Effect of peritoneal dialysis fluid containing osmo-metabolic agents on human endothelial cells

Abstract

BackgroundThe use of glucose as the only osmotic agent in peritoneal dialysis (PD) solutions (PDSs) is believed to exert local (peritoneal) and systemic detrimental actions, particularly in diabetic PD patients. To improve peritoneal biocompatibility, we have developed more biocompatible PDSs containing xylitol and carnitine along with significantly less amounts of glucose and have tested them in cultured Human Vein Endothelial Cells (HUVECs) obtained from the umbilical cords of healthy (C) and gestational diabetic (GD) mothers.MethodsPrimary C- and GD-HUVECs were treated for 72 hours with our PDSs (xylitol 0.7% and 1.5%, whereas carnitine and glucose were fixed at 0.02% and 0.5%, respectively) and two glucose-based PDSs (glucose 1.36% or 2.27%). We examined their effects on endothelial cell proliferation (cell count), viability (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay), intracellular nitro-oxidative stress (peroxynitrite levels), Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 membrane exposure (flow cytometry), and HUVEC-monocyte interactions (U937 adhesion assay).ResultsCompared to glucose-based PDSs, our in vitro studies demonstrated that the tested PDSs did not change the proliferative potential both in C- and GD-HUVECs. Moreover, our PDSs significantly improved endothelial cell viability, compared to glucose-based PDSs and basal condition. Notably, glucose-based PDSs significantly increased the intracellular peroxynitrite levels, Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 membrane exposure, and endothelial cell–monocyte interactions in both C- and GD-HUVECs, as compared with our experimental PDSs.ConclusionPresent results show that in control and diabetic human endothelial cell models, xylitol–carnitine-based PDSs do not cause cytotoxicity, nitro-oxidative stress, and inflammation as caused by hypertonic glucose-based PDSs. Since xylitol and carnitine are also known to favorably affect glucose homeostasis, these findings suggest that our PDSs may represent a desirable hypertonic solution even for diabetic patients in PD.

Proteomic Research in Peritoneal Dialysis

“…Another approach may be that of using PD solution enriched with l-carnitine, which was proven to be more biocompatible than standard glucose-based PD solution in several experimental models [56]. Carnitine can also be combined with other compounds such as xylitol [57], a novel osmo-metabolic approach to formulating novel PD solutions [15], which is to be evaluated by clinical trials in an advanced state of development (NCT 04001036 and NCT 03994471).…”

“…Solute transport through the PM is indicative of the efficacy of PD therapy. On the basis of the removal transport rate of solutes, which are small molecules, as measured in the peritoneal equilibration test (PET), PM can be classified as high, high average, low average, and low transporter [57]. PET yields three parameters: 4-h dialysate to plasma ratio of creatinine (D/P creatinine), 4-to 0-h dialysate glucose ratio, and 4-h ultrafiltration volume [63].…”

Current Opinion on Usage of L-Carnitine in End-Stage Renal Disease Patients on Peritoneal Dialysis

“…L-carnitine in PD fluid may be envisaged as a prototypical osmo-metabolic agent. Osmo-metabolites can be defined as those substances exhibiting both osmotic and metabolic favorable properties [71,72]. The novel osmo-metabolic approach to the composition of PD solutions would ensure not only a reduction of the intraperitoneal glucose load without compromising ultrafiltration, but also the independent mitigation of underlying metabolic disorders—a sort of bioactive glucose sparing.…”

“…Osmo-metabolic agents may also be used in combination, in order to maximize their therapeutic effects. We have recently developed a new PD solution containing L-carnitine (1.24 mmol/L), xylitol (46 or 98.6 mmol/L), and a low amount of glucose (27.7 mmol/L) [72]. Xylitol, another osmo-metabolite, is a five-carbon sugar alcohol (pentitol) produced by the reduction of D-xylulose.…”

“…In human endothelial cell models, such an experimental PD solution [72] did not cause the cytotoxicity, nitro-oxidative stress, and inflammation caused by a glucose-based, neutral pH, low-glucose degradation product PD solution, which is regarded as a “biocompatible” solution [78]. Two clinical trials with new PD solutions based on L-carnitine, xylitol, and low glucose are under advanced development (ClinicalTrials.gov Identifier: NCT04001036 and NCT03994471).…”