The Role of Wall Shear Stress in the Failure of Arteriovenous Fistula for Hemodialysis Vascular Access

Franzoni, Marco (2016). The Role of Wall Shear Stress in the Failure of Arteriovenous Fistula for Hemodialysis Vascular Access. PhD thesis The Open University.



Native arteriovenous fistulas created in the forearm between the radial artery and the cephalic vein are currently considered the best vascular access for hemodialysis in terms of outcome and safety. However, this type of access is associated with a significant failure rate that is generally caused by intimal hyperplasia development and consequent stenosis. Computational studies have shown that intimal hyperplasia is preferentially localized in regions of the fistula that are exposed to disturbed wall shear stresses. This thesis reports the development and testing of a novel, real-time controlled cone-and-plate device to assess the role of changes in shear stress induced by fistula creation on the activation state of endothelial cells and paracrine signalling in vitro. The selected shear stress waveforms were representative of the pulsatile/unidirectional waveforms in zones that are generally not affected by hyperplasia or the disturbed/reciprocating waveforms present in the high-risk stenosis areas. Experimental results showed that after 48 hours of flow exposure, these stimuli elicited differential effects on human umbilical vein endothelial cells monolayers. Pulsatile waveforms induced major cellular shape remodeling and upregulation of the transcription factor KLF2 mRNA expression. On the contrary cells exposed to reciprocating flows showed a lack of cytoskeletal remodeling, upregulation of the enzyme PLDl , the integrin subunit ITGA4 and RASA1 (coding for the protein activator p120RasGAP) mRNA expression and an increased production of chemoattractant cytokines MCP-1 and IL-8. Furthermore, it was observed that human smooth muscle cells incubated for 24 hours with medium conditioned by endothelial cells exposed to reciprocating shear stress stimuli, had an increased rate of proliferation compared to smooth muscle cells cultured in medium conditioned by endothelial cells exposed to pulsatile waveforms. These results confirm potential links between disturbed wall shear stress and arteriovenous fistula failure.

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