Expanded Hemodialysis Therapy Ameliorates Uremia-Induced Systemic Microinflammation and Endothelial Dysfunction by Modulating VEGF, TNF-α and AP-1 Signaling

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 AbstractSystemic 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.

Angiogenic Role of Mesothelium-Derived Chemokine CXCL1 During Unfavorable Peritoneal Tissue Remodeling in Patients Receiving Peritoneal Dialysis as Renal Replacement Therapy

“…Based on our prior studies (43), we have chosen to employ IL-17 as one representative inducer of CXCL1 in the PD setting. However, also other factors, such as TNFa and IL-6, can have a triggering or amplifying effect on endothelial dysfunction in the context of (hemo)-dialysis (8). While the in vitro induction and blocking experiments using the peritonitis effluent clearly demonstrate the pro-angiogenic potential of the IL-17/CXCL1 axis, the histological material from a rather small group of PD patients showed no apparent association between peritoneal IL-17 expression and vascularity.…”

“…Thus, increased scientific efforts are currently ongoing to improve already existing well-established RRT methods, such as HD and PD, and to develop novel technologies (e.g. cellular therapy) to maintain, improve, or replace (lost) kidney (transplant) function (8,(56)(57)(58).…”

“…The socioeconomic burden of RRT is high, since conventional HD is rather costly for healthcare providers, with substantial differences in funds available per capita across different countries (58). As alternative to HD (8), PD is a well-established and viable option for home RRT, which minimizes potential virus exposure and the associated health risks (10)(11)(12)(13)(14)(15). However, its long-term use is limited due to the decline in peritoneal ultrafiltration that typically occurs 2-4 years after initiation of PD (22).…”

“…In addition to the pre-existing high incidence of CKD and socioeconomic burden of RRT (1-3), the recent COVID-19 pandemic has led to a further increase in kidney disease cases, with 25% requiring RRT (4). Hemodialysis (HD) is the most common method of RRT (8,9), while PD is used by ~11% of patients worldwide (with large regional differences ranging from 0% to 75%) (9) (Figure 1A). Being more suited for 'home dialysis', PD may reduce the risk of virus transmission to susceptible patients.…”

“…The effective long-term use of the peritoneal membrane as a dialysis organ is still limited due to the inflammation-induced deterioration of peritoneal membrane function, resulting from peritoneal remodelling and angiogenesis (Figure 1C). Here, we have studied a novel CXC chemokine ligand 1 (CXCL1)dependent angiogenic mechanism (Figure 1D) that leads to peritoneal angiogenesis independent of vascular endothelial growth factor (VEGF), which is typically associated with maladaptive angiogenesis in the RRT setting (8,(16)(17)(18)(19).…”