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1. PRODIG (Prevention of new onset diabetes after transplantation by a short term treatment of Vildagliptin in the early renal post-transplant period) study study protocol for a randomized controlled study

Author

S. Limat, Mathias Büchler, Jonathan M. Chemouny, Jamal Bamoulid, Laetitia Albano, Didier Ducloux, Emilie Gaiffe, Y. Le Meur, Marc Hazzan, Antoine Thierry, Amélie Anota, Gabriel Choukroun, Franck Bonnetain, Nacera Ouali, Dewi Vernerey, Cécile Courivaud, Thomas Crepin, Virginie Nerich, Elisabeth Cassuto, C. Legendre, L. Kessler, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Pontchaillou [Rennes], CHU Amiens-Picardie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Lille Inflammation Research International Center - U 995 (LIRIC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Strasbourg, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHRU Brest - Service de Nephrologie (CHU - BREST - Nephrologie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Urgences néphrologiques et transplantation rénale [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École Pratique des Hautes Études (EPHE), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Néphrologie [CHRU Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (HOTE GREFFON), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Université de Franche-Comté (UFC), Centre d'Investigation Clinique de Besançon (CICB), Etablissement Français du Sang Bourgogne Franche-Comté-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Service de néphrologie et immunologie clinique [CHRU Tours] (EA4245 UT), Hôpital Bretonneau-Université de Tours-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de néphrologie et transplantation rénale [Nice], Hôpital Pasteur [Nice] (CHU), Service de néphrologie, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service de Néphrologie [Amiens], CHU Amiens-Picardie-Hôpital Sud, Service de Néphrologie et Transplantation rénale [CHRU-lille], Service de Médecine Interne, Endocrinologie et Nutrition [CHU Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS)-CHU Strasbourg, Département de Néphrologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Hôpital Tenon, Service de Néphrologie, Assistance Publique - Hôpitaux de Paris, Département de Néphrologie [CHU Poitiers], Départment de pharmacie [CHRU Besançon], Inserm UMR 1098, Methodology and quality of life unit, Methodology and quality of life unit, Besançon, Université de Franche-Comté (UFC)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Lille Inflammation Research International Center (LIRIC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)

Subjects
Cost-Benefit Analysis, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Medicine (miscellaneous), [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, law.invention, Kidney transplantation, Study Protocol, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Outcome Assessment, Health Care, Medicine, Pharmacology (medical), Vildagliptin, 030212 general & internal medicine, Randomized Controlled Trials as Topic, Aged, 80 and over, lcsh:R5-920, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, [SDV.IMM]Life Sciences [q-bio]/Immunology, lcsh:Medicine (General), medicine.drug, medicine.medical_specialty, Nephropathy, 03 medical and health sciences, Double-Blind Method, Diabetes mellitus, Internal medicine, Diabetes Mellitus, Humans, Diabetes prevention, Dialysis, Aged, Glycated Hemoglobin, business.industry, medicine.disease, Transplantation, chemistry, Quality of Life, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Glycated hemoglobin, business, 030217 neurology & neurosurgery
Abstract

Background: Post-transplant diabetes is a frequent and serious complication of kidney transplantation. There is currently no treatment to prevent or delay the disease. Nevertheless, identification of risk factors make possible to target a population at risk to develop de novo diabetes. We hypothesized that a short term treatment with Vildagliptin may prevent new onset diabetes after transplantation (NODAT) in high-risk patients. Methods: This is a multicenter double-blind placebo-controlled randomized clinical trial. Patients undergoing first kidney transplantation will be included in 10 French transplant center. Included patients will be randomized (1:1) to receive either vildagliptin 100 or 50 mg/day (depending on glomerular filtration rate) during 2 months (the first dose being administered before entering the operating blocks) or placebo. Additional antidiabetic therapy could be administered according to glycemic control. The primary outcome is the proportion of diabetic patients 1 year after transplantation, defined as patients receiving a diabetic treatment, or having a fasting glucose above 7 mmol/l, or/and with an abnormal oral glucose tolerance test. Secondary outcomes include the glycated hemoglobin, the occurrence of acute rejection, infection, graft loss and patient death at 3 months, 6 months and 12 months after transplantation. The results will be correlated to clinical and general characteristics of the patient, cardiovascular history, nephropathy, dialysis history, transplantation data, biological data, the health-related quality of life and the cost-effectiveness of prevention of diabetes with vildagliptin. Discussion: There are only few data concerning pharmacological prevention of post-transplant diabetes. If our hypothesis is verified, our results will have a direct application in clinical practice and could limit diabetes-associated morbidity, reduce cardiovascular complications, increase quality of life of renal transplant patients, and consequently promote graft and patient survival. Our results may possibly serve for non-transplant patients carrying a high-risk of diabetes associated with other co-morbidities. Trial registration: ClinicalTrials.gov, NCT02849899 Registered on 8 February 2016. Keywords: Diabetes prevention; Vildagliptin; kidney transplantation; randomized controlled trial.

Published
2019
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2. Heavy-Chain Deposition Disease

Author

Eve Justrabo, François Martin, Michel Cogné, Bruno Chauffert, Jean-Louis Preud'homme, Ahmed Amine Khamlichi, Pierre Aucouturier, Guy Touchard, Laboratoire d'Immunologie et Immunopathologie [CHU Poitiers] (CNRS URA 1172), Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre National de la Recherche Scientifique (CNRS), Département de Néphrologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de Pathologie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Unité Humaine et Expérimentale de Cancérologie Digestive [CHU Dijon] (INSERM U252), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Aucouturier, Pierre

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Pathology, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunoproliferative disorder, 030232 urology & nephrology, Disease, 030204 cardiovascular system & hematology, Immunoglobulin light chain, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 03 medical and health sciences, 0302 clinical medicine, Immunopathology, medicine, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Amyloidosis, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 3. Good health, Heart failure, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, Nephrotic syndrome, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Monoclonal Immunoglobulin Deposition Disease
Abstract

Light-chain amyloidosis and light-chain deposition disease are closely related processes characterized by tissue deposition of organized (fibrillar) or nonorganized material related to monoclonal immunoglobulin light chains. Both conditions can occur in patients with immunoproliferative disorders. The clinical manifestations of light-chain deposition disease result from multivisceral involvement and are heterogeneous. Rapidly progressive renal failure or the nephrotic syndrome is the most common manifestation, but heart failure, arrhythmia, liver involvement (peliosis), and neurologic disorders may also be present. These findings may be caused by structural abnormalities or unusual behavior of deposited light chains. In particular, pathogenic light chains are characterized by unusual . . .

Published
1993
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3. Complementary DNA sequence of human amyloidogenic immunoglobulin light-chain precursors

Author

Guy Touchard, M Bauwens, Michel Cogné, Pierre Aucouturier, Jean-Louis Preud'homme, Ahmed Amine Khamlichi, 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), Département de Néphrologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), and This work was supported by grants from INSERM (CRE 893012) and the Association pour la Recherche sur le Cancer. A.A. K. is a recipient of a fellowship from the Ligue Nationale Centre de Cancer.

Subjects
Glycosylation, Amyloid, [SDV.IMM] Life Sciences [q-bio]/Immunology, Stereochemistry, Molecular Sequence Data, Bone Marrow Cells, Kidney, Immunoglobulin light chain, Biochemistry, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 03 medical and health sciences, 0302 clinical medicine, Bone Marrow, Complementary DNA, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Cloning, Molecular, Protein Precursors, Molecular Biology, Cells, Cultured, 030304 developmental biology, Sequence (medicine), 0303 health sciences, Base Sequence, biology, Amyloidosis, Nucleic acid sequence, Protein primary structure, DNA, Cell Biology, Blotting, Northern, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 030220 oncology & carcinogenesis, biology.protein, RNA, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunoglobulin Light Chains, Antibody, Research Article
Abstract

International audience; The primary structure of three amyloid precursor light chains was deduced from the sequence of complementary DNA (cDNA) from bone marrow cells from patients affected with classical lambda (patient Air) or kappa (patient Arn) amyloidosis and from a patient (Aub) in whom lambda amyloid deposits were unusual by their perimembranous location in the kidney glomerulus. All three RNAs were of normal size, as estimated by Northern blotting, and encoded normal-sized light chains. The deduced light-chain sequence from patient Arn was related to the V kappa 1 subgroup, and included ten residues that had not been previously reported at these positions, only one of which (Leu-21) was located in a beta-sheet (4-2). The unusual presence of Asn-70 determined a potential N-glycosylation site. The sequence of the light chain from patient Air belonged to the V lambda 1 subgroup, and included three unusually located amino acid residues, one of which had already been reported in an amyloidogenic lambda-chain. The sequence of the light chain from patient Aub was related to the V lambda 3 subgroup, and contained five amino acid residues that had not previously been described at the corresponding positions; two of them (His-36 and Ser-77) were located in beta-sheets (3-1 and 4-3 respectively). This sequence was also peculiar because of the presence of numerous acidic residues in the complementarity-determining regions. Such unusual primary structures might be responsible for the amyloidogenic properties of these light-chain precursors.

Published
1992
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4. Structure of a monoclonal kappa chain of the V kappa IV subgroup in the kidney and plasma cells in light chain deposition disease

Author

Jean-Louis Preud'homme, M Bauwens, Guy Touchard, Michel Cogné, Pierre Aucouturier, 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), Département de Néphrologie [CHU Poitiers], and Centre hospitalier universitaire de Poitiers (CHU Poitiers)

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.IMM] Life Sciences [q-bio]/Immunology, Blotting, Western, Molecular Sequence Data, Immunoglobulin Variable Region, Plasma cell, Kidney, Immunoglobulin light chain, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Light chain deposition disease, Immunoglobulin kappa-Chains, 03 medical and health sciences, 0302 clinical medicine, Hypergammaglobulinemia, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene Rearrangement, B-Lymphocyte, Light Chain, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Peptide sequence, 030304 developmental biology, 0303 health sciences, Base Sequence, Genes, Immunoglobulin, biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, Gene rearrangement, medicine.disease, Molecular biology, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Allotype, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, Kappa, Research Article
Abstract

International audience; That structural abnormalities may be responsible for nonamyloid immunoglobulin (Ig) light chain deposition disease (LCDD) is suggested by previous results of Ig biosynthesis studies, but this hypothesis was not documented at the molecular level. We report on the first complete primary sequence deduced from cDNA analysis of a kappa light chain responsible for LCDD associated with an apparently nonsecretory myeloma. Bone marrow myeloma cells contained intracellular kappa chains and no heavy chains by immunofluorescence. Kidney biopsy showed typical nonamyloid PAS-positive kappa chain deposits. SDS-PAGE analysis of material extracted from a kidney biopsy specimen and of Ig produced by the myeloma cells revealed kappa chains of abnormally high apparent molecular mass (30,000). Comparison of the NH2-terminal aminoacid sequence of the kappa chain deposited in the kidney and of the complete sequence of several identical kappa cDNA clones from bone marrow cells showed the identity of the tissue deposited and plasma cell kappa chain. The kappa mRNA had an overall normal structure and corresponded to the V kappa IV gene rearranged to J kappa 1 and followed by a normal constant exon of the Km(3) allotype. The variable sequence differed from the V kappa IV germline gene by nine point mutations, including an Asp----Asn substitution at position +70 resulting in a potential N-glycosylation site. In vitro biosynthesis experiments and treatment with N-glycosidase provided evidence for the intracellular glycosylation of the monoclonal kappa chain. The peculiar sequence and the glycosylation of a kappa chain of the rare V kappa IV subgroup might be responsible for structural abnormalities leading to tissue deposition.

Published
1991
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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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