Biocompatibility of Peritoneal Dialysis Fluids: Long-term Exposure of Nonuremic Rats

Abstract

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.

Effects of Low Glucose Degradation Products Peritoneal Dialysis Fluid on the Peritoneal Fibrosis and Vascularization in a Chronic Rat Model

“…Although we could not show a strong correlation, the D/P urea and D/P protein values correlated positively with the number of blood vessels in the omentum, with an inverse correlation observed between the D/D 0 glucose values and the number of blood vessels in the omentum. Even though no negative effects of GDP were observed in previous acute rat experiments, with respect to peritoneal solute transport (5,6,19), we found significant differences in the peritoneal permeability between conventional and low‐GDP exposure after 8 weeks of dialysis. The present results suggest that GDP might be the principal mediators of peritoneal neoangiogenesis and subsequent ultrafiltration failure.…”

“…However, we could not find evidence relating to GDP-containing PDF with peritoneal fibrosis. Other groups have reported that morphological changes in the peritoneal membrane of low-GDP containing PDF treated animals were much less pronounced, including reduced vascular density, preservation of the mesothelial monolayer and intercellular junction, with no reduplication of the submesothelial basement membrane (5), and also found that the presence of GDP could be connected to the mesothelial changes and the increase of fibrosis in specific regions of the peritoneum (6). In addition, peritoneum exposed to standard PDF were characterized by an increased expression of VEGF, microvascular proliferation and submesothelial fibrosis, which were not observed in peritoneum exposed to low-GDP containing PDF (7).…”

Protection of the Peritoneal Membrane by Peritoneal Dialysis Effluent-Derived Mesenchymal Stromal Cells in a Rat Model of Chronic Peritoneal Dialysis

“…As of today, the mechanisms underlying UFF are not completely understood, but the pathological changes of peritoneal biopsies from PD patients indicate that UFF is associated with the PM alterations such as an increase in macrophage infiltration [29], thickness or fibrosis of the submesothelial layer [30–32], and neoangiogenesis [29, 32, 33]. Similarly in rats, a long term of peritoneal exposure to a hypertonic PD solution leads to mesothelial cell damage, fibrosis or increased thickness of PM, and neoangiogenesis, resulting in an increase in lymph flow or loss of fluid removal [34–36]. Therefore, any therapy that targets these alterations of the PM will prolong the UF in PD patients.…”

The Effect of Statin on Epithelial-Mesenchymal Transition in Peritoneal Mesothelial Cells

“…The slides were then differentiated in phosphomolybdic-phosphotungstic acid solution for 15 min, transferred to aniline blue solution and stained for 10 min, and were reacted with 1% acetic acid solution for 5 min. The thickness of the peritoneum, which was defined as the tissue between the mesothelial surface and the underlying muscle or parenchyma, was assessed as previously described [26] . Briefly, the maximal thickness of the peritoneum was measured in three Masson's trichrome-stained tissue sections per rat and five fields, the center of which included the area of maximal thickness, and were examined under ×400 magnification.…”