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1. Treatment With a Three-Drug Regimen for Pulmonary Tuberculosis Based on Rapid Molecular Detection of Isoniazid Resistance: A Noninferiority Randomized Trial (FAST-TB)

Author

de Castro, N, Mechaï, F, Bachelet, D, Canestri, A, Joly, V, Vandenhende, M, Boutoille, D, Kerjouan, M, Veziris, N, Molina, J, Grall, N, Tattevin, P, Laouénan, C, Yazdanpanah, Y, Jonchère, Laurent, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Avicenne [AP-HP], AP-HP - Hôpital Bichat - Claude Bernard [Paris], INSERM U64 [AP-HP Hôpital Tenon], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Bordeaux [Bordeaux], Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Pontchaillou [Rennes], Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UR)-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 ), and This work was funded by the French Ministry of Health (PHRC n°P 120130/N°AOM12317). The sponsor of the study was Assistance Publique-Hôpitaux de Paris and its clinical research department (Département de la Recherche Clinique et du Développement).

Subjects
Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Oncology, drug-susceptible tuberculosis, ethambutol, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, nucleic acid amplification
Abstract

Background The rationale behind the use of ethambutol in the standard tuberculosis treatment is to prevent the emergence of resistance to rifampicin in case of primary resistance to isoniazid. We evaluated whether early detection of isoniazid resistance using molecular testing allows the use an ethambutol-free regimen. Methods FAST-TB, a phase 4, French, multicenter, open-label, non-inferiority trial, compared 2 strategies: (1) polymerase chain reaction (PCR)-based detection of isoniazid and rifampicin resistance at baseline using Genotype MTBDRplus version 2.0 followed by ethambutol discontinuation if no resistance was detected (PCR arm) and (2) a standard 4-drug combination, pending phenotypic drug-susceptibility results (C arm). Adult patients with smear-positive pulmonary tuberculosis were enrolled. The primary endpoint was the proportion of patients with treatment success defined as bacteriological or clinical cure at the end of treatment. A non-inferiority margin of 10% was used. Results Two hundred three patients were randomized, 104 in the PCR arm and 99 in the C arm: 26.6% were female, median age was 37 (interquartile range, 28–51) years, 72.4% were born in Africa, and 5.4% were infected with human immunodeficiency virus. Chest x-ray showed cavities in 64.5% of the cases. Overall, 169 patients met criteria of treatment success: 87 of 104 (83.7%) in the PCR arm and 82 of 99 (82.8%) in the C arm with a difference of +0.8% (90% confidence interval, −7.9 to 9.6), meeting the noninferiority criteria in the intention-to-treat population (P = .02). Conclusions In a setting with low prevalence of primary isoniazid resistance, a 3-drug combination with isoniazid, rifampicin, and pyrazinamide, based on rapid detection of isoniazid resistance using molecular testing, was noninferior to starting the recommended 4-drug regimen.

Published
2022

2. Validation of Baveno VI Criteria for Screening and Surveillance of Esophageal Varices in Patients With Compensated Cirrhosis and a Sustained Response to Antiviral Therapy

Author

Dominique Thabut, Christophe Bureau, Richard Layese, Valérie Bourcier, Maryam Hammouche, Carole Cagnot, Patrick Marcellin, Dominique Guyader, Stanislas Pol, Dominique Larrey, Victor De Lédinghen, Denis Ouzan, Fabien Zoulim, Dominique Roulot, Albert Tran, Jean-Pierre Bronowicki, Jean-Pierre Zarski, Odile Goria, Paul Calès, Jean-Marie Péron, Laurent Alric, Marc Bourlière, Philippe Mathurin, Jean-Frédéric Blanc, Armand Abergel, Lawrence Serfaty, Ariane Mallat, Jean-Didier Grangé, Pierre Attali, Yannick Bacq, Claire Wartelle-Bladou, Thông Dao, Christophe Pilette, Christine Silvain, Christos Christidis, Dominique Capron, Brigitte Bernard-Chabert, Sophie Hillaire, Vincent Di Martino, Angela Sutton, Etienne Audureau, Françoise Roudot-Thoraval, Pierre Nahon, Hélène Fontaine, Vincent Leroy, Ghassan Riachi, Sebastien Dharancy, Claire Wartelle, Gérard Thiefin, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Toulouse [Toulouse], Clinical Epidemiology and Ageing : Geriatrie Soins Primaires et Santé Publique (CEpiA), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANRS France Recherche Nord & sud Sida-hiv hépatites, Hôpital Beaujon [AP-HP], CHU Pontchaillou [Rennes], Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hôpital Avicenne [AP-HP], Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Hôpital Michallon, Hôpital Charles Nicolle [Rouen], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Saint-Joseph [Marseille], Hôpital Claude Huriez [Lille], CHU Lille, Service d'Hépatologie Gastro-entérologie [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU Saint-Antoine [AP-HP], INSERM U64 [AP-HP Hôpital Tenon], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Tenon [AP-HP], Centre Hépato-Biliaire [Hôpital Paul Brousse] (CHB), Hôpital Paul Brousse-Assistance Publique - Hôpitaux de Paris, Département d'hépato-gastro-entérologie [Hôpital Trousseau : CHRU Tours], CHU Trousseau [APHP], Centre Hospitalier d'Aix en Provence [Aix-en-Provence] (CHIAP ), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Le Mans (CH Le Mans), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Institut Mutualiste de Montsouris (IMM), Service d'Hépato Gastroenterologie [CHU Amiens-Picardie], CHU Amiens-Picardie, Hôpital Robert Debré Paris, Hôpital Robert Debré, Hôpital Foch [Suresnes], Hôpital JeanMinjoz, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Liver Cirrhosis, Male, 0301 basic medicine, Cirrhosis, Sustained Virologic Response, MESH: Sustained Virologic Response, MESH: Elasticity Imaging Techniques, medicine.disease_cause, Gastroenterology, Endoscopy, Gastrointestinal, 0302 clinical medicine, Esophageal varices, MESH: Practice Guidelines as Topic, Interquartile range, Mass Screening, MESH: Middle Aged, medicine.diagnostic_test, Portal Hypertension, Middle Aged, MESH: Endoscopy, Gastrointestinal, MESH: Hepatitis C, Chronic, Survival Rate, Population Surveillance, Hepatocellular carcinoma, Practice Guidelines as Topic, Disease Progression, Elasticity Imaging Techniques, Female, 030211 gastroenterology & hepatology, MESH: Disease Progression, Variceal Bleeding, MESH: Liver Cirrhosis, MESH: Antiviral Agents, medicine.medical_specialty, MESH: Survival Rate, MESH: Hepatitis B, Chronic, Hepatitis C virus, Esophageal and Gastric Varices, Antiviral Agents, MESH: Population Surveillance, 03 medical and health sciences, Elastometry, MESH: Esophageal and Gastric Varices, Hepatitis B, Chronic, Esophagus, Internal medicine, Hypertension, Portal, medicine, Humans, MESH: Mass Screening, MESH: Platelet Count, Hepatitis B virus, Prothrombin time, MESH: Hypertension, Portal, MESH: Humans, Hepatology, Platelet Count, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, Chronic, medicine.disease, digestive system diseases, MESH: Male, 030104 developmental biology, business, Varices, MESH: Female
Abstract

International audience; Background & aims: Management of patients with cirrhosis includes endoscopic screening and surveillance to detect esophageal varices (EV) and prevent bleeding. However, the Baveno VI guidelines recommend avoiding endoscopies for patients with liver stiffness measurements below 20 kPa and platelet counts above 150,000 (favorable Baveno VI status) and endoscopic assessment of patients with higher levels of liver stiffness and platelet counts (unfavorable Baveno VI status). We aimed to validate the Baveno VI guidelines, evaluating outcomes of patients in the ANRS-CO12 CirVir cohort with compensated cirrhosis associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, with or without a sustained response to antiviral therapy.Methods: We performed an ancillary study using data from 891 patients in the ANRS CO12 CirVir cohort, treated at 35 centers in France, with HCV or HBV infection and biopsy-proven cirrhosis, Child-Pugh A scores, no previous complications, and no hepatocellular carcinoma who underwent an endoscopic procedure and had interpretable liver stiffness measurements and platelet counts. Progression of portal hypertension (PHT) was defined as the onset of varices needing treatment (VNT) or PHT-related bleeding. An sustained response to antiviral therapy was defined as undetectable level of HCV RNA by polymerase chain reaction assay (

Published
2019

3. Long-term safety and vaccine-induced seropositivity in healthy volunteers from HIV vaccine trials

Author

Bénédicte Bonnet, Anrs, Jean-Daniel Lelièvre, Christelle Paul, Isabelle Poizot-Martin, Amel Bouakane, Corinne Desaint, Laurence Meyer, Odile Launay, Sophie Grabar, Lise Cuzin, Bruno Spire, Christine Durier, Gilles Pialoux, Benjamin Silbermann, Essais Therapeutiques et Infection Par Le Vih, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Biotherapie - AP-HP (cochin - Pasteur), Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immunologie clinique [Créteil], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de médecine interne et centre de référence des maladies rares [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Maladies infectieuses et tropicales [CHU Tenon], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service Maladies infectieuses et tropicales [CHU Toulouse], Pôle Inflammation, infection, immunologie et loco-moteur [CHU Toulouse] (Pôle I3LM Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Assistance Publique - Hôpitaux de Marseille (APHM), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANRS France Recherche Nord & sud Sida-hiv hépatites, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Cochin Pasteur (CIC 1417), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes, Sorbonne Paris Cité, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Cochin [AP-HP], INSERM U64 [AP-HP Hôpital Tenon], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Tenon [AP-HP], CHU Toulouse [Toulouse], Centre hospitalier universitaire de Nantes (CHU Nantes), Aix Marseille Université (AMU), Santé et droits sexuels et reproductifs (Unité Ined - Inserm - Université Paris Sud - UVSQ) (UR14), Institut national d'études démographiques (INED), Service de Maladies Infectieuses et Tropicales, Service des maladies infectieuses et tropicales [CHU Tenon], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe hospitalier Broca-Université Paris Descartes - Paris 5 (UPD5)-Hôtel-Dieu-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and GRABAR, SOPHIE

Subjects
0301 basic medicine, Vaccine-induced seropositivity, Male, HIV Infections, long-term follow-up, HIV Antibodies, 0302 clinical medicine, vaccine-induced seropositivity, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Surveys and Questionnaires, Immunology and Allergy, 030212 general & internal medicine, Prospective Studies, HIV vaccine, Prospective cohort study, AIDS Vaccines, education.field_of_study, Clinical Trials as Topic, Clinical Trials, Phase I as Topic, risk of HIV exposure, Middle Aged, Healthy Volunteers, 3. Good health, Infectious Diseases, Cohort, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, France, Adult, safety, medicine.medical_specialty, Sexual Behavior, Immunology, Population, Time, 03 medical and health sciences, Clinical Trials, Phase II as Topic, Internal medicine, medicine, Humans, Adverse effect, education, Social Behavior, Retrospective Studies, business.industry, preventive HIV vaccine trials, Retrospective cohort study, 030104 developmental biology, Standardized mortality ratio, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract

International audience; Background: The ANRS COV1-COHVAC cohort was a long-term safety cohort of healthy volunteers who received preventive HIV-vaccine candidates in 17 phase I/II clinical trials.Methods: Data collected from the first vaccine candidate administration and annually after inclusion in the cohort included grade 3/4 adverse events and all grade adverse events suggestive of neurological, ophthalmological and immune disorders, self-administered questionnaires on behaviors and HIV ELISA results. Age-and-sex-standardized mortality ratios (SMRs) were calculated with respect to the French population. The cohort was early terminated in 2016 due to the absence of safety signal.Results: Of 496 volunteers, 488 were included: 355 in the 7-year prospective follow-up and 133 in the retrospective data collection only. The total follow-up after the first vaccination was 4934 person-years (median: 10 years) and 270 (76%) volunteers completed their follow-up. No relevant adverse event possibly related to the vaccine was reported. Breast cancer incidence and woman mortality did not differ from those of the French general population (standardized incidence ratio = 1.47, P = 0.45 and SMR = 0.65, P = 0.28, respectively) while man mortality was significantly lower (SMR = 0.26, P = 0.0003). At the last visit, 21/29 (72%) volunteers who received the recombinant HIV gp160 protein still showed vaccine-induced seropositivity after a median follow-up of 23 years. Only a few volunteers reported risky sexual practices (men: 20/192, women: 2/162).Conclusion: Volunteers showed a sustained high commitment. No long-term safety alert was identified during the postvaccine follow-up. Participating in vaccine trials did not increase risky behaviors for HIV infection. Vaccine-induced seropositivity may persist for more than 23 years after receiving rgp160.

Published
2019

4. T-cell transcriptome analysis points up a thymic disorder in idiopathic nephrotic syndrome

Author

Mansour, Hicham, Cheval, Lydie, Elalouf, Jean-Marc, Aude, Jean-Christophe, Alyanakian, Maria-Alexandra, Mougenot, Béatrice, Doucet, Alain, Deschênes, Georges, Mougenot, Baatrice, Deschanes, Georges, Saint George Hospital University Medical Center [UOB LIBAN], University of Balamand [Liban] (UOB), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Eco-Anthropologie et Ethnobiologie (EAE), Muséum national d'Histoire naturelle (MNHN)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), INSERM U64 [AP-HP Hôpital Tenon], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Néphrologie pédiatrique [Hôpital Robert Debré, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Saint George Hospital University Medical Center [Beirut, Lebanon], Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Nephrotic Syndrome, Cellular differentiation, [SDV]Life Sciences [q-bio], T-Lymphocytes, Kidney Glomerulus, 030232 urology & nephrology, Lymphocyte Activation, Transcriptome, 0302 clinical medicine, Recurrence, MESH: Child, MESH: L-Selectin, L-Selectin, Child, 0303 health sciences, education.field_of_study, Proteinuria, apoptosis, Glomerulonephritis, steroid-sensitive nephrotic syndrome, T-cell differentiation protein, 3. Good health, medicine.anatomical_structure, Nephrology, Child, Preschool, L-selectin, Female, medicine.symptom, MESH: CD2 Antigens, T cell, Population, CD2 Antigens, selection, Thymus Gland, Biology, 03 medical and health sciences, MESH: Gene Expression Profiling, MESH: Proteinuria, medicine, Humans, RNA, Messenger, education, MESH: Lymphocyte Activation, 030304 developmental biology, MESH: RNA, Messenger, MESH: Humans, Gene Expression Profiling, MESH: Child, Preschool, MESH: Kidney Glomerulus, MESH: Thymus Gland, medicine.disease, MESH: Male, MESH: Recurrence, MESH: T-Lymphocytes, Immunology, biology.protein, MESH: Nephrotic Syndrome, Nephrotic syndrome, MESH: Female, NFκB
Abstract

T-cell transcriptome analysis points up a thymic disorder in idiopathic nephrotic syndrome. Background Idiopathic nephrotic syndrome is a proteinuric disease secondary to the release of a nonidentified circulating glomerular permeability factor by T cells. Because specificities of T-cell activation in idiopathic nephrotic syndrome remain unknown, we evaluated transcriptional activation of T cells in nephrotic patients during proteinuria. Methods Transcriptomes of CD2+ cells were analyzed by serial analyis of gene expression (SAGE) in a nephrotic child during proteinuria relapse and after remission, away from any immunosuppressive treatment. Expression of specific transcripts overexpressed during proteinuria relapse was compared by reverse transcription-polymerase chain reaction (RT-PCR) in CD2+ cells from 11 nephrotic patients during relapse and remission and 11 nonnephrotic patients during infection and after recovery. Results Differential analysis of CD2+ cell transcriptome identified >200 mRNA tags overexpressed during proteinuria relapse, including many T-cell markers. RT-PCR analysis of expression of specific transcripts indicated that ( 1 ) under remission conditions, nephrotic children displayed induction of four transcripts, including IKBKB , and repression of NFKBIA as compared to nonnephrotic children after recovery, and ( 2 ) proteinuria relapse was associated with induction of L-selectin and T-lymphocyte maturation–associated protein, two markers of T-cell differentiation and recent emigrant/naive T cells. Conclusion Results indicate that circulating T cells from relapsing nephrotic patients include a significant population of low-mature cells while those from nephrotic patients in remission are characterized by constitutive activation of nuclear factor-κB (NF-κB), altogether suggesting a thymic dysregulation of apoptosis in nephrotic patients.

Published
2005

5. Protease resistance and binding of Ig light chains in myeloma-associated tubulopathies

Author

Anna Rocca, Guy Touchard, Marianne Leboulleux, Pierre Aucouturier, Brigitte Lelongt, Laure-Hélène Noël, Béatrice Mougenot, Raifah Makdassi, Pierre Ronco, Aucouturier, Pierre, Laboratoire d'Immunologie et Immunopathologie [CHU Poitiers] (CNRS URA 1172), Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre National de la Recherche Scientifique (CNRS), INSERM U64 [AP-HP Hôpital Tenon], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de Néphrologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), INSERM U90 [CHU Necker-Enfants Malades, AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by grants from INSERM (CRE 930602), the Association pour la Recherche contre le Cancer (N° 6044), and the Assistance Publique - Hbpitaux de Paris (CRC 940289)., and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Adult, Male, Tamm–Horsfall protein, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Proteolysis, 030204 cardiovascular system & hematology, Immunoglobulin light chain, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Cathepsin B, Antigen-Antibody Reactions, 03 medical and health sciences, 0302 clinical medicine, Mucoproteins, Adjuvants, Immunologic, Uromodulin, medicine, Humans, Aged, 030203 arthritis & rheumatology, chemistry.chemical_classification, Aged, 80 and over, Protease, biology, medicine.diagnostic_test, Chemistry, Middle Aged, Trypsin, Fanconi Syndrome, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Pepsin A, 3. Good health, Enzyme, Kidney Tubules, Myeloma Proteins, Biochemistry, Nephrology, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Immunoglobulin Light Chains, Kidney Diseases, Antibody, Multiple Myeloma, medicine.drug
Abstract

Protease resistance and binding of Ig light chains in myeloma-associated tubulopathies. Kidney tubule dysfunction and lesions are frequent complications of myeloma, related to unknown properties of the monoclonal light chain. We have analyzed protease sensitivity and binding properties of urinary light chains from four patients with Fanconi's syndrome, 12 with cast nephropathy, and four control patients without myeloma-associated tubulopathy. All light chains were normal-sized, monomeric and/or dimeric, and none was N-glycosylated. Kinetic studies of light chain digestion by pepsin and the lysosomal enzyme cathepsin B showed the generation of a protease-resistant 12 kDa fragment, corresponding to the V domain of the κ chain in the four Fanconi's syndrome patients; in two out of four the V domain was also completely resistant to trypsin. Western and dot blots revealed similar patterns of reactivity of light chains from patients with the Fanconi's syndrome towards other light chains. Properties of cast-nephropathy light chains were more heterogeneous but clearly differed from those of Fanconi's syndrome: (i) 9 out of 12 were of the λ-type; (ii) only four yielded a transient 12 kDa fragment after cathepsin B digestion, but all showed some resistance to proteolysis of the entire molecule or a fragment thereof to at least one protease, at variance with control light chains; (iii) they displayed various patterns of reactivity with other light chains; (iv) 7 out of 12 reacted specifically with Tamm-Horsfall protein (THP) by ELISA, in contrast with those of Fanconi's syndrome. In one patient who presented with cast nephropathy and the Fanconi's syndrome, the light chain exhibited both partial resistance of the Vκ domain to cathepsin B and the highest reactivity with THP. These results suggest that light chain toxicity in Fanconi's syndrome is related to the resistance of the V domain to degradation in lysosomes of proximal tubule epithelial cells. In contrast, cast nephropathy is an heterogeneous entity whose pathogenesis may involve multiple factors such as protease resistance, in addition to light chain reactivity with THP.

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