High-volume hemofiltration does not protect human kidney endothelial and tubular epithelial cells from septic plasma-induced injury.

High volume hemofiltration (HVHF) could remove from plasma inflammatory mediators involved in sepsis-associated acute kidney injury (SA-AKI). The IVOIRE trial did not show improvements of outcome and organ dysfunction using HVHF. The aim of this study was to evaluate in vitro the biological effects of plasma of patients treated by HVHF or standard volume hemofiltration (SVHF). We evaluated leukocyte adhesion, apoptosis and functional alterations of endothelial cells (EC) and tubular epithelial cells (TEC). In vitro data were correlated with plasma levels of TNF-α, Fas-Ligand (FasL), CD40-Ligand (CD40L), von Willebrand Factor (vWF) and endothelial-derived microparticles. An experimental model of in vitro hemofiltration using LPS-activated blood was established to assess cytokine mass adsorption during HVHF or SVHF. Plasma concentrations of TNF-ɑ, FasL, CD40L and von Willebrand Factor (vWF) were elevated at the start (d1h0) of both HVHF and SVHF, significantly decreased after 6 h (d1h6), remained stable after 12 h (d1h12) and then newly increased at 48 h (d3h0). Plasma levels of all these molecules were similar between HVHF- and SVHF-treated patients at all time points considered. In addition, the levels of endothelial microparticles remained always elevated, suggesting the presence of a persistent microvascular injury. Plasma from septic patients induced leukocyte adhesion on EC and TEC through up-regulation of adhesion receptors. Moreover, on EC, septic plasma induced a cytotoxic and anti-angiogenic effect. On TEC, septic plasma exerted a direct pro-apoptotic effect via Fas up-regulation and caspase activation, loss of polarity, altered expression of megalin and tight junction molecules with an impaired ability to internalize albumin. The inhibition of plasma-induced cell injury was concomitant to the decrease of TNF-α, Fas-Ligand and CD40-Ligand levels. The protective effect of both HVHF and SVHF was time-limited, since a further increase of circulating mediators and plasma-induced cell injury was observed after 48 h (d3h0). No significant difference of EC/TEC damage were observed using HVHF- or SVHF-treated plasma. The in vitro hemofiltration model confirmed the absence of a significant modulation of cytokine adsorption between HVHF and SVHF. In comparison to SVHF, HVHF did not increase inflammatory cytokine clearance and did not reverse the detrimental effects of septic plasma-induced EC and TEC injury. Further studies using adsorptive membranes are needed to evaluate the potential role of high dose convective therapies in the limitation of the harmful activity of plasma soluble factors involved in SA-AKI.Trial registration IVOIRE randomized clinical trial; ClinicalTrials.gov (NCT00241228) (18/10/2005).

Role of the CD40-CD40 Ligand Pathway in Cardiovascular Events, Neurological Alterations, and Other Clinical Complications of Chronic Hemodialysis Patients: Protective Role of Adsorptive Membranes.

Despite the recent advances in dialysis technology, mortality rate of chronic uremic patients still remains excessively high: of note, in comparison to age- and sex-matched healthy controls, this frail population shows a higher incidence of infections, cancer, cognitive decline, and, in particular, major adverse cardiovascular events (MACE) that represent nowadays the first cause of mortality. Several traditional and nontraditional factors contribute to this increased risk for MACE and accelerated cellular senescence: among these, inflammation has been shown to play a key role. The costimulatory pathway CD40-CD40 Ligand (CD40L) is harmfully activated during inflammation and uremia-associated clinical complications: in particular, the soluble form of CD40L (sCD40L) can bind to the CD40 receptor triggering a cascade of detrimental pathways in immune and nonimmune cells. In this narrative review, we summarize the current concepts of the biological role of the CD40-CD40L pathway in uremia-associated organ dysfunction, focusing on the above-described main causes of mortality. Moreover, we discuss the interaction of the CD40-CD40L pathway with extracellular vesicles, microparticles recently identified as new uremic toxins. The biological effects of sCD40L in MACE, cognitive decline, infections, and cancer will be also briefly commented. Last, based on recent studies and ongoing clinical trials, we herein describe the modulatory activity of adsorptive dialysis membranes in polymethylmethacrylate on CD40-CD40L detrimental activation.

Novel role for mast cells in omental tissue remodeling and cell recruitment in experimental peritoneal dialysis.

Because of its dynamic structure, the omentum plays a key role in the immunity of the peritoneal cavity by orchestrating peritoneal cell recruitment. Because mast cells accumulate in the omentum upon experimental peritoneal dialysis (PD) and may produce angiogenic/profibrotic factors, it was hypothesized that mast cells mediate omental tissue remodeling during PD. Daily treatment with conventional PD fluid (PDF) for 5 wk resulted in a strong omental remodeling response, characterized by an approximately 10-fold increase in mast cell density (P < 0.01), an approximately 20-fold increase in vessel density (P < 0.02), an approximately 20-fold increase in the number of milky spots (P < 0.01), and a four-fold increase in submesothelial matrix thickness (P < 0.0003) in wild-type rats. In contrast, all PDF-induced omental changes were significantly reduced in mast cell-deficient Ws/Ws rats or in wild-type rats that were treated orally with a mast cell stabilizer cromoglycate. A time-course experiment showed mast cell accumulation immediately before the formation of blood vessels and milky spots. Functionally, PDF evoked a peritoneal cell influx, which was significantly reduced in Ws/Ws rats (P < 0.04) and in wild-type rats that were treated with cromoglycate (P < 0.03). Cromoglycate treatment also completely prevented PDF-induced omental adhesions to the catheter tip (P = 0.0002). Mesothelial damage, angiogenesis, and fibrosis of mesentery and parietal peritoneum as well as glucose absorption rate and ultrafiltration capacity proved to be mast cell independent. Data strongly support the hypothesis that mast cells mediate PDF-induced omental tissue remodeling and, subsequently, peritoneal cell influx and adhesion formation, providing therapeutic possibilities of modulating omental function.