Neutral solution low in glucose degradation products is associated with less peritoneal fibrosis and vascular sclerosis in patients receiving peritoneal dialysis

Abstract

Background: The effects of novel biocompatible peritoneal dialysis (PD) solutions on human peritoneal membrane pathology have yet to be determined. Quantitative evaluation of human peritoneal biopsy specimens may reveal the effects of the new solutions on peritoneal membrane pathology. ♢

Methods: Peritoneal specimens from 24 PD patients being treated with either acidic solution containing high-glucose degradation products [GDPs (n = 12)] or neutral solution with low GDPs (n = 12) were investigated at the end of PD. As controls, pre-PD peritoneal specimens, obtained from 13 patients at PD catheter insertion, were also investigated. The extent of peritoneal fibrosis, vascular sclerosis, and advanced glycation end-product (AGE) accumulation were evaluated by quantitative or semi-quantitative methods. The average densities of CD31-positive vessels and podoplanin-positive lymphatic vessels were also determined. ♢

Results: Peritoneal membrane fibrosis, vascular sclerosis, and AGE accumulation were significantly suppressed in the neutral group compared with the acidic group. The neutral group also showed lower peritoneal equilibration test scores and preserved ultrafiltration volume. The density of blood capillaries, but not of lymphatic capillaries, was significantly increased in the neutral group compared with the acidic and pre-PD groups. ♢

Conclusions: Neutral solutions with low GDPs are associated with less peritoneal membrane fibrosis and vascular sclerosis through suppression of AGE accumulation. However, contrary to expectation, blood capillary density was increased in the neutral group. The altered contents of the new PD solutions modified peritoneal membrane morphology and function in patients undergoing PD.

Keywords: AGEs; GDPs; angiogenesis; biocompatible solution; peritoneal fibrosis; vascular sclerosis.

Figure 1

— Peritoneal histology and immunohistochemistry for advanced glycosylation end-products (AGEs), CD31, and podoplanin (Pod) in (a-d) the pre-peritoneal dialysis (PD) group and (e-h) the acidic and (i-l) neutral dialysate groups. 200× original magnification. Peritoneal samples from the acidic dialysate group show significant fibrosis in the submesothelial compact zone, with accompanying hyalinizing degeneration of collagen fibers. In the acidic group, AGEs also accumulated more intensely. Staining for CD31 revealed increased vascularity in the neutral group; however, staining for podoplanin revealed no increase of podoplanin-positive lymphatic vessels, and no differences between the groups. Masson = Masson trichrome stain.

Figure 2

— Double immunostaining with for CD31 and podoplanin for vessel density analysis. (a) CD31-positive vessels (green). (b) Podoplanin-positive vessels (red). (c) Merge of CD31 and podoplanin staining. (d) Vessel density analysis for a representative CD31-positive sample (n = 30, black circles). The area of the submesothelial compact zone is 0.199 mm², yielding a vessel density of 150.7/mm²). (e) Vessel density analysis for a representative podoplanin-positive lymphatic vessel (n = 3, black arrows). The area of the submesothelial compact zone is 0.209 mm², yielding a vessel density of 14.4/mm²).

Figure 3

— Quantitative comparison of peritoneal fibrosis and vascular sclerosis and their correlation with peritoneal dialysis (PD) duration. (a) Thickness of the submesothelial compact zone (SMC). (b) Ratio of lumen-to-vessel (L/V) diameter. (c) Correlation between SMC and PD duration. (d) Correlation between L/V ratio and PD duration. The SMC was thinner and the L/V ratio was greater, significantly so, in the group on neutral dialysate compared with the group on acidic dialysate. The SMC thickness and L/V ratio were significantly correlated with PD duration in the group on acidic dialysate; no significant correlation was found in the group on neutral dialysate.

Figure 4

— Comparison of peritoneal accumulation of advanced glycosylation end-products (AGEs)—interstitial, vascular, and total. The grades of AGE accumulation in the interstitium and vascular wall were significantly higher in the group on acidic dialysate than in the group on neutral dialysate. The total grade of AGE accumulation was also significant higher in the group on acidic dialysate.

Figure 5

— Quantitative comparison of capillary and lymphatic vessel density and correlation between capillary density and peritoneal dialysis (PD) duration. (a) The capillary density determined by CD31 staining was significantly higher in the group on neutral dialysate than in the group on acidic dialysate or not yet on PD. However, lymphatic vessel density did not differ significantly between the groups. (b) The density of CD31-positive (CD31+) capillaries was positively correlated with PD duration in the group on neutral dialysate, but it was negatively correlated with PD duration in the group on acidic dialysate.

Figure 6

— Accumulation of advanced glycosylation end-products (AGEs) and capillary density compared between patients grouped by low and low-average (L/LA) and high-average and high (HA/H) transport categories as determined by dialysate-to-plasma ratio of creatinine (D/P Cr) in a peritoneal equilibration test (PET). (a) In the group on acidic dialysate, the total grade of AGE accumulation was significantly higher in the HA/H patients than in the L/LA patients; however, (b) the capillary density did not differ between the L/LA and HA/H patients. No correlation was observed between PET category and AGE accumulation or capillary density in the group on neutral dialysate.