Heavy-Chain Deposition Disease

Aucouturier, Pièrre; Khamlichi, Ahmed Amine; Touchard, Guy; Justrabo, E; Cogné, Michel; Chauffert, Bruno; Martin, F.; Preud’homme, Jean-Louis

doi:10.1056/nejm199311043291905

Cited by 114 publications

(68 citation statements)

References 7 publications

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“…(3). In most reported cases of gHCDD, there was a deletion of the CH1 domain in the circulated or deposited g heavy chains (1,3,15), which is required for secretion of free heavy chains by plasma cells. The inability to detect a corresponding monoclonal heavy chain component in the serum in three of our patients may relate to its presence at very low titers, below the level of detection by our standard SIFE, or to rapid rates of tissue deposition (13).…”

Section: Discussionmentioning

confidence: 99%

Renal Monoclonal Immunoglobulin Deposition Disease

Nasr¹,

Valeri²,

Cornell³

et al. 2012

Clinical Journal of the American Society of Nephrology

250

214

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SummaryBackground and objectives To better define the clinical-pathologic spectrum and prognosis of monoclonal immunoglobulin deposition disease (MIDD), this study reports the largest series.Design, setting, participants, & measurements Characteristics of 64 MIDD patients who were seen at Mayo Clinic are provided.Results Of 64 patients with MIDD, 51 had light chain deposition disease, 7 had heavy chain deposition disease, and 6 had light and heavy chain deposition disease. The mean age at diagnosis was 56 years, and 23 patients (36%) were #50 years of age. Clinical evidence of dysproteinemia was present in 62 patients (97%), including multiple myeloma in 38 (59%). M-spike was detected on serum protein electrophoresis in 47 (73%). Serum free light chain ratio was abnormal in all 51 patients tested. Presentation included renal insufficiency, proteinuria, hematuria, and hypertension. Nodular mesangial sclerosis was seen in 39 patients (61%). During a median of 25 months of follow-up (range, 1-140) in 56 patients, 32 (57%) had stable/improved renal function, 2 (4%) had worsening renal function, and 22 (39%) progressed to ESRD. The mean renal and patient survivals were 64 and 90 months, respectively. The disease recurred in three of four patients who received a kidney transplant.Conclusions Patients with MIDD generally present at a younger age than those with light chain amyloidosis or light chain cast nephropathy. Serum free light chain ratio is abnormal in all MIDD patients, whereas only threequarters have abnormal serum protein electrophoresis. The prognosis for MIDD is improving compared with historical controls, likely reflecting earlier detection and improved therapies.

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Section: Discussionmentioning

confidence: 99%

Renal Monoclonal Immunoglobulin Deposition Disease

Nasr¹,

Valeri²,

Cornell³

et al. 2012

Clinical Journal of the American Society of Nephrology

250

214

View full text Add to dashboard Cite

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“…It also was suggested in a patient with ␣ HCDD (23). A larger deletion that also included the C H 1 domain, the hinge, and the C H 2 domain was found in one case (6). In the blood, the deleted HC could be associated with an LC, mostly of the isotype, or circulated in small amounts as a free unassembled subunit (7).…”

Section: Hcdd: a Disease Featured By Hc Deletionsmentioning

confidence: 99%

“…Deposits that contain monoclonal HC only first were observed in 1993 in patients who were affected with otherwise typical Randall's disease (HC deposition disease [HCDD]) (6), and two series of similar patients were published later (7,8).…”

mentioning

confidence: 99%

Immunoglobulin Light (Heavy)-Chain Deposition Disease

Ronco¹,

Plaisier²,

Mougenot³

et al. 2006

Clinical Journal of the American Society of Nephrology

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111

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Light-, light-and heavy-, and heavy-chain deposition diseases belong to a family of diseases that include light-chain (AL)-amyloid, nonamyloid fibrillary and immunotactoid glomerulonephritis, and cryoglobulinemic glomerulonephritis, in which monoclonal Ig or their subunits become deposited in kidney. In clinical and pathologic terms, light-, light-and heavy-, and heavy-chain deposition diseases essentially are similar and are characterized by prominent renal involvement with severe renal failure; extrarenal manifestations; diabetes-like nodular glomerulosclerosis; marked thickening of tubular basement membranes; and monotypic deposits of light chain, mostly , and/or heavy chain that feature a nonorganized granular, electron-dense appearance by electron microscopy. The most common cause is myeloma. Recent progress has been made in the understanding of the molecular pathomechanisms of Ig-chain deposition and extracellular matrix accumulation, which opens up new therapeutic avenues in addition to eradication of the Ig-secreting plasma cell clone. Because these diseases represent a model of glomerular and interstitial fibrosis that is induced by a single molecule species, a better understanding of their pathomechanisms may help to unravel the pathophysiology of kidney fibrosis and renal disease progression.

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“…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 of nephrotoxic LCs in LCDD have been suggested to govern their propensity to form insoluble aggregates that precipitate in extracellular spaces, including the presence of hydrophobic residues in the solvent-exposed complementary determining region, N-glycosylation, or small protein truncation.…”

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confidence: 99%

A mouse model recapitulating human monoclonal heavy chain deposition disease evidences the relevance of proteasome inhibitor therapy

Bonaud

Bender

Touchard

et al. 2015

Blood

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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...

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Heavy-Chain Deposition Disease

Cited by 114 publications

References 7 publications

Renal Monoclonal Immunoglobulin Deposition Disease

Renal Monoclonal Immunoglobulin Deposition Disease

Immunoglobulin Light (Heavy)-Chain Deposition Disease

A mouse model recapitulating human monoclonal heavy chain deposition disease evidences the relevance of proteasome inhibitor therapy

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