title: The pathogenesis of acute kidney impairment in patients with multiple myeloma.
abstract: Acute kidney injury in myeloma, a serious complication associated with poor prognosis, is generally mediated by the toxic and inflammatory effects of monoclonal free light chains (FLCs) on kidney proximal tubule cells and by the formation of intratubular casts through interaction with Tamm-Horsfall proteins. Production of excessive quantities of FLCs is seen in most cases of FLC-associated kidney injury, although a direct relation between quantity and nephrotoxicity does not exist, indicating variable toxicity among light chain species. Toxic effects of FLCs include inhibition of transport functions, Fanconi syndrome, generation of reactive oxygen species, cytoskeletal abnormalities, and apoptosis and necrosis in proximal tubule cells. Excessive endocytosis of FLCs in proximal tubule cells also induces cell stress responses that result in stimulation of inflammatory pathways through activation of nuclear transcription factors κB and mitogen-activated protein kinases, induction of proinflammatory cytokines, and epithelial to mesenchymal transition. The mechanisms of nephrotoxicity of FLC described here explain the basis of acute kidney injury seen in patients with multiple myeloma and provide the rationale for eliminating or reducing the FLC burden in myeloma patients with renal involvement. The inflammatory pathways that are activated as a result of FLC toxicity also show clearly how severe chronic tubulointerstitial nephritis can occur in patients with myeloma kidney and identify several attractive opportunities for novel therapeutic interventions.
authors.affiliation: Section of Nephrology and Hypertension, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA. vbatuma@tulane.edu
authors.forename: Vecihi
authors.initials: V
authors.lastname: Batuman
mesh_terms: D058186:Acute Kidney Injury / Q000276:immunology*; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000097:blood*; D007687:Kidney Tubules, Proximal / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D009101:Multiple Myeloma / Q000150:complications / Q000276:immunology*; D009393:Nephritis / Q000276:immunology*; D009399:Nephrons / Q000473:pathology; D058949:Uromodulin
chemical_list: D007147:Immunoglobulin Light Chains; D058949:Uromodulin