Myeloma light chains are ligands for cubilin (gp280)

Batuman, Vecihi; Verroust, P; Navar, L. Gabriel; Kaysen, James H.; Goda, F. O.; Campbell, W. C.; Simon, Eric E.; Pontillon, F.; Lyles, Michelle M.; Bruno, Joanne; Hammond, Timothy G.

doi:10.1152/ajprenal.1998.275.2.f246

Cited by 93 publications

(85 citation statements)

References 19 publications

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“…4,5,29 They are endocytosed in the proximal tubules via the megalin-cubilin receptor. [30][31][32][33][34] Light chains are normally catabolized in the apical portions of the proximal tubules by endosomes. While the primary function of early lysosomes is sorting, late endosomes and lysosomes attempt to digest the internalized light chains.…”

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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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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“…Some FLC clones bind to megalin and some to cubilin (Batuman et al, 1990;Batuman et al, 1998;Sengul et al, 2003). As MM evolves, the amount of clonal FLC available in glomerular ultrafiltrate progressively increases, ultimately to the levels that overwhelm the reabsorptive capacity of proximal tubular epithelial cells.…”

Section: Decreased Hdl-dependent Paraoxonase and Arylesterase Enzyme mentioning

confidence: 99%

Decreased HDL-Dependent Paraoxonase and Arylesterase Enzyme Activity May Indicate a Worse Prognosis in Multiple Myeloma

Elli̇dağ¹,

Aydın²,

Eren³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: Multiple myeloma (MM) is a haematological cancer characterized by clonal proliferation of plasma cells.The aim of this study was to investigate the activity of serum paraoxonase-1 (PON1) and arylesterase (ARE) in multiple myeloma with and without free light chain excretion(FLCe-MM and NFLCe-MM); as well as to investigate possible alterations in oxidative stress parameters. Materials and Methods: Total thiol (T.thl), oxidative stress index (OSI), total oxidant status (TOS) and total antioxidant status (TAS) were examined in addition to the PON1 and ARE enzyme activities in twenty one FLCe-MM and nineteen NFLCe-MM subjects. Routine parameters like lipid panel, serum total protein, albumin, creatinine, blood urea nitrogen (BUN), uric acid and hemoglobin levels were compared with the oxidative stress markers. Results: Serum total protein, BUN, creatinin, and uric acid levels were significantly higher (p=0.04, p=0.001, p=0.001 and p=0.0022, respectively), while hemoglobin and albumin levels were significantly lower in FLCe-MM patients (p=0.009 and p=0.04,respectively). PON1 and ARE activities were significantly lower in patients with FLCe-MM compared to those with NFLCe-MM (p=0.001 and p=0.008, respectively). Conclusions: Depending on our results of prognostic markers of MM such as age, hemoglobin, albumin, and creatinine we feel confident to presume FLCe-MM as a subgroup with a worse prognosis. A decrease in PON1 and ARE activities may contribute to the prognosis and may be used as a prognostic tool in MM.

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“…Free light chains are endocytosed by proximal tubule cells, through a receptor-mediated process, by binding to the tandem scavenger receptor system cubilin/ megalin. Then, they are endocytosed through the clathrindependent endosomal/lysosomal pathway and degraded within lysosomes [7][8][9][10] (Figure 1). In MM, excess light chain production overcomes the capacity of the tubular cells to catabolize the free light chains that appear in the tubular fluid of distal nephron segments where they form tubular casts with Tamm-Horsfall protein (uromodulin), a glycoprotein synthesized by the cells in the medullary thick ascending limb of the loop of Henle with affinity for monoclonal light chains.…”

Section: Pathogenesismentioning

confidence: 99%

Pathogenesis and treatment of renal failure in multiple myeloma

et al. 2008

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Renal failure is a frequent complication in patients with multiple myeloma (MM) that causes significant morbidity. In the majority of cases, renal impairment is caused by the accumulation and precipitation of light chains, which form casts in the distal tubules, resulting in renal obstruction. In addition, myeloma light chains are also directly toxic on proximal renal tubules, further adding to renal dysfunction. Adequate hydration, correction of hypercalcemia and hyperuricemia and antimyeloma therapy should be initiated promptly. Recovery of renal function has been reported in a significant proportion of patients treated with conventional chemotherapy, especially when high-dose dexamethasone is also used. Severe renal impairment and large amount of proteinuria are associated with a lower probability of renal recovery. Novel agents, such as thalidomide, bortezomib and lenalidomide, have significant activity in pretreated and untreated MM patients. Although there is limited experience with thalidomide and lenalidomide in patients with renal failure, data suggest that bortezomib may be beneficial in this population. Clinical studies that have included newly diagnosed and refractory patients indicate that bortezomib-based regimens may result in rapid reversal of renal failure in up to 50% of patients and that full doses of bortezomib can be administered without additional toxicity.

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Myeloma light chains are ligands for cubilin (gp280)

Cited by 93 publications

References 19 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

Decreased HDL-Dependent Paraoxonase and Arylesterase Enzyme Activity May Indicate a Worse Prognosis in Multiple Myeloma

Pathogenesis and treatment of renal failure in multiple myeloma

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