Abstract
In patients with advanced chronic kidney disease (CKD), the accumulation of uremic toxins, caused by a combination of decreased excretion secondary to reduced kidney function and increased generation secondary to aberrant expression of metabolite genes, interferes with different biological functions of cells and organs, contributing to a state of chronic inflammation and other adverse biologic effects that may cause tissue damage. Several uremic toxins have been implicated in severe vascular smooth muscle cells (VSMCs) changes and other alterations leading to vascular calcification (VC) and early vascular ageing (EVA). The above mentioned are predominant clinical features of patients with CKD, contributing to their exceptionally high cardiovascular mortality. Herein, we present an update on pathophysiological processes and mediators underlying VC and EVA induced by uremic toxins. Moreover, we discuss their clinical impact, and possible therapeutic targets aiming at preventing or ameliorating the harmful effects of uremic toxins on the vasculature.
Highlights
Chronic kidney disease (CKD) is an increasingly prevalent condition with an estimated worldwide prevalence of 10–12% and an overwhelmingly high mortality rate projecting CKD to become one of the top five causes of death by 2040 [1].The progressive loss of kidney function is accompanied by the retention of numerous solutes that would normally be excreted in the urine; in so far these substances have been shown to have a negative impact on the function of organs and systems of the body they are called uremic toxins
The uremic milieu that accompanies CKD has been linked to a clinical model of premature ageing [7], characterized by low grade chronic inflammation, muscle wasting, osteoporosis and frailty, and an extremely high cardiovascular mortality [8,9] which in end stage kidney disease (ESKD) patients is more than 10 times higher compared to the general population [10]
It is increasingly recognized that vascular calcification (VC) is a multistep and cell-mediated dynamic process whereby vascular smooth muscle cells (VSMCs) progressively adopt an osteoblast-like phenotype with concomitant expression of bone-related genes such as Runt-related transcription factor 2 (RUNX2) known as core-binding factor subunit alpha-1 (Cbfa1), Msx2 (Msh Homeobox 2), bone morphogenetic protein 2 (BMP2), and alkaline phosphatase (ALP)
Summary
Chronic kidney disease (CKD) is an increasingly prevalent condition with an estimated worldwide prevalence of 10–12% and an overwhelmingly high mortality rate projecting CKD to become one of the top five causes of death by 2040 [1]. Large uremic toxins belonging to the middle molecules group that comprise among others pro-inflammatory mediators and other cytokines have been estimated to constitute 23% of the number of uremic retention solutes identified as uremic toxins [5]. These solutes deserve special attention because of the challenges for their elimination using conventional dialysis strategies [6]. Low molecular weight and protein bound solutes play an important role in the physiopathology and clinical phenotype produced by the uremic milieu. We discuss the pathophysiological links between the different uremic toxins, with special emphasis on middle molecules, and their impact on vascular calcification (VC) and early vascular ageing (EVA) in CKD, and potential therapeutic strategies to slow down the appearance of this condition
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