Interstitial Fibrosis Restricts Osmotic Water Transport in Encapsulating Peritoneal Sclerosis

Abstract

Encapsulating peritoneal sclerosis (EPS) is a rare but severe complication of peritoneal dialysis (PD) characterized by extensive fibrosis of the peritoneum. Changes in peritoneal water transport may precede EPS, but the mechanisms and potential predictive value of that transport defect are unknown. Among 234 patients with ESRD who initiated PD at our institution over a 20-year period, 7 subsequently developed EPS. We evaluated changes in peritoneal transport over time on PD in these 7 patients and in 28 matched controls using 3.86% glucose peritoneal equilibration tests. Compared with long-term PD controls, patients with EPS showed early loss of ultrafiltration capacity and sodium sieving before the onset of overt EPS. Multivariate analysis revealed that loss of sodium sieving was the most powerful predictor of EPS. Compared with long-term PD control and uremic peritoneum, EPS peritoneum showed thicker submesothelial fibrosis, with increased collagen density and a greater amount of thick collagen fibers. Reduced osmotic conductance strongly correlated with the degree of peritoneal fibrosis, but not with vasculopathy. Peritoneal fibrosis was paralleled by an excessive upregulation of vascular endothelial growth factor and endothelial nitric oxide synthase, but the expression of endothelial aquaporin-1 water channels was unaltered. Our findings suggest that an early and disproportionate reduction in osmotic conductance during the course of PD is an independent predictor of EPS. This functional change is linked to specific alterations of the collagen matrix in the peritoneal membrane of patients with EPS, thereby validating the serial three-pore membrane/fiber matrix and distributed models of peritoneal transport.

Length of Time on Peritoneal Dialysis and Encapsulating Peritoneal Sclerosis — Position Paper for ISPD: 2017 Update

“…The combination of functional and structural analysis of the membrane of patients with EPS demonstrated that reduced osmotic water transport is directly related to the degree of fibrosis and to changes in collagen density and structure in the peritoneal interstitium (88), in line with predictions based on the serial pore-membrane/fiber matrix and distributed models (94)(95)(96). Of note, the low osmotic (50).…”

Ultrafiltration Failure and Impaired Sodium Sieving during Long-Term Peritoneal Dialysis: More than Aquaporin Dysfunction?

“…The use of human biopsy samples has been approved by the Ethical Review Board of the Cliniques universitaires Saint-Luc. Adequacy of each peritoneal specimen, peritoneal fibrosis, collagen volume fraction, and collagen structure were assessed as previously described (7,16). Immunofluorescence was performed using purified rabbit anti-von Willebrand factor (DAKO, Glostrup, Denmark) and polyclonal rabbit anti-human AQP1 (Chemicon International, Temecula, CA, USA) antibodies (16).…”

Recommendations for pathological diagnosis on biopsy samples from peritoneal dialysis patients

“…However, recent analysis with biopsy samples from EPS patients showed that AQP-1 expression did not change between EPS and long-term PD or uremic peritoneum, instead of significant upregulated VEGF and endothelial nitric oxide synthase (eNOS) with increasing vascular density in EPS cases [89]. In this study, SMC thickness and collagen volume fraction showed significant correlation with UF failure and sodium sieving, but not with small solute transport, and these pathological parameters were significantly severe in EPS than in other groups [89]. This meaningful study showed that UF capacity and sodium sieving could be used as a predicting risk factor for EPS, however, SMC thickness and collagen in EPS cases should have been measured from existing peritoneum (HPS lesion) excluding newly formed membrane of EPS (the study included EPS membrane in the pathological analysis), because the EPS membrane does not reflect functional test histories before the lesion is formed.…”

“…Aquaporin (AQP)-1 null mice study showed that AQP-1 expressed in peritoneal endothelium plays an essential role in water permeability and UF during PD [88]. However, recent analysis with biopsy samples from EPS patients showed that AQP-1 expression did not change between EPS and long-term PD or uremic peritoneum, instead of significant upregulated VEGF and endothelial nitric oxide synthase (eNOS) with increasing vascular density in EPS cases [89]. In this study, SMC thickness and collagen volume fraction showed significant correlation with UF failure and sodium sieving, but not with small solute transport, and these pathological parameters were significantly severe in EPS than in other groups [89].…”