title: Unravelling the immunopathological mechanisms of heavy chain deposition disease with implications for clinical management.
abstract: Randall-type heavy chain deposition disease (HCDD) is a rare disorder characterized by tissue deposition of a truncated monoclonal immunoglobulin heavy chain lacking the first constant domain. Pathophysiological mechanisms are unclear and management remains to be defined. Here we retrospectively studied 15 patients with biopsy-proven HCDD of whom 14 presented with stage 3 or higher chronic kidney disease, with nephrotic syndrome in 9. Renal lesions were characterized by nodular glomerulosclerosis, with linear peritubular and glomerular deposits of γ-heavy chain in 12 patients or α-heavy chain in 3 patients, without concurrent light chain staining. Only 2 patients had symptomatic myeloma. By serum protein electrophoresis/immunofixation, 13 patients had detectable monoclonal gammopathy. However, none of these techniques allowed detection of the nephrotoxic truncated heavy chain, which was achieved by immunoblot and/or bone marrow heavy chain sequencing in 14 of 15 patients. Serum-free kappa to lambda light chain ratio was abnormal in 11 of 11 patients so examined. Immunofluorescence studies of bone marrow plasma cells showed coexpression of the pathogenic heavy chain with light chain matching the abnormal serum-free light chain in all 3 tested patients. Heavy chain sequencing showed first constant domain deletion in 11 of 11 patients, with high isoelectric point values of the variable domain in 10 of 11 patients. All patients received chemotherapy, including bortezomib in 10 cases. Renal parameters improved in 11 patients who achieved a hematological response, as assessed by normalization of the free light chain ratio in 8 cases. Tissue deposition in HCDD relates to physicochemical peculiarities of both variable and constant heavy chain domains. Early diagnosis and treatment with bortezomib-based combinations appear important to preserve renal prognosis. Thus, monitoring of serum-free light chain is an indirect but useful method to evaluate the hematological response.
authors: Department of Nephrology, University Hospital of Poitiers, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Poitiers, France; Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Limoges, France. Electronic address: Franck.BRIDOUX@chu-poitiers.fr.
authors: Frank
authors: F
authors: Bridoux
authors: Department of Nephrology, University Hospital of Poitiers, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Poitiers, France.
authors: Vincent
authors: V
authors: Javaugue
authors: Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Limoges, France.
authors: Sébastien
authors: S
authors: Bender
authors: Department of Nephrology, University Hospital of Poitiers, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Poitiers, France.
authors: Fannie
authors: F
authors: Leroy
authors: Department of Immunology, Inserm UMRS 938, Saint Antoine Hospital; Université Pierre et Marie Curie - Paris6, Paris, France.
authors: Pierre
authors: P
authors: Aucouturier
authors: Department of Pathology and Ultrastructural Pathology, University Hospital of Poitiers, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Poitiers, France.
authors: Céline
authors: C
authors: Debiais-Delpech
authors: Department of Pathology and Ultrastructural Pathology, University Hospital of Poitiers, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Poitiers, France.
authors: Jean-Michel
authors: JM
authors: Goujon
authors: Department of Pathology and Ultrastructural Pathology, University Hospital of Poitiers, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Poitiers, France.
authors: Nathalie
authors: N
authors: Quellard
authors: Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Limoges, France.
authors: Amélie
authors: A
authors: Bonaud
authors: Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Limoges, France.
authors: Marie
authors: M
authors: Clavel
authors: INSERM UMR 850, University of Limoges, School of Pharmacy, Limoges, France; Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University Olomouc, Olomouc, Czech Republic.
authors: Patrick
authors: P
authors: Trouillas
authors: INSERM UMR 850, University of Limoges, School of Pharmacy, Limoges, France.
authors: Florent
authors: F
authors: Di Meo
authors: Department of Immunology, University Hospital of Poitiers, Poitiers, France.
authors: Jean-Marc
authors: JM
authors: Gombert
authors: Department of Hematology and Clinical Immunology, Saint Louis University Hospital, Paris, France.
authors: Jean-Paul
authors: JP
authors: Fermand
authors: Department of Hematology, University Hospital of Limoges, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Limoges, France.
authors: Arnaud
authors: A
authors: Jaccard
authors: Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Limoges, France.
authors: Michel
authors: M
authors: Cogné
authors: Department of Nephrology, University Hospital of Poitiers, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Poitiers, France.
authors: Guy
authors: G
authors: Touchard
authors: Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Limoges, France.
authors: Christophe
authors: C
authors: Sirac
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D000069286:Bortezomib / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D005455:Fluorescent Antibody Technique; D005602:France; D005921:Glomerulonephritis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D006362:Heavy Chain Disease / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D007137:Immunoglobulin alpha-Chains / Q000032:analysis; D007142:Immunoglobulin gamma-Chains / Q000032:analysis* / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000032:analysis; D007146:Immunoglobulin lambda-Chains / Q000032:analysis; D007668:Kidney / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D007674:Kidney Diseases / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009404:Nephrotic Syndrome / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D010265:Paraproteinemias / Q000188:drug therapy / Q000276:immunology; D016133:Polymerase Chain Reaction; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: C483999:CHA heavy chain disease protein, human; D007137:Immunoglobulin alpha-Chains; D007142:Immunoglobulin gamma-Chains; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; C032598:heavy chain disease proteins, human; D000069286:Bortezomib
keywords: free light chains; glomerulosclerosis; immunoglobulin heavy chains; monoclonal gammopathy