Mechanisms of Vascular Pathology Following Peritonitis in Peritoneal Dialysis Patients and Therapeutic Intervention

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Background: In PD patients, CV death is 10 times more likely than in the general population and this risk further increases following each peritonitis episode. Damage-Associated Molecular Patterns (DAMPs) play a critical role in inflammatory pathologies, notably via their activation of Toll-like receptors (TLRs), but their specific role in mediating long-term vascular pathology following an infection remains undescribed. Methods: We investigated a potential role for DAMPs in mediating long-term CV risk following peritonitis by i) characterising the long-term vascular inflammatory changes induced by peritonitis in mice, ii) identifying potential target DAMPs following peritonitis by analysis of in vivo and PD patients' plasma samples, iii) mechanistically characterising the potential of our selected DAMP to promote key vascular inflammatory responses by critical cell types in vitro, iv) demonstrating, by pharmacologic inhibition, the critical contribution of a DAMP candidate to the maintenance of vascular pro-atherogenic responses following peritonitis in mice. Results: Bacterial peritonitis in mice was resolved in 24h but led to vascular inflammatory responses, expected to promote CVD, that were maintained up to 28 days. These included higher proportions of inflammatory leukocytes, increased cytokine levels, higher adhesion molecules, and increased blood and aortic inflammatory and atherosclerosis-associated gene expression. These findings were maintained in nephropathic animals and exacerbated in animals routinely exposed to PD fluids. In parallel to these changes, a peritonitis episode led to elevated plasma levels of a specific TLR DAMP, Calprotectin, both in animals and PD patients. In vitro, Calprotectin could promote typical vascular inflammatory and pro-atherosclerotic responses: monocyte chemotaxis, foam cell formation, via a reduction of cholesterol efflux by macrophages and loss of endothelial resistance. In vivo, Calprotectin blockade robustly inhibited the short and long-term vascular inflammatory consequences of peritonitis. Conclusions: This study demonstrates the major role that the Calprotectin-TLR pathway plays in driving long-term vascular pathology following a peritonitis episode.

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