Neointimal hyperplasia (IH) Inward remodeling (Fibrosis)

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3 Neointimal hyperplasia (IH) Inward remodeling (Fibrosis)

4 AVF Failure Risk Neointimal Hyperplasia (um)

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6 Was not a Demonstrated Scientific Fact Was a Scientific Assumption

7 Pre-Existing (pre-access vein) Post Operative ( AVF)

8 Demonstrate the contribution of preexisting and post-operative neointimal hyperplasia to AVF failure

9 Matched-pair tissue cohort of patients undergoing surgery for two-stage transposition fistula Patient consent and surgeries were performed by Dr. Marwan Tabbara s team One surgeon, one surgical technique

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12 Venous biopsies taken before anastomosis and superficialization were formalin-fixed and crosssectioned for detailed histological, immunohistochemical and morphometric analysis Area Method Vein AVF Thickness Method

13 Anatomical failure was defined as an AVF that was created but never met clinical maturation criteria (AVF size more than 6 mm in diameter) Primary patency was defined as the time between the second stage surgery until first intervention

14 Is there any association between pre-existing IH and AVF outcomes? Is there any association between pre-existing and postoperative IH? Is there any association between postoperative IH and AVF outcomes?

15 Collection of Veins and AVF Veins (N=66) AVF Unavailable (N=10) AVF (N=86) Matched Pairs (N=56) Vein Unavailable (N=30) Poor Quality (N=7) Poor Quality (N=5) Loss to FollowUp (N=2) Loss to FollowUp (N=2) Poor Quality (N=5) Assessment of Pre-Existing IH (N=57) Assessment of Change in IH over Time (N=51) Assessment of Postoperative IH (N=79) Evaluation of Statistical Associations Between: 1) Pre-Existing IH and AVF Outcomes 2) Change in IH over Time and AVF Outcomes 3) Postoperative IH and AVF Outcomes AVF Outcomes: A natom ic M atu ration Failu re and P rim ary Unas s isted P atenc y Covariates: A ge, Gend er, D iabetes

16 > 0.17 mm 15 No. of Veins Median: 0.17 mm < 0.17 mm mm Pre-existing Intimal Hyperplasia (mm)

17 No Association Between Pre-existing IH and Primary Patency Access Survival (Prob) <0.20 mm 0.2 >0.20 mm Duration (days) 500

18 Is there any association between pre-existing IH and AVF outcomes? Is there any association between pre-existing and postoperative IH? Is there any association between pre-existing or postoperative IH and AVF outcomes?

19 Postoperative Median Intimal Thickness Increased but Independently of the Pre-existing Lesion Size Neointima Thickness (AVF) 1.5 b= ± 0.30 r2= p= Neointimal Thickness (Vein) 0.8

20 Is there any association between pre-existing IH and AVF outcomes? Is there any association between pre-existing and postoperative IH? Is there any association between postoperative IH and AVF outcomes?

21 Collection of Veins and AVF Veins (N=66) AVF Unavailable (N=10) AVF (N=86) Matched Pairs (N=56) Vein Unavailable (N=30) Poor Quality (N=7) Poor Quality (N=5) Loss to FollowUp (N=2) Loss to FollowUp (N=2) Poor Quality (N=5) Assessment of Pre-Existing IH (N=57) Assessment of Change in IH over Time (N=51) Assessment of Postoperative IH (N=79) Evaluation of Statistical Associations Between: 1) Pre-Existing IH and AVF Outcomes 2) Change in IH over Time and AVF Outcomes 3) Postoperative IH and AVF Outcomes AVF Outcomes: A natom ic M atu ration Failu re and P rim ary Unas s isted P atenc y Covariates: A ge, Gend er, D iabetes

22 No Association Between Post-operative IH in AVF and Primary Failure Mature Failure Low Moderate High

23 Primary Unassisted Patency No Association Between Postoperative IH in AVF and Primary Patency 1 POST-OPERATIVE <0.57 mm 0.6 >0.57 mm Log-rank P= Duration (days) Number 34 at risk: < >0.57

24 Thickness of the pre-existing lesion in the vein does not predict the degree of postoperative IH in the AVF Neither pre-existing IH in the vein nor postoperative IH in the AVF are associated with AVF patency or failure rate.

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27 1st Stage Brachiobasilic Arteriovenous Fistula Anastomosis Vein Stenotic Vein Non Stenotic

28 1.5 1 m m Non stenotic 200 µm 0.69 mm Intimal to Media Area Stenotic 200 µm N os tenotic S tenotic

29 We really don t know Neointimal hyperplasia Inward hypertrophic remodeling (fibrosis) Thrombosis

30 Collection of Veins and AVF Veins (1st Stage) N=117 Poor Quality (N=4) AVF Unavailable (N=30) Loss to Follow-Up (N=3) AVF (2nd Stage) N=135 Matched Pairs N=87 Poor Quality (N=17) Vein Unavailable (N=48) Loss to Follow-Up (N=4) Poor Quality (N=16) Pre-Existing Fibrosis, N=110 Change in Fibrosis over Time, N=71 Post-Operative Fibrosis N=114 Evaluation of Statistical Associations Between: 1) P re-e xisting Fibros is and A V F O u tc om es 2) P os t-o perative Fibros is and A V F O u tc om es 3) C hange in Fibros is and A V F O u tc om es AVF Outcomes (A natom ic M atu ration Failu re and 1 -YearP rim ary Unas s isted P atenc y) Covariates: A ge, S ex, D iabetes

31 Failure Increased Fibrosis Loss of SMC Matured

32 Post-Operative Fibrosis Explains Maturation Failure but not AVF Survival Time Survival Maturation Failure B = P = MF 46.1% MF < 46.1% P = Medial Fibrosis (%) Primary Patency (days) 400

33 The Interaction of Post-Operative Fibrosis and Intimal Hyperplasia strongly explains Maturation Failure Maturation Failure 1 B = P = I/M Ratio x Medial Fibrosis 250

34 These results may imply that: The contribution of IH to stenosis is minimal or none The balance between outward expansion and luminal narrowing due to IH ultimately determines stenosis Post-operative fibrosis but no intimal thickness is the aspect of the lesion that determines its impact on stenosis and AVF outcomes.

35 The limited number of matched pairs in our cohort. Due to the small fragment of vein and AVF analyzed, our findings may not accurately reflect all vascular changes occurring in distal areas or in the arterial component of the vascular access. Low incidence of first-stage anatomical failure in our cohort decreased the power of our model to find meaningful associations between this endpoint and baseline variables. These results therefore need to be further confirmed in a larger and multicenter cohort

36 Vascular Surgeon Interventional Nephrologist Scientist

37 Fellow Post Doc

38 Vazquez-Padron s Lab Laisel Martinez PharmD Nieves Santos Angela Paez Guillermo Selman, PhD. Juan Camilo Duque, MD Luis Alberto Escobar, MD Loay H. Salman, MD Marwan Tabbara, MD NIDDK and NHLBI for funding this Research through RO1HL and RO1DK to RIV-P and LHS FIU Biostatistical Division Wensung Wu, PhD Yen Pan, PhDc