Mechanisms of Light Chain Injury along the Tubular Nephron

Sanders, Paul W.

doi:10.1681/asn.2012040388

Cited by 90 publications

(89 citation statements)

References 53 publications

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“…Previous studies showed that free LCs can block metabolites transport and promote oxidative stress, leading to NF-kB activation and inflammation. 3 However, characteristics of cellular and animal models cause significant limitations to investigation of mechanisms of PT dysfunction in general and potential defects in the endolysosomal apparatus in particular. 20 Immortalized cell systems may be dedifferentiated, with loss of polarity and low levels (if any) of endogenous receptors and endocytic uptake, which is problematic for studies of endolysosomal disorders in PT cells.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 In normal conditions, the kidney is essential for the clearance of free light chains (LCs) produced by plasma cells. 3 The polyclonal LCs are filtered by the glomerulus and like other low molecular weight (LMW) proteins, reabsorbed in proximal tubule (PT) cells by receptor-mediated endocytosis. The latter involves two multiligand receptors, megalin and cubilin, that are expressed in the apical membrane of PT cells.…”

mentioning

confidence: 99%

“…These LCs can overwhelm the endocytic capacity of PT cells, being then lost in urine, 6 whereas their intracellular accumulation leads to tubulointerstitial inflammation and fibrosis through different pathways that include oxidative stress, activation of NF-kB, and release of inflammatory mediators. 3,7 In high-mass myeloma, massive quantities of LCs in distal tubular segments may trigger the formation of casts that obstruct the lumen, also leading to tubulointerstitial fibrosis. 6 Alternatively, monoclonal LCs may cause renal Fanconi syndrome (RFS), a general dysfunction of PT cells leading to the urinary leak of LMW proteins, phosphate, uric acid, glucose, and amino acids often associated with osteomalacia and progressive renal failure.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Luciani

Sirac

Terryn

et al. 2015

JASN

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“…Several publications [42][43][44][45] have addressed specifically tubulointerstitial pathology associated with plasma cell dyscrasias, including a recent comprehensive review, 46 but proximal tubulopathies have not been entirely conceptualized, classified into different variants with specific clinicopathologic implications, or defined (understood) in terms of pathogenesis. In addition, the incidence of these conditions in the daily practice of nephropathology has never been analyzed.…”

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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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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“…Rare cases of diabetes insipidus have been reported with AL amyloidosis that have deposited in the distal tubules (19). Monoclonal light chains are also capable of generating hydrogen peroxides, which activates the mitogen-activated protein kinase kinase kinase, known as apoptosis signal regulating kinase 1, causing apoptosis and NF k-light-chain enhancer of activated B cells (Nf-kB) via Src kinase resulting in fibrosis (20). Vascular involvement is common with amyloidosis and MIDD (5,21).…”

Section: The Role Of Monoclonal Proteins In Kidney Diseasesmentioning

confidence: 99%

A Patient with Abnormal Kidney Function and a Monoclonal Light Chain in the Urine

Leung

Nasr

2016

CJASN

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Monoclonal gammopathy is increasingly recognized as a cause of kidney injury. These renal conditions behave differently than ones without monoclonal gammopathy and require specific treatment. To avoid misdiagnosis, testing for paraprotein should be performed in addition to vasculitis and autoimmune diseases serologies in adults with unexplained AKI or proteinuria. Because the prevalence of monoclonal gammopathy is much more common than glomerular diseases, the nephrotoxicity of the monoclonal protein must be confirmed before cytotoxic therapy is initiated. This can only be done by a kidney biopsy. After a monoclonal gammopathy of renal significant is verified, the evaluation should then focus on the identification of the pathologic clone, because therapy is clone specific. We present this patient to illustrate the clinical presentation of a patient with renal dysfunction and a monoclonal gammopathy. This patient is also used to discuss the diagnostic process in detail when monoclonal gammopathy-associated renal disease is suspected.

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Mechanisms of Light Chain Injury along the Tubular Nephron

Cited by 90 publications

References 53 publications

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

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

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

A Patient with Abnormal Kidney Function and a Monoclonal Light Chain in the Urine

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