Structural and Functional Alterations of the Peritoneum after Prolonged Exposure to Dialysis Solutions: Role of Aminoguanidine

Abstract

Objective The effect of long-term use of high glucose dialysate on peritoneal structure and function, and its relation with accumulation of advanced glycosylation end-product (AGE) in the peritoneum was investigated in this study. Methods Dialysates with 4.25% glucose were injected into the peritoneal cavity of normal rats for 12 weeks without (PD, n = 7) and with (1 g/L, PD+AG, n = 7) aminoguanidine in their drinking water. Rats not having intraperitoneal (IP) injection served as control ( n = 9). After 12 weeks of IP injection, a 2-hour peritoneal equilibration test (PET) was performed using 30 mL 4.25% glucose dialysate. Intraperitoneal volume (IPV), dialysate-to-plasma urea ratio at 2 hours (D2/P2), the ratio of dialysate glucose at 2 hours to initial dialysate glucose (D2/D0), and the peritoneal fluid absorption rate (Qa) were evaluated. After the PET, samples of the parietal peritoneum were taken for hematoxylin and eosin (H&E) staining and immunohistochemical staining for AGE. Results The IPV and D2/D0 glucose were significantly lower and Qa and D2/P2 urea significantly higher in the PD group than in the control group. Aminoguanidine reversed in part the changes in IPV and D2/P2 urea in the PD group; it had no effect on Qa and D2/D0 glucose. The H&E staining showed a linear mesothelial lining with negligible cells and capillaries in the narrow submesothelial space in the control group. Mesothelial denudation and submesothelial infiltration of monocytes and capillary formation were observed in the PD group. Mesothelial denudation was relatively intact in the PD+AG group compared with the PD group. Submesothelial monocyte infiltration and capillary formation in the PD+AG group were not as prominent as in the PD group. Positive AGE staining was found in the submesothelial space, vascular walls, and endomysium in the PD group, while it was markedly attenuated in PD+AG group and negligible in the control group. Conclusion Long-term use of high glucose solutions induced peritoneal AGE accumulation and mesothelial denudation, and increased peritoneal permeability and peritoneal fluid absorption rate. Inhibition of peritoneal AGE accumulation prevented those functional and structural damages to the peritoneum.

Role of Advanced Glycation Endproducts and Potential Therapeutic Interventions in Dialysis Patients

“…Although other agents such as aminoguanidine, a nucleophile hydrazine group that binds to carbonyl groups and prevents cross‐linking, are effective in lower serum AGEs in in vitro and in vivo studies (118,119), adverse reactions have been documented (52). For example, in rat models of peritoneal dialysis, the administration of aminoguanidine limited AGE accumulation in the peritoneal cavity leads to attenuation in functional and structural damage to the peritoneum (119,120).…”

“…Although other agents such as aminoguanidine, a nucleophile hydrazine group that binds to carbonyl groups and prevents cross‐linking, are effective in lower serum AGEs in in vitro and in vivo studies (118,119), adverse reactions have been documented (52). For example, in rat models of peritoneal dialysis, the administration of aminoguanidine limited AGE accumulation in the peritoneal cavity leads to attenuation in functional and structural damage to the peritoneum (119,120). Although the earlier data showed promise, it has been clouded by a serious side effect profile that includes pernicious anemia (121), development of antinuclear antibodies and myeloperoxidase‐antinuclear cytoplasmic antibodies, and rare cases of crescentic glomerulonephritis in clinical studies (122).…”

Retinoic Acid Improves Morphology of Cultured Peritoneal Mesothelial Cells from Patients Undergoing Dialysis

“…CAPD induces deleterious changes in mesothelial cells, such as loss of microvilli, widening of the intercellular spaces, and exfoliation [ 8 , 9 ]. After exposure to nonphysiological dialysis solutions, mesothelial cells undergo epithelial to mesenchymal transition (EMT) [ 10 , 11 ].…”

Bioincompatible Impact of Different Peritoneal Dialysis Fluid Components and Therapeutic Interventions as Tested in a Rat Peritoneal Dialysis Model

“…In addition, supplementing PDF with aminoguanidine, which scavenges GDPs and prevents AGE formation, resulted in less mesothelial denudation [ 18 ], reduced fibrosis, and less angiogenesis in omentum and parietal peritoneum, but not in mesentery [ 19 ] as shown in our own rat PD-exposure model.…”