Abstract
Chronic inflammatory conditions during peritoneal dialysis (PD)-treatment lead to the impairment of peritoneal tissue integrity. The resulting structural and functional reorganization of the peritoneal membrane diminishes ultrafiltration rate and thereby enhances mortality by limiting dialysis effectiveness over time. Tumour necrosis factor (TNF) and its receptors TNFR1 and TNFR2 are key players during inflammatory processes. To date, the role of TNFR1 in peritoneal tissue damage during PD-treatment is completely undefined. In this study, we used an acute PD-mouse model to investigate the role of TNFR1 on structural and morphological changes of the peritoneal membrane. TNFR1-mediated TNF signalling in transgenic mice expressing human TNFR1 was specifically blocked by applying a monoclonal antibody (H398) highly selective for human TNFR1 prior to PD-treatment. Cancer antigen-125 (CA125) plasma concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Western blot analyses were applied to determine TNFR2 protein concentrations. Histological staining of peritoneal tissue sections was performed to assess granulocytes within the peritoneal membrane as well as the content of hyaluronic acid and collagen. We show for the first time that the number of granulocytes within the peritoneal membrane is significantly reduced in mice pre-treated with H398. Moreover, we demonstrate that blocking of TNFR1 not only influences CA125 values but also hyaluronic acid and collagen contents of the peritoneal tissue in these mice. These results strongly suggest that TNFR1 inhibition attenuates peritoneal damage caused by peritoneal dialysis fluid (PDF) and therefore may represent a new therapeutic approach in the treatment of PD-related side effects.
Highlights
peritoneal dialysis (PD) is an effective renal replacement therapy and a well-established alternative to haemodialysis
Cancer antigen-125 (CA125) concentrations were less reduced in mice treated with H398 prior to the application of peritoneal dialysis fluid (PDF) compared to mice treated with PDF solely (Fig 1C, gray and black bar)
We show that blocking of TNFR1 in these mice has a strong impact on PD-related inflammatory reactions of the peritoneal membrane, and on plasma concentrations of
Summary
PD is an effective renal replacement therapy and a well-established alternative to haemodialysis. Success as well as efficacy of this treatment is dependent on the integrity of the peritoneal membrane. Acute and chronic inflammatory conditions such as recurring peritonitis are causal. Epithelial-mesenchymal transition (EMT) of human peritoneal mesothelial cells (HPMCs), specialized epithelial cells lining the peritoneal cavity, plays a central role in the onset and progression of peritoneal fibrosis during PD-treatment [2]. This process is causal for the failure of the peritoneal membrane function and the subsequent loss of ultrafiltration which accounts for the time restriction of PD-treatment
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