Date of Award

January 2018

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Alan Dardik

Abstract

The arteriovenous fistula (AVF) is the preferred method of dialysis access. However, women have lower rates of AVF maturation than men (38% vs. 60%), preventing optimal AVF use. We used a novel mouse AVF model that recapitulates human AVF maturation to test the hypothesis that there is a difference in male and female AVF maturation.

Aortocaval fistulae were created in male and female C57BL/6 mice (9-10wk). Aortic and IVC diameters and flow velocity were monitored by Doppler ultrasound at days 0, 3, 7, 14 and 21; shear stress was calculated. Messenger RNA (mRNA) expression was measured by qPCR. AVF were examined at day 21 and AVF wall thickness was measured by computer morphometry.

We found that female mice weighed less preoperatively and at day 21 (p < 0.05) and had larger suprarenal aortic diameter (p = 0.002) but smaller infra-renal IVC diameter (p < 0.05) at baseline. After AVF creation, the percent increase in IVC and aortic diameter was similar at day 21 (p > 0.05). Infra-renal IVC mean velocity was decreased in female mice at baseline and at day 3, 14 and 21 (p < 0.05). Similarly, mean laminar shear stress magnitude in the infra-renal IVC was decreased in female mice at day 7 (p = 0.03), 14 (p = 0.04) and 21 (p = 0.01) but was similar in the infra-renal aorta (p = 0.80). mRNA of KLF2, a marker of laminar shear stress, was decreased in the IVC of female AVF on day 21 (p = 0.048). Preoperatively, female mice had thinner venous walls (p = 0.035). At day 21, AVF wall thickness was similar (p = 0.18). There was no statistically significant difference in AVF patency rates at day 21 (p = 0.53) and 42 (p = 0.17).

In conclusion, AVF in female mice have lower magnitudes of laminar shear stress, lower expression of KLF2 mRNA and a higher percent increase in wall thickness suggesting a mechanism underlying the diminished rates of AVF maturation in women.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 06/25/2100

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