Transcriptional Patterns in Peritoneal Tissue of Encapsulating Peritoneal Sclerosis, a Complication of Chronic Peritoneal Dialysis

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.

A prospective, proteomics study identified potential biomarkers of encapsulating peritoneal sclerosis in peritoneal effluent

“…Therefore, lower levels of 1-PI and apo A-IV may indicate an active inflammatory process which might contribute to EPS development (49) . The latter is further supported by the observed increases in Complement factor expression (43) . Complement Factor I and factor B were consistently detected prior Orosomucoid-1 is a major APP.…”

“…Elevation of collagen-α1(I) may reflect increased ECM turnover and the deposition of type-I collagen in the peritoneal tissues (42) . Expression of collagen-α1(I) mRNA is upregulated in EPS patient peritoneum, while its accumulation in the sub-mesothelial compact zone and EPS-derived tissue has been demonstrated by immunostaining (43)(44) . Remodelling of γ-actin cytoskeleton is a feature of EMT (45) .…”

Peritoneal macrophage heterogeneity is associated with different peritoneal dialysis outcomes

“…In the future, it would be interesting to investigate how these altered MØ/DC distributions and MØ activation/maturation states correlate to membrane dysfunction/fibrosis in patients receiving long-term PD. Indeed, the importance of this connection has been addressed very recently 43 . By transcriptional profiling of peritoneal tissues from PD patients with encapsulating peritoneal sclerosis, those without encapsulating peritoneal sclerosis or uremic patients without history of PD, the pathway analysis of the differentially expressed genes has revealed enrichment in several pathways relating to MØ/DC function and activation/maturation in patients developing encapsulating peritoneal sclerosis.…”

Surgical Management of Encapsulating Peritoneal Sclerosis: A Case Report in Kidney Transplant Patient

“…EPS is characterized by marked inflammation and severe fibrosis of the peritoneum and is associated with high morbidity and mortality. It can occur years after termination of peritoneal dialysis (PD) and, in severe cases, leads to intestinal obstruction and ileus requiring surgical intervention [ 2 ]. The most common and well-characterized risk factor is peritoneal dialysis (PD), where EPS is the end result of progressive fibrotic change in response to prolonged, repetitive, and often severe insult to the peritoneal mesothelium [ 3 , 4 ].…”