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.

Monoclonal gammopathies are frequently complicated by kidney lesions that increase the disease morbidity and mortality. In particular, abnormal Ig free light chains (LCs) may accumulate within epithelial cells, causing proximal tubule (PT) dysfunction and renal Fanconi syndrome (RFS). To investigate the mechanisms linking LC accumulation and PT dysfunction, we used transgenic mice overexpressing human control or RFS-associated kLCs (RFS-kLCs) and primary cultures of mouse PT cells exposed to low doses of corresponding human kLCs (25 mg/ml). Before the onset of renal failure, mice overexpressing RFS-kLCs showed PT dysfunction related to loss of apical transporters and receptors and increased PT cell proliferation rates associated with lysosomal accumulation of kLCs. Exposure of PT cells to RFS-kLCs resulted in kLC accumulation within enlarged and dysfunctional lysosomes, alteration of cellular dynamics, defective proteolysis and hydrolase maturation, and impaired lysosomal acidification. These changes were specific to the RFS-kLC variable (V) sequence, because they did not occur with control LCs or the same RFS-kLC carrying a single substitution (Ala30→Ser) in the V domain. The lysosomal alterations induced by RFS-kLCs were reflected in increased cell proliferation, decreased apical expression of endocytic receptors, and defective endocytosis. These results reveal that specific kLCs accumulate within lysosomes, altering lysosome dynamics and proteolytic function through defective acidification, thereby causing dedifferentiation and loss of reabsorptive capacity of PT cells. The characterization of these early events, which are similar to those encountered in congenital lysosomal disorders, provides a basis for the reported differential LC toxicity and new perspectives on LC-induced RFS.

Key Points• We created the first transgenic mouse model recapitulating the early pathologic features of Randall-type heavy chain deposition disease.• Production of a truncated immunoglobulin heavy chain heightens plasma cell sensitivity to bortezomib via a terminal unfolded protein response.Randall-type heavy chain deposition disease (HCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a truncated monoclonal immunoglobulin heavy chain (HC) bearing a deletion of the first constant domain (CH1). We created a transgenic mouse model of HCDD using targeted insertion in the immunoglobulin k locus of a human HC extracted from a HCDD patient. Our strategy allows the efficient expression of the human HC in mouse B and plasma cells, and conditional deletion of the CH1 domain reproduces the major event underlying HCDD. We show that the deletion of the CH1 domain dramatically reduced serum HC levels. Strikingly, even with very low serum level of truncated monoclonal HC, histologic studies revealed typical Randall-type renal lesions that were absent in mice expressing the complete human HC. Bortezomibbased treatment resulted in a strong decrease of renal deposits. We further demonstrated that this efficient response to proteasome inhibitors mostly relies on the presence of the isolated truncated HC that sensitizes plasma cells to bortezomib through an elevated unfolded protein response (UPR). This new transgenic model of HCDD efficiently recapitulates the pathophysiologic features of the disease and demonstrates that the renal damage in HCDD relies on the production of an isolated truncated HC, which, in the absence of a LC partner, displays a high propensity to aggregate even at very low concentration. It also brings new insights into the efficacy of proteasome inhibitor-based therapy in this pathology. (Blood. 2015;126(6):757-765) IntroductionTissue deposition of a monoclonal immunoglobulin fragment frequently complicates plasma cell disorders.1,2 Among the wide spectrum of renal diseases associated with monoclonal gammopathies, Randall-type monoclonal immunoglobulin deposition disease (MIDD) is a multisystemic disorder with prominent renal manifestations including glomerular proteinuria and renal failure. 1,[3][4][5] Kidney lesions in MIDD are characterized by nonamyloid amorphous linear deposits of a monoclonal immunoglobulin fragment along tubular, and in most cases, vascular and glomerular basement membranes (BMs). Nodular glomerulosclerosis and diffuse thickening of tubular BMs are commonly observed. 3,6 The most frequent type of MIDD is related to deposition of monoclonal light chain (LC) (LCDD), mostly of the k isotype, but deposits composed of monoclonal heavy chain (HC) only (HCDD) or of light and heavy chain (LHCDD) have been also described. 3,7 Most reported cases of HCDD were characterized by gHC deposits. 4,5,[8][9][10][11] The mechanisms involved in the deposition of monoclonal Ig fragments in MIDD remain poorly understood. Structural peculiarities of the V domains o...