Are the Mesothelial-to-Mesenchymal Transition, Sclerotic Peritonitis Syndromes, and Encapsulating Peritoneal Sclerosis Part of the Same Process?

Abstract

Mesothelial-to-mesenchymal transition (MMT) is an autoregulated physiological process of tissue repair that in uncontrolled conditions, such as peritoneal dialysis (PD), can lead to peritoneal fibrosis. The maximum expression of sclerotic peritoneal syndromes (SPS) is the encapsulating peritoneal sclerosis (EPS) for which no specific treatment exists. The SPS includes a wide range of peritoneal fibrosis that appears progressively and is considered as a reversible process, while EPS does not. EPS is a serious complication of PD characterized by a progressive intra-abdominal inflammatory process that results in bridles and severe fibrous tissue formation which cover and constrict the viscera. Recent studies show that transdifferentiated mesothelial cells isolated from the PD effluent correlate very well with the clinical events such as the number of hemoperitoneum and peritonitis, as well as with PD function (lower ultrafiltration and high Cr-MTC). In addition, in peritoneal biopsies from PD patients, the MMT correlates very well with anatomical changes (fibrosis and angiogenesis). However, the pathway to reach EPS from SPS has not been fully and completely established. Herein, we present important evidence pointing to the MMT that is present in the initial peritoneal fibrosis stages and it is perpetual over time, with at least theoretical possibility that MMT initiated the fibrosing process to reach EPS.

Figure 1

Mechanism for MMT, SPS, and EPS induction as a single process. The PD fluids bioincompatibility induces overproduction of TGF-β that initiates and perpetuates the MMT. MMT includes angiogenesis (VEGF), decreased in fibrinolytic capacity by decrease in tPA, increased in extracellular matrix component production (collagen-1, fibronectin, etc.), and migration mediated by MMPs. MCs lost their gene expression of E-cadherin, cytokeratins, and other and gain the expression of snail, slag, N-cadherin, and so forth. All of these changes become to peritoneal fibrosis and sclerotic peritoneal syndromes (SPS) which are originally reversible. MMT increases in parallel to fibrosis but its role in EPS pathogenesis is unknown. EPS is considered as irreversible process. ICAM, TGF-β, and Ca-125 expression remains stables.

Figure 2

Evidence of MMT in EPS. Light microscopy analysis of a parietal peritoneal biopsy from a patient with EPS. Despite significant denudation of the peritoneal membrane, a submesothelial cytokeratin staining (brown) in submesothelial area is observed. This cytokeratin staining suggests the superficial precedence of these cells (arrows). Magnification ×200.