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Review
. 2019 Feb;23(2):151-157.
doi: 10.1007/s10157-018-1588-9. Epub 2018 Jun 5.

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

Suguru Yamamoto  1
Affiliations
Review

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

Suguru Yamamoto. Clin Exp Nephrol. 2019 Feb.

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.

Keywords: Atherosclerosis; Dialysis-related amyloidosis; Indoxyl sulfate; Macrophages; Uremic toxins; β2-Microglobulin.

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Conflict of interest statement

Conflict of interest

All authors declared that they have no conflict of interest.

Ethical approval

This article does not contain any original studies with human participants or animals performed by any of the authors.

Figures

Fig. 1
Fig. 1
Pathogenesis of dialysis-related amyloidosis. β2-Microglobulin (β2-m), a water-soluble, middle sized uremic toxin, increases with the deterioration of kidney function. Some biological molecules, such as glycosaminoglycans and proteoglycans, change the conformation of β2-m and stabilize and extend the amyloid fibrils. In contrast, extracellular chaperones including α2-macroglobulin may inhibit amyloid fibril formation by capturing unfolded and misfolded β2-m
Fig. 2
Fig. 2
Indoxyl sulfate induces macrophage foam cell formation in atherosclerotic lesions. Indoxyl sulfate, a protein-bound uremic toxin, reacts directly with macrophages and induces production of inflammatory cytokines as well as impairment of cholesterol efflux to high-density lipoprotein, leading to macrophage foam cell formation. ABCG1 ATP-binding cassette transporter G1, CKD chronic kidney disease, FC free cholesterol, LDL low-density lipoprotein, HDL high-density lipoprotein
Fig. 3
Fig. 3
Therapeutic strategies for uremic toxin-related systemic disorders. Therapeutic strategies for the reduction of uremic toxins should include (A) preservation of kidney function, (B) inhibition of uremic toxin production, (C) prevention of the interaction between uremic toxins and tissues/cells, and (D) removal of uremic toxins with medication or blood purification therapy
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