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Objectives Long-term peritoneal dialysis (PD) leads to structural and functional changes in the peritoneum. The aim of the present study was to investigate the long-term effects of PD fluid components, glucose and glucose degradation products (GDP), and lactate-buffered solution on morphology and transport characteristics in a nonuremic rat model. Methods Rats were subjected to two daily intraperitoneal injections (20 mL/day) during 12 weeks of one of the following: commercial PD fluid (Gambrosol, 4%; Gambro AB, Lund, Sweden), commercial PD fluid with low GDP levels (Gambrosol trio, 4%; Gambro AB), sterile-filtered PD fluid (4%) without GDP, or a glucose-free lactate-buffered PD fluid. Punctured and untreated controls were used. Following exposure, the rats underwent a single 4-hour PD dwell (30 mL, 4% glucose) to determine peritoneal function. Additionally, submesothelial tissue thickness, percentage of high mesothelial cells (perpendicular diameter > 2 μm), vascular density, vascular endothelial growth factor (VEGF), and transforming growth factor (TGF) β1 mRNA expression were determined. Submesothelial collagen concentration was estimated by van Gieson staining. Results Submesothelial tissue thickness and vascular density, mediated by VEGF and TGFβ production, in the diaphragmatic peritoneum increased significantly in rats exposed to any PD fluid. Gambrosol induced a marked increased fibrosis of the hepatic peritoneum. A significant increase in high mesothelial cells was observed in the Gambrosol group only. Net ultrafiltration was reduced in the Gambrosol and in the glucose-free groups compared to untreated controls. Small solute transport was unchanged, but all groups exposed to fluids showed significantly increased lymph flow. Conclusions Our results show that long-term exposure to different components of PD fluids leads to mesothelial cell damage, submesothelial fibrosis, and neoangiogenesis. Mesothelial cell damage could be connected to the presence of GDP; the other changes were similar for all fluids. Peritoneal transport characteristics did not change in any consistent way and the neoangiogenesis observed was not paralleled by increased solute transport.

Objective When peritoneal dialysis (PD) fluids are heat sterilized, glucose is degraded to carbonyl compounds. These compounds are known to interfere with many cellular functions and to promote the formation of advanced glycation end-products. However, little is known about what actually happens with glucose degradation products (GDPs) after infusion into the peritoneal cavity. The aim of the present study was to investigate possible targets for GDPs in the peritoneal cavity. Design In vitro reactions between residual fluid and GDPs were studied by incubating unused PD fluid with overnight dialysate. Confluent monolayer cultures of human mesothelial cells were used as a model to study the reactions of GDPs with the cells lining the peritoneal cavity. Methods Samples were analyzed, using high pressure liquid chromatography, for the presence of formaldehyde, acetaldehyde, 5-hydroxymethyl-2-furaldehyde (5-HMF), methylglyoxal, and 3-deoxyglucosone (3-DG). Cytotoxicity was determined as inhibition of proliferation of cultured fibroblasts. Results None of the analyzed GDPs reacted with overnight dialysate. Formaldehyde and methylglyoxal, in contrast to 3-DG and 5-HMF, reacted with the cultured mesothelial cells. Conclusions Low molecular weight carbonyls such as formaldehyde and methylglyoxal most probably react with the mesothelial cells lining the peritoneal cavity, and could be responsible for the disappearance of these cells during long-term treatment. 3-Deoxyglucosone showed remarkably low reactivity and was most probably transported within the patient.

Carbohydrates are not stable when exposed to energy; they degrade into new molecules. In peritoneal dialysis (PD) fluids, degradation of glucose occurs during the heat sterilization procedure. The biological consequences of this degradation are side effects such as impaired proliferation and impaired host defense mechanisms, demonstrated in vitro for a great variety of cells. Several highly toxic compounds—such as formaldehyde and 3-deoxyglucosone—have been identified in PD fluids. Carbonyl compounds, apart from being cytotoxic, are also well-known promoters of irreversible advanced glycation end-products (AGEs), which might participate in the long-term remodeling of the peritoneal membrane. Various approaches can be used to reduce the formation of glucose degradation products (GDPs) during heat sterilization. Some examples are shortening the sterilization time, lowering the pH, removing catalyzing substances, and increasing glucose concentration. The latter three factors are employed in the multi-compartment bag with a separate chamber containing pure glucose at high concentration and low pH. Gambrosol trio, a PD fluid produced in this way, shows reduced cytotoxicity, normalized host defense reactions, less AGE formation, and reduced concentrations of formaldehyde and 3-deoxyglucosone. Moreover, in the clinical situation, the fluid turns out to be more biocompatible for the patient, causing less mesothelial cell damage, which in the long term could lead to a more intact peritoneal membrane. Conclusion Glucose degradation products in heat-sterilized fluids for peritoneal dialysis are cytotoxic, promote AGE formation, and cause negative side effects for the patient. Using improved and well-controlled manufacturing processes, it is possible to produce sterile PD fluids with glucose as the osmotic agent but without the negative side effects related to GDPs.

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