Uremia Induces Functional and Histological Changes in a Mouse Model of AVF Stenosis

Abstract

Background: Arteriovenous Fistula (AVF) stenosis is responsible for a very significant morbidity, mortality and economic cost. Despite the magnitude of the clinical problem there are currently no effective therapies for AVF stenosis. The focus of this project was therefore to identify uremia specific functional and histological differences in AVF stenosis in a mouse model. Methods: Mice were made uremic through the removal of the upper and lower poles of one kidney followed by a nephrectomy of the contralateral kidney. AVFs were created through an end (vein) to side (artery) anastomosis using standard techniques. Functional parameters included flow mediated dilation (FMD) and the area enclosed within the elastic lamina at 100 micron intervals x 12 from the AV anastomosis. The histological end point was the ratio of thrombus area/perimeter at 100 micron intervals x 12 from the AV anastomosis (with the first 600 microns being considered proximal and the second 600 microns as distal). Results: A total of 22 mice were used in these experiments. The mean +/- SE for BUN in the uremic animals was 109+/-4.8 mg/dL as compared to 17.4 +/- 1.0 mg/dL in the control animals (p<0.05). FMD at 60 seconds was decreased significantly in uremic animals (13.4 +/- 1.5%) as compared to the control animals (19.5 +/- 1.1%), although there was no difference at the 90 second peak. There was a trend towards a smaller area enclosed by the elastic lamina (an indicator of inward remodeling) in the uremic animals, although this achieved statistical significance only in the distal segments (at 1000-1200 microns beyond the AV anastomosis). Finally, uremic animals had significantly more attached thrombus (thrombus area/perimeter) in the distal portions of the AVF (9414.7 +/- 7187.5) as compared to the proximal portions (1055.0 +/- 529.5). Conclusion: These data document impairment of endothelial linked, functional (FMD and inward remodeling) and histological (thrombus formation) pathways in a mouse model of AVF stenosis. Further elucidation of the uremia specific mechanistic pathways responsible for these differences, could result in the development of novel drugs and devices for the treatment of AVF stenosis in patients with CKD and ESRD.