Role of the monoclonal   chain V domain and reversibility of renal damage in a transgenic model of acquired Fanconi syndrome

Sirac, Christophe

doi:10.1182/blood-2005-11-4419

Cited by 60 publications

(49 citation statements)

References 44 publications

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“…[53][54][55][56][57] An animal model for this variant has shown that the primary structure of the light chains is directly responsible for the pathologic findings observed, and a transgenic model has been created where the disease has been reversed with experimental manipulations. 57,[59][60][61] An incomplete form of this condition has also been reported, 62 emphasizing once more the importance of the physicochemical characteristics of the light chains in producing pathologic processes. Light chains from most of these cases (j type) exhibit a specific amino acid substitution at position 30, which provides resistance to catabolism, [59][60][61] promoting the formation of cytoplasmic inclusions.…”

Section: Metabolism Of Light Chains In Proximal Tubules/handling Of Pmentioning

confidence: 99%

“…57,[59][60][61] An incomplete form of this condition has also been reported, 62 emphasizing once more the importance of the physicochemical characteristics of the light chains in producing pathologic processes. Light chains from most of these cases (j type) exhibit a specific amino acid substitution at position 30, which provides resistance to catabolism, [59][60][61] promoting the formation of cytoplasmic inclusions.…”

Section: Metabolism Of Light Chains In Proximal Tubules/handling Of Pmentioning

confidence: 99%

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Proximal Tubulopathies Associated With Monoclonal Light Chains: The Spectrum of Clinicopathologic Manifestations and Molecular Pathogenesis

Herrera

2014

Archives of Pathology &Amp; Laboratory Medicine

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Context.—Lesions associated with monoclonal light and heavy chains display a variety of glomerular, tubular interstitial, and vascular manifestations. While some of the entities are well recognized, including light and heavy chain deposition diseases, AL (light chain) and AH (heavy chain) amyloidosis, and light chain (“myeloma”) cast nephropathy, other lesions centered on proximal tubules are much less accurately identified, properly diagnosed, and adequately understood in terms of pathogenesis and molecular mechanisms involved. These proximal tubule–centered lesions are typically associated with monoclonal light chains and have not been reported in patients with circulating monoclonal heavy chains. Objective.—To determine the incidence of proximal tubulopathies in a series of patients with monoclonal light chain–related renal lesions and characterize them with an emphasis on clinical correlations and elucidation of molecular mechanisms involved in their pathogenesis. Design.—A study of 5410 renal biopsies with careful evaluation of light microscopic, immunofluorescence, and electron microscopic findings was conducted to identify these monoclonal light/heavy chain–related lesions. In selected cases, ultrastructural immunolabeling was performed to better illustrate and understand molecular mechanisms involved or to resolve specific diagnostic difficulties. Results.—In all, 2.5% of the biopsies were diagnosed as demonstrating renal pathology associated with monoclonal light or heavy chains. Of these, approximately 46% were classified as proximal tubule–centered lesions, also referred to as monoclonal light chain–associated proximal tubulopathies. These proximal tubulopathies were divided into 4 groups defined by characteristic immunomorphologic manifestations associated with specific clinical settings. Conclusions.—These are important lesions whose recognition in the different clinical settings is extremely important for patients' clinical management, therapeutic purposes, and prognosis. These entities have been segregated into 4 distinct variants, conceptualized morphologically and clinically. Specific mechanisms involved in their pathogenesis are proposed.

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Section: Metabolism Of Light Chains In Proximal Tubules/handling Of Pmentioning

confidence: 99%

Section: Metabolism Of Light Chains In Proximal Tubules/handling Of Pmentioning

confidence: 99%

Proximal Tubulopathies Associated With Monoclonal Light Chains: The Spectrum of Clinicopathologic Manifestations and Molecular Pathogenesis

Herrera

2014

Archives of Pathology &Amp; Laboratory Medicine

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“…Light chains are filtered at the glomerulus and undergo clathrin-dependent endocytosis by the megalin/cubilin receptor system. Some of these light chains are resistant to chemical degradation and accumulate as precipitates that interfere with proximal tubule function (30,31). Light chains that are degraded induce proinflammatory cytokines, such as monocyte chemoattractant protein-1 and IL-6 and -8 (32,33).…”

Section: Mechanisms Of Myeloma and Plasma Cell-associated Kidney Injurymentioning

confidence: 99%

Kidney Disease and Multiple Myeloma

Heher

Rennke

Laubach

et al. 2013

Clinical Journal of the American Society of Nephrology

146

122

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SummaryKidney injury is a common complication of multiple myeloma and other plasma cell dyscrasias, and it is associated with increased mortality. Multiple pathogenic mechanisms can contribute to kidney injury in the patient with myeloma, some of which are the result of nephrotoxic monoclonal Ig and some of which are independent of paraprotein deposition. The pathogenic mechanisms that underlie paraprotein-related kidney disease are increasingly well understood. A novel assay allowing the quantification of free light chains in the serum has aided the diagnosis of new onset disease and allowed for the earlier detection of relapse. Novel myeloma agents have shown considerable promise in reversing renal failure in some patients and improving outcomes. Stem cell transplantation remains a mainstay of management for younger patients with myeloma who are suitable candidates for intensive therapy, whereas the role of new drugs, plasma exchange, and kidney transplantation continues to evolve.

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“…We investigated transgenic mice expressing similar levels of human kLCs from a patient with RFS (kCH mice) 21 or a patient with biopsy-proven renal AL amyloidosis but without RFS and kidney damage (kDE mice). We also exposed primary cultured cells isolated from PT segments of mouse kidney to low doses of human kLCs.…”

mentioning

confidence: 99%

Impaired Lysosomal Function Underlies Monoclonal Light Chain–Associated Renal Fanconi Syndrome

Luciani

Sirac

Terryn

et al. 2015

JASN

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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.

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Role of the monoclonal chain V domain and reversibility of renal damage in a transgenic model of acquired Fanconi syndrome

Cited by 60 publications

References 44 publications

Proximal Tubulopathies Associated With Monoclonal Light Chains: The Spectrum of Clinicopathologic Manifestations and Molecular Pathogenesis

Proximal Tubulopathies Associated With Monoclonal Light Chains: The Spectrum of Clinicopathologic Manifestations and Molecular Pathogenesis

Kidney Disease and Multiple Myeloma

Impaired Lysosomal Function Underlies Monoclonal Light Chain–Associated Renal Fanconi Syndrome

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