeynep Demir, Charlotte Debiais, Olivier Aubert, Yassine Bouatou, Carmen Lefaucheur, Patricia Jabre, Longshan Liu, Changxi Wang, Xavier Jouven, Peter Reese, Jean-Philippe Empana, and Alexandre Loupy

Subjects
COVID-19, Systematic review, Critical appraisal, Quality of research, Medicine (General), R5-920
Abstract

Abstract Background Since the start of the COVID-19 outbreak, a large number of COVID-19-related papers have been published. However, concerns about the risk of expedited science have been raised. We aimed at reviewing and categorizing COVID-19-related medical research and to critically appraise peer-reviewed original articles. Methods The data sources were Pubmed, Cochrane COVID-19 register study, arXiv, medRxiv and bioRxiv, from 01/11/2019 to 01/05/2020. Peer-reviewed and preprints publications related to COVID-19 were included, written in English or Chinese. No limitations were placed on study design. Reviewers screened and categorized studies according to i) publication type, ii) country of publication, and iii) topics covered. Original articles were critically appraised using validated quality assessment tools. Results Among the 11,452 publications identified, 10,516 met the inclusion criteria, among which 7468 (71.0%) were peer-reviewed articles. Among these, 4190 publications (56.1%) did not include any data or analytics (comprising expert opinion pieces). Overall, the most represented topics were infectious disease (n = 2326, 22.1%), epidemiology (n = 1802, 17.1%), and global health (n = 1602, 15.2%). The top five publishing countries were China (25.8%), United States (22.3%), United Kingdom (8.8%), Italy (8.1%) and India (3.4%). The dynamic of publication showed that the exponential growth of COVID-19 peer-reviewed articles was mainly driven by publications without original data (mean 261.5 articles ± 51.1 per week) as compared with original articles (mean of 69.3 ± 22.3 articles per week). Original articles including patient data accounted for 713 (9.5%) of peer-reviewed studies. A total of 576 original articles (80.8%) showed intermediate to high risk of bias. Last, except for simulation studies that mainly used large-scale open data, the median number of patients enrolled was of 102 (IQR = 37–337). Conclusions Since the beginning of the COVID-19 pandemic, the majority of research is composed by publications without original data. Peer-reviewed original articles with data showed a high risk of bias and included a limited number of patients. Together, these findings underscore the urgent need to strike a balance between the velocity and quality of research, and to cautiously consider medical information and clinical applicability in a pressing, pandemic context. Systematic review registration https://osf.io/5zjyx/

Published
2021
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4. C5b9 Deposition in Glomerular Capillaries Is Associated With Poor Kidney Allograft Survival in Antibody-Mediated Rejection

Author

Valentin Goutaudier, Hélène Perrochia, Simon Mucha, Marie Bonnet, Sylvie Delmas, Florian Garo, Valérie Garrigue, Sébastien Lepreux, Vincent Pernin, Jean-Emmanuel Serre, Ilan Szwarc, Pierre Merville, Annie Ramounau-Pigot, Céline René, Jonathan Visentin, Bryan Paul Morgan, Véronique Frémeaux-Bacchi, Georges Mourad, Lionel Couzi, and Moglie Le Quintrec

Subjects
antibody-mediated rejection, kidney transplantation, complement, C4d, C5b9, Immunologic diseases. Allergy, RC581-607
Abstract

C4d deposition in peritubular capillaries (PTC) reflects complement activation in antibody-mediated rejection (ABMR) of kidney allograft. However, its association with allograft survival is controversial. We hypothesized that capillary deposition of C5b9—indicative of complement-mediated injury—is a severity marker of ABMR. This pilot study aimed to determine the frequency, location and prognostic impact of these deposits in ABMR. We retrospectively selected patients diagnosed with ABMR in two French transplantation centers from January 2005 to December 2014 and performed C4d and C5b9 staining by immunohistochemistry. Fifty-four patients were included. Median follow-up was 52.5 (34.25–73.5) months. Thirteen patients (24%) had C5b9 deposits along glomerular capillaries (GC). Among these, seven (54%) had a global and diffuse staining pattern. Twelve of the C5b9+ patients also had deposition of C4d in GC and PTC. C4d deposits along GC and PTC were not associated with death-censored allograft survival (p = 0.42 and 0.69, respectively). However, death-censored allograft survival was significantly lower in patients with global and diffuse deposition of C5b9 in GC than those with a segmental pattern or no deposition (median survival after ABMR diagnosis, 6 months, 40.5 months and 44 months, respectively; p = 0.015). Double contour of glomerular basement membrane was diagnosed earlier after transplantation in C5b9+ ABMR than in C5b9– ABMR (median time after transplantation, 28 vs. 85 months; p = 0.058). In conclusion, we identified a new pattern of C5b9+ ABMR, associated with early onset of glomerular basement membrane duplication and poor allograft survival. Complement inhibitors might be a therapeutic option for this subgroup of patients.

Published
2019
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5. Subclinical rejection-free diagnostic after kidney transplantation using blood gene expression

Author

Richard Danger, Ludmilla Le Berre, Marion Cadoux, Clarisse Kerleau, Emmanuelle Papuchon, Hoa Le Mai, Thi-Van-Ha Nguyen, Pierrick Guérif, Emmanuel Morelon, Olivier Thaunat, Christophe Legendre, Dany Anglicheau, Carmen Lefaucheur, Lionel Couzi, Arnaud Del Bello, Nassim Kamar, Moglie Le Quintrec, Valentin Goutaudier, Karine Renaudin, Magali Giral, Sophie Brouard, Lionel Badet, Maria Brunet, Fanny Buron, Rémi Cahen, Ricardo Codas, Sameh Daoud, Valérie Dubois, Coralie Fournie, François Gaillard, Arnaud Grégoire, Alice Koenig, Charlène Lévi, Claire Pouteil-Noble, Maud Rabeyrin, Thomas Rimmelé, Gilles Blancho, Julien Branchereau, Diego Cantarovich, Agnès Chapelet, Jacques Dantal, Clément Deltombe, Lucile Figueres, Raphael Gaisne, Claire Garandeau, Caroline Gourraud-Vercel, Maryvonne Hourmant, Georges Karam, Delphine Kervella, Christophe Masset, Aurélie Meurette, Simon Ville, Christine Kandell, Anne Moreau, Florent Delbos, Alexandre Walencik, Anne Devis, Lucile Amrouche, Olivier Aubert, Lynda Bererhi, Alexandre Loupy, Frank Martinez, Arnaud Méjean, Rébecca Sberro-Soussan, Anne Scemla, Marc-Olivier Timsit, and Julien Zuber

Subjects
Nephrology
Published
2023
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6. An automated histological classification system for precision diagnostics of kidney allografts

Author

Daniel Yoo, Valentin Goutaudier, Gillian Divard, Juliette Gueguen, Brad C. Astor, Olivier Aubert, Marc Raynaud, Zeynep Demir, Julien Hogan, Patricia Weng, Jodi Smith, Rouba Garro, Bradley A. Warady, Rima S. Zahr, Marta Sablik, Katherine Twombley, Lionel Couzi, Thierry Berney, Olivia Boyer, Jean-Paul Duong-Van-Huyen, Magali Giral, Alaa Alsadi, Pierre A. Gourraud, Emmanuel Morelon, Moglie Le Quintrec, Sophie Brouard, Christophe Legendre, Dany Anglicheau, Jean Villard, Weixiong Zhong, Nassim Kamar, Oriol Bestard, Arjang Djamali, Klemens Budde, Mark Haas, Carmen Lefaucheur, Marion Rabant, and Alexandre Loupy

Subjects
General Medicine, General Biochemistry, Genetics and Molecular Biology
Published
2023
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7. Solid organ procurement and transplantation from deceased donors with vaccine-induced thrombosis and thrombocytopenia

Author

Valentin Goutaudier, Christian Jacquelinet, Alexandre Loupy, and François Kerbaul

Subjects
Transplantation, biology, business.industry, Heparin, medicine.disease, Thrombosis, Viral vector, Immunization, Immunology, biology.protein, Immunology and Allergy, Medicine, Pharmacology (medical), Platelet, Antibody, business, Platelet factor 4, medicine.drug
Abstract

In late February 2021, the first cases of vaccine-induced thrombosis and thrombocytopenia (VITT) were observed in patients after immunization with the ChAdOx1 nCoV-19 adenoviral vector vaccine (Oxford, AstraZeneca) against SARS-CoV-2.1 This prothrombotic response is presumed to be mediated by anti-platelet factor 4 (PF4) antibodies that activate platelets and induce activation and extracellular traps formation of neutrophils.2 These antibodies can also be seen in autoimmune heparin-induced thrombocytopenia, but all the described cases had no previous exposure to heparin.

Published
2021
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8. Absence of Mortality Differences Between the First and Second COVID-19 Waves in Kidney Transplant Recipients

Author

Bastien Berger, Marc Hazzan, Nassim Kamar, Hélène Francois, Marie Matignon, Clarisse Greze, Philippe Gatault, Luc Frimat, Pierre F. Westeel, Valentin Goutaudier, Renaud Snanoudj, Charlotte Colosio, Antoine Sicard, Dominique Bertrand, Christiane Mousson, Jamal Bamoulid, Antoine Thierry, Dany Anglicheau, Lionel Couzi, Jonathan M. Chemouny, Agnes Duveau, Valerie Moal, Yannick Le Meur, Gilles Blancho, Jérôme Tourret, Paolo Malvezzi, Christophe Mariat, Jean-Philippe Rerolle, Nicolas Bouvier, Sophie Caillard, Olivier Thaunat, Hospices Civils de Lyon (HCL), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques Nancy, Cancéropôle du Grand Est-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Inserm UMR 1227 Immunothérapies et Pathologies Lymphocytaires B, Hôpital Morvan - CHRU de Brest (CHU - BREST ), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), OT is supported by the Etablissement Français du Sang and the Fondation pour la Recherche Médicale (PME20180639518)., Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Transplantation, Nephrology, [SDV]Life Sciences [q-bio], SARS-CoV2
Abstract

International audience; Introduction - SARS-CoV-2 pandemic evolved in 2 consecutive waves during 2020. Improvements in the management of COVID-19 led to a reduction in mortality rates among hospitalized patients during the second wave. Whether this progress benefited kidney transplant recipients (KTRs), a population particularly vulnerable to severe COVID-19, remained unclear. Methods - In France, 957 KTRs were hospitalized for COVID-19 in 2020 and their data were prospectively collected into the French Solid Organ Transplant (SOT) COVID registry. The presentation, management, and outcomes of the 359 KTRs diagnosed during the first wave were compared to those of the 598 of the second wave. Results - Baseline comorbidities were similar between KTRs of the 2 waves. Maintenance immunosuppression was reduced in most patients but withdrawal of antimetabolite (73.7% vs. 58.4%, < 0.001) or calcineurin inhibitor (32.1% vs. 16.6%, < 0.001) was less frequent during the second wave. Hydroxychloroquine and azithromycin that were commonly used during the first wave (21.7% and 30.9%, respectively) but were almost abandoned during the second wave. In contrast, the use of high dose corticosteroids doubled (19.5% vs. 41.6%, < 0.001). Despite these changing trends in COVID-19 management, 60-day mortality was not statistically different between the 2 waves (25.3% vs. 23.9%; Log Rank, = 0.48) and COVID-19 hospitalization period was not associated with death due to COVID-19 in multivariate analysis (Hazard ratio 0.89, 95% confidence interval 0.67-1.17, = 0.4). Conclusion - We conclude that changing of therapeutic trends during 2020 did not reduce COVID-19 related mortality among KTRs. Our data indirectly support the importance of vaccination and neutralizing monoclonal anti-SARS-CoV-2 antibodies to protect KTRS from severe COVID-19.

Published
2022
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9. Changing of therapeutic trends between the 1st and 2nd wave did not reduce COVID-19 related mortality of renal transplant recipients: a national registry study

Author

Valentin Goutaudier, Philippe Gatault, Marc Hazzan, Bastien Berger, Sophie Caillard, and Nassim Kamar

Abstract

SARS-CoV-2 pandemic evolved in two consecutive waves over 2020 (for France: 1st wave from March 1 to July 31; and 2nd wave from August 1 to December 31). Improvements in the management of COVID-19 led to a reduction of mortality rates in hospitalized patients during the second wave. Whether this progress also benefited to kidney transplant recipients (KTR), a population particularly vulnerable to severe COVID-19, remained unclear.In France, 957 KTR were hospitalized for COVID-19 in 2020 and their data were prospectively collected in the French SOT COVID registry. The presentation, management, and outcomes of the 359 KTR diagnosed during the 1st wave were compared to those of the 598 of the 2nd wave. Baseline comorbidities were largely similar between KTR of the 2 waves. Maintenance immunosuppression was reduced in most patients but withdrawal of antimetabolite (73.7% vs 58.4%, pWe conclude that changing of therapeutic trends during 2020 did not reduce COVID-19 related mortality in KTR. Our data indirectly support the importance of vaccination and monoclonal neutralizing anti-SARS-CoV-2 antibodies to protect KTR from severe COVID-19.

Published
2021
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11. Global Perspective on Kidney Transplantation: France

Author

Valentin Goutaudier and Gillian Divard

Subjects
education.field_of_study, medicine.medical_specialty, Tissue and Organ Procurement, business.industry, medicine.medical_treatment, Population, Global Perspectives, General Medicine, medicine.disease, Kidney Transplantation, Transplantation, Donation, Family medicine, Health care, Medicine, Humans, Kidney Failure, Chronic, Organ donation, France, business, education, Kidney transplantation, Dialysis, Kidney disease
Abstract

France is a country in Western Europe with a population of 6706 million in 2020 (1). This country has a universal health care system financed by a compulsory health insurance taxation on the basis of worker income, which refunds patients 70% of most health care costs and 100% for costly or long-term diseases, such as Chronic kidney disease (CKD). CKD affects nearly 3 million people, and the prevalence increases by 2% each year (1). Among them, 89,692 are treated by dialysis or received a kidney transplant. France has been a pioneer in transplantation, with the first living donor kidney transplant performed in 1952 (2). After two decades of transplants with living donors, the first bioethics laws were enacted in 1976, authorizing deceased donor procurement and instituting three rules for organ donation: ( 1 ) all adult residents are presumed to be consenting to donate except in case of expression of refusal during lifetime, ( 2 ) donation is anonymized, and ( 3 ) donation is free of charge. Since 2004, organ procurement is organized by the Biomedicine Agency, which is in charge of ensuring equity and safety of organ allocation and collecting donor characteristics, recipient characteristics, and follow-up through the French national database called CRISTAL. The national allocation system for deceased donors is made on the basis of a scoring system from the local and national levels and also, some national allocation priorities (Figure 1). Kidney transplantation is currently performed in 47 centers, mostly public university hospitals, of which 14 perform 60% of the transplants (3). Figure 1. French national allocation policy for kidney from deceased donors. Adapted from the (rules of allocation of organs from deceased donor), Agence de la biomedecine, 2015. The French allocation system for deceased donors is on the basis of a scoring system, from the local and national levels and also, some …

Published
2021

12. Is COVID‐19 infection more severe in kidney transplant recipients?

Author

Nathalie Chavarot, Bruno Moulin, Valérie Moal, Olivier Thaunat, Marc Hazzan, Jamal Bamoulid, Antoine Durrbach, Christiane Mousson, Nassim Kamar, Yannick Lemeur, Charlotte Kaeuffer, Clarisse Greze, Philippe Grimbert, Ilies Benotmane, Dominique Bertrand, Antoine Thierry, Tristan Legris, Gilles Blancho, Pierre François Westeel, Mariam Jdidou, Hélène François, Sophie Caillard, Marie Matignon, Yvon Ruch, Morgane Solis, Antoine Sicard, Dany Anglicheau, Philippe Gatault, Valentin Goutaudier, François Danion, Lionel Couzi, Charlotte Colosio, Renaud Snanoudj, Christophe Masset, Agnès Duveau, Jonathan M. Chemouny, Luc Frimat, CHU Strasbourg, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor [Créteil], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Tours (UT), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Aix Marseille Université (AMU), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques Nancy, Cancéropôle du Grand Est-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Amiens-Picardie, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre Hospitalier Universitaire de Reims (CHU Reims), Unité de Recherche Clinique de la Côte d’Azur (URRIS UR2CA), Centre Hospitalier Universitaire de Nice (CHU Nice)-Université Côte d'Azur (UCA), Hôpital Pasteur [Nice] (CHU), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Université de Bourgogne (UB), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Poitiers, Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), CHU de Bordeaux Pellegrin [Bordeaux], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université d'Angers (UA), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), CHRU Brest - Service de Nephrologie (CHU - BREST - Nephrologie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), University of Lille, This study was supported by the Strasbourg University Hospital (COVIS-HUS Study- HUS number 7760), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), AP-HP Hôpital Tenon [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, CHU Toulouse [Toulouse], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre d'Investigation Clinique - Innovation Technologique [Nancy] (CIC-IT), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), University Hospital of Montpellier, Hôpital Bicêtre, Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Rouen, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Bordeaux [Bordeaux], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Henri Mondor, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche Clinique de la Côte d’Azur [Nice] (URRIS UR2CA), Université Côte d'Azur (UCA), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Tours, Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), PINIER, CHRISTINE, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)

Subjects
medicine.medical_treatment, [SDV]Life Sciences [q-bio], MESH: Registries, Aucun, MESH: Comorbidity, 030230 surgery, law.invention, chemistry.chemical_compound, 0302 clinical medicine, law, cardiovascular disease, MESH: Risk Factors, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, clinical research / practice, Immunology and Allergy, Cumulative incidence, Pharmacology (medical), kidney transplantation / nephrology, MESH: Incidence, MESH: Aged, Univariate analysis, MESH: France / epidemiology, MESH: Middle Aged, MESH: Transplant Recipients / statistics & numerical data, Acute kidney injury, Intensive care unit, 3. Good health, MESH: COVID-19 / epidemiology, Cohort, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, glomerular filtration rate (GFR), kidney failure / injury, medicine.medical_specialty, infection and infectious agents - viral, infectious disease, Brief Communication, MESH: Graft Rejection / prevention & control, 03 medical and health sciences, Internal medicine, Diabetes mellitus, MESH: Severity of Illness Index, MESH: COVID-19 / diagnosis, medicine, Humans, MESH: SARS-CoV-2, Mechanical ventilation, Creatinine, Transplantation, MESH: Humans, business.industry, SARS-CoV-2, MESH: Graft Rejection / epidemiology, COVID-19, MESH: Retrospective Studies, medicine.disease, Kidney Transplantation, Transplant Recipients, MESH: Male, immunosuppressive regimens, MESH: Immunosuppressive Agents / therapeutic use, MESH: Pandemics, MESH: Propensity Score, chemistry, Reinfection, MESH: Immunosuppression / methods, MESH: Intensive Care Units, business, MESH: Female, MESH: Kidney Transplantation
Abstract

International audience; There are no studies which have compared the risk of severe Covid-19 and related mortality between transplant recipients and non-transplant patients. We enrolled two groups of patients hospitalized for Covid-19, i.e., kidney transplant recipients from the French Registry of Solid Organ Transplant (n=306) and a single-center cohort of non-transplant patients (n=795). An analysis was performed among subgroups matched for age and risk factors for severe Covid-19 or mortality. Severe Covid-19 was defined as admission (or transfer) to an intensive care unit, need for mechanical ventilation, or death.Transplant recipients were younger and had more comorbidities compared to non-transplant patients. They presented with higher creatinine levels and developed more episodes of acute kidney injury. After matching, the 30-day cumulative incidence of severe Covid-19 did not differ between KTR and non-transplant patients; however, 30-day Covid-19-related mortality was significantly higher in KTR (17.9% versus 11.4%, respectively, p=0.038). Age >60 years, cardiovascular disease, dyspnea, fever, lymphopenia, and C-reactive protein (CRP) were associated with severe Covid-19 in univariate analysis, whereas transplant status and serum creatinine levels were not. Age >60 years, hypertension, cardiovascular disease, diabetes, CRP >60 mg/L, lymphopenia, kidney transplant status (HR=1.55), and creatinine level >115 µmol/L (HR=2.32) were associated with Covid-19-related mortality in univariate analysis. In multivariable analysis, cardiovascular disease, dyspnea, and fever were associated with severe disease, whereas age >60 years, cardiovascular disease, dyspnea, fever, and creatinine level>115 µmol/L retained their independent associations with mortality. Kidney transplant recipients had a higher Covid-19-related mortality compared to non-transplant hospitalized patients.

Published
2021
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13. C5b9 Deposition in Glomerular Capillaries Is Associated With Poor Kidney Allograft Survival in Antibody-Mediated Rejection

Author

Valentin Goutaudier, Hélène Perrochia, Simon Mucha, Marie Bonnet, Sylvie Delmas, Florian Garo, Valérie Garrigue, Sébastien Lepreux, Vincent Pernin, Jean-Emmanuel Serre, Ilan Szwarc, Pierre Merville, Annie Ramounau-Pigot, Céline René, Jonathan Visentin, Bryan Paul Morgan, Véronique Frémeaux-Bacchi, Georges Mourad, Lionel Couzi, Moglie Le Quintrec, Salvy-Córdoba, Nathalie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pôle Biologie-Pathologie [CHRU Montpellier], Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Service d'immunologie et d'immunogénétique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], Service d'immunologie [HEGP, Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)

Subjects
0301 basic medicine, Graft Rejection, Male, Pathology, Kidney Glomerulus, MESH: Graft Rejection / immunology, Kidney Glomerulus / immunology, Renal Artery / immunology, Retrospective Studies, Complement Membrane Attack Complex, Peritubular capillaries, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 0302 clinical medicine, Renal Artery, Immunology and Allergy, complement, Complement Activation, Kidney transplantation, Original Research, Kidney, Glomerular basement membrane, Middle Aged, Allografts, C4d, 3. Good health, medicine.anatomical_structure, Kidney Tubules, antibody-mediated rejection, Immunohistochemistry, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Kidney Diseases, lcsh:Immunologic diseases. Allergy, Adult, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, C5b9, Immunology, kidney transplantation, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Antibodies, 03 medical and health sciences, medicine, Humans, business.industry, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Staining, Complement system, Capillaries, Transplantation, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Allografts / immunotherapy, Antibodies / immunology, Capillaries / immunology, Complement Membrane Attack Complex / immunology, business, lcsh:RC581-607, 030215 immunology
Abstract

International audience; C4d deposition in peritubular capillaries (PTC) reflects complement activation in antibody-mediated rejection (ABMR) of kidney allograft. However, its association with allograft survival is controversial. We hypothesized that capillary deposition of C5b9-indicative of complement-mediated injury-is a severity marker of ABMR. This pilot study aimed to determine the frequency, location and prognostic impact of these deposits in ABMR. We retrospectively selected patients diagnosed with ABMR in two French transplantation centers from January 2005 to December 2014 and performed C4d and C5b9 staining by immunohistochemistry. Fifty-four patients were included. Median follow-up was 52.5 (34.25-73.5) months. Thirteen patients (24%) had C5b9 deposits along glomerular capillaries (GC). Among these, seven (54%) had a global and diffuse staining pattern. Twelve of the C5b9+ patients also had deposition of C4d in GC and PTC. C4d deposits along GC and PTC were not associated with death-censored allograft survival (p = 0.42 and 0.69, respectively). However, death-censored allograft survival was significantly lower in patients with global and diffuse deposition of C5b9 in GC than those with a segmental pattern or no deposition (median survival after ABMR diagnosis, 6 months, 40.5 months and 44 months, respectively; p = 0.015). Double contour of glomerular basement membrane was diagnosed earlier after transplantation in C5b9+ ABMR than in C5b9- ABMR (median time after transplantation, 28 vs. 85 months; p = 0.058). In conclusion, we identified a new pattern of C5b9+ ABMR, associated with early onset of glomerular basement membrane duplication and poor allograft survival. Complement inhibitors might be a therapeutic option for this subgroup of patients.

Published
2018
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14. Primary sclerosing cholangitis: a new cause of distal renal tubular acidosis

Author

I. Szwarc, Àngel Argilés, Jean Ribstein, Georges-Philippe Pageaux, Jean-Emmanuel Serre, Valentin Goutaudier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Néphrologie Dialyse Saint Guilhem (NDSG), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), and Néphrologie Dialyse Saint Guilhem ( NDSG )

Subjects
medicine.medical_specialty, Pathology, Urinary system, 030232 urology & nephrology, distal renal tubular acidosis, Gastroenterology, Primary sclerosing cholangitis, Nephropathy, Renal tubular acidosis, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, Distal renal tubular acidosis, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Internal medicine, medicine, 030212 general & internal medicine, Transplantation, liver transplantation, business.industry, primary sclerosing cholangitis, Metabolic acidosis, Jaundice, medicine.disease, Hypokalemia, 3. Good health, Nephrology, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; We describe the first case of distal renal tubular acidosis (dRTA) associated with primary sclerosing cholangitis. A 26-year-old Lao-Thai male patient presented with severe jaundice, metabolic acidosis and hypokalaemia. He was diagnosed of dRTA. Liver transplantation resulted in correction of electrolyte disturbances and hyperbilirubinaemia. A fludrocortisone-furosemide test revealed normal urinary acidification, demonstrating no residual dRTA. This observation suggests that dRTA may be an early manifestation of bilirubin-associated nephropathy or the consequence of an immune mechanism.

Published
2016
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