Steviol glycosides as an alternative osmotic agent for peritoneal dialysis fluid

Abstract

Background: Peritoneal dialysis (PD) is a renal replacement technique that requires repeated exposure of the peritoneum to hyperosmolar PD fluids (PDFs). Unfortunately, it promotes alterations of the peritoneal membrane (PM) that affects its functionality, including mesothelial-mesenchymal transition (MMT) of mesothelial cells (MCs), inflammation, angiogenesis, and fibrosis. Glucose is the most used osmotic agent, but it is known to be at least partially responsible, together with its degradation products (GDP), for those changes. Therefore, there is a need for more biocompatible osmotic agents to better maintain the PM. Herein we evaluated the biocompatibility of Steviol glycosides (SG)-based fluids.Methods: The ultrafiltration and transport capacities of SG-containing and glucose-based fluids were analyzed using artificial membranes and an in vivo mouse model, respectively. To investigate the biocompatibility of the fluids, Met-5A and human omental peritoneal MCs (HOMCs) were exposed in vitro to different types of glucose-based PDFs (conventional 4.25% glucose solution with high-GDP level and biocompatible 2.3% glucose solution with low-GDP level), SG-based fluids or treated with TGF-β1. Mice submitted to surgery of intraperitoneal catheter insertion were treated for 40 days with SG- or glucose-based fluids. Peritoneal tissues were collected to determine thickness, MMT, angiogenesis, as well as peritoneal washings to analyze inflammation.Results: Dialysis membrane experiments demonstrated that SG-based fluids at 1.5%, 1%, and 0.75% had a similar trend in weight gain, based on curve slope, as glucose-based fluids. Analyzing transport capacity in vivo, 1% and 0.75% SG-based fluid-exposed nephrectomized mice extracted a similar amount of urea as the glucose 2.3% group. In vitro, PDF with high-glucose (4.25%) and high-GDP content induced mesenchymal markers and angiogenic factors (Snail1, Fibronectin, VEGF-A, FGF-2) and downregulates the epithelial marker E-Cadherin. In contrast, exposition to low-glucose-based fluids with low-GDP content or SG-based fluids showed higher viability and had less MMT. In vivo, SG-based fluids preserved MC monolayer, induced less PM thickness, angiogenesis, leukocyte infiltration, inflammatory cytokines release, and MMT compared with glucose-based fluids.Conclusion: SG showed better biocompatibility as an osmotic agent than glucose in vitro and in vivo, therefore, it could alternatively substitute glucose in PDF.

Coupling Osmotic Efficacy with Biocompatibility in Peritoneal Dialysis: A Stiff Challenge

“…Kopytina et al [ 51 ] examined the biocompatibility of SG-containing fluids (which are glucose free) as compared to glucose-based fluids. Dialysis membrane experiments showed that SG has an osmotic capacity similar to that of glucose.…”

“…These results indicate that SG may be used as an osmotic agent for PDS, to replace glucose, and with a better biocompatibility profile than glucose both in vitro and in vivo. These results, however, are preliminary: the safety and clinical efficacy of SG require further investigation [ 51 ], particularly in consideration of the very high daily SG exposures required to achieve an adequate osmotic action for fluid removal and depuration.…”

Intercellular communication in peritoneal dialysis

“…The communication between peritoneal mesothelial cells and myofibroblasts primarily occurs through paracrine factors such as cytokines or growth factors, direct cell-to-cell contacts facilitated by gap junctions, or indirect interactions mediated by ECM proteins. Both cell types have the ability to produce and secrete various chemokines, cytokines, and growth factors such as transforming growth factor ß (TGF-β), vascular endothelial growth factor (VEGF) ( Kariya et al, 2018 ), connective tissue growth factor ( Sakai et al, 2017 ), fibroblast growth factor-2 (FGF-2) ( Kopytina et al, 2022 ), tumor necrosis factor α (TNF-α), high mobility group protein B1 (HMGB1) ( Chu et al, 2017 ), or interleukin (IL)-1β ( Shentu et al, 2021 ), which act in an autocrine or paracrine manner and contribute to peritoneal fibrosis by stimulating the proliferation of resident fibroblasts and ECM component deposition, and by inducing MMT of mesothelial cells, which further increases the number of peritoneal myofibroblasts. IL-6 is a vital inflammatory factor in the peritoneal cavity of patients undergoing PD.…”

Novel Aspects of the Immune Response Involved in the Peritoneal Damage in Chronic Kidney Disease Patients under Dialysis

“…The impact of this to patient outcome has, however, not yet been properly delineated. Importantly, the newer PDFs, including biocompatible glucose-based solutions, icodextrin, taurine, and other recently proposed solutions based in alternative osmotic agents (stevia, xylitol, and L-carnitine), as well as the addition of potentially protective compounds, such as alanyl-glutamine supplementation, exert lower deleterious effects in the PM [ 9 , 10 , 11 , 12 , 13 ]. Despite PD therapy, CKD patients remain at high risk of poor outcomes.…”