Abnormalities of vascular histology and collagen fiber configuration in patients with advanced chronic kidney disease.

INTRODUCTION:: Several histologic features have been identified in the upper-extremity arteries and veins of patients with advanced chronic kidney disease, which may affect arteriovenous fistula maturation. However, it is unclear whether these chronic kidney disease vascular features are abnormal. METHODS:: We obtained upper-extremity arterial and venous specimens from 125 advanced chronic kidney disease patients undergoing arteriovenous fistula creation and from 15 control subjects. We quantified medial fibrosis, micro-calcification, and intimal hyperplasia with appropriate histology stains. We characterized medial collagen fiber configuration in second-harmonic-generation microscopy images for the fiber anisotropy index and the dominant fiber direction. RESULTS:: The advanced chronic kidney disease patients were significantly younger than control subjects (53 ± 14 years vs 76 ± 11 years, p < 0.001). After controlling for age, the chronic kidney disease patients had greater arterial medial fibrosis (69% ± 14% vs 51% ± 10%, p < 0.001) and greater arterial micro-calcification (3.03% ± 5.17% vs 0.01% ± 0.03%, p = 0.02), but less arterial intimal thickness (30 ± 25 µm vs 63 ± 25 µm, p < 0.001), as compared to control subjects. The anisotropy index of medial collagen fibers was lower in both arteries (0.24 ± 0.10 vs 0.44 ± 0.04, p < 0.001) and veins (0.28 ± 0.09 vs 0.53 ± 0.10, p < 0.001) in chronic kidney disease patients, indicating that orientation of the fibers was more disordered. The dominant direction of medial collagen fibers in chronic kidney disease patients was greater in the arteries (49.3° ± 23.6° vs 4.0° ± 2.0°, p < 0.001) and the veins (30.0° ± 19.6° vs 3.9° ± 2.1°, p < 0.001), indicating that the fibers in general were aligned more perpendicular to the lumen. CONCLUSION:: Advanced chronic kidney disease is associated with several abnormalities in vascular histology and collagen fiber configuration. Future research is needed to investigate whether these abnormalities affect the maturation outcomes of arteriovenous fistulas.

Fibrotic Venous Remodeling and Nonmaturation of Arteriovenous Fistulas.

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.

Preoperative Vascular Medial Fibrosis and Arteriovenous Fistula Development.

BACKGROUND AND OBJECTIVES: Arteriovenous fistula maturation requires an increase in the diameter and blood flow of the feeding artery and the draining vein after its creation. The structural properties of the native vessels may affect the magnitude of these changes. We hypothesized that an increase in the collagen content of the vascular media (medial fibrosis) preoperatively would impair vascular dilation and thereby, limit the postoperative increase in arteriovenous fistula diameter and blood flow and clinical arteriovenous fistula maturation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We enrolled 125 patients undergoing arteriovenous fistula creation between October of 2008 and April of 2012 and followed them prospectively. Any consenting subject was eligible. Arterial and venous specimens were sampled during arteriovenous fistula surgery. Masson's trichrome-stained samples were used to quantify medial fibrosis. Arteriovenous fistula diameter and blood flow were quantified using 6-week postoperative ultrasound. Clinical arteriovenous fistula maturation was assessed using a predefined protocol. The association of preexisting vascular medial fibrosis with arteriovenous fistula outcomes was evaluated after controlling for baseline demographics, comorbidities, and the preoperative venous diameter. RESULTS: The mean medial fibrosis was 69%±14% in the arteries and 63%±12% in the veins. Arterial medial fibrosis was associated with greater increases in arteriovenous fistula diameter (Δdiameter =0.58 mm; 95% confidence interval [95% CI], 0.27 to 0.89 mm; P<0.001) and arteriovenous fistula blood flow (Δblood flow =85 ml/min; 95% CI, 19 to 150 ml/min; P=0.01) and a lower risk of clinical arteriovenous fistula nonmaturation (odds ratio, 0.71; 95% CI, 0.51 to 0.99; P=0.04), all per 10% absolute difference in medial fibrosis. In contrast, venous medial fibrosis was not associated with the postoperative arteriovenous fistula diameter, blood flow, or clinical maturation. CONCLUSIONS: Preoperative arterial medial fibrosis was associated with greater arteriovenous fistula diameter and blood flow and a lower risk of clinical arteriovenous fistula nonmaturation. This unexpected observation suggests that medial fibrosis promotes arteriovenous fistula development by yet undefined mechanisms or alternatively, that a third factor promotes both medial fibrosis and arteriovenous fistula maturation.