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.
Highlights
Patients with impaired renal function, or chronic kidney disease (CKD), exhibit a high cardiovascular risk [1], which is frequently attributed to co-existing morbidities such as hypertension, diabetes, and dyslipidemia
Large cohort studies have shown that higher serum phosphate levels are independently associated with an increased mortality and accelerated progression of vascular calcification (VC) among CKD patients [12], while an elevated serum uric acid level predicts worse survival among those with end-stage renal disease (ESRD) [13]
As proposed by the European Uremic Toxin (EUTox) workgroup [17], candidate uremic toxins are recognized when they are retained during periods of renal function decline
Summary
Patients with impaired renal function, or chronic kidney disease (CKD), exhibit a high cardiovascular risk [1], which is frequently attributed to co-existing morbidities such as hypertension, diabetes, and dyslipidemia. Among the spectrum of cardiovascular diseases, vascular calcification (VC) is dreadful because of its multifactorial pathophysiology and limited therapeutic options [2]. Studies from large CKD and end-stage renal disease (ESRD) cohorts report a high VC prevalence, up to 65% in the Chronic Renal Insufficiency Cohort (CRIC) [3] and 74%. The observed cardiovascular risk increases substantially during transition from non-dialysis CKD to ESRD, likely because of the progression of subclinical vascular lesions, especially VC. The existing literature fails to emphasize the multifaceted role of uremic toxin removal through the gastrointestinal route. We will provide an overview of the relationship between uremic toxins and VC; the plausible options for mitigating the adverse influences posed by uremic toxins; and, most importantly, the under-recognized role of gastrointestinal tract-based elimination of these toxins
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