Current Insights into Cellular Determinants of Peritoneal Fibrosis in Peritoneal Dialysis: A Narrative Review

Abstract

Peritoneal fibrosis is the final process of progressive changes in the peritoneal membrane due to chronic inflammation and infection. It is one of the main causes of discontinuation of peritoneal dialysis (PD), apart from peritonitis and cardiovascular complications. Over time, morphological changes occur in the peritoneal membranes of patients who use PD. Of those are mesothelial-to-mesenchymal transition (MMT), neoangiogenesis, sub-mesothelial fibrosis, and hyalinizing vasculopathy. Several key molecules are involved in the complex pathophysiology of peritoneal fibrosis, including advanced glycosylation end products (AGEs), transforming growth factor beta (TGF-β), and vascular endothelial growth factor (VEGF). This narrative review will first discuss the physiology of the peritoneum and PD. Next, the multifaceted pathophysiology of peritoneal fibrosis, including the effects of hyperglycemia and diabetes mellitus on the peritoneal membrane, and the promising biomarkers of peritoneal fibrosis will be reviewed. Finally, the current and future management of peritoneal fibrosis will be discussed, including the potential benefits of new-generation glucose-lowering medications to prevent or slow down the progression of peritoneal fibrosis.

High Salt Promotes Inflammatory and Fibrotic Response in Peritoneal Cells

“…Therefore, we aimed to investigate how dietary habits, such as high salt intake, can lead to fibrotic alterations in the peritoneal wall. To this purpose, we modeled the high sodium and osmotic environment, which can affect the cellular determinants of peritoneal fibrosis including, mesothelial, endothelial, immune cells, and fibroblasts [ 8 ].…”

“…PF is a result of a complex pathological cross-talk among peritoneal mesothelial, endothelial, and immune cells, and fibroblasts, respectively. In response to injury, they produce inflammatory cytokines and profibrotic growth factors, among which the following can be highlighted due to their role in peritoneal pathologies: interleukin (IL)-1ß, IL-6, monocyte chemoattractant protein (MCP-1) and transforming growth factor ß (TGF-ß1), platelet-derived growth factor B (PDGF-B), and connective tissue growth factor (CTGF) [ 8 ]. Furthermore, recent experimental and human data suggest the role of the activation of the peritoneal renin–angiotensin–aldosterone system (RAAS) in peritoneal fibrosis [ 9 , 10 ].…”

Coupling Osmotic Efficacy with Biocompatibility in Peritoneal Dialysis: A Stiff Challenge

“…Long-term changes to the peritoneum in PD, including the mechanisms of peritoneal fibrosis, have been described in recent extensive reviews [ 5 , 14 , 15 ] and will not be covered in detail here.…”

“…The existing evidence indicates that EMT in peritoneal fibrosis (PF) is primarily influenced by Smad and non-Smad signaling pathways activated by transforming growth factor (TGF)-β1 [ 18 ]. During the early stages of fibrosis, glucose, glucose degradation products (GDPs) and advanced glycosylation end products (AGEs) have been shown to enhance the expression of type I and type II TGF-β receptors in mesothelial cells through the activation of protein kinase C-α [ 15 ]. TGF-β1 signalling initiates the phosphorylation of Smad2 and Smad3 via type I TGF-β receptors.…”

A review of research progress on mechanisms of peritoneal fibrosis related to peritoneal dialysis

“…Evidence suggests that Smad and non-Smad signalling pathways induced by TGF-β1 play a dominant role in the EMT of peritoneal fibrosis ( Lho et al, 2021 ). In the early phase of fibrosis, glucose, GDPs, and advanced glycosylation end products (AGEs) can upregulate type I and type II TGF-β receptors in mesothelial cells ( Suryantoro et al, 2023 ) by activating protein kinase C-α (PKC-α) ( Wang et al, 2016 ). TGF-β1 signalling activates the phosphorylation of Smad2 and Smad3 via type I TGF-β receptors, and Smad2/Smad3 are transported to the nucleus, where they directly bind to DNA and regulate the transcription of target genes, including Snail, collagen, α-SMA, fibronectin, CTGF, β-catenin, plasminogen activator inhibitor-1 (PAI-1), and matrix metalloproteinase-2 (MMP2), promoting fibrosis ( Derynck and Zhang, 2003 ; Hirahara et al, 2009 ; Xiao et al, 2010 ; Lei et al, 2012 ; Zhang et al, 2022a ; Huang et al, 2022 ; Masola et al, 2022 ) ( Figure 1 ).…”