Preventing Peritoneal Dialysis-Associated Fibrosis by Therapeutic Blunting of Peritoneal Toll-Like Receptor Activity

Abstract

Peritoneal dialysis (PD) is an essential daily life-saving treatment for end-stage renal failure. PD therapy is limited by peritoneal inflammation, which leads to peritoneal membrane failure as a result of progressive fibrosis. Peritoneal infections, with the concomitant acute inflammatory response and membrane fibrosis development, worsen PD patient outcomes. Patients who remain infection-free, however, also show evidence of inflammation-induced membrane damage and fibrosis, leading to PD cessation. In this case, uraemia, prolonged exposure to bio-incompatible PD solutions and surgical catheter insertion have been reported to induce sterile peritoneal inflammation and fibrosis as a result of cellular stress or tissue injury. Attempts to reduce inflammation (either infection-induced or sterile) and, thus, minimize fibrosis development in PD have been hampered because the immunological mechanisms underlying this PD-associated pathology remain to be fully defined. Toll-like receptors (TLRs) are central to mediating inflammatory responses by recognizing a wide variety of microorganisms and endogenous components released following cellular stress or generated as a consequence of extracellular matrix degradation during tissue injury. Given the close link between inflammation and fibrosis, recent investigations have evaluated the role that TLRs play in infection-induced and sterile peritoneal fibrosis development during PD. Here, we review the findings and discuss the potential of reducing peritoneal TLR activity by using a TLR inhibitor, soluble TLR2, as a therapeutic strategy to prevent PD-associated peritoneal fibrosis.

Mechanisms of Peritoneal Fibrosis: Focus on Immune Cells–Peritoneal Stroma Interactions

“…While the last protein may interact with several TLRs, the majority of these ligands are direct agonists of TLR2 and TLR4 ( 42 , 43 ). Interestingly, exposure to PD fluids promotes the expression of Hsp60, Hsp70 and hyaluronic acid (HA), all TLR2 and TLR4 ligands, by leukocytes and MCs, thus driving an inflammatory response in the absence of infectious stimuli (see below) ( 44 ). Accordingly, treatment with soluble TLR2 (sTLR2) reduces pro-inflammatory and fibrotic response in mice exposed to PD fluids.…”

“…Accordingly, treatment with soluble TLR2 (sTLR2) reduces pro-inflammatory and fibrotic response in mice exposed to PD fluids. These discoveries open to future clinical trials testing the clinical efficacy of these compound in patients undergoing long term PD ( 44 ).…”

Abnormalities in Glucose Metabolism, Appetite-Related Peptide Release, and Pro-inflammatory Cytokines Play a Central Role in Appetite Disorders in Peritoneal Dialysis

“…In renal patients there is an accumulation in plasma of uremic toxins., PD is an essential daily life-saving treatment for end-stage renal failure and involves the exchange of solutes and the excess of water between blood and dialysis solution across the peritoneal membrane, which results in gradual reduction of uremic solutes and toxins (Raby and Labéta, 2018; Nigam and Bush, 2019). Reduced appetite (anorexia) is an early and usual symptom of uremic syndrome (Carrero et al, 2007, 2008).…”

Effect of astragaloside IV and the role of nuclear receptor RXRα in human peritoneal mesothelial cells in high glucose‑based peritoneal dialysis fluids

“…Peritoneal fibrosis is also one of the primary factors leading to withdrawal from treatment (5)(6)(7). The components and some bioincompatible properties of peritoneal dialysates, such as low pH, lactate buffer, high sugar, low calcium, plasticizer and glucose degradation products, cause loss of peritoneal mesothelial cells (PMCs), subcutaneous dense zone thickening, interstitial fibrosis, inflammation and neovascularization (8)(9)(10)(11)(12). Damage to PMCs is a key initiating factor that leads to peritoneal fibrosis (13)(14)(15).…”

“…Damage to PMCs is a key initiating factor that leads to peritoneal fibrosis (13)(14)(15). After PMCs are damaged, extracellular matrix (ECM) components, including collagen, fibronectin, laminin, proteoglycan and various fibrogenic factors, such as transforming growth factor (TGF)-β1, fibroblast growth factor, connective tissue growth factor, platelet derived growth factor, toll-like receptors (TLRs), angiotensin II receptor and receptor tyrosine kinases, are highly expressed or secreted, which interferes with the normal metabolism of the ECM and promoting its overdeposition, ultimately leading to peritoneal fibrosis (10,(16)(17)(18)(19)(20)(21)(22)(23). Peritoneal fibrosis can be delayed or inhibited by promoting PMC survival and inhibiting PMC epithelial-to-mesenchymal transition (EMT) (14,(16)(17)(18)(19)21,22,24).…”