Glucose Degradation Products and Peritoneal Membrane Function

2001 ◽  
Vol 21 (2) ◽  
pp. 201-207 ◽  
Author(s):  
Janusz Witowski ◽  
Thorsten O. Bender ◽  
Gerhard M. Gahl ◽  
Ulrich Frei ◽  
Achim Jörres
Keyword(s):  
Peritoneal Dialysis ◽  
Cell Viability ◽  
Degradation Products ◽  
Membrane Function ◽  
Peritoneal Mesothelial Cells ◽  
Glucose Degradation Products ◽  
And Function ◽  
The Impact ◽  
Dialysis Fluids

Background The bioincompatibility of peritoneal dialysis fluids (PDF) in current use has been partially attributed to the presence of glucose degradation products (GDPs), which are generated during heat sterilization of PDF. Several of the GDPs have been identified and we have recently demonstrated that these GDPs per se may impair the viability and function of human peritoneal mesothelial cells (HPMC) in vitro. It is also possible that GDP-related toxicity is further exacerbated by the milieu of PDF. We review the current literature on GDP and present the results of experiments comparing the impact of heat- and filter-sterilized PDF on the viability and function of HPMC. Methods Peritoneal dialysis fluids with low (1.5%) and high (4.25%) glucose concentrations were laboratory prepared according to the standard formula and sterilized either by heat (H-PDF; 121°C, 0.2 MPa, 20 minutes) or filtration (F-PDF; 0.2 μ). The buildup of GDP was confirmed by UV absorbance at 284 nm. Confluent HPMC monolayers were exposed to these solutions mixed 1:1 with standard M199 culture medium. After 24 hours, cell viability was assessed with the MTT assay, and interleukin-1β–stimulated monocyte chemotactic protein-1 (MCP-1) release with specific immunoassay. Results Exposure of HPMC to H-PDF resulted in a significant decrease in cell viability, with solutions containing 4.25% glucose being more toxic than 1.5% glucose-based PDF (27.4% ± 3.4% and 53.4% ± 11.0% of control values, respectively). In contrast, viability of HPMC exposed to F-PDF was not different from that of control cells. Moreover, treatment with H-PDF impaired the release of MCP-1 from HPMC to a significantly greater degree compared to F-PDF (17.4% and 24.9% difference for low and high glucose PDF, respectively). Conclusions Exposure of HPMC to H-PDF significantly impairs cell viability and the capacity for generating MCP-1 compared to F-PDF. This effect is likely to be mediated by GDPs present in H-PDF but not in F-PDF.

scholarly journals Prolonged Exposure to Glucose Degradation Products Impairs Viability and Function of Human Peritoneal Mesothelial Cells

2001 ◽  
Vol 12 (11) ◽  
pp. 2434-2441 ◽  
Author(s):  
JANUSZ WITOWSKI ◽  
JUSTYNA WISNIEWSKA ◽  
KATARZYNA KORYBALSKA ◽  
THORSTEN O. BENDER ◽  
ANDRZEJ BREBOROWICZ ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Cell Viability ◽  
Degradation Products ◽  
Mesothelial Cells ◽  
Peritoneal Mesothelial Cells ◽  
Glucose Degradation Products ◽  
Human Peritoneal Mesothelial Cells ◽  
And Function ◽  
The Impact

Abstract. Bioincompatibility of peritoneal dialysis fluids (PDF) has been linked to the presence of glucose degradation products (GDP). Previous experiments have shown that short-term exposure to several GDP at concentrations found in commercially available PDF had no significant effect on human peritoneal mesothelial cells (HPMC). During continuous ambulatory peritoneal dialysis, however, cells are continually exposed to GDP for extended periods of time. Thus, the impact of GDP on HPMC during long-term exposure was assessed. HPMC were cultured for up to 36 d in the presence of 6 identified GDP (acetaldehyde, formaldehyde, furaldehyde, glyoxal, methylglyoxal, and 5-HMF) at doses that reflect their concentrations in conventional PDF. At regular time intervals, the ability of HPMC to secrete cytokines (interleukin-6 [IL-6]) and extracellular matrix molecules (fibronectin) was evaluated. In addition, cell viability, morphology, and proliferative potential were assessed. Exposure to GDP resulted in a significant reduction in mesothelial IL-6 and fibronectin release. Approximately 80% of this decrease occurred during the first 12 d of the exposure and was paralleled by a gradual loss of cell viability and development of morphologic alterations. After 36 d of exposure, the number of cells in GDP-treated cultures was reduced by nearly 60%. However, GDP-treated cells were able to resume normal proliferation when transferred to a normal GDP-free medium. HPMC viability and function may be impaired during long-term exposure to clinically relevant concentrations of GDP, which suggests a potential role of GDP in the pathogenesis of peritoneal membrane dysfunction during chronic peritoneal dialysis.

The Role of the Glyoxalase Pathway in Reducing Mesothelial Toxicity of Glucose Degradation Products

2006 ◽  
Vol 26 (2) ◽  
pp. 259-265 ◽  
Author(s):  
Katarzyna Korybalska ◽  
Justyna Wisniewska–Elnur ◽  
Joanna Trómińska ◽  
Achim Jörres ◽  
Andrzej Bre¸borowicz ◽  
...  
Keyword(s):  
Cell Viability ◽  
Interleukin 6 ◽  
Degradation Products ◽  
Inhibitory Effects ◽  
Peritoneal Mesothelial Cells ◽  
Glucose Degradation Products ◽  
Human Peritoneal Mesothelial Cells ◽  
And Function ◽  
The Impact

Background The glucose degradation products (GDP) present in conventional peritoneal dialysis fluids (PDF) may exert adverse effects toward human peritoneal mesothelial cells (HPMC). Some GDP can be detoxified by the glyoxalase/glutathione pathway. It has been shown that the addition of glyoxalase I (GLO-I) and reduced glutathione (GSH) to PDF effectively eliminates GDP. We have therefore examined the GLO-I/GSH system in HPMC and assessed the impact of GLO-I/GSH-treated PDF on the viability and function of HPMC. Methods Heat-sterilized PDF (H-PDF) was incubated in the presence or absence of GLO-I and GSH for 1 hour at 37°C, and then mixed with an equal volume of serum-free M199 medium and applied to HPMC in culture. After 24 hours, HPMC were assessed for viability, the release of interleukin-6, GLO-I activity, and cellular glutathione. The effects were compared to those exerted by filter-sterilized PDF (F-PDF), which was devoid of GDP. Results Exposure of HPMC to H-PDF resulted in reduced GLO-I activity, GSH depletion, and a decrease in cell viability. Pretreatment of H-PDF with either a combination of GLO-I and GSH or GSH alone markedly reduced inhibitory effects of H-PDF toward HPMC, as measured by cell viability and interleukin-6 generation. Exposure of HPMC to the GSH precursor L-2-oxothiazolidine-carboxylic acid increased cellular GSH and prevented the loss of GLO-I activity in response to H-PDF. Conclusions Exposure to conventional GDP-rich PDF impairs the activity of the glyoxalase/glutathione system in HPMC. Pretreatment of PDF with GSH or replenishment of cellular GSH protects HPMC against GDP-mediated toxicity.

Glucose Degradation Products and the Peritoneal Mesothelium

2000 ◽  
Vol 20 (5_suppl) ◽  
pp. 19-22 ◽  
Author(s):  
Achim Jörres ◽  
Thorsten O. Bender ◽  
Janusz Witowski
Keyword(s):  
Peritoneal Dialysis ◽  
Degradation Products ◽  
Experimental Models ◽  
Buffer System ◽  
Peritoneal Fibrosis ◽  
High Concentration ◽  
Peritoneal Mesothelial Cells ◽  
Cell Functions ◽  
Glucose Degradation Products

Conventional heat-sterilized, glucose-based peritoneal dialysis (PD) fluids contain significant amounts of glucose degradation products (GDPs) such as aldehydes and dicarbonyl compounds (glyoxal, methylglyoxal). These GDPs have been shown to impair cell functions in various in vitro experimental models. In peritoneal mesothelial cells, GDPs dose-dependently inhibit cell proliferation and mediator synthesis. In addition, some GDPs potently promote generation of advanced glycation end-products (AGEs). Immunohistochemistry finds AGEs in the peritoneal membrane of chronic continuous ambulatory peritoneal dialysis (CAPD) patients, suggesting that peritoneal AGE accumulation may be involved in chronic peritoneal fibrosis. The formation of GDPs might be prevented by filter-sterilization of PD fluids. Another option is to separate the glucose and the buffer system in dual-chambered or multi-chambered containers. In these systems, the glucose is kept in a separate compartment at high concentration and very low pH—both conditions being known to minimize the degree of glucose decomposition during autoclaving. Initial experimental evidence suggests that these novel, multi-chambered fluids significantly improve in vitro biocompatibility; however, the clinical relevance of these results remains to be established in clinical trials.

3,4-DGE in Peritoneal Dialysis Fluids Cannot be Found in Plasma after Infusion into the Peritoneal Cavity

2008 ◽  
Vol 28 (3) ◽  
pp. 277-282 ◽  
Author(s):  
Martin Erixon ◽  
Anders Wieslander ◽  
Torbjörn Lindén ◽  
Ola Carlsson ◽  
Jan Åke Jönsson ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Human Plasma ◽  
Peritoneal Cavity ◽  
Degradation Products ◽  
High Reactivity ◽  
The Other ◽  
Glucose Degradation Products ◽  
Pass Through ◽  
Dialysis Fluids

Objective Glucose degradation products (GDPs) are important in the outcome of peritoneal dialysis (PD) treatment. 3,4-dideoxyglucosone-3-ene (3,4-DGE) is the most cytotoxic GDP found in conventionally manufactured fluids and may, in addition, be recruited from 3-deoxyglucosone (3-DG). It is not known what happens with those GDPs in patients during PD. The aim of this study was to investigate if the 3,4-DGE and 3-DG in PD fluids can be found in plasma during treatment. Design PD patients were dialyzed with a conventional PD fluid containing 43 μmol/L 3,4-DGE and 281 μmol/L 3-DG. Parallel experiments were performed in rats as well as in vitro with human plasma. The rats were dialyzed with a PD fluid containing 100 μmol/L 3,4-DGE and 200 μmol/L 3-DG. Results The concentration of 3,4-DGE in the peritoneum decreased at a much higher rate than 3-DG during the dwell. 3,4-DGE was not, however, detected in the plasma of patients or rats during dialysis. The concentration of 3-DG in plasma peaked shortly after infusion of the fluid to the peritoneal cavity. The concentration of 3,4-DGE during experimental incubation in plasma decreased rapidly, while the concentration of 3-DG decreased only 10% as rapidly or less. Conclusion 3,4-DGE could not be detected in plasma from either PD patients or rats during dialysis. This is presumably due to its high reactivity. 3-DG may, on the other hand, pass through the membrane and be detected in the blood.

Glucose Degradation Products in Peritoneal Dialysis Fluids: How they can be Avoided

2001 ◽  
Vol 21 (3_suppl) ◽  
pp. 119-124 ◽  
Author(s):  
Anders Wieslander ◽  
Torbjörn Linden ◽  
Per Kjellstrand
Keyword(s):  
Peritoneal Dialysis ◽  
Degradation Products ◽  
Low Ph ◽  
Relative Importance ◽  
In Vitro Methods ◽  
Glucose Degradation Products ◽  
Peritoneal Tissue ◽  
In Vitro Inhibition ◽  
Dialysis Fluids

♦ Objectives A patient on peritoneal dialysis (PD) uses 3 – 7 tons of PD fluid every year. The result is considerable stress on the peritoneal tissue. Aspects of PD fluids that have been considered responsible for bioincompatibility are low pH, high osmolality, high glucose and lactate concentrations, and the presence of glucose degradation products (GDPs). However, the relative importance of each factor in PD fluid has so far not been investigated. Discovering their relative importance was the aim of the present study. ♦ Methods Two main methods for investigating biocompatibility were used in this study: cytotoxicity measured as in vitro inhibition of cell growth, and in vitro AGE formation measured as albumin-linked fluorescence. ♦ Results The two most important factors for determining in vitro bioincompatibility of PD fluids were the presence of GDPs, which caused both severe cytotoxicity and strong AGE promotion, and low pH, which induced severe cytotoxicity. ♦ Conclusions The biocompatibility of PD fluids can be monitored through fairly simple in vitro methods such as cell proliferation and AGE formation. Bioincompatibility of PD fluids is caused mainly by the presence of GDPs and low pH. These findings correlate well with known clinical bioincompatibility.

3,4-Dideoxyglucosone-3-Ene in Peritoneal Dialysis Fluids Infused into the Peritoneal Cavity Cannot be Found in Plasma

2009 ◽  
Vol 29 (2_suppl) ◽  
pp. 28-31 ◽  
Author(s):  
Martin Erixon ◽  
Anders Wieslander ◽  
Torbjörn Lindén ◽  
Ola Carlsson ◽  
Jan Åke Jönsson ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Human Plasma ◽  
Peritoneal Cavity ◽  
Degradation Products ◽  
High Reactivity ◽  
The Other ◽  
Glucose Degradation Products ◽  
Pass Through ◽  
Dialysis Fluids

Objective Glucose degradation products (GDPs) are important for the outcome of peritoneal dialysis (PD) treatment. The most cytotoxic GDP found in conventionally manufactured fluids, 3,4-dideoxyglucosone-3-ene (3,4-DGE), may in addition be recruited from 3-deoxyglucosone (3-DG). What happens with the GDPs in the fluid infused into patients during PD is not known. We investigated whether 3,4-DGE and 3-DG in PD fluid can be found in plasma during treatment. Design Patients on PD were dialyzed with a conventional PD fluid containing 43 μmol/L 3,4-DGE and 281 μmol/L 3-DG. Parallel experiments were performed in rats and in vitro with human plasma. The rats were dialyzed with a PD fluid containing 100 μmol/L 3,4-DGE and 200 μmol/L 3-DG. Results The 3,4-DGE concentration in the peritoneum declined at a much higher rate during the dwell than did the 3-DG concentration. However, 3,4-DGE was not detected in the plasma of patients or of rats during dialysis. The 3-DG concentration in plasma peaked shortly after infusion of fluid into the peritoneal cavity. The 3,4-DGE concentration during experimental incubation in plasma declined rapidly; the 3-DG concentration declined only 10% as rapidly (or less). Conclusion During dialysis, 3,4-DGE could not be detected in plasma of either PD patients or rats, presumably because of its high reactivity. On the other hand, 3-DG may pass through the membrane and be detected in the blood.

Mesothelial Toxicity of Peritoneal Dialysis Fluids is Related Primarily to Glucose Degradation Products, Not to Glucose Per Se

2003 ◽  
Vol 23 (4) ◽  
pp. 381-390
Author(s):  
Janusz Witowski ◽  
Thorsten O. Bender ◽  
Justyna Wisniewska–Elnur ◽  
Krzysztof Ksiazek ◽  
Jutta Passlick–Deetjen ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Degradation Products ◽  
Mesothelial Cell ◽  
Key Factors ◽  
Glucose Degradation Products ◽  
Per Se ◽  
High Concentrations ◽  
And Function ◽  
Peritoneal Mesothelial Cell ◽  
Dialysis Fluids

♦ Objectives High concentrations of glucose and/or formation of glucose degradation products (GDPs) during heat sterilization of peritoneal dialysis fluids (PDFs) are believed to be key factors in the limited biocompatibility of PDFs. We have previously shown that several identified GDPs can specifically impair human peritoneal mesothelial cell (HPMC) function. In the present study we aimed at differentiating the respective roles of glucose and GDPs in the toxicity of PDF to mesothelial cells. ♦ Methods HPMCs were acutely pre-exposed to or incubated chronically in the presence of pH-neutral PDF sterilized by either heat (H-PDF) or filtration (F-PDF). In addition, HPMCs were treated with commercially available H-PDF manufactured either conventionally, that is, in single-chamber containers, or using novel dual-chamber bags that help to substantially decrease GDP formation. Functional assessment of HPMCs included viability, release of interleukin (IL)-6, and proliferation. ♦ Results Viability and release of IL-6 from HPMCs pretreated with H-PDF (pH 7.3) for 1 to 4 hours were significantly reduced compared to cells exposed to corresponding F-PDF. Incubation in medium mixed (1:1) with H-PDF considerably impaired growth of HPMCs, and over a period of 10 days gradually decreased both the viability of HPMCs and their ability to generate IL-6. These effects were either absent from or significantly less in HPMCs exposed to F-PDF. Similar differences were observed when commercial GDP-containing H-PDFs were compared with newly designed H-PDFs free of GDPs. ♦ Conclusions Impaired viability and function of HPMCs exposed to glucose-containing pH-neutral PDF is related predominantly to the presence of GDP and, to a significantly lesser extent, to the presence of glucose per se. Prevention of GDP formation during auto-claving markedly improves the biocompatibility of H-PDF with HPMCs.

Peritoneal Dialysis Solutions Low in Glucose Degradation Products—evidence for Clinical Benefits

2008 ◽  
Vol 28 (3_suppl) ◽  
pp. 123-127
Author(s):  
Tadashi Tomo
Keyword(s):  
Peritoneal Dialysis ◽  
Vascular Function ◽  
Degradation Products ◽  
Peritoneal Mesothelial Cells ◽  
Advanced Glycosylation End Products ◽  
Glucose Degradation Products ◽  
Peritoneal Dialysis Fluid ◽  
Clinical Benefits ◽  
Human Peritoneal Mesothelial Cells ◽  
Peritoneal Function

In Japan, two types of new peritoneal dialysis fluid (PDF) are ordinarily used: two-chambered PDF, and icodextrin PDF. Two-chambered PDF has several biocompatible characteristics, one being low glucose degradation products (GDPs). Of the several GDPs in PDF, 3,4-dideoxyglucosone-3-ene (3,4-DGE) is thought to be strongly associated with the cytotoxicity of standard PDF. Using a PDF low in GDPs may reduce exposure of the peritoneum to 3,4-DGE, helping to preserve peritoneal function in PD patients. Additionally, use of a PDF low in GDPs may reduce plasma levels of advanced glycosylation end-products in PD patients, a change that may help to preserve vascular function in PD patients. Peritoneal rest for 24 hours after exposure to a PDF with low GDPs improves the activity of human peritoneal mesothelial cells. As compared with the use of standard PDF, the use of low-GDP PDF in combination therapy (peritoneal dialysis plus hemodialysis) may more effectively preserve peritoneal function. The new PDF low in GDPs has bio-compatible characteristics relative to peritoneum and system that may help to preserve peritoneal function or reduce complications such as atherosclerosis or dialysis-related amyloidosis in dialysis patients.

In Vitro Biocompatibility of a Heat -Sterilized, Low Toxic, and Less Acidic Fluid for Peritoneal Dialysis

1995 ◽  
Vol 15 (2) ◽  
pp. 158-164 ◽  
Author(s):  
Anders P. Wieslander ◽  
Reinhold Deppisch ◽  
Eva Svensson ◽  
Gunita Forsbäck ◽  
Rose Speidel ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
High Performance ◽  
Mononuclear Cells ◽  
Degradation Products ◽  
Fibroblast Cell ◽  
Interleukin 1Β ◽  
Uv Absorbance ◽  
Glucose Degradation Products ◽  
In Vitro Biocompatibility

Objective The aim of this study was to investigate a peritoneal dialysis (PD) fluid (PD-Bio), produced with the intention of reducing the amount of glucose degradation products and to increase the final pH. The heat sterilization of the fluid was performed with the glucose separated from the electrolytes. After sterilization the two solutions were combined. Methods The in vitro biocompatibility of PD-Bio was measured as the inhibition of cell growth of a cultured fibroblast cell line and as the stimulated release of interleukin-1β from cultured human mononuclear cells. The glucose degradation products were measured as UV absorbance at 228 nm or 284 nm and the concentration of aldehydes was estimated with high-performance liquid chromatography and gas chromatography. Results Our results demonstrate that in comparison to conventional PD fluids the pH of PD-Bio was increased, to about 6.5. Due to less contaminating glucose degradation products in PD-Bio, basal cytotoxicity was significantly decreased for both 1.5% and 4% glucose-containing fluids, and the stimulated release of interleukin-1β was normalized compared to sterile filtered controls with the same pH. UV absorbance measured at 228 nm was decreased, whereas the absorbance at 284 nm was equal to that of a conventional fluid. In PD-Bio the concentrations of formaldehyde, acetaldehyde, methylglyoxal, and 2-furaldehyde were found to be below the detection limit, whereas glyoxal was present in the same and 5hydroxymethylfurfural (5-HMF) in higher concentrations than in conventionally produced PD fluid. Conclusions The results demonstrate that it is possible to improve biocompatibility of PD fluids by simply changing the way the fluid is produced.

scholarly journals Effect of Glucose Degradation Products on Human Peritoneal Mesothelial Cell Function

2000 ◽  
Vol 11 (4) ◽  
pp. 729-739 ◽  
Author(s):  
JANUSZ WITOWSKI ◽  
KATARZYNA KORYBALSKA ◽  
JUSTYNA WISNIEWSKA ◽  
ANDRZEJ BREBOROWICZ ◽  
GERHARD M. GAHL ◽  
...  
Keyword(s):  
Cell Function ◽  
Degradation Products ◽  
Mesothelial Cell ◽  
L929 Cells ◽  
Glucose Degradation Products ◽  
Transformed Cell Lines ◽  
The Impact ◽  
Peritoneal Mesothelial Cell ◽  
Dialysis Fluids ◽  
Human Peritoneal Mesothelial Cell

Abstract. Bioincompatibility of conventional glucose-based peritoneal dialysis fluids (PDF) has been partially attributed to the presence of glucose degradation products (GDP) generated during heat sterilization of PDF. Most previous studies on GDP toxicity were performed on animal and/or transformed cell lines, and the impact of GDP on peritoneal cells remains obscure. The short-term effects of six identified GDP on human peritoneal mesothelial cell (HPMC) functions were examined in comparison to murine L929 fibroblasts. Exposure of HPMC to acetaldehyde, formaldehyde, glyoxal, methylglyoxal, furaldehyde, but not to 5-hydroxymethyl-furfural, resulted in dose-dependent inhibition of cell growth, viability, and interleukin-1 β (IL-1 β)-stimulated IL-6 release; for several GDP, this suppression was significantly greater compared with L929 cells. Although the addition of GDP to culture medium at concentrations found in PDF had no major impact on HPMC function, the exposure of HPMC to filter-sterilized PDF led to a significantly smaller suppression of HPMC proliferation compared to that induced by heat-sterilized PDF. The growth inhibition mediated by filter-sterilized PDF could be increased after the addition of clinically relevant doses of GDP. These effects were equally evident in L929 cells. In conclusion, GDP reveal a significant cytotoxic potential toward HPMC that may be underestimated in test systems using L929 cells. GDP-related toxicity appears to be particularly evident in experimental systems using proliferating cells and the milieu of dialysis fluids. Thus, these observations may bear biologic relevance in vivo where HPMC are repeatedly exposed to GDP-containing PDF for extended periods of time.

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