Peritoneal fibrosis is mouse strain dependent

Abstract

Peritoneal dialysis is a widely used mode of renal replacement therapy in which preservation of the structural and functional integrity of the peritoneal membrane is critical for continued success. Progressive scarring, or fibrosis, in the peritoneal membrane is now well described in peritoneal dialysis patients, but its extent is variable. While some patients survive for long periods on peritoneal dialysis, others suffer from ‘fibrosis-related’ membrane failure, or rarely, more severe complications such as encapsulating peritoneal sclerosis (EPS). The reasons for these variations in responses are unlikely to be explained by variations in the therapy, which has remained largely unchanged over the past 20 years, and are suggestive of a genetic component to the susceptibility of individuals to different outcomes. In this issue of NDT, Margetts et al. [1] describe how they used genetically different mouse strains to examine the variability in responses to a defined, constant pro-fibrotic stimulus in a model of peritoneal fibrosis. The data highlight a possible genetic linkage to susceptibility to fibrosis that adds significant insights into our understanding of the mechanisms driving peritoneal damage. The key to continued success of peritoneal dialysis as a therapy remains in preservation of the performance of the peritoneal membrane as a dialysing organ. In health, the visceral and parietal peritoneum and its phospholipid-rich secretions and anti-friction surfaces facilitate bowel motility within the abdominal cavity. The outer surface of the whole comprises a single layer of mesothelial cells, specialized to provide a low friction and non-adhesive surface. The mesothelium that lines the peritoneal membrane sits on the sub-mesothelial compact zone, comprising a collagen-rich extracellular matrix in which larger blood vessels and capillaries are sited. Peritoneal dialysis is associated with a spectrum of alterations in the morphology of the peritoneal membrane which includes alterations in the mesothelial cell morphology, thickening of the sub-mesothelial compact zone and progressive vascular damage (vasculopathy) [2]. Cross-sectional studies have linked these changes to long-term glucose exposure and episodic infection [2].These alterations to the peritoneal membrane associate with alterations in peritoneal solute transport, loss of ultrafiltration and eventual technique failure. More recent data suggest that the changes in the mesothelium play a key role in driving the changes in peritoneal structure and function. Data primarily from animal models and corroborated with the limited clinical studies suggest that the acquisition of a fibroblast-like phenotype by mesothelial cells, so-called trans-differentiation or epithelial-mesenchymal transition, is key in driving changes in extracellular matrix turnover and fibrogenesis (reviewed in [3]). As the genesis of peritoneal fibrosis is insidious without overt clinical symptoms, except in cases of EPS, there are at present no tests that can predict its onset, nor are there any therapeutic approaches other than a switch of renal replacement therapy modality from peritoneal dialysis to haemodialysis when membrane function is seriously compromised. In the case of EPS, surgery can be used to relieve intestinal obstruction, but while outcomes have improved from this intervention the risk of mortality from the condition remains significant. The clinical consequences of peritoneal fibrosis are thus clear, but the processes that initiate and drive it in peritoneal