NDT Advance Access originally published online on November 23, 2007
Nephrology Dialysis Transplantation 2008 23(2):525-533; doi:10.1093/ndt/gfm547
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Venous stenosis in a pig arteriovenous fistula model—anatomy, mechanisms and cellular phenotypes*
1Cincinnati Dialysis Access Research Program, Department of Medicine, Division of Nephrology, 2Department of Mechanical, Industrial and Nuclear Engineering, 3Department of Surgery, 4Department of Biomedical Engineering and 5Department of Pathology, University of Cincinnati, Cincinnati, OH, USA
Correspondence to: Prabir Roy-Chaudhury MD, PhD, Division of Nephrology, University of Cincinnati, MSB G-251, 231, Albert Sabin Way, Cincinnati OH 45267-0585, USA. Email: Prabir.roychaudhury{at}uc.edu
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Abstract |
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Background. Haemodialysis vascular access dysfunction is currently a huge clinical problem. Although arteriovenous (AV) fistulae are the preferred mode of dialysis access, they have significant problems with both early (failure to mature) and late fistula failure. Both are characterized radiologically as a stenosis of the venous segment. Despite the magnitude of the clinical problem, the exact pathogenesis of AV fistula failure remains unclear. The aim of this study was to develop and validate a pig model of AV fistula stenosis and then use it to dissect out the mechanisms responsible for this lesion.
Methods. AV fistulae were created between the femoral artery and vein of Yorkshire Cross pigs. Animals were sacrificed at 2 days, 7 days, 28 days and 42 days post-surgery. At the time of sacrifice the entire specimen was divided into four regions; the arterial (AV-A) and venous (AV-V) portions of the AV anastomosis, the juxta-anastomotic segment (JA) and the proximal vein (PV), and assessed for the degree of intima-media thickening and the presence of specific cellular phenotypes. Haemodynamic parameters were not measured in this set of experiments.
Results. Significant luminal stenosis and intima-media thickening were present as early as 28 days and 42 days post-surgery in the pig model. In addition, within specimens from a single time point, these two parameters were maximal within the proximal vein and juxta-anastomotic segment as compared to the AV anastomosis (P < 0.0001). The vast majority of cells within the region of intima-media thickening were myofibroblasts.
Conclusions. These studies suggest that early and aggressive intima-media thickening (which is made up primarily of myofibroblasts) plays an important role in AV fistula stenosis in a pig model of AV fistula placement. Interventions that target the mechanisms and cellular phenotypes described in this model, may be effective in reducing the very significant morbidity and economic costs currently associated with AV fistula failure.
Keywords: arteriovenous fistula stenosis; cellular phenotypes; hemodialysis vascular access dysfunction; myofibroblast; neointimal hyperplasia; pig model
*Parts of this work have been presented in abstract form at the ASAIO Annual Conference, Chicago, June 2006 and at the American Society of Nephrology Annual Meeting, San Diego, November 2006.
Received for publication: 8. 1.07
Accepted in revised form: 18. 7.07
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