Uremic Vascular Calcification: The Pathogenic Roles and Gastrointestinal Decontamination of Uremic Toxins

Abstract

Uremic vascular calcification (VC) commonly occurs during advanced chronic kidney disease (CKD) and significantly increases cardiovascular morbidity and mortality. Uremic toxins are integral within VC pathogenesis, as they exhibit adverse vascular influences ranging from atherosclerosis, vascular inflammation, to VC. Experimental removal of these toxins, including small molecular (phosphate, trimethylamine-N-oxide), large molecular (fibroblast growth factor-23, cytokines), and protein-bound ones (indoxyl sulfate, p-cresyl sulfate), ameliorates VC. As most uremic toxins share a gut origin, interventions through gastrointestinal tract are expected to demonstrate particular efficacy. The "gastrointestinal decontamination" through the removal of toxin in situ or impediment of toxin absorption within the gastrointestinal tract is a practical and potential strategy to reduce uremic toxins. First and foremost, the modulation of gut microbiota through optimizing dietary composition, the use of prebiotics or probiotics, can be implemented. Other promising strategies such as reducing calcium load, minimizing intestinal phosphate absorption through the optimization of phosphate binders and the inhibition of gut luminal phosphate transporters, the administration of magnesium, and the use of oral toxin adsorbent for protein-bound uremic toxins may potentially counteract uremic VC. Novel agents such as tenapanor have been actively tested in clinical trials for their potential vascular benefits. Further advanced studies are still warranted to validate the beneficial effects of gastrointestinal decontamination in the retardation and treatment of uremic VC.

Keywords: aortic calcification; chronic kidney disease; chronic kidney disease-mineral bone disorder; indoxyl sulfate; oral adsorbent; uremic toxin; vascular calcification; vascular smooth muscle cell.

Figure 1

A schematic diagram showing the potential contribution of different size groups of uremic toxins, from small molecules, large molecules, to protein-bound ones, to the development of uremic vascular calcification. AGE, advanced glycation endproduct; BMP, bone morphogenetic protein; IL, interleukin; IS, indoxyl sulfate; miR, microRNA; Pi, inorganic phosphate; TMAO, trimethylamine-N-oxide; TNF, tumor necrosis factor; UA, uric acid; VSMC, vascular smooth muscle cell.

Figure 2

A brief summary of existing strategies for reducing uremic toxin levels and their related complications, especially uremic vascular calcification.

Figure 3

Promising approaches against vascular calcification based on gastrointestinal decontamination for uremic toxins. NHE, sodium-hydrogen exchanger; NaPi, sodium-phosphate cotransporter.