TY - JOUR
T1 - Transcriptomics of Human Arteriovenous Fistula Failure
T2 - Genes Associated With Nonmaturation
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.
N1 - Funding Information:
This study was supported by the National Institutes of Health (NIH) grant R01DK098511 to Drs Salman and Vazquez-Padron. The NIH had no role in the study design; collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication.
Funding Information:
Laisel Martinez, PharmD, Marwan Tabbara, MD, Juan C. Duque, MD, Guillermo Selman, PhD, Nieves Santos Falcon, BS, Angela Paez, MD, Anthony J. Griswold, PhD, Gioser Ramos-Echazabal, MS, Diana R. Hernandez, PhD, Omaida C. Velazquez, MD, Loay H. Salman, MD, and Roberto I. Vazquez-Padron, PhD. Research idea and study design: RIV-P, LM, MT, GS, LHS; data acquisition: LM, JCD, GS, NSF, AP, AJG, GR-E, DRH; data analysis/interpretation: LM, JCD, GS, AJG, GR-E; statistical analysis: LM, AJG; supervision or mentorship: RIV-P, MT, OCV, LHS. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. This study was supported by the National Institutes of Health (NIH) grant R01DK098511 to Drs Salman and Vazquez-Padron. The NIH had no role in the study design; collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication. The authors declare that they have no relevant financial interests. We acknowledge the statistical assistance of Marie J.M. Seignon at the John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL. Received April 23, 2018. Evaluated by 3 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form December 17, 2018.
Publisher Copyright:
© 2019 National Kidney Foundation, Inc.
PY - 2019/7
Y1 - 2019/7
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.
AB - 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.
KW - Arteriovenous fistula (AVF)
KW - RNA-seq
KW - S100A8
KW - S100A9
KW - calprotectin
KW - differential gene expression
KW - fistula failure
KW - gene discovery
KW - hemodialysis access
KW - inflammation
KW - maturation
KW - transcriptomics
KW - vein
UR - http://www.scopus.com/inward/record.url?scp=85062027066&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062027066&partnerID=8YFLogxK
U2 - 10.1053/j.ajkd.2018.12.035
DO - 10.1053/j.ajkd.2018.12.035
M3 - Article
C2 - 30826088
AN - SCOPUS:85062027066
VL - 74
SP - 73
EP - 81
JO - American Journal of Kidney Diseases
JF - American Journal of Kidney Diseases
SN - 0272-6386
IS - 1
ER -