Glucose degradation products in peritoneal dialysis fluids: Do they harm?

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.

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

Peritoneal Dialysis International ◽

10.1177/089686080802800315 ◽

2008 ◽

Vol 28 (3) ◽

pp. 277-282 ◽

Cited By ~ 6

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.

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Rapid and Reliable Measurement for Evaluating Directly the Reactivity ofN-Acetylcysteine with Glucose Degradation Products in Peritoneal Dialysis Fluids

Analytical Chemistry ◽

10.1021/ac200046y ◽

2011 ◽

Vol 83 (5) ◽

pp. 1518-1522 ◽

Cited By ~ 2

Author(s):

Eunyoung Lee ◽

Eun-young Seo ◽

Youngjoo Kwon ◽

Hunjoo Ha

Keyword(s):

Peritoneal Dialysis ◽

Degradation Products ◽

Reliable Measurement ◽

Glucose Degradation Products ◽

Dialysis Fluids

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

Peritoneal Dialysis International ◽

10.1177/089686080102103s21 ◽

2001 ◽

Vol 21 (3_suppl) ◽

pp. 119-124 ◽

Cited By ~ 13

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.

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How to Avoid Glucose Degradation Products in Peritoneal Dialysis Fluids

Peritoneal Dialysis International ◽

10.1177/089686080602600414 ◽

2006 ◽

Vol 26 (4) ◽

pp. 490-497 ◽

Cited By ~ 51

Author(s):

Martin Erixon ◽

Anders Wieslander ◽

Torbjörn Lindén ◽

Ola Carlsson ◽

Gunita Forsbäck ◽

...

Keyword(s):

Peritoneal Dialysis ◽

High Glucose ◽

Glucose Concentration ◽

Degradation Products ◽

Minor Effect ◽

High Glucose Concentration ◽

Temperature Dependent ◽

Glucose Degradation Products ◽

A Minor ◽

Dialysis Fluids

Objective The formation of glucose degradation products (GDPs) during sterilization of peritoneal dialysis fluids (PDFs) is one of the most important aspects of biocompatibility of glucose-containing PDFs. Producers of PDFs are thus trying to minimize the level of GDPs in their products. 3,4-Dideoxyglucosone-3-ene (3,4-DGE) has been identified as the most bioreactive GDP in PDFs. It exists in a temperature-dependent equilibrium with a pool of 3-deoxyglucosone (3-DG) and is a precursor in the irreversible formation of 5-hydroxymethyl furaldehyde (5-HMF). The aim of the present study was to investigate how to minimize GDPs in PDFs and how different manufacturers have succeeded in doing so. Design Glucose solutions at different pHs and concentrations were heat sterilized and 3-DG, 3,4-DGE, 5-HMF, formaldehyde, and acetaldehyde were analyzed. Conventional as well as biocompatible fluids from different manufacturers were analyzed in parallel for GDP concentrations. Results The concentrations of 3-DG and 3,4-DGE produced during heat sterilization decreased when pH was reduced to about 2. Concentration of 5-HMF decreased when pH was reduced to 2.6. After further decrease to a pH of 2.0, concentration of 5-HMF increased slightly, and below a pH of 2.0 it increased considerably, together with formaldehyde; 3-DG continued to drop and 3,4-DGE remained constant. Inhibition of cell growth was paralleled by 3,4-DGE concentration at pH 2.0 – 6.0. A high glucose concentration lowered concentrations of 3,4-DGE and 3-DG at pH 5.5 and of 5-HMF at pH 1. At pH 2.2 and 3.2, glucose concentration had a minor effect on the formation of GDPs. All conventional PDFs contained high levels of 3,4-DGE and 3-DG. Concentrations were considerably lower in the biocompatible fluids. However, the concentration of 5-HMF was slightly higher in all the biocompatible fluids. Conclusion The best way to avoid reactive GDPs is to have a pH between 2.0 and 2.6 during sterilization. If pHs outside this range are used, it becomes more important to have high glucose concentration during the sterilization process. There are large variations in GDPs, both within and between biocompatible and conventionally manufactured PDFs.

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

Peritoneal Dialysis International ◽

10.1177/089686080902902s04 ◽

2009 ◽

Vol 29 (2_suppl) ◽

pp. 28-31 ◽

Cited By ~ 6

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.

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

Peritoneal Dialysis International ◽

10.1177/089686080302300412 ◽

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.

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