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: Frank Bridoux, Vincent Javaugue, Sébastien Bender, Fannie Leroy, Pierre Aucouturier, Céline Debiais-Delpech, Jean-Michel Goujon, Nathalie Quellard, Amélie Bonaud, Marie Clavel, Patrick Trouillas, Florent Di Meo, Jean-Marc Gombert, Jean-Paul Fermand, Arnaud Jaccard, Michel Cogné, Guy Touchard, Christophe Sirac
• Journal: Kidney international (Kidney Int) Vol. 91 Issue 2 Pg. 423-434 (02 2017) ISSN: 1523-1755 [Electronic] United States
• PMID: 27773425 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• CHA heavy chain disease protein, human
• Immunoglobulin alpha-Chains
• Immunoglobulin gamma-Chains
• Immunoglobulin kappa-Chains
• Immunoglobulin lambda-Chains
• heavy chain disease proteins, human
• Bortezomib

Topics

• Aged
• Aged, 80 and over
• Biopsy
• Bortezomib (therapeutic use)
• Drug Therapy, Combination
• Female
• Fluorescent Antibody Technique
• France
• Glomerulonephritis (drug therapy, immunology, pathology)
• Heavy Chain Disease (drug therapy, genetics, immunology, pathology)
• Humans
• Immunoglobulin alpha-Chains (analysis)
• Immunoglobulin gamma-Chains (analysis, genetics)
• Immunoglobulin kappa-Chains (analysis)
• Immunoglobulin lambda-Chains (analysis)
• Kidney (drug effects, immunology, pathology)
• Kidney Diseases (drug therapy, immunology, pathology)
• Male
• Middle Aged
• Nephrotic Syndrome (drug therapy, immunology, pathology)
• Paraproteinemias (drug therapy, immunology)
• Polymerase Chain Reaction
• Renal Insufficiency, Chronic (drug therapy, immunology, pathology)
• Retrospective Studies
• Treatment Outcome