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Open Access 01-02-2019 | Invited review article

Molecular mechanisms underlying uremic toxin-related systemic disorders in chronic kidney disease: focused on β₂-microglobulin-related amyloidosis and indoxyl sulfate-induced atherosclerosis—Oshima Award Address 2016

Author: Suguru Yamamoto

Published in: Clinical and Experimental Nephrology | Issue 2/2019

Abstract

Uremic toxins are linked to chronic kidney disease (CKD)-related systemic diseases. β₂-Microglobulin (β₂-m), a water-soluble, middle-sized molecule, is associated with mortality and dialysis-related amyloidosis (DRA). DRA occurs in long-term dialysis patients, with β₂-m amyloid deposited mainly in osteoarticular tissues. We investigated a model of β₂-m amyloid fibril extension at neutral pH in the presence of trifluoroethanol or sodium dodecyl sulfate. Using this model, some biological molecules, including glycosaminoglycans and lysophospholipids, were found to be chaperones for β₂-m amyloid fibril extension. Several protein-bound solutes, such as indoxyl sulfate (IS) and p-cresyl sulfate, are independent risk factors for cardiovascular disease in CKD patients, especially those undergoing dialysis. We investigated kidney injury-induced acceleration of atherosclerosis in association with macrophage phenotypic change to a proinflammatory state as well as increased IS deposition in lesions in an animal model. IS directly induced macrophage inflammation and impaired cholesterol efflux to high-density lipoprotein (HDL) in vitro. In addition, a clinical study showed that HDL isolated from CKD patients induced proinflammatory reactions and impaired cholesterol efflux to macrophages. These findings suggest that protein-bound solutes, including IS, will induce dysfunction of both macrophages and HDL in atherosclerotic lesions. To remove uremic toxins efficiently, we demonstrated the potential efficacy of oral charcoal adsorbent and hexadecyl-immobilized cellulose beads in hemodialysis patients. These findings suggest that uremic toxins induce various CKD-related systemic disorders, and further therapeutic strategies will be needed to reduce uremic toxins enough and improve life expectancy in CKD patients.

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Title: Molecular mechanisms underlying uremic toxin-related systemic disorders in chronic kidney disease: focused on β2-microglobulin-related amyloidosis and indoxyl sulfate-induced atherosclerosis—Oshima Award Address 2016
Author: Suguru Yamamoto
Publication date: 01-02-2019
Publisher: Springer Singapore
Published in: Clinical and Experimental Nephrology / Issue 2/2019
Print ISSN: 1342-1751
Electronic ISSN: 1437-7799
DOI: https://doi.org/10.1007/s10157-018-1588-9

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