Fibrotic Venous Remodeling and Nonmaturation of Arteriovenous Fistulas

Abstract

The frequency of primary failure in arteriovenous fistulas (AVFs) remains unacceptably high. This lack of improvement is due in part to a poor understanding of the pathobiology underlying AVF nonmaturation. This observational study quantified the progression of three vascular features, medial fibrosis, intimal hyperplasia (IH), and collagen fiber organization, during early AVF remodeling and evaluated the associations thereof with AVF nonmaturation. We obtained venous samples from patients undergoing two-stage upper-arm AVF surgeries at a single center, including intraoperative veins at the first-stage access creation surgery and AVFs at the second-stage transposition procedure. Paired venous samples from both stages were used to evaluate change in these vascular features after anastomosis. Anatomic nonmaturation (AVF diameter never ≥6 mm) occurred in 39 of 161 (24%) patients. Neither preexisting fibrosis nor IH predicted AVF outcomes. Postoperative medial fibrosis associated with nonmaturation (odds ratio [OR], 1.55; 95% confidence interval [95% CI], 1.05 to 2.30; P=0.03, per 10% absolute increase in fibrosis), whereas postoperative IH only associated with failure in those individuals with medial fibrosis over the population's median value (OR, 2.63; 95% CI, 1.07 to 6.46; P=0.04, per increase of 1 in the intima/media ratio). Analysis of postoperative medial collagen organization revealed that circumferential alignment of fibers around the lumen associated with AVF nonmaturation (OR, 1.38; 95% CI, 1.03 to 1.84; P=0.03, per 10° increase in angle). This study demonstrates that excessive fibrotic remodeling of the vein after AVF creation is an important risk factor for nonmaturation and that high medial fibrosis determines the stenotic potential of IH.

Keywords: arteriovenous fistula; fibrosis; vascular access.

Graphical abstract

Figure 1.

Surgeries, sample collection, and flow diagram of the study design. (A) Schematic representation illustrating the two surgical steps involved in creating a two-stage brachio-basilic AVF: (1) creation of the arteriovenous anastomosis (first-stage surgery), and (2) transposition of the remodeled AVF (second-stage surgery). The anatomic locations for the collection of native veins (first-stage) and AVF samples (second-stage) are shown. (B) Flow diagram indicating the sample collection algorithm, exclusion criteria, and subsequent histopathologic and statistical analyses. A total of 165 patients undergoing two-stage AVF creation were enrolled in the study. Native vein and AVF venous samples were obtained intraoperatively before the first-stage and second-stage procedures, respectively. If tissue sampling was not possible, the event was designated as vein or AVF unavailable.

Figure 2.

Preexisting medial fibrosis is not associated with AVF nonmaturation. (A and B) Close-up photographs of Masson’s trichrome–stained cross-sections of native veins with (A) high and (B) low degree of medial fibrosis. Cells stain in red/pink, whereas collagen is shown in blue. Distances are in micrometers. I, intima; M, media. (C) Distribution of preexisting medial fibrosis in the first-stage veins cohort. (D) Probability of anatomic nonmaturation as predicted by preexisting medial fibrosis using logistic regression analysis. The black line represents the model, whereas gray lines indicate the upper and lower levels of the 95% CI.

Figure 3.

Postoperative medial fibrosis predicts AVF nonmaturation. (A) Distribution of medial fibrosis in the second-stage AVFs cohort. (B) Probability of anatomic nonmaturation as predicted by postoperative medial fibrosis using logistic regression analysis. The black line represents the model, whereas gray lines indicate the upper and lower levels of the 95% CI. (C) Anatomic nonmaturation as predicted by postoperative medial fibrosis using a logistic regression model adjusted for sex. The combined nonlinear B coefficient (for both sexes) is shown in the graph.

Figure 4.

Postoperative histology shows increased fibrosis in failed AVFs. Close-up photographs of Masson’s trichrome–stained cross-sections of AVFs with (A and B) anatomic nonmaturation and (C and D) successful maturation. Cells stain in red/pink, whereas collagen is shown in blue. Distances are in micrometers. I, intima; M, media.

Figure 5.

Postoperative IH is associated with AVF nonmaturation in the presence of high medial fibrosis. (A and B) Probability of anatomic nonmaturation as predicted by postoperative IH (expressed as I/M area ratio) in AVFs with postoperative medial fibrosis (A) over and (B) under the median value in the second-stage AVFs cohort. (C) Probability of anatomic nonmaturation as predicted by the product of IH (expressed as I/M area ratio) and percent medial fibrosis (expressed as a decimal) in AVFs using logistic regression analysis. The black lines represent the models, whereas gray lines indicate the upper and lower levels of the 95% CIs.

Figure 6.

Circumferential orientation of medial collagen fibers predicts AVF nonmaturation. (A) Angle of collagen fibers relative to the lumen, ranging from 0° (perpendicular to the lumen, radial direction) to 90° (circumferential direction). (B) Distribution of postoperative orientation angles in the second-stage AVFs cohort. (C and D) Probability of anatomic maturation failure as predicted by (C) the postoperative angle of medial collagen fibers and (D) the product of the postoperative angle and percent medial fibrosis (expressed as a decimal) using logistic regression analyses. The black lines represent the models, whereas gray lines indicate the upper and lower levels of the 95% CIs.