Abstract
Systemic chronic microinflammation and altered cytokine signaling, with adjunct cardiovascular disease (CVD), endothelial maladaptation and dysfunction is common in dialysis patients suffering from end-stage renal disease and associated with increased morbidity and mortality. New hemodialysis filters might offer improvements. We here studied the impact of novel improved molecular cut-off hemodialysis filters on systemic microinflammation, uremia and endothelial dysfunction. Human endothelial cells (ECs) were incubated with uremic serum obtained from patients treated with two different hemodialysis regimens in the Permeability Enhancement to Reduce Chronic Inflammation (PERCI-II) crossover clinical trial, comparing High-Flux (HF) and Medium Cut-Off (MCO) membranes, and then assessed for their vascular endothelial growth factor (VEGF) production and angiogenesis. Compared to HF membranes, dialysis with MCO membranes lead to a reduction in proinflammatory mediators and reduced endothelial VEGF production and angiogenesis. Cytokine multiplex screening identified tumor necrosis factor (TNF) superfamily members as promising targets. The influence of TNF-α and its soluble receptors (sTNF-R1 and sTNF-R2) on endothelial VEGF promoter activation, protein release, and the involved signaling pathways was analyzed, revealing that this detrimental signaling was indeed induced by TNF-α and mediated by AP-1/c-FOS signaling. In conclusion, uremic toxins, in particular TNF-signaling, promote endothelial maladaptation, VEGF expression and aberrant angiogenesis, which can be positively modulated by dialysis with novel MCO membranes.Translational Perspective and Graphical Systemic microinflammation, altered cytokine signaling, cardiovascular disease, and endothelial maladaptation/dysfunction are common clinical complications in dialysis patients suffering from end-stage renal disease. We studied the impact of novel improved medium-cut-off hemodialysis filters on uremia and endothelial dysfunction. We can show that uremic toxins, especially TNF-signaling, promote endothelial maladaptation, VEGF expression and aberrant angiogenesis, which can be positively modulated by dialysis with novel improved medium-cut-off membranes.
Highlights
Kidney disease is a major public health burden [1, 2]
This was followed by mechanistic validation, employing healthy and uremic serum pools (HSP and USP, please see Figure 4) and selective blocking strategies and promoter studies, to decipher the underlying cellular signaling events (Figures 3–6)
In line with the above, we found a correlation between TNFa/sTNF-R1-ratio in the patient serum and endothelial vascular endothelial growth factor (VEGF) production and angiogenic capacity upon exposure of endothelial cells (ECs) to corresponding serum in vitro (P=0.01 and P=0.08; Figure 3C left panel), which was not observed for the respective tumor necrosis factor (TNF)-a/sTNFR2-ratio (P=0.94 and P=0.63; Figure 3C right panel), indicating that sTNF-R1 is of crucial importance
Summary
The population prevalence of chronic kidney disease (CKD) is ~10% and the portion thereof with end-stage renal disease (ESRD) requiring renal replacement therapy (RRT) is increasing steadily [3]. HD has been effectively employed in the management of ESRD in the past, patients still suffer from considerable side effects, such as greatly enhanced cardiovascular morbidity and mortality [1, 13, 14]. In addition to progressive vascular media calcification [15,16,17,18,19], endothelial dysfunction is another key attribute of the cardiovascular disease (CVD) apparent in patients with CKD/ESRD, contributing to the increased morbidity and mortality [20,21,22,23]. Due to the complexity of the cellular and molecular crosstalk, the pathomechanisms how these mediators influence the functional outcome remain largely elusive to date and need to be explored further in both the chronic and acute setting [24,25,26]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
