TISSUE REACTIONS TO PERITONEAL DIALYSIS
Peritoneal dialysis (PD) over time provokes a characteristic inflammatory response in the peritoneal membrane and typical functional changes in peritoneal transport characteristics that may ultimately lead to ultrafiltration failure. The tissue reaction to PD has been characterized by a large number of studies and during recent years effort has been focused on angiogenesis, fibrosis and epithelial-to-mesenchymal Transition (EMT). The triggering mechanisms behind the peritoneal inflammatory response are, however, not fully elucidated.
The development of bio-compatible PD fluids, with low levels of glucose degradation products (GDP) and/or alternative osmotic agents and buffers, was expected to eliminate the PD-induced tissue reactions, but results from systematic studies are partly discouraging. The use of new biocompatible fluids has not eliminated the inflammatory response. Furthermore, experimental studies in animals have shown that even "physiological" buffer solutions trigger inflammatory responses following intraperitoneal administration.
Consequently, there must exist hitherto unknown pro-inflammatory effects of intraperitoneal fluid exposure. In an earlier study, we were able to show that a single PD dwell in rats was accompanied by an intraperitoneal release of histamine. Blocking the effects of the neuropeptide Substance P eliminated the histamine release and substantially reduced the leakage of albumin from plasma to the peritoneal cavity. Blocking the receptor for calcitonin gene-related peptide (CGRP), another neuropeptide, reduced the tissue albumin space and improved net ultrafiltration. We concluded that neuropeptides were involved in the acute tissue response to PD fluid, indicating that neurogenic inflammation may be involved.
Neurogenic inflammation is triggered by mechanoreceptors of the transient receptor potential (TRP) family (the classic activator being TRPV1) and involves a rapid release of vaso-active neuropeptides, like CGRP and substance P, that in turn trigger a secondary response in e.g. lymphocytes, mast cells, macrophages and fibroblasts. TRPV1 is often co-expressed with the receptor TRPA1 and they are believed to interact in the initiation of the neurogenic inflammatory response. The secondary response, mainly mediated by Substance P, provides a connection between the neurogenic inflammation and a more conventional inflammatory state, including cytokine release (IL-1β, IL-6, TNF-α, IL-8), recruitment of inflammatory cells and, ultimately, fibrosis and angiogenesis.
In addition to neuronal cells, functional TRP receptors are also present on fibroblasts and epithelial cells where they trigger pro-inflammatory responses such as eicosanoid and cytokine release. We have demonstrated that blocking TRPA1 in a rat model of peritoneal dialysis significantly reduced the transcription of cytokine IL-6 in peritoneal tissue and its release into the peritoneal cavity during a single PD dwell. TRPA1 is a mechanoreceptor and, hypothetically, the triggering of TRPA1 may be attributed to the osmotic and hydrostatic effects of the peritoneal dialysis fluid.
We are now planning a long-term study in rats in order to study the effects of Substance P and activation of the TRPA1 receptor on the development of peritoneal fibrosis and ultrafiltration capacity. Receptor blocking technique will be combined with an established experimental model that allows repeated transport measurements and a final evaluation of peritoneal tissues, including transcription histochemistry and morphology.