Abstract
Peritoneal hyalinizing vasculopathy (PHV) represents the cornerstone of long-term peritoneal dialysis (PD), and especially characterizes patients associated with encapsulating peritoneal sclerosis. However, the mechanisms of PHV development remain unknown. A cross sectional study was performed in 100 non-selected peritoneal biopsies of PD patients. Clinical data were collected and lesions were evaluated by immunohistochemistry. In selected biopsies a microRNA (miRNA)-sequencing analysis was performed. Only fifteen patients (15%) showed PHV at different degrees. PHV prevalence was significantly lower among patients using PD fluids containing low glucose degradation products (GDP) (5.9% vs. 24.5%), angiotensin converting enzyme inhibitors (ACEIs) (7.5% vs. 23.4%), statins (6.5% vs. 22.6%) or presenting residual renal function, suggesting the existence of several PHV protective factors. Peritoneal biopsies from PHV samples showed loss of endothelial markers and induction of mesenchymal proteins, associated with collagen IV accumulation and wide reduplication of the basement membrane. Moreover, co-expression of endothelial and mesenchymal markers, as well as TGF-β1/Smad3 signaling activation were found in PHV biopsies. These findings suggest that an endothelial-to-mesenchymal transition (EndMT) process was taking place. Additionally, significantly higher levels of miR-7641 were observed in severe PHV compared to non-PHV peritoneal biopsies. Peritoneal damage by GDPs induce miRNA deregulation and an EndMT process in submesothelial vessels, which could contribute to collagen IV accumulation and PHV.
Highlights
Nowadays peritoneal dialysis (PD) is one of the most convenient replacement treatments for end-stage renal disease patients (ESRD) [1]
The Peritoneal hyalinizing vasculopathy (PHV) prevalence was significantly lower in patients receiving low-glucose degradation products (GDP) PD fluids (PDFs) than those treated with high-GDP PDFs (5.9% vs. 24.5%, p = 0.008) (Figure 2A)
We consider a large series of non-selected PD patient biopsies, leading us to show a strong association between high-GDP PDFs and PHV events
Summary
Nowadays peritoneal dialysis (PD) is one of the most convenient replacement treatments for end-stage renal disease patients (ESRD) [1]. The repeated exposure of the peritoneum to PD fluids (PDFs) evokes several cellular responses in the peritoneal membrane, including activation of an inflammatory response, angiogenesis and fibrosis, leading to a functional membrane failure that limits PD performance [2] These alterations remain specially marked by the reiterated presence of unsolved peritonitis episodes in some PD patients [3,4,5]. Most of the preclinical studies, based on in vitro studies in mesothelial cells (MCs) and in animal models of PDFs exposure, have investigated the mechanisms involved in the peritoneal membrane damage [6] These studies have demonstrated that MCs acquire myofibroblast characteristics through an epithelial-to-mesenchymal transition (EMT) process, known as mesothelial-to-mesenchymal transition (MMT) [7]. Many studies have proposed that MMT is an important process in peritoneal fibrosis and targeting MMT could prevent peritoneal membrane functionality failure [12]
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