Abstract
Creation of an autologous arteriovenous fistula (AVF) for vascular access in haemodialysis is the modality of choice. However neointimal hyperplasia and loss of the luminal compartment result in AVF patency rates of ~60% at 12months. The exact cause of neointimal hyperplasia in the AVF is poorly understood. Vascular trauma has long been associated with hyperplasia. With this in mind in our rabbit model of AVF we simulated cannulation autologous to that undertaken in vascular access procedures and observed significant neointimal hyperplasia as a direct consequence of cannulation. The neointimal hyperplasia was completely inhibited by topical transdermal delivery of the non-steroidal anti-inflammatory (NSAID) diclofenac. In addition to the well documented anti-inflammatory properties we have identified novel anti-proliferative mechanisms demonstrating diclofenac increases AMPK-dependent signalling and reduced expression of the cell cycle protein cyclin D1. In summary prophylactic transdermal delivery of diclofenac to the sight of AVF cannulation prevents adverse neointimal hyperplasic remodelling and potentially offers a novel treatment option that may help prolong AVF patency and flow rates.
Highlights
Vascular access is the Achilles heel of modern haemodialysis [1]
In this study we have demonstrated for the first time that the procedural practice of cannulation, as used in gaining vascular access in haemodialysis, drives a vascular proliferative response resulting in luminal occlusion, reduced blood flow and failure in terms of vascular access and haemodialysis (Fig. 2)
This study has a number of novel observations; we have demonstrated that diclofenac causes a concentration dependent inhibition of VSM cell proliferation
Summary
Vascular access is the Achilles heel of modern haemodialysis [1]. The complications of vascular access are responsible for over 20% of all hospitalisations of patients on haemodialysis and account for one third of all in-patient renal bed usage [2]. Autologous arteriovenous fistulae created from native artery and vein are the modality of choice to provide vascular access for haemodialysis. A systematic review and meta-analysis on AVF patency was published using rigorous methodology to examine 62 unique cohorts [3]. The hallmark of AVF failure is neointimal hyperplasia leading to stenosis with occlusion of the fistula outflow vein [4,5]
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