ArticleJournal of the American Society of Nephrology : JASN2016
Impaired Lysosomal Function Underlies Monoclonal Light Chain-Associated Renal Fanconi Syndrome.
Article in Journal of the American Society of Nephrology : JASN, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 68 citations in OpenAlex.
- Hydroxychloroquine-induced renal phospholipidosis manifesting as proximal tubulopathy in systemic lupus erythematosus.BMC nephrology · 2026Article
- B Cell-Derived and Non-B Cell-Derived Free Light Chains: From Generation to Biological and Pathophysiological Roles.International journal of molecular sciences · 2025Review
- Clinical characteristics of monoclonal immunoglobulin-associated renal disease: a retrospective cohort study.Clinical and experimental nephrology · 2025Observational
- Incidence of and factors associated with hypophosphatemia in children and adolescents receiving cancer treatment: a single-center, retrospective study.European journal of pediatrics · 2025Article
- A case of acute kidney injury and Fanconi syndrome while taking multiple supplements, including Red Yeast Rice Cholesterol HelpCEN case reports · 2025Article
- Update on kidney injury caused by multiple myeloma.Annals of hematology · 2024Review
- Clinical Presentation and Long-Term Survival Outcomes of Patients With Monoclonal Gammopathy of Renal Significance (MGRS): A Multicenter Retrospective Study.Cancer medicine · 2024Article
- Lambda light chain - restricted non - crystalline proximal tubulopathy with cast nephropathy in multiple myeloma: a case report and literature review.BMC nephrology · 2024Review
- Review
- Inherited Fanconi syndrome.World journal of pediatrics : WJP · 2023Review
- Hypophosphatemia in Patients With Multiple Myeloma.Cureus · 2023Review
- Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy.The Journal of clinical investigation · 2023Article
- Emerging roles of proximal tubular endocytosis in renal fibrosis.Frontiers in cell and developmental biology · 2023Review
- Monoclonal Gammopathy of Renal Significance: A Molecular Middle Earth between Oncology, Nephrology, and Pathology.Kidney diseases (Basel, Switzerland) · 2022Review
- Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications.Physiological reviews · 2022Review
- Metabolic mechanisms of acute proximal tubular injury.Pflugers Archiv : European journal of physiology · 2022Review
- Multisystem involvement, defective lysosomes and impaired autophagy in a novel rat model of nephropathic cystinosis.Human molecular genetics · 2022Article
- Review
- Hypophosphatemia in cancer patients.Clinical kidney journal · 2021Article
- Kidney injury and disease in patients with haematological malignancies.Nature reviews. Nephrology · 2021Review
Corrections and comments
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Authors and funding
12 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 κLCs (RFS-κLCs) and primary cultures of mouse PT cells exposed to low doses of corresponding human κLCs (25 μg/ml). Before the onset of renal failure, mice overexpressing RFS-κLCs showed PT dysfunction related to loss of apical transporters and receptors and increased PT cell proliferation rates associated with lysosomal accumulation of κLCs. Exposure of PT cells to RFS-κLCs resulted in κLC 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-κLC variable (V) sequence, because they did not occur with control LCs or the same RFS-κLC carrying a single substitution (Ala30→Ser) in the V domain. The lysosomal alterations induced by RFS-κLCs were reflected in increased cell proliferation, decreased apical expression of endocytic receptors, and defective endocytosis. These results reveal that specific κLCs 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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