Although arteriovenous fistulae (AVFs) are widely considered to be the best form of dialysis vascular access they currently have very significant problems with maturation failure, which is an inability to achieve adequate venous dilatation and flow to support dialysis. At a radiological level AVF maturation failure is characterized by a perianastomotic venous segment stenosis, while at a histological and pathogenetic level it is due to a combination of neointimal hyperplasia and an absence of outward remodeling. At a mechanistic level, work performed by us during the current grant period has clearly demonstrated that differing hemodynamic profiles result in very different clinical (flow and diameter) and histological end points. We therefore believe that hemodynamic injury is the critical upstream event, which then results in a downstream cascade of events (the vascular biology response to injury). An important unknown, however, remains the potential impact of uremia within this cascade, especially in the context of being able to modulate the downstream biological response to upstream hemodynamic injury. The reason that uremia is likely to be important is that it is characterized by significant increases in oxidative stress, inflammation and endothelial dysfunction, all of which are key players in the downstream biological response to hemodynamic injury. In addition we, and others have been able to demonstrate the presence of neointimal hyperplasia within venous tissue samples taken at the time of dialysis vascular access creation (even before exposure to hemodynamic changes) suggesting that uremia per se (with its linkages to inflammation, oxidative stress and endothelial dysfunction), could be an important independent risk factor for venous stenosis/remodeling. The central hypothesis of the current proposal therefore is that AVF maturation is the end result of interactions between a wide spectrum of two prominent mechanistic pathways (upstream hemodynamic injury and uremia influenced downstream vascular biology). Put another way we want to explore how the presence or absence of uremia modulates the biological response to hemodynamic injury. We plan to address this central hypothesis through three Specific Aims.
In Specific Aim 1, we will expand on the hypothesis that differential hemodynamic shear stress profiles (curved versus straight AVFs) initiate a sequence of differential biological (gene expression and cellular phenotyping) profiles, which then result in different morphometric (wall thickness) and clinical (flow and diameter) end points.
This Specific Aim will also provide a historically concurrent comparator for the studies in Specific Aim 2.
In Specific Aim 2, we will address the hypothesis that uremia per se can influence/modulate the biological response to hemodynamic injury, through a detailed comparison of the biological, morphometric and clinical end points described in Specific Aim 1 in the setting of a uremic pig model as compared to control animals (from Specific Aim 1). Finally in Specific Aim 3, we will combine the power of next generation sequencing technology (RNA Seq. analyses) with our unique animal model of uremia in order to look to the future, with regard to the identification of novel genes, pathways and mechanisms. This information could then be used to identify novel predictive markers for AVF maturation, or alternatively, as a knowledge base for the development of future biologically relevant therapies to prevent or treat AVF maturation failure. In summary, we believe that this proposal is significant because it focuses on an important clinical problem for which there are currently no effective therapies;it is unique in that it addresses head on the complex issue of uremia per se as a modulator of AVF maturation, and finally it is innovative in that it links advanced sequencing technology and bioinformatics to a clinically relevant uremic model.
The current renewal proposal on the mechanisms of arteriovenous fistula (AVF) failure in patients with end stage renal disease (ESRD) who require hemodialysis, is of great clinical relevance to the VA, because of the increasing number of veterans who are on hemodialysis within the VA system. A well-functioning AVF is of course a lifeline for veterans on hemodialysis, while on the other hand a dysfunctional AVF can become the Achilles heel of the hemodialysis patient. It is likely that the studies described in this proposal could result in new therapies for AVF failure and so significantly reduce both the comorbidities and cost associated with AVF failure. More importantly, the information obtained from this proposal could allow us to better understand the impact of kidney failure or uremia on the vascular system (blood vessels) of patients with ESRD. This would likely have a huge clinical impact, because patients with ESRD suffer from aggressive atherosclerotic vascular disease and also have a poorer response to interventions such as angioplasty (balloon dilatation of a vessel).
|Sun, Rong; Wu, Dong-Dong; Wang, Ke et al. (2012) (4R,7S)-2-Amino-4-(3,4-dimeth-oxy-phen-yl)-5-oxo-7-phenyl-5,6,7,8-tetra-hydro-4H-chromene-3-carbonitrile monohydrate. Acta Crystallogr Sect E Struct Rep Online 68:o409-10|