Transcriptomics of Human Arteriovenous Fistula Failure: Genes Associated With Nonmaturation

Laisel Martinez, Marwan Tabbara, Juan C. Duque, Guillermo Selman, Nieves Santos Falcon, Angela Paez, Anthony J. Griswold, Gioser Ramos-Echazabal, Diana R. Hernandez, Omaida C. Velazquez, Loay H. Salman, Roberto I. Vazquez-Padron

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Rationale & Objective: Improving arteriovenous fistula (AVF) outcomes requires better understanding of the biology underlying maturation or failure. Our current knowledge of maturation relies on extrapolation from other vascular pathologies, which does not incorporate unique aspects of AVF remodeling. This study compares the RNA expression of pre-access (native) veins and AVFs with distinct maturation outcomes. Study Design: Case-control study. Setting & Participants: 64 patients undergoing 2-stage AVF surgeries at a single center. 19 native veins and 19 AVF samples were analyzed using RNA sequencing (RNA-seq). 58 native veins were studied using real-time polymerase chain reaction; 45, using immunohistochemistry; and 19, using Western blot analysis. Predictor: RNA expression in native veins and AVFs. Outcome: Anatomic nonmaturation, defined as an AVF that never achieved an internal diameter ≥ 6 mm. Analytical Approach: Pre-access native veins and AVF samples were obtained from patients undergoing 2-stage AVF creation. Veins that subsequently matured or failed after access creation were analyzed using RNA-seq to search for genes associated with maturation failure. Genes associated with nonmaturation were confirmed using real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis. In addition, the association between pre-access gene expression and postoperative morphology was evaluated. RNA-seq was also performed on AVFs to search for transcriptional differences between AVFs that matured and those that failed at the time of transposition. Results: Pro-inflammatory genes (CSF3R, FPR1, S100A8, S100A9, and VNN2) were upregulated in pre-access veins that failed (false discovery rate < 0.05), and their expression colocalized to smooth muscle cells. Expression of S100A8 and S100A9 correlated with postoperative intimal hyperplasia and the product of medial fibrosis and intimal hyperplasia (r = 0.32-0.38; P < 0.05). AVFs that matured or failed were transcriptionally similar at the time of transposition. Limitations: Small sample size, analysis of only upper-arm veins and transposed fistulas. Conclusions: Increased expression of proinflammatory genes in pre-access veins appears to be associated with greater risk for AVF nonmaturation.

Original languageEnglish (US)
JournalAmerican Journal of Kidney Diseases
DOIs
StatePublished - Jan 1 2019

Fingerprint

Arteriovenous Fistula
Veins
Genes
RNA Sequence Analysis
Tunica Intima
Hyperplasia
Real-Time Polymerase Chain Reaction
Western Blotting
Immunohistochemistry
RNA
Gene Expression
Sample Size
Fistula
Smooth Muscle Myocytes
Blood Vessels
Case-Control Studies
Arm
Fibrosis
Pathology

Keywords

  • Arteriovenous fistula (AVF)
  • calprotectin
  • differential gene expression
  • fistula failure
  • gene discovery
  • hemodialysis access
  • inflammation
  • maturation
  • RNA-seq
  • S100A8
  • S100A9
  • transcriptomics
  • vein

ASJC Scopus subject areas

  • Nephrology

Cite this

Transcriptomics of Human Arteriovenous Fistula Failure : Genes Associated With Nonmaturation. / Martinez, Laisel; Tabbara, Marwan; Duque, Juan C.; Selman, Guillermo; Falcon, Nieves Santos; Paez, Angela; Griswold, Anthony J.; Ramos-Echazabal, Gioser; Hernandez, Diana R.; Velazquez, Omaida C.; Salman, Loay H.; Vazquez-Padron, Roberto I.

In: American Journal of Kidney Diseases, 01.01.2019.

Research output: Contribution to journalArticle

Martinez, Laisel ; Tabbara, Marwan ; Duque, Juan C. ; Selman, Guillermo ; Falcon, Nieves Santos ; Paez, Angela ; Griswold, Anthony J. ; Ramos-Echazabal, Gioser ; Hernandez, Diana R. ; Velazquez, Omaida C. ; Salman, Loay H. ; Vazquez-Padron, Roberto I. / Transcriptomics of Human Arteriovenous Fistula Failure : Genes Associated With Nonmaturation. In: American Journal of Kidney Diseases. 2019.
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abstract = "Rationale & Objective: Improving arteriovenous fistula (AVF) outcomes requires better understanding of the biology underlying maturation or failure. Our current knowledge of maturation relies on extrapolation from other vascular pathologies, which does not incorporate unique aspects of AVF remodeling. This study compares the RNA expression of pre-access (native) veins and AVFs with distinct maturation outcomes. Study Design: Case-control study. Setting & Participants: 64 patients undergoing 2-stage AVF surgeries at a single center. 19 native veins and 19 AVF samples were analyzed using RNA sequencing (RNA-seq). 58 native veins were studied using real-time polymerase chain reaction; 45, using immunohistochemistry; and 19, using Western blot analysis. Predictor: RNA expression in native veins and AVFs. Outcome: Anatomic nonmaturation, defined as an AVF that never achieved an internal diameter ≥ 6 mm. Analytical Approach: Pre-access native veins and AVF samples were obtained from patients undergoing 2-stage AVF creation. Veins that subsequently matured or failed after access creation were analyzed using RNA-seq to search for genes associated with maturation failure. Genes associated with nonmaturation were confirmed using real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis. In addition, the association between pre-access gene expression and postoperative morphology was evaluated. RNA-seq was also performed on AVFs to search for transcriptional differences between AVFs that matured and those that failed at the time of transposition. Results: Pro-inflammatory genes (CSF3R, FPR1, S100A8, S100A9, and VNN2) were upregulated in pre-access veins that failed (false discovery rate < 0.05), and their expression colocalized to smooth muscle cells. Expression of S100A8 and S100A9 correlated with postoperative intimal hyperplasia and the product of medial fibrosis and intimal hyperplasia (r = 0.32-0.38; P < 0.05). AVFs that matured or failed were transcriptionally similar at the time of transposition. Limitations: Small sample size, analysis of only upper-arm veins and transposed fistulas. Conclusions: Increased expression of proinflammatory genes in pre-access veins appears to be associated with greater risk for AVF nonmaturation.",
keywords = "Arteriovenous fistula (AVF), calprotectin, differential gene expression, fistula failure, gene discovery, hemodialysis access, inflammation, maturation, RNA-seq, S100A8, S100A9, transcriptomics, vein",
author = "Laisel Martinez and Marwan Tabbara and Duque, {Juan C.} and Guillermo Selman and Falcon, {Nieves Santos} and Angela Paez and Griswold, {Anthony J.} and Gioser Ramos-Echazabal and Hernandez, {Diana R.} and Velazquez, {Omaida C.} and Salman, {Loay H.} and Vazquez-Padron, {Roberto I.}",
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AU - Martinez, Laisel

AU - Tabbara, Marwan

AU - Duque, Juan C.

AU - Selman, Guillermo

AU - Falcon, Nieves Santos

AU - Paez, Angela

AU - Griswold, Anthony J.

AU - Ramos-Echazabal, Gioser

AU - Hernandez, Diana R.

AU - Velazquez, Omaida C.

AU - Salman, Loay H.

AU - Vazquez-Padron, Roberto I.

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N2 - Rationale & Objective: Improving arteriovenous fistula (AVF) outcomes requires better understanding of the biology underlying maturation or failure. Our current knowledge of maturation relies on extrapolation from other vascular pathologies, which does not incorporate unique aspects of AVF remodeling. This study compares the RNA expression of pre-access (native) veins and AVFs with distinct maturation outcomes. Study Design: Case-control study. Setting & Participants: 64 patients undergoing 2-stage AVF surgeries at a single center. 19 native veins and 19 AVF samples were analyzed using RNA sequencing (RNA-seq). 58 native veins were studied using real-time polymerase chain reaction; 45, using immunohistochemistry; and 19, using Western blot analysis. Predictor: RNA expression in native veins and AVFs. Outcome: Anatomic nonmaturation, defined as an AVF that never achieved an internal diameter ≥ 6 mm. Analytical Approach: Pre-access native veins and AVF samples were obtained from patients undergoing 2-stage AVF creation. Veins that subsequently matured or failed after access creation were analyzed using RNA-seq to search for genes associated with maturation failure. Genes associated with nonmaturation were confirmed using real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis. In addition, the association between pre-access gene expression and postoperative morphology was evaluated. RNA-seq was also performed on AVFs to search for transcriptional differences between AVFs that matured and those that failed at the time of transposition. Results: Pro-inflammatory genes (CSF3R, FPR1, S100A8, S100A9, and VNN2) were upregulated in pre-access veins that failed (false discovery rate < 0.05), and their expression colocalized to smooth muscle cells. Expression of S100A8 and S100A9 correlated with postoperative intimal hyperplasia and the product of medial fibrosis and intimal hyperplasia (r = 0.32-0.38; P < 0.05). AVFs that matured or failed were transcriptionally similar at the time of transposition. Limitations: Small sample size, analysis of only upper-arm veins and transposed fistulas. Conclusions: Increased expression of proinflammatory genes in pre-access veins appears to be associated with greater risk for AVF nonmaturation.

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KW - Arteriovenous fistula (AVF)

KW - calprotectin

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KW - hemodialysis access

KW - inflammation

KW - maturation

KW - RNA-seq

KW - S100A8

KW - S100A9

KW - transcriptomics

KW - vein

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