Peritoneal Dialysis Vintage and Glucose Exposure but Not Peritonitis Episodes Drive Peritoneal Membrane Transformation During the First Years of PD

Abstract

The impact of peritoneal dialysis (PD) associated peritonitis on peritoneal membrane integrity is incompletely understood. Children are particularly suited to address this question, since they are largely devoid of preexisting tissue damage and life-style related alterations. Within the International Peritoneal Biobank, 85 standardized parietal peritoneal tissue samples were obtained from 82 children on neutral pH PD fluids with low glucose degradation product (GDP) content. 37 patients had a history of peritonitis and 16 of the 37 had two or more episodes. Time interval between tissue sampling and the last peritonitis episode was 9 (4, 36) weeks. Tissue specimen underwent digital imaging and molecular analyses. Patients with and without peritonitis were on PD for 21.0 (12.0, 36.0) and 12.8 (7.3, 27.0) months ( p = 0.053), respectively. They did not differ in anthropometric or histomorphometric parameters [mesothelial coverage, submesothelial fibrosis, blood, and lymphatic vascularization, leukocyte, macrophage and activated fibroblast counts, epithelial-mesenchymal transition (EMT), podoplanin positivity and vasculopathy]. VEGF and TGF-ß induced pSMAD abundance were similar. Similar findings were also obtained after matching for age and PD vintage and a subgroup analysis according to time since last peritonitis (<3, <6, >6 months). In patients with more than 24 months of PD vintage, submesothelial thickness, vessel number per mmm section length and ASMA fibroblast positivity were higher in patients with peritonitis history; only the difference in ASMA positivity persisted in multivariable analyses. While PD duration and EMT were independently associated with submesothelial thickness, and glucose exposure and EMT with peritoneal vessel density in the combined groups, submesothelial thickness was independently associated with EMT in the peritonitis free patients, and with duration of PD in patients with previous peritonitis. This detailed analysis of the peritoneal membrane in pediatric patients on PD with neutral pH, low GDP fluids, does not support the notion of a consistent long-term impact of peritonitis episodes on peritoneal membrane ultrastructure, on inflammatory and fibrotic cell activity and EMT. Peritoneal alterations are mainly driven by PD duration, dialytic glucose exposure, and associated EMT.

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

“…It has previously been established that Astragalus membranaceus inhibits peritoneal fibrosis during PD (18)(19)(20)22). The data from the present study, and the study by Zhang et al (31), showed that astragaloside IV, a component of Astragalus membranaceus, increased cell viability and inhibited apoptosis and EMT in PMCs in high glucose-based PD fluids without affecting PMCs under normal conditions, suggesting that astragaloside IV is an active, key component of Astragalus membranaceus that contributes to its anti-fibrosis function.…”

“…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).…”

Comparison of Longitudinal Membrane Function in Peritoneal Dialysis Patients According to Dialysis Fluid Biocompatibility

“…J o u r n a l P r e -p r o o f INTRODUCTION Problems related to the quality of the peritoneal membrane are likely to develop more frequently than in the past, as the duration of peritoneal dialysis increases. They can be provoked by long-term exposure to dialysis solutions, both in adults (1) and in children (2). The use of conventional PD solutions (CON) can cause alterations in peritoneal transport, like ultrafiltration (UF) failure and an increase in the transport of low molecular weight solutes (3).…”

Encapsulating Peritoneal Sclerosis: Pathophysiology and Current Treatment Options

“…Improvement of the manufacturing process, i.e., the introduction of double chamber PD fluids, separating the glucose at a very low pH from the buffer compound, significantly reduced the fluid GDP content and allowed for the introduction of a physiological buffer, namely bicarbonate. In vitro and experimental in vivo studies suggest less peritoneal toxicity [37], but even low GDP fluids with a neutral to physiological pH confer major peritoneal toxicity, and within a few months of PD, induce profibrogenic cytokines, such as transforming growth factor β 1 (TGF-β1), and angiogenic factors, such as vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) [38], altogether resulting in excessive fibrosis and angiogenesis [21,28]. Mesothelial cells lining the peritoneal cavity are primarily exposed to toxic PD fluids.…”