Glucose-based Fluids Research Articles

Glucose-Free Solutions Mediated Inhibition of Oxidative Stress and Oxidative Stress-Related Damages in Peritoneal Dialysis: A Promising Solution.

Oxidative stress (OxSt) and inflammation are common in end-stage renal disease and dialysis patients; they are known risk factors for cardiovascular disease and mortality. In peritoneal dialysis (PD), OxSt and inflammation are even further increased compared to the already increased oxidative stress of their pre-dialysis phase. This is due to the high glucose-based solutions currently used, whose continuous contact with the peritoneal membrane can induce significant long-term morphological and functional changes (mesothelial to mesenchymal transition, thickening, neo-angiogenesis and fibrosis) of the peritoneal membrane. Oxidative stress plays a very important role in these processes, which may compromise the peritoneal dialysis procedure. There is, therefore, the need for more biocompatible dialysis fluids with polymers other than glucose to prevent and treat OxSt and inflammation. The most known and used of such glucose-free and more biocompatible peritoneal dialysis solutions is icodextrin, which has shown a protective effect from oxidative stress. This has supported the consideration of the use of glucose-free-based peritoneal dialysis fluids in order to reduce oxidative stress and improve peritoneal membrane survival. Studies investigating peritoneal dialysis with the use of osmo-metabolic agents (L-carnitine, xylitol and their combination) in peritoneal fluids replacing glucose-based fluids are, in fact, ongoing. They represent a promising strategy to reduce OxSt, preserve the peritoneal membrane's integrity and improve patients' outcome.

Oxidative stress reduction by icodextrin-based glucose-free solutions in peritoneal dialysis: Support for new promising approaches.

Oxidative stress (OxSt) and inflammation are common in CKD and are known CV and mortality risk factors. In peritoneal dialysis (PD) OxSt and Inflammation even increase due to the use of glucose-based solutions. This study analyzed in 15 PD patients the effect of 3 and 6 months of treatment with icodextrin-based glucose-free solutions on OxSt and inflammation, evaluating p22phox protein expression (Western blot), NADPH oxidase subunit, essential for OxSt activation, MYPT-1 phosphorylation state, marker of RhoA/Rho kinase pathway (ROCK) activity, involved in the induction of OxSt (Western blot) and Malondialdehyde (MDA) production (fluorimetric assay). Interleukin (IL)-6 blood level (chemiluminescence assay) has been measured and used as a marker of inflammation. p22phox protein expression, MYPT 1 phosphorylation, and MDA were reduced after 3 months from the start of icodextrin (1.28 ± 0.18 d.u. vs. 1.50 ± 0.19, p = 0.049; 0.89 ± 0.03 vs. 0.98 ± 0.03, p = 0.004; 4.20 ± 0.18 nmol/mL vs. 4.84 ± 0.32 nmol/mL, p = 0.045, respectively). In a subgroup of 9 patients who continued the treatment up to 6 months, MYPT-1 phosphorylation was further reduced at 6 months compared to baseline (0.84 ± 0.06 vs. 0.99 ± 0.04, p = 0.043), while p22phox protein expression was reduced only at 6 months versus baseline (1.03 ± 0.05 vs. 1.68 ± 0.22, p = 0.021). In this subgroup, MDA was reduced at 6 months versus baseline (4.03 ± 0.24 nmol/mL vs. 4.68 ± 0,32, p = 0.024) and also versus 3 months (4.03 ± 0.24 vs. 4.35 ± 0.21, p = 0.008). IL-6 level although reduced both at 3 and 6 months, did not reach statistical significance. The reduction of OxSt with icodextrin-based PD solutions, although obtained in a small patients cohort and in a limited time duration study, strongly supports the rationale of using osmo-metabolic agents-based fluids replacing glucose-based fluids. Ongoing studies with these agents will provide information regarding preservation of peritoneal membrane integrity, residual renal function, and reduction of CVD risk factors such as OxSt and inflammation.

#2881 Glucose free-based solutions reduce oxidative stress in peritoneal dialysis: support for a new promising approach

Abstract Background and Aims Oxidative stress (OxSt) and inflammation are common in CKD which are known CV and mortality risk factors. In peritoneal dialysis (PD) OxSt and Inflammation even increase due to the use of glucose-based solutions. This study evaluated in PD patients the effect of 3 and 6 months treatment with icodextrin-based glucose-free solutions on OxSt and inflammation. Method In 15 PD patients using a molecular biology approach, p22phox protein expression (Western blot), subunit of NADPH oxidase, essential for OxSt activation, MYPT-1 phosphorylation state, marker of RhoA/Rho kinase pathway activity, deeply involved in OxSt generation (Western blot) and Malondialdehyde (MDA) production (fluorimetric assay), marker of lipid peroxidation, have been evaluated. High-sensitive C Reactive Protein (hsCRP) (immunoturbidimetric assay) and interleukin (IL)-6 (chemiluminescence assay), have been used as marker of inflammation. Results p22phox protein expression, MYPT-1 phosphorylation, and MDA level were reduced after 3 months from the start of icodextrin based solutions (1.28 ± 0.18 d.u. vs 1.50 ± 0.19, p = 0.049; 0.89 ± 0.03 vs 0.98 ± 0.03, p = 0.004; 4.20 ± 0.18 nmol/mL vs 4.84 ± 0.32 nmol/mL, p = 0.045, respectively). In a subgroup of 9 patients who continued the treatment up to 6 months MYPT-1 phosphorylation was further reduced at 6 months compared to baseline (0.84 ± 0.06 vs 0.99 ± 0.04, p = 0.043), while p22phox protein expression was reduced only at 6 months from baseline (1.03 ± 0.05 vs 1.68 ± 0.22, p = 0.021). In this subgroup MDA blood level was reduced at 6 months from baseline (4.03 ± 0.24 nmol/mL vs 4.68 ± 0.32, p = 0.024) and was also significantly reduced vs 3 months (4.03 ± 0.24 vs 4.35 ± 0.21, p = 0.008). IL-6 level, although reduced compared to baseline, did not reach statistical significance both at 3 and 6 months, while hsPCR was unchanged. Conclusion The icodextrin-based PD solutions mediated reduction of OxSt related proteins and inflammation we have provided, although obtained in a small cohort of patients and for a limited time duration, strongly support the rationale of using in PD osmo-metabolic agents-based solutions replacing the currently used glucose-based fluids. The results of ongoing studies with these agents in PD patients will provide definitive proofs to better preserve peritoneal membrane integrity and residual renal function but also to reduce CV risk factors such as OxSt and inflammation.

Steviol glycosides as an alternative osmotic agent for peritoneal dialysis fluid.

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.

Mesenchymal Conversion of Mesothelial Cells Is a Key Event in the Pathophysiology of the Peritoneum during Peritoneal Dialysis.

Peritoneal dialysis (PD) is a therapeutic option for the treatment of end-stage renal disease and is based on the use of the peritoneum as a semipermeable membrane for the exchange of toxic solutes and water. Long-term exposure of the peritoneal membrane to hyperosmotic PD fluids causes inflammation, loss of the mesothelial cells monolayer, fibrosis, vasculopathy, and angiogenesis, which may lead to peritoneal functional decline. Peritonitis may further exacerbate the injury of the peritoneal membrane. In parallel with these peritoneal alterations, mesothelial cells undergo an epithelial to mesenchymal transition (EMT), which has been associated with peritoneal deterioration. Factors contributing to the bioincompatibility of classical PD fluids include the high content of glucose/glucose degradation products (GDPs) and their acidic pH. New generation low-GDPs-neutral pH fluids have improved biocompatibility resulting in better preservation of the peritoneum. However, standard glucose-based fluids are still needed, as biocompatible solutions are expensive for many potential users. An alternative approach to preserve the peritoneal membrane, complementary to the efforts to improve fluid biocompatibility, is the use of pharmacological agents protecting the mesothelium. This paper provides a comprehensive review of recent advances that point to the EMT of mesothelial cells as a potential therapeutic target to preserve membrane function.

Mathematical Modeling of the Glucose-Insulin System During Peritoneal Dialysis With Glucose-Based Fluids

The purpose of this study was to analyze the effect of peritoneal dialysis with glucose-based solution on plasma glucose and insulin responses in patients on continuous ambulatory peritoneal dialysis (CAPD), describe the glucose-insulin system using a mathematical model, and identify abnormalities in this system. Six-hour dwell studies--using glucose 3.86% solution with a volume marker--were performed in 13 stable, fasting, nondiabetic CAPD patients. We used a mathematical model based on the previous works of Stolwijk and Hardy (1974) and Tolic et al (2000) to estimate the parameters of glucose-insulin system, insulin sensitivity index (Sl), and glucose effectiveness at basal (SG) and zero (GEZI) insulin. The individual peaks in plasma glucose and insulin concentrations occurred after 30-60 minutes of the dwell, with the average increase of 52% and 168% over the initial values, respectively. Increased insulin resistance was found in most of these patients. Both clinical and simulation results demonstrated a high interpatient variability in glucose and insulin kinetics and glucose-insulin system parameters in the patients. We demonstrated a successful control of increasing plasma glucose by insulin, despite an increased insulin resistance, during CAPD.

The haemodynamic and metabolic effects of hypertonic-glucose and amino-acid-based peritoneal dialysis fluids

Continuous ambulatory peritoneal dialysis (CAPD) may exert significant effects on systemic haemodynamics. We have previously demonstrated that hypertonic glucose solutions are associated with higher blood pressure (BP) due to a rise in stroke volume (SV) and cardiac output (CO). However, the mechanisms underlying these changes have not been established. Ten non-diabetic CAPD patients entered a randomized crossover study (eight completed) to compare conventional glucose-based fluid, biocompatible pH-neutral glucose-based fluid and 1.1% amino acid solution (lactate-buffered but completely free of glucose degradation products). BP and haemodynamic variables were measured using continuous arterial pulse wave analysis, and serial plasma glucose and insulin concentrations were collected. Left ventricular (LV) diameters were measured at the start and end of each dwell period using M-mode echocardiography. BP was similar during 1.36% glucose and 1.1% amino acid dwells, but was significantly higher during 3.86% glucose dwells with both conventional and biocompatible fluids (P < 0.001). This was associated with a significantly higher SV and CO (P < 0.001), although the haemodynamic response differed between conventional and biocompatible 3.86% solutions. Plasma glucose and insulin levels did not differ from baseline during 1.36% and amino acid dwells, but increased significantly during 3.86% glucose dwells. Despite a significantly higher ultrafiltration volume with 3.86% glucose, LV diameters were similar throughout. In conclusion, we have confirmed our previous findings demonstrating higher BP and adverse haemodynamics during 3.86% glucose dwells. These changes are associated with hyperglycaemia and hyperinsulinaemia, but are not related to differences in cardiac filling.

Effect of N-Acetylglucosamine on Function of Peritoneal Leukocytes

To compare effects of N-acetylglucosamine (NAG)-based and glucose-based dialysis fluids on the function of peritoneal leukocytes in conditions of peritoneal dialysis. In vitro experiments on ex vivo isolated rat peritoneal leukocytes. Peritoneal leukocytes were isolated from rats on chronic peritoneal dialysis. On alternate days, fluid exchanges were performed with NAG-based or glucose-based dialysis solutions. After a 4-hour dwell, dialysate was drained and peritoneal leukocytes were incubated in vitro +/- lipopolysaccharide (LPS). Production of nitrites (index of NO synthesis), tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and interferon gamma (IFN-gamma) by unstimulated or stimulated peritoneal leukocytes originating from NAG-based or glucose-based fluid was measured. Dialysate cell count was lower during exchanges with NAG-based fluid (2113+/-615 cells/microL) as compared to glucose-based fluid (3643+/-1108 cells/microL; p < 0.01). Differential cell count was similar in both studied groups. Unstimulated peritoneal leukocytes from NAG-based dialysate produced more NO (nitrites) (0.65+/-0.07 micromol per 10(6) cells) than did cells from glucose-based dialysate (0.26+/-0.09 micromol per 106 cells, p < 0.01). Stimulated peritoneal leukocytes from NAG-based dialysate produced more cytokines than did cells from glucose-based dialysate: TNFalpha, 135.2+/-37.0 pg versus 70.2+/-21.8 pg per 10(6) cells respectively, p < 0.01; IL-1beta, 143.2+/-60.9 pg versus 99.1+/-22.4 pg per 10(6) cells respectively, p < 0.05; IFN-gamma, 16.2+/-12.5 pg versus 6.0+/-1.8 pg per 10(6) cells respectively, p < 0.01. We demonstrated that rat peritoneal leukocytes exposed in vivo to NAG-based dialysis fluid have better ability to produce inflammatory mediators than do peritoneal leukocytes from the same donor, but exposed in vivo to glucose-based dialysis solution.