Regulation of arteriovenous fistula maturation in high-risk groups of occlusion

• Project/Area Number: 19K24006
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0905:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Isaji Toshihiko 東京大学, 医学部附属病院, 助教 (40779790)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000)
• Keywords: 動静脈瘻 / 内膜肥厚 / 内皮機能 / eNOS / 糖尿病 / 性差 / Sildenafil / ブラッドアクセス / ハイリスク群

Outline of Research at the Start

自己静脈を用いた動静脈瘻は維持透析用ブラッドアクセスの第一選択であるが、造設後一年の一次開存率は約60％と極めて成績が悪く、これまでの研究で動静脈瘻不全に至る症例の疫学的なハイリスク群が明らかにされている。本研究の目的は、マウス動静脈瘻モデルを用いて、動静脈瘻不全ハイリスク群における内膜肥厚のメカニズムを解明し、ハイリスク患者の手術成績改善につなげることである。性ホルモンの内膜肥厚に対する影響を検討し、動静脈瘻不全に対するホルモン療法の可能性を探る。ストレプトゾトシン投与によるⅠ型糖尿病マウスの動静脈瘻モデルを作成し動静脈瘻不全のメカニズムを解明する。

Outline of Final Research Achievements

Diabetes mellitus is a known risk factor for occlusion of arteriovenous fistulas for dialysis due to intimal thickening. We focused on vascular endothelial damage in diabetic patients and compared postoperative maturation of arteriovenous fistulas with and without sildenafil, which enhances eNOS, in a mouse model. Although there was no difference in arteriovenous fistula patency and degree of intimal thickening at 6 weeks postoperatively, the diameter of shunted vena cava tended to be dilated in the sildenafil-treated group. We attempted to create an arteriovenous fistula model in mice with type I diabetes mellitus by administering streptozotocin, but the mortality rate during the postoperative course made it difficult to conduct a comparative study with the control group. We also created an ovariectomy model in mice, but the postoperative mortality rate was so high that we were unable to create an arteriovenous fistula model.

Academic Significance and Societal Importance of the Research Achievements

人工透析を要する慢性腎不全患者におけるブラッドアクセスの長期開存の確保は喫緊の課題である。これまで我々は動静脈瘻造設術後の成熟と不全を司るいくつかの分子に着目してきたが、いずれも動物実験段階から実臨床への応用の道のりには数多くのプロセスを経る必要がある。シルデナフィルは勃起不全症に対する治療薬として薬事承認を受けた薬剤であり、本研究を発展させて動静脈瘻に対する内膜肥厚制御効果さらに長期開存率改善効果が認められれば、比較的早期の臨床応用が期待できる。

Research Products

• [Journal Article] TGFβ (Transforming Growth Factor-Beta)?Activated Kinase 1 Regulates Arteriovenous Fistula Maturation (2020)
  • Author(s): Hu Haidi、Lee Shin-Rong、Bai Hualong、Guo Jianming、Hashimoto Takuya、Isaji Toshihiko、Guo Xiangjiang、Wang Tun、Wolf Katharine、Liu Shirley、Ono Shun、Yatsula Bogdan、Dardik Alan
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 40
  • DOI: 10.1161/atvbaha.119.313848
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Altered hemodynamics during arteriovenous fistula remodeling leads to reduced fistula patency in female mice (2020)
  • Author(s): Kudze Tambudzai、Ono Shun、Fereydooni Arash、Gonzalez Luis、Isaji Toshihiko、Hu Haidi、Yatsula Bogdan、Taniguchi Ryosuke、Koizumi Jun、Nishibe Toshiya、Dardik Alan
  • Journal Title: JVS: Vascular Science Volume: 1 Pages: 42-56
  • DOI: 10.1016/j.jvssci.2020.03.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A mouse model of stenosis distal to an arteriovenous fistula recapitulates human central venous stenosis (2020)
  • Author(s): Taniguchi Ryosuke、Ono Shun、Isaji Toshihiko、Gorecka Jolanta、Lee Shin-Rong、Matsubara Yutaka、Yatsula Bogdan、Koizumi Jun、Nishibe Toshiya、Hoshina Katsuyuki、Dardik Alan
  • Journal Title: JVS: Vascular Science Volume: 1 Pages: 109-122
  • DOI: 10.1016/j.jvssci.2020.07.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Venous Mechanical Properties After Arteriovenous Fistulae in Mice. (2020)
  • Author(s): Brownson KE, Khosravi R, Lee SR, Goldstein K, Isaji T, Ono S, Protack CD, Humphrey JD, Dardik A.
  • Journal Title: Journal of Surgical Research Volume: 248 Pages: 129136-129136
  • DOI: 10.1016/j.jss.2019.12.007
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Egg-shell like Calcification as a Protective Factor for Splenic Artery Aneurysm Dilatation (2020)
  • Author(s): Sano Masaya、Hoshina Katsuyuki、Kawahara Takuya、Kimura Masaru、Akai Takafumi、Isaji Toshihiko、Yamamoto Kota、Takayama Toshio
  • Journal Title: Annals of Vascular Surgery Volume: 63 Pages: 193197-193197
  • DOI: 10.1016/j.avsg.2019.08.102
  • Peer Reviewed / Open Access
• [Journal Article] Murine Model of Central Venous Stenosis using Aortocaval Fistula with an Outflow Stenosis. (2019)
  • Author(s): Toshihiko Isaji, Shun Ono, Takuya Hashimoto, Kota Yamamoto, Ryosuke Taniguchi, Haidi Hu, Tun Wang, Jun Koizumi, Toshiya Nishibe, Katsuyuki Hoshina, Alan Dardik
  • Journal Title: Journal of Visualized Experiments Volume: 149
  • DOI: 10.3791/59540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of the Akt1-mTORC1 Axis Alters Venous Remodeling to Improve Arteriovenous Fistula Patency. (2019)
  • Author(s): Guo X, Fereydooni A, Isaji T, Gorecka J, Liu S, Hu H, Ono S, Alozie M, Lee SR, Taniguchi R, Yatsula B, Nassiri N, Zhang L, Dardik A.
  • Journal Title: Scientific Reports Volume: 9(1) Pages: 11046-11046
  • DOI: 10.1038/s41598-019-47542-5
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Long-term outcomes of vein grafts used in distal bypass for critical limb-threatening ischemia (2019)
  • Author(s): Isaji T, Hanada K, Matsuura S, Okata S, Ohashi Y, Sano M, Miyahara K, Fukuhara N, Akai T, Takayama T, Hoshina K
  • Organizer: International Union of Angiology, Japan Chapter Meeting
  • Int'l Joint Research