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.

Long-term renal survival of γ3-heavy chain deposition disease: a case report

“…Renal clinical manifestation ameliorated in 11 patients who achieved a hematological response. In this report, the importance of early diagnosis and bortezomib-based treatment is mentioned for the preservation of renal prognosis [19]. In bortezomib-based therapy, serum free light chain response is consider to be a favorable prognostic factor for renal survival [27].…”

“…In HCDD, deletion of the first constant heavy chain domain (CH1) might be one possible pathogenesis [9, 14, 17, 18]. Deletion of the CH1 is a required condition for the secretion of a free monoclonal heavy chain by the underlying clonal plasma cell disorder [19]. Based on this pathogenesis, therapies targeting pathological plasma cell clones may be useful.…”

Comprehensive molecular characterization of a heavy chain deposition disease case

“…We have recently published the most important series of HCDD cases 3 , unraveling some pathophysiological mechanisms of the disease. However, the molecular events leading to HC deposits are still incompletely understood.…”

“…*These authors contributed equally to this work. 2 We herein report the complete characterization of the monoclonal Ig fragments produced by the plasma cell clone in a 65-year-old patient with a typical heavy chain deposition disease (HCDD) [1][2][3] . The patient was referred for nephrotic syndrome and the main biological parameters are summarized in supplemental Table 1 months after chemotherapy showed a complete hematological and renal response (supplemental Table 1).…”

Dysproteinemias and Glomerular Disease

“…They can only be separated by immunofluorescence. The Ig heavy chain in HCDD is typically truncated (41). Patients with HCDD have heavier proteinuria, but otherwise, all patients with monoclonal Ig deposition disease behave similarly (19).…”