The mouse aortocaval fistula recapitulates human arteriovenous fistula maturation

Abstract

Several models of arteriovenous fistula (AVF) have excellent patency and help in understanding the mechanisms of venous adaptation to the arterial environment. However, these models fail to exhibit either maturation failure or fail to develop stenoses, both of which are critical modes of AVF failure in human patients. We used high-resolution Doppler ultrasound to serially follow mice with AVFs created by direct 25-gauge needle puncture. By day 21, 75% of AVFs dilate, thicken, and increase flow, i.e., mature, and 25% fail due to immediate thrombosis or maturation failure. Mature AVF thicken due to increased amounts of smooth muscle cells. By day 42, 67% of mature AVFs remain patent, but 33% of AVFs fail due to perianastomotic thickening. These results show that the mouse aortocaval model has an easily detectable maturation phase in the first 21 days followed by a potential failure phase in the subsequent 21 days. This model is the first animal model of AVF to show a course that recapitulates aspects of human AVF maturation.

Keywords: aortocaval fistula; arteriovenous fistula; maturation; model; mouse.

Fig. 1.

Assessment of arteriovenous fistula (AVF) technical success. A: schematic showing the definitions of the terminology used. IVC, inferior vena cava. B: ultrasound findings of the waveforms in the IVC. Top: cranial to the AVF (near the diaphragm); middle, at the AVF; bottom, caudal to the AVF (near bifurcation of IVC). C: cross-section at the AVF. Ao, aortic lumen; IVC, IVC lumen. Overgrowth of aortic tissue into the IVC can be seen (*). D: partial pressures of O₂ and CO₂ of the infrarenal IVC in the sham group and infrarenal venous limb of the AVF group. *P = 0.0008 by t-test. E: time course of the change of osteopontin (OPN) mRNA expression in the venous limb of the successful AVF group as well as the sham group.

Fig. 2.

Systemic effects of the AVF. A: survival curve comparing AVF and sham surgery groups (Kaplan-Meier statistics). B: photograph showing collateral veins (black arrows) developing in the abdominal wall of a mouse with a successful AVF (day 21). C: photograph showing ultrasound assessment of the dilated distal IVC (*), representing venous congestion of the lower limb due to arterial blood flowing into the IVC through the AVF (arrow). D: line graph showing the change in cardiac diameter over time, as measured using ultrasound. E: body weights of mice with either sham or successful AVF surgery (day 21).

Fig. 3.

AVF technical success and patency rate. A: technical success rate according to groups of every 50 AVF surgeries performed. The success rate in the fourth period was 83.0%. B: mean AVF patency over time. Postoperative days 0–1 were termed the immediate thrombosis phase, days 1–21 were termed the maturation phase, and days 21–42 were termed the failure phase.

Fig. 4.

Schema of the AVF groups.

Fig. 5.

AVF assessment with ultrasound. A: bar graph summarizing the changes of aortic diameter after 42 days. *P < 0.05 compared with the sham group by ANOVA. B: bar graph summarizing the changes of suprarenal IVC diameter after 42 days. *P < 0.05 compared with the sham group by ANOVA. C: blood flow velocity in the supra- and infrarenal IVC. *P < 0.01 by ANOVA. D: diameter of the supra- and infrarenal IVC. *P < 0.01 by ANOVA. E: shear stress in the supra-and infrarenal IVC. *P < 0.01 by ANOVA.

Fig. 6.

Histology of a successful AVF (day 21). A–C: cross-sections of the IVC just below the renal veins in preoperative mice (A), sham mice at day 21 (B), and AVF mice at day 21 (C). Scale bars = 200 μm D: bar graph showing mean venous intima-media thickness. n = 3. *P < 0.05 by ANOVA with post hoc test. E: photomicrographs showing representative immunohistochemsitry for CD31 (top) or smooth muscle α-actin (bottom). For each group of pictures, the top image shows the aorta and the bottom image shows the IVC. Scale bars = 100 μm.

Fig. 7.

Histology of an AVF (day 42). A: photomicrograph showing a successful AVF (day 42). Some perianastomotic tissue (*) extends from the aorta into the IVC at the site of the fistula. B: photomicrograph showing a failed AVF (day 42). The perianastomotic tissue (*) is thicker, and there is no detectable lumen between the aorta and IVC. Scale bars = 100 μm.