J. Rozowsky1, K. Staton1, K. O’Malley1, M. S. Conte2, M. R. Spite3, S. Berceli1 1University Of Florida,Vascular Surgery,Gainesville, FL, USA 2University Of California – San Francisco,Vascular Surgery,San Francisco, CA, USA 3Brigham And Women’s Hospital,Anaesthesia,Boston, MA, USA
Introduction:
Active resolution of acute inflammation occurs at the interface between innate and adaptive immunity. Once thought to be a passive process, endogenous lipid mediators (resolvins and protectins) have been shown to be key promotors during this resolution phase. These mediators have been traditionally thought to protect organs from collateral damage and stimulate the clearance of inflammatory debris, more recently they have been shown to be important in monocyte recruitment and activation. The link between cell-mediated inflammation and vascular pathophysiology has been firmly established and mounting evidence suggests an important role for these cells in flow-mediated vascular adaptation. Undefined, however, is the importance of inflammation, and its subsequent resolution, in modulating adaptation in the extreme flow environment that characterizes a dialysis access arteriovenous fistula (AVF). We hypothesize active inflammation is critical to AVF maturation, and elevated levels of circulating, pro-resolving mediators act to dampen inflammation and impede AVF maturation.
Methods:
In patients undergoing single-stage AVF (n=20), plasma was collected at two time points (pre-op and 6 weeks post-op) and analyzed for 22 different lipid mediators using liquid chromatography/mass spectrometry. AVFs were categorized as successful (n=10) if they were used for dialysis in four subsequent visits or failed (n=10) if they did not meet this benchmark. Because of the non-normal distribution, a two-factor Scheirer-Ray-Hare test, was used to identify lipids that are differentially expressed between the outcome groups or over time.
Results:
Six of 22 lipids (14-HDHA, 13-HDHA, 7-HDHA, 4-HDHA, 5-HEPE, and 15-HETE), all precursors to the bioactive mediators, were significantly associated with AVF maturation outcome (p-value < 0.05; false discovery rate (FDR) < 0.1), with all 6 of these compounds elevated in AVFs that failed to mature. None of the lipids demonstrated significant time dependent variations or time*outcome interactions.
Conclusion:
AVF maturation failure was associated with elevated levels of select precursors, upstream of the bioactive pro-resolvin mediators. While it is tempting to speculate that this pattern of compounds results in early dampening of the inflammatory process and maturation failure, it is also plausible that the observed accumulation of precursors is secondary to a stalled production of pro-resolving mediators and an overall escalation of inflammatory processes. Further investigation regarding the biologic activity of these precursor compounds, and their overall implication in modulating local inflammation, is needed.
