Update on Mechanisms of Ultrafiltration Failure

2009 ◽  
Vol 29 (2_suppl) ◽  
pp. 123-127 ◽  
Author(s):  
Yong-Lim Kim
Keyword(s):  
Growth Factor ◽  
Mast Cells ◽  
Solute Transport ◽  
Gene Polymorphisms ◽  
Transforming Growth Factor ◽  
Continuous Exposure ◽  
Peritoneal Membrane ◽  
Membrane Function ◽  
Mesenchymal Transition ◽  
Ultrafiltration Failure

Ultrafiltration failure (UFF) continues to be a major complication of peritoneal dialysis (PD), particularly long-term PD. Continuous exposure to bioincompatible PD solutions causes inflammation of the peritoneal membrane, which progressively undergoes fibrosis and angiogenesis and, ultimately, UFF. There is emerging evidence that epithelial–mesenchymal transition (EMT) of peritoneal mesothelial cells (MCs) may play an important role in the failure of peritoneal membrane function. Submesothelial myofibroblasts originating from MCs through EMT and from activated resident fibroblasts participate in inflammatory responses, extracellular matrix accumulation, and angiogenesis. High glucose and glucose degradation products from PD solutions are responsible for production of transforming growth factor β (TGFβ) and vascular endothelial growth factor (VEGF) by MCs, which induce EMT. Leptin and receptor for advanced glycation end-products (AGEs) augment myofibroblastic conversion through the TGFβ signaling system. A reduction in osmotic conductance in addition to increased solute transport causes UFF. This situation may be caused by loss of aquaporin (AQP) function and formation of the submesothelial fibrotic layer. During PD, AQP1 plays an essential role in water permeability and ultrafiltration (UF), modulating processes such as endothelial permeability and angiogenesis. During a hypertonic dwell, AQP1 mediates 50% of UF. Insufficient AQP1 function may be causative for inadequate UFF. A significant amount of evidence from animal studies now exists to show that mast cells communicate with fibroblasts and are implicated in fibrogenesis, angiogenesis, and UFF. However, it is not confirmed in human studies that mast cells contribute to the fibrosis seen in the peritoneum of PD patients. The patterns of UFF in PD patients depend on duration of treatment. Inherently high small-solute transport status is associated with hypoalbuminemia and a greater comorbidity index. However, most of the variability in peritoneal transport remains unexplained, pointing to the potential role of genetic factors. Gene polymorphisms associated with peritoneal membrane transport have been identified. Recent studies have shown that VEGF, interleukin-6, endothelial NO synthase, AGE receptor, and RAS gene polymorphisms are associated with transport properties in PD patients. Current insights into the mechanisms of UFF will provide rationales for new therapeutic strategies.

scholarly journals Gene Transfer of Transforming Growth Factor-β1 to the Rat Peritoneum: Effects on Membrane Function

2001 ◽  
Vol 12 (10) ◽  
pp. 2029-2039 ◽  
Author(s):  
PETER J. MARGETTS ◽  
MARTIN KOLB ◽  
TOM GALT ◽  
CATHERINE M. HOFF ◽  
TY R. SHOCKLEY ◽  
...  
Keyword(s):  
Growth Factor ◽  
Gene Transfer ◽  
Cellular Proliferation ◽  
Transforming Growth Factor ◽  
Active Form ◽  
Peritoneal Membrane ◽  
Peritoneal Fibrosis ◽  
Membrane Function ◽  
Ultrafiltration Failure ◽  
Tgf Β1

Abstract. Long-term peritoneal dialysis is limited by physiologic changes in the peritoneum that lead to ultrafiltration failure. To determine the role of profibrotic cytokines in the alteration of peritoneal transport, a rodent model of transforming growth factor-β (TGF-β)-mediated peritoneal fibrosis was established. An adenoviral vector driving the active form of TGF-β1 (AdTGFβ1) was administered intraperitoneally, and peritoneal structure and function were evaluated for 28 d after infection. Seven days after AdTGFβ1 infection, thickening of the peritoneum, with cellular proliferation and increased vascularization, was noted. By day 28, there was persistent thickening and extensive collagen deposition. The mesenteric collagen content was significantly elevated, compared with control adenovirus-treated animals, 21 d after infection (2.9versus1.8 mg hydroxyproline/g tissue,P= 0.006). Blood vessel density, as measured using factor VIII immunohistochemical analyses, was significantly increased from day 4 to day 21 but decreased by day 28. Animals infected with AdTGFβ1 demonstrated increased transport of solutes and decreased net ultrafiltration, which was maximal on day 7 and returned to baseline levels by day 28. It was demonstratedin vitroandin vivothat TGF-β1 induced production of vascular endothelial growth factor. Overexpression of TGF-β1 after adenovirus-mediated gene transfer causes peritoneal fibrosis, neoangiogenesis, and increased peritoneal membrane solute transport. This model should allow further delineation of the relative contributions of profibrotic and angiogenic cytokines to changes in peritoneal function and may lead to potential new interventions for peritoneal membrane failure.

Monitoring of Long-Term Peritoneal Membrane Function

2001 ◽  
Vol 21 (2) ◽  
pp. 225-232 ◽  
Author(s):  
Simon J. Davies
Keyword(s):  
Peritoneal Dialysis ◽  
Solute Transport ◽  
Water Transport ◽  
Drop Out ◽  
Published Data ◽  
Peritoneal Membrane ◽  
Membrane Function ◽  
Technique Survival ◽  
Ultrafiltration Failure

Objective Peritoneal membrane function influences dialysis prescription and clinical outcome and may change with time on treatment. Increasingly sophisticated tools, ranging from the peritoneal equilibration test (PET) to the standard permeability analysis (SPA) and personal dialysis capacity (PDC) test, are available to the clinician and clinical researcher. These tests allow assessment of a number of aspects of membrane function, including solute transport rates, ultrafiltration capacity, effective reabsorption, transcellular water transport, and permeability to macromolecules. In considering which tests are of greatest value in monitoring long-term membrane function, two criteria were set: those that result in clinically relevant interpatient differences in achieved ultrafiltration or solute clearances, and those that change with time in treatment. Study Selection Clinical validation studies of the PET, SPA, and PDC tests. Studies reporting membrane function using these methods in either long-term (5 years) peritoneal dialysis patients or longitudinal observations (> 2 years). Data Extraction Directly from published data. Additional, previously unpublished analysis of data from the Stoke PD Study. Results Solute transport is the most important parameter. In addition to predicting patient and technique survival at baseline, there is strong evidence that it can increase with time on treatment. Whereas patients with initially high solute transport drop out early from treatment, those with low transport remain longer on treatment, although, over 5 years, a proportion develop increasing transport rates. Ultrafiltration capacity, while being a composite measure of membrane function, is a useful guide for the clinician. Using the PET (2.27% glucose), a net ultrafiltration capacity of < 200 mL is associated with a 50% chance of achieving less than 1 L daily ultrafiltration at the expense of 1.8 hypertonic (3.86%) exchanges in anuric patients. Using a SPA (3.86% glucose), a net ultrafiltration capacity of < 400 mL indicates ultrafiltration failure. While there is circumstantial evidence that, with time on peritoneal dialysis, loss of transcellular water transport might contribute to ultrafiltration failure, none of the current tests is able to demonstrate this unequivocally. Of the other membrane parameters, evidence that interpatient differences are clinically relevant (permeability to macro-molecules), or that they change significantly with time on treatment (effective reabsorption), is lacking. Conclusion A strong case can be made for the regular assessment by clinicians of solute transport and ultrafiltration capacity, a task made simple to achieve using any of the three tools available.

The John F. Maher Recipient Lecture 2004: Rage in the Peritoneum

2005 ◽  
Vol 25 (1) ◽  
pp. 8-11 ◽  
Author(s):  
An S. De Vriese
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
High Glucose ◽  
Transforming Growth Factor ◽  
Degradation Products ◽  
Mesothelial Cells ◽  
Cell Surface Receptor ◽  
Peritoneal Membrane ◽  
Peritoneal Fibrosis ◽  
Mesenchymal Transition

Several conditions in the peritoneal membrane of peritoneal dialysis (PD) patients promote the accumulation of advanced glycation end-products (AGEs), that is, the uremic state, exposure to high glucose concentrations, and exposure to glucose degradation products (GDPs). AGEs exert some of their biologic actions through binding with a cell surface receptor, termed RAGE. Interaction of AGEs with RAGE induces sustained cellular activation, including the production of the fibrogenic growth factor, transforming growth factor-beta (TGF-β). TGF-β is pivotal in the process of epithelial-to-mesenchymal transition, through which cells of epithelial origin acquire myofibroblastic characteristics. Myofibroblasts are involved in virtually all conditions of pathological fibrosis. Submesothelial fibrosis is an important feature in peritoneal biopsies of PD patients, especially of those with clinical problems. We therefore examined the role of RAGE in peritoneal fibrosis, in an animal model of uremia, of high glucose exposure, and of peritoneal dialysate exposure. All three models were characterized by accumulation of AGEs, upregulation of RAGE, and fibrosis. Antagonism of RAGE prevented the upregulation of TGF-β and fibrosis in the peritoneal membrane. We further examined the underlying mechanism of peritoneal fibrosis in the uremic model. Prominent myofibroblast transdifferentiation of mesothelial cells was identified by co-localization of cytokeratin and α-smooth muscle actin in submesothelial and interstitial fibrotic tissue. Antagonism of RAGE prevented conversion of mesothelial cells to myofibroblasts in uremia. In conclusion, we hypothesize that accumulation of AGEs in the peritoneal membrane, as a consequence of the uremic environment, chronic exposure to high glucose, and exposure to GDPs, results in an increased expression of RAGE. The interaction of AGEs with RAGE induces peritoneal fibrosis by virtue of upregulation of TGF-β and subsequent conversion of mesothelial cells into myofibroblasts.

scholarly journals Genetic Polymorphisms and Peritoneal Membrane Function

2015 ◽  
Vol 35 (5) ◽  
pp. 517-529 ◽  
Author(s):  
Imad Siddique ◽  
K. Scott Brimble ◽  
Louise Walkin ◽  
Angela Summers ◽  
Paul Brenchley ◽  
...  
Keyword(s):  
Solute Transport ◽  
Clinical Outcomes ◽  
Genetic Polymorphisms ◽  
Gene Polymorphisms ◽  
Candidate Gene Approach ◽  
Peritoneal Membrane ◽  
Membrane Function ◽  
Technique Survival ◽  
Endothelial Growth Factor ◽  
Endothelial Nitric Oxide

BackgroundOutcomes for peritoneal dialysis (PD) patients are affected by the characteristics of the peritoneal membrane, which may be determined by genetic variants. We carried out a systematic review of the literature to identify studies which assessed the association between genetic polymorphisms, peritoneal membrane solute transport, and clinical outcomes for PD patients.MethodsThe National Library of Medicine was searched using a variety of strategies. Studies which met our inclusion criteria were reviewed and data abstracted. Our outcomes of interest included: high transport status peritoneal membrane, risk for peritonitis, encapsulating peritoneal sclerosis (EPS), patient and technique survival. We combined data from studies which evaluated the same genetic polymorphism and the same outcome.ResultsWe evaluated 18 relevant studies. All studies used a candidate gene approach. Gene polymorphisms in the interleukin (IL)-6 gene were associated with peritoneal membrane solute transport in several studies in different ethnic populations. Associations with solute transport and polymorphisms in endothelial nitric oxide synthase and receptor for advanced glycation end product genes were also identified. There was evidence of a genetic predisposition for peritonitis found in 2 studies, and for EPS in 1 study. Survival was found to be associated with a polymorphism in vascular endothelial growth factor and technique failure was associated with a polymorphism in the IL-1 receptor antagonist.ConclusionsThere is evidence that characteristics of the peritoneal membrane and clinical outcomes for PD patients have genetic determinants. The most consistent association was between IL-6 gene polymorphisms and peritoneal membrane solute transport.

scholarly journals Antiangiogenic and Antifibrotic Gene Therapy in a Chronic Infusion Model of Peritoneal Dialysis in Rats

2002 ◽  
Vol 13 (3) ◽  
pp. 721-728 ◽  
Author(s):  
Peter J. Margetts ◽  
Steve Gyorffy ◽  
Martin Kolb ◽  
Lisa Yu ◽  
Catherine M. Hoff ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Growth Factor ◽  
Gene Transfer ◽  
Transforming Growth Factor ◽  
Angiogenesis Inhibitor ◽  
Transforming Growth Factor Β ◽  
Collagen Content ◽  
Peritoneal Membrane ◽  
Peritoneal Fibrosis ◽  
Membrane Function

ABSTRACT. To identify the relative importance of peritoneal fibrosis and angiogenesis in peritoneal membrane dysfunction, adenoviral mediated gene transfer of angiostatin, a recognized angiogenesis inhibitor, and decorin, a transforming growth factor-β–inhibiting proteoglycan, were used in a daily infusion model of peritoneal dialysis. A peritoneal catheter and subcutaneous port were inserted in rats. Five and fourteen d after insertion, adenovirus-expressing angiostatin, decorin, or AdDL70, a null control virus, were administered. Daily infusion of 4.25% Baxter Dianeal was initiated 7 d after catheter insertion and continued until day 35. Three initial doses of lipopolysaccharide were administered on days 8, 10, and 12 to promote an inflammatory response. Net ultrafiltration was used as a measure of membrane function, and peritoneum-associated vasculature and mesenteric collagen content was quantified. Ultrafiltration dysfunction, angiogenesis, and fibrosis were observed in daily infusion control animals. Animals treated with AdAngiostatin demonstrated an improvement in net ultrafiltration (−3.1 versus −7.8 ml for control animals; P = 0.0004) with a significant reduction in vessel density. AdDecorin-treated animals showed a reduction in mesenteric collagen content (1.8 versus 2.9 μg/mg; P = 0.04); however, AdDecorin treatment had no effect on net ultrafiltration. In a rodent model of peritoneal membrane failure, net ultrafiltration was significantly improved and peritoneal-associated blood vessels were significantly reduced by using adenovirus-mediated gene transfer of angiostatin. Decorin, a transforming growth factor-β–inhibiting proteoglycan, reduced collagen content but did not affect net ultrafiltration. Improvement in the function of the peritoneum as a dialysis membrane after treatment with angiostatin has implications for treatment of peritoneal membrane dysfunction seen in patients on long-term dialysis.

A Chronic Inflammatory Infusion Model of Peritoneal Dialysis in Rats

2001 ◽  
Vol 21 (3_suppl) ◽  
pp. 368-372 ◽  
Author(s):  
Peter J. Margetts ◽  
Martin Kolb ◽  
Lisa Yu ◽  
Catherine M. Hoff ◽  
Jack Gauldie
Keyword(s):  
Peritoneal Dialysis ◽  
Growth Factor ◽  
Gene Transfer ◽  
Peritoneal Fluid ◽  
Transforming Growth Factor ◽  
Membrane Damage ◽  
Intraperitoneal Administration ◽  
Peritoneal Membrane ◽  
Ultrafiltration Failure ◽  
Physiologic Saline

Objectives Peritoneal membrane changes are related to daily exposure to non physiologic dialysate and recurrent acute inflammation. We modified a daily infusion and inflammation model and evaluated it for fibrotic and angiogenic features. The feasibility of adenovirus-mediated gene transfer in the model was also assessed. Methods Peritoneal catheters were implanted in rats. Over a period of 4 weeks, the animals received a daily infusion of Dianeal 4.25% (Baxter Healthcare Corporation, Deerfield, IL, U.S.A.) with an initial three doses of lipopolysaccharide (LPS) or physiologic saline. Peritoneal fluid was assayed for transforming growth factor beta (TGFβ) and vascular endothelial growth factor (VEGF). Animals were humanely killed at week 5. Net ultrafiltration was then measured, and tissue samples were immunostained for factor VIII. Mesenteric tissue was assayed for hydroxyproline content. Adenovirus-mediated gene transfer of β-galactosidase was assayed by intraperitoneal administration of the virus, 4 days before the end of the experiment. Results Animals treated with either Dianeal or physiologic saline showed peritoneal membrane thickening and increased vascularity. Fibrosis was demonstrated by increased hydroxyproline concentration. Ultrafiltration was impaired. We found increased concentrations of VEGF and TGFβ in the peritoneal fluid of animals treated with LPS and daily infusion. Adenovirus-mediated gene transfer to the peritoneal membrane was demonstrated in the model. Conclusions Exposure to LPS and daily Dianeal or physiologic saline leads to peritoneal fibrosis and neoangiogenesis. Vascularization and glucose transport correlate with ultrafiltration failure. The present animal model mimics changes seen in humans on peritoneal dialysis and may be valuable for evaluating short-term interventions to prevent membrane damage.

scholarly journals Peritoneal Fibrosis and High Transport are Induced in Mildly Pre-Injured Peritoneum by 3,4-Dideoxyglucosone-3-Ene in Mice

2013 ◽  
Vol 33 (2) ◽  
pp. 143-154 ◽  
Author(s):  
Hideki Yokoi ◽  
Masato Kasahara ◽  
Kiyoshi Mori ◽  
Takashige Kuwabara ◽  
Naohiro Toda ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Abdominal Cavity ◽  
Mesothelial Cell ◽  
Tissue Growth ◽  
Peritoneal Membrane ◽  
Peritoneal Fibrosis ◽  
Membrane Function ◽  
Peritoneal Tissue ◽  
High Concentrations

Peritoneal dialysis (PD) solution contains high concentrations of glucose and glucose degradation products (GDPs). One of several GDPs—3,4-dideoxyglucosone-3-ene (3,4-DGE)—was recently identified as the most reactive and toxic GDP in PD fluids. In vitro, 3,4-DGE has been shown to induce mesothelial cell damage; however, its role in peritoneal fibrosis in vivo remains unclear. In the present study, we intraperitoneally administered chlorhexidine gluconate (CG) for mild peritoneal injury, and we then injected 3,4-DGE [38μmol/L (low concentration) or 145μmol/L (high concentration)] 5 times weekly for 4 weeks. Significant thickening of the parietal peritoneal membrane was observed only when treatment with low or high concentrations of 3,4-DGE occurred after CG administration, but not when either CG or 3,4-DGE alone was given. The combination of CG and 3,4-DGE also caused upregulation of messenger RNA expression of transforming growth factor β1, connective tissue growth factor, fibronectin, collagen type 1 α1 chain, alpha smooth muscle actin (α–SMA), vascular endothelial growth factor 164, NADPH oxidase 1 and 4, p22phox, p47phox, and gp91phox in peritoneal tissue. Treatment with CG alone was sufficient to cause significant F4/80-positive macrophage infiltration, appearance of α–SMA-positive cells, and vessel formation in the submesothelial layer. Addition of 3,4-DGE markedly enhanced those changes and induced apoptosis, mainly in leukocytes. The concentration of 3,4-DGE in the abdominal cavity declined more rapidly in CG-treated mice than in PBS-treated mice. Peritoneal membrane permeability determined by peritoneal equilibration test showed high transport conditions in peritoneum treated with both CG and 3,4-DGE. These results indicate that, when mild peritoneal damage is already present, 3,4-DGE causes peritoneal thickening and fibrosis, resulting in deterioration of peritoneal membrane function.

scholarly journals WNT signaling is required for peritoneal membrane angiogenesis

2018 ◽  
Vol 314 (6) ◽  
pp. F1036-F1045 ◽  
Author(s):  
Manreet Padwal ◽  
Genyang Cheng ◽  
Limin Liu ◽  
Felix Boivin ◽  
Azim S. Gangji ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Wnt Signaling ◽  
Solute Transport ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Peritoneal Membrane ◽  
Peritoneal Fibrosis ◽  
Membrane Injury ◽  
Mesenchymal Transition

The wingless-type mouse mammary tumor virus integration site family (WNT) signaling pathway is involved in wound healing and fibrosis. We evaluated the WNT signaling pathway in peritoneal membrane injury. We assessed WNT1 protein expression in the peritoneal effluents of 54 stable peritoneal dialysis (PD) patients and WNT-related gene expression in ex vivo mesothelial cell cultures from 21 PD patients. In a transforming growth factor-β (TGF-β)-mediated animal model of peritoneal fibrosis, we evaluated regulation of the WNT pathway and the effect of WNT inhibition on peritoneal fibrosis and angiogenesis. WNT1 and WNT2 gene expression were positively correlated with peritoneal membrane solute transport in PD patients. In the mouse peritoneum, TGF-β-induced peritoneal fibrosis was associated with increased expression of WNT2 and WNT4. Peritoneal β-catenin protein was significantly upregulated after infection with adenovirus expressing TGF-β (AdTGF-β) along with elements of the WNT signaling pathway. Treatment with a β-catenin inhibitor (ICG-001) in mice with AdTGF-β-induced peritoneal fibrosis resulted in attenuation of peritoneal angiogenesis and reduced vascular endothelial growth factor. Similar results were also observed with the WNT antagonist Dickkopf-related protein (DKK)-1. In addition to this, DKK-1 blocked epithelial-mesenchymal transition and increased levels of the cell adhesion protein E-cadherin. We provide evidence that WNT signaling is active in the setting of experimental peritoneal fibrosis and WNT1 correlates with patient peritoneal membrane solute transport in PD patients. Intervention in this pathway is a possible therapy for peritoneal membrane injury.

scholarly journals Survival of Peritoneal Membrane Function on Biocompatible Dialysis Solutions in a Peritoneal Dialysis Cohort Assessed by a Novel Test

2021 ◽  
Vol 10 (16) ◽  
pp. 3650
Author(s):  
Olga Balafa ◽  
Anila Duni ◽  
Paraskevi Tseke ◽  
Karolos Rapsomanikis ◽  
Paraskevi Pavlakou ◽  
...  
Keyword(s):  
Solute Transport ◽  
Water Transport ◽  
Repeated Measures ◽  
Urine Volume ◽  
Free Water ◽  
Test Methods ◽  
Peritoneal Membrane ◽  
Membrane Function ◽  
Sodium Removal ◽  
Ultrafiltration Failure

Background: Longitudinal surveillance of peritoneal membrane function is crucial in defining patients with a risk of ultrafiltration failure. Long PD is associated with increased low molecular weight solute transport and decreased ultrafiltration and free water transport. Classic PET test only provides information about low molecular solute transport, and the vast majority of longitudinal studies are based on this test and include patients using conventional dialysates. Our aim was to prospectively analyze longitudinal data on peritoneal function in patients on biocompatible solutions using a novel test. Methods: Membrane function data were collected based on uni-PET (a combination of modified and mini PET). A total of 85 patients (age 61.1 ± 15.1 years) with at least one test/year were included. Results: The median follow up was 36 months (21.3, 67.2). A total of 219 PETs were performed. One-way repeated measures ANOVA showed that there were no statistically significant differences over time in ultrafiltration, free water transport, ultrafiltration through small pores, sodium removal, D/D0 and D/PCre in repeated PET-tests. Twenty-three tests revealed ultrafiltration failure in 16 (18.8%) patients. Those patients were longer on PD, had higher D/P creatinine ratios, lower ultrafiltration at one hour with lower free water transport and higher urine volume at baseline. Multivariate analysis revealed that the variation of ultrafiltration over repeated PET-tests independently correlated only with D/Pcreatinine, free water transport and ultrafiltration through small pores. Conclusions. Uni-PET is a combination of two tests that provides more information on the function of the membrane compared with PET. Our study on a PD cohort using only biocompatible solutions revealed that function membrane parameters remained stable over a long time. Ultrafiltration failure was correlated with increased D/P creatinine and decreased free water transport and ultrafiltration through small pores.

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