Conventional Peritoneal Dialysis Fluids Research Articles

Effects of bicarbonate/lactate-buffered neutral peritoneal dialysis fluids on angiogenesis-related proteins in patients undergoing peritoneal dialysis

BackgroundIn order to facilitate the safe and long-term delivery of peritoneal dialysis (PD), it is necessary to improve the biocompatibility of peritoneal dialysis fluids (PDFs). The novel bicarbonate/lactate-buffered neutral PDFs (B/L-PDFs) are expected to be improved biocompatible. This study evaluated the biocompatibility of B/L-PDFs by analysis on the profile of angiogenesis-related proteins in drained dialysate of patients undergoing PD.MethodsConcentrations of 20 angiogenesis-related proteins in the dialysate were semi-quantitatively determined using a RayBio® Human Angiogenesis Antibody Array and were compared between B/L-PDFs and conventional lactate-buffered neutral PDFs (L-PDFs).ResultsThe expression of growth-related oncogene (GRO α/β/γ), which belongs to the CXC chemokine family, decreased significantly after use of the B/L-PDFs compared to the L-PDFs (P = 0.03). The number of the proteins with lower level in the B/L-PDFs compared with L-PDFs was significantly negatively correlated with the PD duration (Spearman ρ = − 0.81, P = 0.004).ConclusionThis study suggested that B/L-PDFs are more biocompatible than conventional PDFs.

Effect of lactate as a peritoneal dialysis fluid buffer on rat peritoneal mesothelial cells

BackgroundNeutral, low-glucose degradation product (GDP) peritoneal dialysis fluid (PDF) is less damaging to the peritoneum than conventional PDF but is still insufficient for biocompatibility. One remaining issue is the problem of buffering.MethodsUsing cultured rat peritoneal mesothelial cells (PMCs), the present study examined the difference between the effects of neutral low-GDP lactate PDF and neutral low-GDP bicarbonate/lactate PDF on cells. The effects of lactate stimulation on these cells were also examined.ResultsLactate PDF enhanced mRNA expressions of α-smooth muscle actin (αSMA) and type 1 and type 3 collagens and lowered expression of e-cadherin mRNA in PMCs compared to bicarbonate/lactate PDF. Lactate stimulation increased mRNA expressions of αSMA, matrix metalloproteinase 2 (MMP2), and basic fibroblast growth factor (bFGF) and suppressed e-cadherin mRNA expression. Transforming growth factor (TGF)-β1 and TGF-β2 and collagen type 1 and 3 mRNA expressions were also enhanced by lactate stimulation.ConclusionsThese results suggest that lactate as a PDF buffer may act on PMCs to promote epithelial-mesenchymal transition (EMT) and production of TGF-β, bFGF, and collagen.

Alanyl-Glutamine Restores Tight Junction Organization after Disruption by a Conventional Peritoneal Dialysis Fluid.

Understanding and targeting the molecular basis of peritoneal solute and protein transport is essential to improve peritoneal dialysis (PD) efficacy and patient outcome. Supplementation of PD fluids (PDF) with alanyl-glutamine (AlaGln) increased small solute transport and reduced peritoneal protein loss in a recent clinical trial. Transepithelial resistance and 10 kDa and 70 kDa dextran transport were measured in primary human endothelial cells (HUVEC) exposed to conventional acidic, glucose degradation products (GDP) containing PDF (CPDF) and to low GDP containing PDF (LPDF) with and without AlaGln. Zonula occludens-1 (ZO-1) and claudin-5 were quantified by Western blot and immunofluorescence and in mice exposed to saline and CPDF for 7 weeks by digital imaging analyses. Spatial clustering of ZO-1 molecules was assessed by single molecule localization microscopy. AlaGln increased transepithelial resistance, and in CPDF exposed HUVEC decreased dextran transport rates and preserved claudin-5 and ZO-1 abundance. Endothelial clustering of membrane bound ZO-1 was higher in CPDF supplemented with AlaGln. In mice, arteriolar endothelial claudin-5 was reduced in CPDF, but restored with AlaGln, while mesothelial claudin-5 abundance was unchanged. AlaGln supplementation seals the peritoneal endothelial barrier, and when supplemented to conventional PD fluid increases claudin-5 and ZO-1 abundance and clustering of ZO-1 in the endothelial cell membrane.

Biocompatible Peritoneal Dialysis: The Target Is Still Way Off.

Peritoneal dialysis (PD) is a cost-effective, home-based therapy for patients with end-stage renal disease achieving similar outcome as compared to hemodialysis. Still, a minority of patients only receive PD. To a significant extend, this discrepancy is explained by major limitations regarding PD efficiency and sustainability. Due to highly unphysiological composition of PD fluids, the peritoneal membrane undergoes rapid morphological and long-term functional alterations, which limit the treatment and contribute to adverse patient outcome. This review is focused on the peritoneal membrane ultrastructure and its transformation in patients with kidney disease and chronic PD, underlying molecular mechanisms, and potential systemic sequelae. Current knowledge on the impact of conventional and second-generation PD fluids is described; novel strategies and innovative PD fluid types are discussed.

Differences in peritoneal response after exposure to low-GDP bicarbonate/lactate-buffered dialysis solution compared to conventional dialysis solution in a uremic mouse model

BackgroundLong-term exposure of conventional peritoneal dialysis (PD) fluid is associated with structural membrane alterations and technique failure. Previously, it has been shown that infiltrating IL-17-secreting CD4+T cells and pro-fibrotic M2 macrophages play a critical role in the PD-induced pathogenesis. Although more biocompatible PD solutions are recognized to better preserve the peritoneal membrane integrity, the impact of these fluids on the composition of the peritoneal cell infiltrate is unknown.Materials and methodsIn a uremic PD mouse model, we compared the effects of daily instillation of standard lactate (LS) or bicarbonate/lactate-buffered solutions (BLS) and respective controls on peritoneal fibrosis, vascularisation, and inflammation.ResultsDaily exposure of LS fluid during a period of 8 weeks resulted in a peritoneal increase of αSMA and collagen accompanied with new vessel formation compared to the BLS group. Effluent from LS-treated mouse showed a higher percentage of CD4+ IL-17+ cell population while BLS exposure resulted in an increased macrophage population. Significantly enhanced inflammatory cytokines such as TGFβ1, TNFα, INFγ, and MIP-1β were detected in the effluent of BLS-exposed mice when compared to other groups. Further, immunohistochemistry of macrophage subset infiltrates in the BLS group confirmed a higher ratio of pro-inflammatory M1 macrophages over the pro-fibrotic M2 subset compared to LS.ConclusionDevelopment of the peritoneal fibrosis and angiogenesis was prevented in the BLS-exposed mice, which may underlie its improved biocompatibility. Peritoneal recruitment of M1 macrophages and lower number of CD4+ IL-17+ cells might explain the peritoneal integrity preservation observed in BLS-exposed mouse.

Liposome-supported peritoneal dialysis in the treatment of severe hyperammonemia: An investigation on potential interactions

Peritoneal dialysis (PD) performed with transmembrane pH-gradient liposomes was reported to efficiently remove ammonia from the body, representing a promising alternative to current standard-of-care for patients with severe hepatic encephalopathy. In this study, we further characterized the properties of liposome-supported peritoneal dialysis (LSPD) by 1) assessing its in-use stability in the presence of ascitic fluids from liver-disease patients; 2) investigating its interactions with drugs that are commonly administered to acute-on-chronic liver failure patients; and 3) analyzing the in vivo extraction profile of LSPD. We found that LSPD fluid maintained its in vitro ammonia uptake capability when combined with ascitic fluids. The co-incubation of selected drugs (e.g., beta-blockers, antibiotics, diuretics) with LSPD fluids and ammonia resulted in limited interaction effects for most compounds except for two fluoroquinolones and propranolol. However, considering the experimental set-up, these results should be interpreted with caution and confirmatory drug-drug interaction studies in a clinical setting will be required. Finally, metabolite-mapping analysis on dialysates of LSPD-treated rats revealed that the liposomes did not remove important metabolites more than a conventional PD fluid. Overall, these findings confirm that LSPD is a potentially safe and effective approach for treating hyperammonemic crises in the context of acute-on-chronic liver failure.

Newly Developed Neutralized pH Icodextrin Dialysis Fluid: Nonclinical Evaluation.

A two-compartment system (NICOPELIQ; NICO, Terumo Co., Tokyo, Japan) has recently been developed to neutralize icodextrin peritoneal dialysis fluid (PDF). In this study, a nonclinical evaluation of NICO was carried out to evaluate biocompatibility as well as water transport ability. Glucose degradation products (GDPs) in the icodextrin PDFs were analyzed via high-performance liquid chromatography (HPLC). The cell viability of human peritoneal mesothelial cells derived from peritoneal dialysis effluent (PDE-HPMCs) was evaluated as well as the amount of lactate dehydrogenase (LDH) released after exposure to different PDFs (NICO and EXTRANEAL [EX, Baxter Healthcare Corp., Chicago, IL, USA]) and neutralized pH glucose PDF MIDPELIQ 250 (M250, Terumo). The water transport ability of NICO, EX, and M250 was tested using dialysis tube membranes with various pore sizes: 1, 2, 6-8, and 12-16 kDa. Although cell viability decreased by 30% after 30 min exposure to NICO, it was maintained for 6 h while a significant decrease was observed after 6 h exposure to EX. However, following adjustment of the pH to the same pre-exposure pH value, there was no significant difference in cell viability within the same pH group despite a doubling of the difference in the total amount of GDPs (44.6 ± 8.6 µM in NICO and 91.9 ± 9.5 µM in EX, respectively). In contrast, a significant decrease in cell viability was observed when the pH decreased to less than pH 6. Levels of released LDH, a cytotoxic marker, were within 5% after a 6-h exposure of NICO to PDE-HPMCs. There was no significant difference in water transport ability represented as overall osmotic gradients between NICO and EX. In conclusion, neutralization of icodextrin PDF is beneficial for maintaining cell viability and minimizing LDH release while water transport ability is comparable to the conventional icodextrin PDF.

High glucose concentration-induced expression of pentraxin-3 in a rat model of continuous peritoneal dialysis.

Continuous exposure to peritoneal dialysis fluids (PDFs) is associated with pathological responses such as persistent micro-inflammation, which leads to ultrafiltration failure. Pentraxin-3 (PTX3), a multifunctional soluble pattern recognition receptor, is produced at sites of inflammation by a wide range of cell types. This study investigates the in vivo expression of PTX3 in the peritoneal membrane of a rat continuous peritoneal dialysis (PD) model, as well as the effect of high glucose on the in vitro expression of PTX3. The expression of PTX3 was analyzed using RT-PCR, real-time PCR, immunohistochemistry and western blotting in a PD rat model receiving saline or conventional PDF containing 3.86% glucose for 8 weeks. The effects of high glucose on the expression of PTX3 were examined in cultured rat peritoneal mesothelial cells (RPMCs), mouse macrophage-like cells, and mouse fibroblasts. In a rat model of PD, eight-week instillation of the conventional PDF produced increased submesothelial thickening, followed by substantially enhanced PTX3 protein levels in the submesothelial layer of peritoneal membrane. PTX3 was detected in peritoneal mesothelial cells, macrophages and fibroblasts in the thickened submesothelial area. Glucose was found to induce PTX3 protein expression in RPMCs as well as macrophage-like cells and fibroblasts. Continuous exposure to conventional PDF induces PTX3 expression in the peritoneal membrane of rats. High glucose may be involved in the mechanism of PDF-induced local micro-inflammation in the peritoneum.

Attenuation of methylglyoxal-induced peritoneal fibrosis: immunomodulation by interleukin-10

Peritoneal fibrosis (PF), a serious pathophysiology of peritoneal dialysis (PD), is implicated in various types of chronic inflammation. In the present study, we examined the benefits of interleukin (IL)-10, which exerts anti-inflammatory effects, in an experimental rat model of methylglyoxal (MGO)-induced PF. We injected an adeno-associated virus (AAV) vector encoding rat IL-10 or enhanced green fluorescent protein (GFP) into male Sprague-Dawley rats at 6 weeks of age. Four weeks later, the rats received continuous peritoneal injections of conventional PD fluid (PDF) with MGO for 3 weeks. Then, the peritoneal histology and the expression levels of fibrogenic mediators and proinflammatory cytokines were analyzed. The rats demonstrating persistent IL-10 expression showed significantly reduced fibrous peritoneal thickening compared with those with GFP expression. The infiltration of macrophages, the expression of tumor necrosis factor-α, IL-1β, IL-6, transforming growth factor-β1, Snail, and matrix metalloproteinase 2 genes as well as the proliferation of mesenchymal-like mesothelial cells augmented by MGO were all significantly suppressed by IL-10 expression. IL-10 also abrogated the extent of MGO-induced bowel adhesions mimicking a cocoon-like mass. Our findings provide valuable insight into the potential benefit of immunomodulation with IL-10 as one potentially effective therapeutic strategy for preventing the onset of peritoneal injury resulting in PF.

Peritoneal Fibrosis Induced by Intraperitoneal Methylglyoxal Injection: The Role of Concurrent Renal Dysfunction

Background: Peritoneal fibrosis (PF) is a serious pathophysiology of peritoneal dialysis (PD). An ongoing focus of research is the potential fibrogenic nature of methylglyoxal (MGO) in conventional PD fluid (PDF). The aim of the current study was to explore the effects of the uremic milieu on the promotion of PF by MGO using rats with adenine-induced renal failure (RF). Methods: Adenine-treated Sprague-Dawley rats were randomly assigned to receive continuous peritoneal injections of PDF with or without MGO for three weeks or were left untreated for the same duration. Rats without RF were also assigned to three groups. The peritoneal histology and expression levels of type I collagen, transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (αSMA), Snail, matrix metalloproteinase-2 (MMP-2), advanced glycation end-products (AGEs) and the receptor for AGE (RAGE) were then analyzed. Results: Peritoneal treatment with 5 m<smlcap>M</smlcap> MGO accelerated the fibrous peritoneal thickening progression promoted by exposure to standard PDF in the rats with RF, but not in the rats with a normal renal function. Treatment with MGO significantly augmented the proliferation of mesenchymal-like mesothelial cells, accumulation of AGE, de novo expression of αSMA and RAGE and gene expression of type I collagen, TGF-β1, Snail and MMP-2, whereas both MGO and RF alone had, at most, marginal effects on the changes in these biological parameters. Conclusions: In the present study, the adverse effects of MGO on the peritoneum became more prominent under conditions of a uremic milieu. These findings imply that MGO and uremia act cooperatively to induce PF.

Structure- and concentration-specific assessment of the physiological reactivity of α-dicarbonyl glucose degradation products in peritoneal dialysis fluids.

In peritoneal dialysis (PD), glucose degradation products (GDPs), which are formed during heat sterilization of dialysis fluids, lead to structural and functional changes in the peritoneal membrane, which eventually result in the loss of its ultrafiltration capacity. To determine the molecular mechanisms behind these processes, the present study tested the influence of the six major α-dicarbonyl GDPs in PD fluids, namely, glyoxal, methylglyoxal, 3-deoxyglucosone (3-DG), 3-deoxygalactosone (3-DGal), 3,4-dideoxyglucosone-3-ene (3,4-DGE), and glucosone with respect to their potential to impair the enzymatic activity of RNase A as well as their effects on cell viability. For comprehensive risk assessment, the α-dicarbonyl GDPs were applied separately and in concentrations as present in conventional PD fluids. Thus, it was shown that after 5 days, glucosone impaired RNase A activity most distinctly (58% remaining activity, p < 0.001 compared to that of the control), followed by 3,4-DGE (62%, p < 0.001), 3-DGal (66%, p < 0.001), and 3-DG (76%, p < 0.01). Methylglyoxal and glyoxal caused weaker inactivation with significant effects only after 10 days of incubation (79%, 81%, p < 0.001). Profiling of the advanced glycation end products formed during the incubation of RNase A with methylglyoxal revealed predominant formation of the arginine modifications imidazolinone, CEA/dihydroxyimidazoline, and tetrahydropyrimidine at Arg10, Arg33, Arg39, and Arg85. Particularly, modification at Arg39 may severely affect the active site of the enzyme. Additionally, structure- and concentration-specific assessment of the cytotoxicity of the α-dicarbonyl GDPs was performed. Although present at very low concentration, the cytotoxic effect of PD fluids after 2 days of incubation was exclusively caused by 3,4-DGE (14% cell viability, p < 0.001). After 4 days of incubation, 3-DGal (13% cell viability, p < 0.001), 3-DG (24%, p < 0.001), and, to a lower extent, glyoxal and methylglyoxal (both 57%, p < 0.01) also reduced cell viability significantly. In conclusion, 3,4-DGE, 3-DGal, and glucosone appear to be the most relevant parameters for the biocompatibility of PD fluids.

Longitudinal Analysis of Peritoneal Fluid Transport and Its Determinants in a Cohort of Incident Peritoneal Dialysis Patients

There is a paucity of large longitudinal studies on the time course of peritoneal fluid transport. The aim of the present study was to longitudinally analyze changes in fluid transport and relevant solute transport parameters in patients treated with a conventional peritoneal dialysis (PD) fluid and, to mimic clinical reality, not selected for the presence or absence of ultrafiltration (UF) failure. This prospective single-center cohort study followed 138 consecutive incident PD patients from July 1994 until censoring in August 2004. The design was longitudinal, with repeated measures over time in each patient. Patients had undergone at least 1 and a maximum of 5 annual standard peritoneal permeability analyses (SPAs) using 3.86% glucose dialysate. A linear mixed model was used to analyze the longitudinal data. No differences in patient characteristics were present at baseline in relation to the number of available SPAs. There were also no differences in patient withdrawal during the years of follow-up. A gradual decline in fluid transport, expressed as free water transport (FWT), small-pore fluid transport (SPFT), and transcapillary UF (TCUF), was observed with duration of PD. The decline was mainly attributable to patients who developed UF failure. The time courses for the determinants of fluid transport, such as the reflection coefficient (σ) and the UF coefficient (LpA), were not different. However, they were associated with an increase in the mass transfer area coefficient of creatinine, reflecting the peritoneal vascular surface area. Fluid profiles for FWT and SPFT during a dwell can be explained by current knowledge of the three-pore model. Fluid transport declines with the duration of PD because of an increase in the vascular surface area, leading to a rapid dissipation of glucose as the osmotic agent. The absence of a trend in the time course of osmotic conductance and its constituents-that is, LpA and σ-suggests that, in an unselected population, these parameters are affected only late in the time course of PD.

GSK-3β inhibition protects mesothelial cells during experimental peritoneal dialysis through upregulation of the heat shock response

Non-physiological components of peritoneal dialysis fluids (PDF) lead to the injury of peritoneal mesothelial cells resulting in the failure of peritoneal dialysis (PD) potentially via inadequate induction of the protective heat shock response (HSR). Glycogen synthase kinase-3β (GSK-3β) is a negative regulator of cell survival partly by suppression of the HSR and is influenced by stress stimuli also present in conventional PDF. The effects of PDF on GSK-3β activation and the impact of GSK-3β inhibition with lithium (LiCl) were investigated on cell survival with special regard to HSR, in particular to heat shock transcription factor 1 (HSF-1) activation and Hsp72 production in an in vitro model of PD using MeT-5A and primary mesothelial cells. Incubation of cells with the PDF Dianeal® (glucose-based, low pH, high glucose degradation products (GDP)) and Extraneal® (icodextrin-based, low pH, low GDP) caused activation of GSK-3β compared to the other tested PDF, i.e. Balance®, Physioneal® (normal pH, glucose-based, low GDP) and Nutrineal® (moderately acidic, amino acid-based). Inhibition of GSK-3β with LiCl in Dianeal® and Extraneal®-treated cells dose-dependently decreased cell damage and death rate and was paralleled by higher HSF-1 activation and Hsp72 expression. GSK-3β is activated by low pH GDP containing PDF with and without glucose as osmotic agent, indicating that GSK-3β is involved in mesothelial cell signalling in response to experimental PD. Inhibition of GSK-3β with LiCl ameliorated cell injury and improved HSR upon PDF exposure. Thus, GSK-3β inhibitors likely have therapeutic potential as cytoprotective additive for decreasing PDF toxicity.

Effect of the Dialysis Fluid Buffer on Peritoneal Membrane Function in Children

Double-chamber peritoneal dialysis fluids exert less toxicity by their neutral pH and reduced glucose degradation product content. The role of the buffer compound (lactate and bicarbonate) has not been defined in humans. A multicenter randomized controlled trial in 37 children on automated peritoneal dialysis was performed. After a 2-month run-in period with conventional peritoneal dialysis fluids, patients were randomized to neutral-pH, low-glucose degradation product peritoneal dialysis fluids with 35 mM lactate or 34 mM bicarbonate content. Clinical and biochemical monitoring was performed monthly, and peritoneal equilibration tests and 24-hour clearance studies were performed at 0, 3, 6, and 10 months. No statistically significant difference in capillary blood pH, serum bicarbonate, or oral buffer supplementation emerged during the study. At baseline, peritoneal solute equilibration and clearance rates were similar. During the study, 4-hour dialysis to plasma ratio of creatinine tended to increase, and 24-hour dialytic creatinine and phosphate clearance increased with lactate peritoneal dialysis fluid but not with bicarbonate peritoneal dialysis fluid. Daily net ultrafiltration, which was similar at baseline (lactate fluid=5.4±2.6 ml/g glucose exposure, bicarbonate fluid=4.9±1.9 ml/g glucose exposure), decreased to 4.6±1.0 ml/g glucose exposure in the lactate peritoneal dialysis fluid group, whereas it increased to 5.1±1.7 ml/g glucose exposure in the bicarbonate content peritoneal dialysis fluid group (P=0.006 for interaction). When using biocompatible peritoneal dialysis fluids, equally good acidosis control is achieved with lactate and bicarbonate buffers. Improved long-term preservation of peritoneal membrane function may, however, be achieved with bicarbonate-based peritoneal dialysis fluids.

A Combination of Biocompatible Peritoneal Dialysis Solutions and Residual Renal Function, Peritoneal Transport, and Inflammation Markers: A Randomized Clinical Trial

The benefits of biocompatible peritoneal dialysis (PD) fluids, particularly for residual renal function (RRF), are controversial. Moreover, the clinical effects of a PD regimen consisting of different biocompatible PD fluids have not been fully established. Prospective, randomized, controlled, open-label study. Patients with end-stage kidney disease newly started on continuous ambulatory PD therapy (N = 150). A 12-month intervention with 3 biocompatible PD fluids (a neutral-pH, low glucose degradation product, 1.5% glucose solution; a solution with 1.1% amino acid; and a fluid with 7.5% icodextrin) or conventional PD fluid. The primary outcome was change in RRF and daily urine volume. Secondary outcomes were peritoneal transport and inflammation markers. RRF, daily urine volume, serum and dialysate cytokine levels. RRF(3.24 ± 1.98 vs 2.88 ± 2.43 mL/min/1.73 m(2); P = 0.9) and rate of decline in RRF (-0.76 ± 1.77 vs -0.91 ± 1.92 mL/min/1.73 m(2) per year; P = 0.6) did not differ between the biocompatible- and conventional-PD-fluid groups. However, patients using the biocompatible PD fluids had better preservation of daily urine volume (959 ± 515 vs 798 ± 615 mL/d in the conventional group, P = 0.02 by comparison of difference in overall change by repeated-measures analysis of variance). Their dialysate-plasma creatinine ratio at 4 hours was higher at 12 months (0.78 ± 0.13 vs 0.68 ± 0.12; P = 0.01 for comparison of the difference in overall change by repeated-measures analysis of variance). They also had significantly higher serum levels of adiponectin and overnight spent dialysate levels of cancer antigen 125, adiponectin, and interleukin 6 (IL-6). No differences between the 2 groups were observed for serum C-reactive protein and IL-6 levels. Unblinded, relatively short follow-up; no formal sample-size calculations. Use of a combination of 3 biocompatible PD fluids for 12 months compared with conventional PD fluid did not affect RRF, but was associated with better preservation of daily urine volume. The biocompatible PD fluids also lead to changes in small-solute transport and an increase in dialysate cancer antigen 125, IL-6, adiponectin, and systemic adiponectin levels, but have no effect on systemic inflammatory response. The clinical significance of these changes, while of great interest, remains to be determined by further studies.

A Study of the Clinical and Biochemical Profile of Peritoneal Dialysis Fluid Low in Glucose Degradation Products

Although peritoneal dialysis (PD) is a widely accepted form of renal replacement therapy, concerns remain regarding the bioincompatible nature of standard PD fluid (PDF). Short-term studies of new biocompatible PDFs low in glucose degradation products (GDPs) reveal divergent results with respect to peritoneal integrity. We studied 125 patients on maintenance PD who were assigned, by simple randomization, to receive either conventional or low-GDP PDF at PD initiation. Parameters of dialysis adequacy and peritoneal transport of small solutes were determined at initiation and after a period of maintenance PD at the time when serum and overnight effluent dialysate were simultaneously collected and assayed for various cytokines, chemokines, adipokines, and cardiac biomarkers. All patients were further followed prospectively for an average of 15 months from the day of serum and effluent collection to determine patient survival and cardiovascular events. Patients treated with conventional or low-GDP PDF were matched for sex, age, duration of dialysis, dialysis adequacy, and incidence of cardiovascular disease or diabetes. After an average of 2.3 years of PD treatment, the weekly total and peritoneal creatinine clearance, and the total and peritoneal Kt/V were comparable in the groups. However, urine output was higher in patients using low-GDP PDF despite there having been no difference between the groups at PD initiation. Patients using low-GDP PDF also experienced a slower rate of decline of residual glomerular filtration and urine output than did patients on conventional PDF. Compared with serum concentrations, effluent concentrations of tumor necrosis factor α, hepatocyte growth factor, macrophage migration inhibitory factor, interleukins 8 and 6, C-reactive protein, and leptin were found to be higher in both groups of patients after long-term PD, suggesting that the peritoneal cavity was the major source of those mediators. Compared with patients on low-GDP PDF, patients on conventional fluid showed elevated leptin and reduced adiponectin levels in serum and effluent. The effluent concentration of interleukin 8 was significantly lower in patients using low-GDP PDF. The survival rate and incidence of cardiovascular complications did not differ between these groups after maintenance PD for an average of 3.6 years. It appears that low-GDP PDF results in an improvement of local peritoneal homeostasis through a reduction of chronic inflammatory status in the peritoneum.

Impacts of icodextrin on integrin-mediated wound healing of peritoneal mesothelial cells

AimsExposure to glucose and its metabolites in peritoneal dialysis fluid (PDF) results in structural alterations of the peritoneal membrane. Icodextrin-containing PDF eliminates glucose and reduces deterioration of peritoneal membrane function, but direct effects of icodextrin molecules on peritoneal mesothelial cells have yet to be elucidated. We compared the impacts of icodextrin itself with those of glucose under PDF-free conditions on wound healing processes of injured mesothelial cell monolayers, focusing on integrin-mediated cell adhesion mechanisms. Main methodsRegeneration processes of the peritoneal mesothelial cell monolayer were investigated employing an in vitro wound healing assay of cultured rat peritoneal mesothelial cells treated with icodextrin powder- or glucose-dissolved culture medium without PDF, as well as icodextrin- or glucose-containing PDF. The effects of icodextrin on integrin-mediated cell adhesions were examined by immunocytochemistry and Western blotting against focal adhesion kinase (FAK). Key findingsCell migration over fibronectin was inhibited in conventional glucose-containing PDF, while icodextrin-containing PDF exerted no significant inhibitory effects. Culture medium containing 1.5% glucose without PDF also inhibited wound healing of mesothelial cells, while 7.5% icodextrin-dissolved culture medium without PDF had no inhibitory effects. Glucose suppressed cell motility by inhibiting tyrosine phosphorylation of FAK, formation of focal adhesions, and cell spreading, while icodextrin had no effects on any of these mesothelial cell functions. SignificanceOur results demonstrate icodextrin to have no adverse effects on wound healing processes of peritoneal mesothelial cells. Preservation of integrin-mediated cell adhesion might be one of the molecular mechanisms accounting for the superior biocompatibility of icodextrin-containing PDF.

Effects of neutral pH and low-glucose degradation product-containing peritoneal dialysis fluid on systemic markers of inflammation and endothelial dysfunction: a randomized controlled 1-year follow-up study

The local peritoneal effects of low-glucose degradation product (GDP)-containing peritoneal dialysis fluid (PDF) have been extensively described. However, the systemic effects of prolonged prescription of these solutions are unknown. This study aimed to evaluate the effects of neutral pH and low-GDP PDF on systemic inflammation and endothelial dysfunction markers in peritoneal dialysis (PD) patients. This is a multicenter, open labeled, randomized controlled trial including one hundred fifty-two patients initiating continuous ambulatory peritoneal dialysis for end-stage renal disease from seven centers in Korea. Participants were randomly allocated to conventional PDF (Stay safe®; Fresenius Medical Care, Bad Homburg, Germany) or low-GDP PDF (Balance®; Fresenius Medical Care) and were followed for 1 year. Primary outcome variable was the inflammation and endothelial dysfunction index (IEDI), a composite score derived from serum levels of soluble intercellular adhesion molecule (sICAM)-1, soluble vascular cellular adhesion molecule (sVCAM)-1 and high-sensitivity C-reactive protein (hs-CRP). sICAM-1, sVCAM-1, residual renal function (RRF), peritoneal membrane transport characteristics, ultrafiltration volume and nutritional parameters were measured as secondary outcome variables. Of 152 patients randomized, 146 (low-GDP: conventional PDF, 79:67) patients entered the trial (46% male, 53% with diabetes mellitus). At 12-month follow-up, the low-GDP group had significantly lower levels of IEDI, sICAM-1 and sVCAM-1 compared to the conventional group; hs-CRP was not different between groups. Peritoneal transport characteristics, RRF, nutritional parameters, incidence of peritonitis and death-censored technique survival were not different between groups. Neutral pH and low-GDP PDF likely produce fewer changes in markers of endothelial dysfunction compared to conventional PDF in incident PD patients.

The impact of dialysis solution biocompatibility on ultrafiltration and on free water transport in rats

This study compares different peritoneal dialysis fluids (PDF) in rats over a short contact time. For greater accuracy, net ultrafiltration (UF) and peritoneal transport indices, mass transfer area coefficient (MTAC) were scaled for the in vivo peritoneal surface area recruited (ivPSA) measured by microcomputerized tomography. Wistar rats underwent nephrectomy (5/6ths), were randomized into two groups and given 1.5% glucose PDF, either conventional acidic lactate (n = 14) or pH neutral bicarbonate (BicaVera) (n = 13); MTAC and UF were measured using a 90-min peritoneal equilibrium test (PET), fill volume (IPV) of 10 ml/100 g; small pore fluid transport was determined from sodium balance and used to calculate free water transport (FWT). Each ivPSA value was significantly correlated with the actual IPV, which varied from one rat to another. At 90 min of contact, there was no difference in recruited ivPSA in relation to PDFs. There was a difference (p < 0.01) in net UF/ivPSA 0.45 vs. 1.41 cm(2)/ml for bicarbonate versus lactate, as there was in the proportion of FWT with bicarbonate (42 ± 5% of net UF) compared to lactate (29 ± 4% of net UF). Net UF for individual values of ivPSA differs between conventional PDF and more biocompatible solutions, such as bicarbonate PDF. This observed change in UF cannot be fully explained by differences in glucose transport. The changes in FWT may be explained by the impact of the PDF biocompatibility on aquaporin function.

A Peritoneal Dialysis Regimen Low in Glucose and Glucose Degradation Products Results in Increased Cancer Antigen 125 and Peritoneal Activation

Glucose and glucose degradation products (GDPs) in peritoneal dialysis fluids (PDFs) are both thought to mediate progressive peritoneal worsening. In a multicenter, prospective, randomized crossover study, incident continuous ambulatory peritoneal dialysis patients were treated either with conventional lactate-buffered PDF (sPD regimen) or with a regimen low in glucose and GDPs: Nutrineal×1, Extraneal×1, and Physioneal×2 (NEPP regimen; all solutions: Baxter Healthcare, Utrecht, The Netherlands). After 6 months, patients were switched to the alternative regimen for another 6 months. After 6 weeks of run-in, before the switch, and at the end of the study, 4-hour peritoneal equilibration tests were performed, and overnight effluents were analyzed for cells and biomarkers. Differences between the regimens were assessed by multivariate analysis corrected for time and regimen sequence. The 45 patients who completed the study were equally distributed over both groups. During NEPP treatment, D(4)/D(0) glucose was lower (p < 0.01) and D/P creatinine was higher (p = 0.04). In NEPP overnight effluent, mesothelial cells (p < 0.0001), cancer antigen 125 (p < 0.0001), hyaluronan (p < 0.0001), leukocytes (p < 0.001), interleukins 6 (p = 0.001) and 8 (p = 0.0001), and vascular endothelial growth factor (VEGF, p < 0.0001) were increased by a factor of 2-3 compared with levels in sPD effluent. The NEPP regimen was associated with higher transport parameters, but that association disappeared after the addition of VEGF to the model. The association between NEPP and higher effluent levels of VEGF could not be attributed to glucose and GDP loads. Study results indicate preservation of the mesothelium and increased peritoneal activation during NEPP treatment. Whether the increase in VEGF reflects an increase in mesothelial cell mass or whether it points to another, undesirable mechanism cannot be determined from the present study. Longitudinal studies are needed to finally evaluate the usefulness of the NEPP regimen for further clinical use.