Chronic kidney disease aggravates arteriovenous fistula damage in rats

Abstract

Neointimal hyperplasia (NIH) and impaired dilatation are important contributors to arteriovenous fistula (AVF) failure. It is unclear whether chronic kidney disease (CKD) itself causes adverse remodeling in arterialized veins. Here we determined if CKD specifically triggers adverse effects on vascular remodeling and assessed whether these changes affect the function of AVFs. For this purpose, we used rats on a normal diet or on an adenine-rich diet to induce CKD and created a fistula between the right femoral artery and vein. Fistula maturation was followed noninvasively by high-resolution ultrasound (US), and groups of rats were killed on 42 and 84 days after surgery for histological and immunohistochemical analyses of the AVFs and contralateral femoral vessels. In vivo US and ex vivo morphometric analyses confirmed a significant increase in NIH in the AVFs of both groups with CKD compared to those receiving a normal diet. Furthermore, we found using histological evaluation of the fistula veins in the rats with CKD that the media shrank and their calcification increased significantly. Afferent artery dilatation was significantly impaired in CKD and the downstream fistula vein had delayed dilation after surgery. These changes were accompanied by significantly increased peak systolic velocity at the site of the anastomosis, implying stenosis. Thus, CKD triggers adverse effects on vascular remodeling in AVFs, all of which contribute to anatomical and/or functional stenosis.

c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae

“…Chronic kidney failure was induced in eight Sprague-Dawley rats as previously described by Langer et al (23). Briefly, rats were fed an adenine-rich diet (0.75% adenine, Tecklad Custom Research Diets, Harlan) starting at 3 wk before surgery and continuing until fistulae were collected 21 days after creation.…”

“…To this end, we created fistulae in healthy rats (n ϭ 8) and CKD rats (n ϭ 8) that had received an adenine-rich diet starting at 3 wk before surgery and until euthanization. The dietary delivery of adenine mixed in a casein-based diet caused tubulointerstitial lesions that led to CKD (23). Fistulae were collected from both healthy and CKD animals at 21 days after creation, when serum creatinine values in CKD rats were 3.25 times higher than in healthy animals (1.08 Ϯ 0.57 vs. 0.33 Ϯ 0.05).…”

The Transcription Factor E26 Transformation–Specific Sequence-1 Mediates Neointima Formation in Arteriovenous Fistula

“…9,34,37 The administration of ETS-DN resulted in significant reductions in the formation of neointima at both 1 and 3 weeks after the creation of AVF, demonstrating that ETS-1 plays an important role in the adaptive vascular changes that occur after the creation of AVF and lead to the formation of neointima. These results would suggest that ETS-1 could be a target for the treatment and prevention of excessive neointima formation in AVF and improvement of AVF maturation.…”

“…37,38 Whether the vascular expression of ETS-1 is further upregulated under uremic conditions is not known. We speculate, Figure 10.…”

Novel Paradigms for Dialysis Vascular Access

“…It develops within 3 weeks in experimental models of AVF (13)(14)(15)(16), and has been documented in a small number of hemodialysis patients who underwent surgical revision due to AVF nonmaturation 2-6 months after their initial AVF creation (17,18). Experimental models have evaluated the role of some specific mediators in regulating neointimal hyperplasia after AVF creation.…”