Abstract
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.
Highlights
Renal replacement therapy is currently restricted to renal transplantation, hemodialysis (HD), and peritoneal dialysis (PD)
Patient characteristics Tissue samples were available from 8 patients: 4 with encapsulating peritoneal sclerosis (EPS, 2 males and 2 females, of mean age 60.8 yrs and mean PD duration 74634 months), 2 chronic peritoneal dialysis patients (PD, 1 male and 1 female, of mean age 68.5 yrs and mean PD duration 23 months), and 2 male Uremic patients of mean age 56.5 yrs, as yet undialyzed (Table 1, Table S1)
We demonstrated that samples separated according to Encapsulating peritoneal sclerosis (EPS) status along primary component (PC) 1, which accounted for 42.2% of the variation between samples
Summary
Renal replacement therapy is currently restricted to renal transplantation, hemodialysis (HD), and peritoneal dialysis (PD). Peritoneal dialysis constitutes ,10% of current renal replacement therapy in the US and in much of Europe, but up to 80% in Mexico and Taiwan [1]. Encapsulating peritoneal sclerosis (EPS) is a rare but dangerous complication of peritoneal dialysis (PD). EPS epidemiology has been complicated by regional differences in PD use and in reported EPS incidence, likely exacerbated by non-uniform diagnostic criteria. In a Japanese cohort of PD patients with overall EPS incidence of 2.5%, EPS was diagnosed in 17–70% of patients with PD duration .15 years [11,12,13]. Among transplanted PD patients in the Dutch multicenter EPS study, EPS was the fourth most common cause of death after infection, cardiovascular disease, and malignancy [14]
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