Unravelling the immunopathological mechanisms of heavy chain deposition disease with implications for clinical management
Language English Country United States Media print-electronic
Document type Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't
PubMed
27773425
DOI
10.1016/j.kint.2016.09.004
PII: S0085-2538(16)30487-2
Knihovny.cz E-resources
- Keywords
- free light chains, glomerulosclerosis, immunoglobulin heavy chains, monoclonal gammopathy,
- MeSH
- Biopsy MeSH
- Bortezomib therapeutic use MeSH
- Renal Insufficiency, Chronic drug therapy immunology pathology MeSH
- Fluorescent Antibody Technique MeSH
- Glomerulonephritis drug therapy immunology pathology MeSH
- Immunoglobulin alpha-Chains analysis MeSH
- Immunoglobulin gamma-Chains analysis genetics MeSH
- Immunoglobulin kappa-Chains analysis MeSH
- Immunoglobulin lambda-Chains analysis MeSH
- Drug Therapy, Combination MeSH
- Kidney drug effects immunology pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Nephrotic Syndrome drug therapy immunology pathology MeSH
- Heavy Chain Disease drug therapy genetics immunology pathology MeSH
- Kidney Diseases drug therapy immunology pathology MeSH
- Paraproteinemias drug therapy immunology MeSH
- Polymerase Chain Reaction MeSH
- Retrospective Studies MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Treatment Outcome MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- France MeSH
- Names of Substances
- Bortezomib MeSH
- CHA heavy chain disease protein, human MeSH Browser
- heavy chain disease proteins, human MeSH Browser
- Immunoglobulin alpha-Chains MeSH
- Immunoglobulin gamma-Chains MeSH
- Immunoglobulin kappa-Chains MeSH
- Immunoglobulin lambda-Chains MeSH
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.
Department of Hematology and Clinical Immunology Saint Louis University Hospital Paris France
Department of Immunology University Hospital of Poitiers Poitiers France
INSERM UMR 850 University of Limoges School of Pharmacy Limoges France
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