Dataset Information

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.

SUBMITTER: Morelle J

PROVIDER: S-EPMC4587704 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Interstitial Fibrosis Restricts Osmotic Water Transport in Encapsulating Peritoneal Sclerosis.

Morelle Johann J Sow Amadou A Hautem Nicolas N Bouzin Caroline C Crott Ralph R Devuyst Olivier O Goffin Eric E

Journal of the American Society of Nephrology : JASN 20150130 10

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 ...[more]

PMID: 25636412

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Project description:Encapsulating peritoneal sclerosis (EPS) is a life threatening complication of peritoneal dialysis (PD). Podoplanin is a glycoprotein expressed by mesothelial cells, lymphatic endothelial cells, and myofibroblasts in peritoneal biopsies from patients with EPS. To evaluate podoplanin as a marker of EPS we measured podoplanin mRNA and described the morphological patterns of podoplanin-positive cells in EPS. Included were 20 peritoneal biopsies from patients with the diagnosis of EPS (n = 5), patients on PD without signs of EPS (n = 5), and control patients (uremic patients not on PD, n = 5, non-uremic patients n = 5). EPS patient biopsies revealed significantly elevated levels of podoplanin mRNA (p<0.05). In 24 peritoneal biopsies from patients with EPS, podoplanin and smooth muscle actin (SMA) were localized by immunohistochemistry. Four patterns of podoplanin distribution were distinguishable. The most common pattern (8 of 24) consisted of organized, longitudinal layers of podoplanin-positive cells and vessels in the fibrotic zone ("organized" pattern). 7 of 24 biopsies demonstrated a diffuse distribution of podoplanin-positive cells, accompanied by occasional, dense clusters of podoplanin-positive cells. Five biopsies exhibited a mixed pattern, with some diffuse areas and some organized areas ("mixed"). These contained cuboidal podoplanin-positive cells within SMA-negative epithelial structures embedded in extracellular matrix. Less frequently observed was the complete absence of, or only focal accumulations of podoplanin-positive fibroblasts outside of lymphatic vessels (podoplanin "low", 4 of 24 biopsies). Patients in this group exhibited a lower index of systemic inflammation and a longer symptomatic period than in EPS patients with biopsies of the "mixed" type (p<0.05). In summary we confirm the increased expression of podoplanin in EPS, and distinguish EPS biopsies according to different podoplanin expression patterns which are associated with clinical parameters. Podoplanin might serve as a useful adjunct to the morphological workup of peritoneal biopsies.

Project description:Encapsulating peritoneal sclerosis (EPS) is a devastating complication of peritoneal dialysis (PD), characterized by marked inflammation and severe fibrosis of the peritoneum, and associated with high morbidity and mortality. EPS can occur years after termination of PD and, in severe cases, leads to intestinal obstruction and ileus requiring surgical intervention. Despite ongoing research, the pathogenesis of EPS remains unclear. We performed a global transcriptome analysis of peritoneal tissue specimens from EPS patients, PD patients without EPS, and uremic patients without history of PD or EPS (Uremic). Unsupervised and supervised bioinformatics analysis revealed distinct transcriptional patterns that discriminated these three clinical groups. The analysis identified a signature of 219 genes expressed differentially in EPS as compared to PD and Uremic groups. Canonical pathway analysis of differentially expressed genes showed enrichment in several pathways, including antigen presentation, dendritic cell maturation, B cell development, chemokine signaling and humoral and cellular immunity (P value<0.05). Further interactive network analysis depicted effects of EPS-associated genes on networks linked to inflammation, immunological response, and cell proliferation. Gene expression changes were confirmed by qRT-PCR for a subset of the differentially expressed genes. EPS patient tissues exhibited elevated expression of genes encoding sulfatase1, thrombospondin 1, fibronectin 1 and alpha smooth muscle actin, among many others, while in EPS and PD tissues mRNAs encoding leptin and retinol-binding protein 4 were markedly down-regulated, compared to Uremic group patients. Immunolocalization of Collagen 1 alpha 1 revealed that Col1a1 protein was predominantly expressed in the submesothelial compact zone of EPS patient peritoneal samples, whereas PD patient peritoneal samples exhibited homogenous Col1a1 staining throughout the tissue samples. The results are compatible with the hypothesis that encapsulating peritoneal sclerosis is a distinct pathological process from the simple peritoneal fibrosis that accompanies all PD treatment.

Project description:BackgroundEncapsulating peritoneal sclerosis (EPS) is a rare but serious complication of long-term peritoneal dialysis (PD). However, previous studies reported large variations in its mortality rates that may associate with a different degree of EPS severity. This study reports the incidence and outcomes of EPS and identifies the risk factors associated with severe EPS.MethodsWe retrospectively analyzed clinical data of EPS patients from 3 medical centers in Taiwan from January 1982 to September 2015, and classified patients as having mild/moderate or severe EPS. Patients with intractable intestinal obstruction/gut-related sepsis that needed surgical intervention or resulted in mortality were in severe EPS group. Follow-up for outcome was through December 31, 2015. Clinical characteristics, peritoneal dialysis (PD)-related parameters, biochemical and imaging results were analyzed and compared between groups.ResultsFifty-eight of 3202 patients undergoing PD during the study period had EPS (prevalence 1.8%). The incidence of EPS increased for patients on PD for >6-8 years (≤6 yrs. vs. >6-8 yrs., 0.0% vs. 1.8%, p = 0.001). Relative to those on PD for >6-8 years, the risk of EPS significantly increased with PD duration longer than 10 years (>10-12 years vs. >6-8 years: OR: 5.5, 95% CI: 1.7-17.1, p < 0.01). Twenty-three patients fulfilled the criteria for severe EPS. The overall mortality rate of EPS was 35% (20/58), and was 74% (17/23) in the severe EPS group. The average serum levels of C-reactive protein (CRP) and intact-parathyroid hormone (i-PTH), which were checked every 3~6 months within one year before diagnosis of EPS, were higher in severe EPS group than in mild/moderate group (p = 0.02, p = 0.08, respectively). Multivariate analysis revealed severe EPS was independently associated with bowel tethering (based on CT), presentation with bloody ascites, diagnosis of EPS after withdrawal from PD, and i-PTH ≥ 384 pg/mL. Receiver operating characteristic analysis indicated that presentation with 2 or more of the 5 risk factors (EPS diagnosis after PD withdrawal, bloody ascites, bowel tethering, CRP ≥ 29 mg/L, and i-PTH ≥ 384 pg/mL) had a good accuracy (AUC = 0.80, p = 0.001) for prediction of severe EPS.ConclusionsThe incidence of EPS increases with PD duration. Severe EPS has high mortality rate and is associated with bowel tethering, presentation of bloody ascites, diagnosis after PD withdrawal, and higher serum levels of i-PTH before EPS diagnosis. Having 2 or more of the 5 risk factors can provide a good accuracy for prediction of severe EPS.

Project description:Expression data from peritoneal biopsies of patients with encapsulating peritoneal sclerosis (EPS), patients undergoing first implantation of a peritoneal dialysis catheter (PD), and patients undergoing abdominal surgery for non-peritoneal conditions (controls) We used microarrays to determine the transcriptional profiles of peritoneal membrane in patients with encapsulating peritoneal sclerosis (EPS), patients undergoing first insertion of a peritoneal dialysis cathetier (PD), and uremic patients without history of PD or EPS, undergoing abdominal surgery for non-peritoneal problems (CON) Encapsulating peritoneal sclerosis (EPS) is a devastating complication of peritoneal dialysis (PD), characterized by marked inflammation and severe fibrosis of the peritoneum, and associated with high morbidity and mortality. EPS can occur years after termination of PD and, in severe cases, leads to intestinal obstruction and ileus requiring surgical intervention. Despite ongoing research, the pathogenesis of EPS remains unclear. We performed a global transcriptome analysis of peritoneal tissue specimens from EPS patients, PD patients without EPS, and uremic patients without history of PD or EPS (Uremic). Unsupervised and supervised bioinformatics analysis revealed distinct transcriptional patterns that discriminated these three clinical groups. The analysis identified a signature of 219 genes expressed differentially in EPS as compared to PD and Uremic groups. Canonical pathway analysis of differentially expressed genes showed enrichment in several pathways, including antigen presentation, dendritic cell maturation, B cell development, chemokine signaling and humoral and cellular immunity (P value <0.05). Further interactive network analysis depicted effects of EPS-associated genes on networks linked to inflammation, immunological response, and cell proliferation. Gene expression changes were confirmed by qRT-PCR for a subset of the differentially expressed genes. EPS patient tissues exhibited elevated expression of genes encoding sulfatase1, thrombospondin 1, fibronectin 1 and alpha smooth muscle actin, among many others, while in EPS and PD tissues mRNAs encoding leptin and retinol-binding protein 4 were markedly down-regulated, compared to Uremic group patients. Immunolocalization of Collagen 1 alpha 1 revealed that Col1a1 protein was predominantly expressed in the submesothelial compact zone of EPS patient peritoneal samples, whereas PD patient peritoneal samples exhibited homogenous Col1a1 staining throughout the tissue samples. The results are compatible with the hypothesis that encapsulating peritoneal sclerosis is a distinct pathological process from the simple peritoneal fibrosis that accompanies all PD treatment. Total RNA was isolated from frozen peritoneal biopsy specimens obtained at time of surgery. RNA was hybridized to Affymetrix arrays, and analyzed. Select transcripts were subjected to validation by rt-pcr and by immunodetection.

Dataset Information

Interstitial Fibrosis Restricts Osmotic Water Transport in Encapsulating Peritoneal Sclerosis.

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Interstitial Fibrosis Restricts Osmotic Water Transport in Encapsulating Peritoneal Sclerosis.

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