Preoperative Vascular Medial Fibrosis and Arteriovenous Fistula Development

Abstract

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.

Introduction

The pathogenesis of arteriovenous fistula (AVF) nonmaturation is poorly understood (1). Successful AVF maturation requires a sustained, irreversible increase in the diameter and blood flow rate of the feeding artery and draining vein after surgical anastomosis of the artery to the vein (2–4). The Hemodialysis Fistula Maturation Study reported that the preoperative arterial function was associated with the 6-week postoperative AVF diameter and blood flow rate (5). Specifically, patients with greater brachial artery reactivity, as quantified by the flow–mediated dilation and nitroglycerin–mediated dilation tests, had significantly greater AVF diameter and blood flow.

Vascular reactivity in patients with CKD may be influenced by preexisting vascular pathology. Elastin and collagen are the major extracellular matrix proteins in the wall of large blood vessels, conferring on the wall elasticity and tensile strength, respectively (6). The wall’s mechanical properties are dependent on the absolute and relative contents of these two proteins as well as their respective fiber organizations. Because peripheral arteries, such as the brachial artery, have relatively low amounts of elastin compared with central arteries (7), collagen may be a key determinant of their mechanical properties. Arteries or veins with a higher medial collagen content may be stiffer and therefore, have a more limited ability to dilate. In healthy blood vessels, medial collagen fibers are organized into lamellar units and oriented circumferentially with small crimps (6). Abnormal vascular collagen fiber organization has been linked to several diseases, including aortic abdominal aneurysms and aneurysms in Marfan syndrome (8). We postulated that an orientation of fibers parallel to the vascular lumen, as observed in healthy blood vessels, would maximize the capacity of vessels to dilate.

This study evaluated two hypotheses regarding the effect of vascular medial collagen on postoperative AVF changes. Our primary hypothesis was that greater medial fibrosis would be associated with poor postoperative AVF development. The secondary hypothesis was that an orientation of collagen fibers parallel to the vascular lumen would promote vascular dilation better than a perpendicular orientation. To test these hypotheses, we assessed the amount and pattern of collagen fibers in arterial and venous samples obtained at AVF creation and evaluated their association with postoperative AVF diameter, blood flow, and clinical maturation.

Materials and Methods

Overview of the Study Design

Patients scheduled for AVF creation at the University of Alabama at Birmingham (UAB) were invited to participate in a prospective clinical research study adherent to the Declaration of Helsinki and approved by the UAB Institutional Review Board, and they provided informed consent for participation. Routine preoperative ultrasounds were used for vascular access planning. The surgeons obtained small samples of the artery and vein used to create the AVF anastomosis. The amount of medial fibrosis and pattern of collagen fibers were determined in each vascular specimen. The AVF diameter and blood flow were measured using the 6-week ultrasound postoperatively. Finally, we evaluated the association of medial fibrosis and collagen fiber patterns with postoperative AVF diameter, blood flow, and clinical maturation.

Patient Population and Vascular Access Management

Approximately 500 patients on hemodialysis receive their medical care from the UAB nephrologists. All patients underwent standardized preoperative sonographic vascular mapping to quantify the upper extremity arterial and venous diameters and exclude stenosis or thrombosis of the draining vein (9). Four transplant surgeons used this information to plan the AVF location. The patients underwent a standardized 6-week postoperative ultrasound to quantify the AVF diameter and blood flow.

Histological Staining of Vascular Specimens

A single pathologist (S.H.L.) who was blinded to the patient’s clinical characteristics and AVF outcomes quantified the medial fibrosis. The vascular specimens were fixed in formalin, embedded in paraffin, and then, cut to obtain thin sections. Each arterial and venous sample was subjected to two types of stains: Masson’s trichrome stain and elastic van Gieson stain. In the trichrome stain, smooth muscle appears red, and collagen appears blue. Arterial or venous media staining blue was quantified using the Bioquant Image Analysis software. Medial fibrosis was calculated as the medial area that stained blue divided by total medial area ×100%. In the van Gieson stain, elastic lamellae appear black and delineate the media from the intima and adventitia by highlighting the internal elastic lamina and external elastic lamina.

Second Harmonic Generation Microscopy and Collagen Fiber Analyses

Collagen fiber bundles are highly ordered noncentrosymmetric structures that generate strong second harmonic generation (SHG) signals, in which two photons with the same frequency interacting with a material (collagen) are combined to generate a new photon with twice the energy of the initial photons. SHG detects only collagen in fiber bundles and not diffuse collagen molecules. In addition, SHG does not require exogenous labeling of collagen, because the signals result from the collagen fiber’s inherent optical property (10). SHG signals of collagen fiber bundles in unstained paraffin–embedded tissue sections were acquired at 850-nm excitation under a Prairie Two–Photon Microscope (Bruker Corp.). At least three fields per sample were acquired (by Y.-T.S.) and then, analyzed for fiber patterns by three independent observers (Y.-T.S., D.B.P., and J.C.S.T.) blinded to the patient’s clinical characteristics and AVF outcomes.

Preoperative Arterial Elastic Modulus by Ultrasound

The arterial wall is stretched during systole and relaxes during diastole. Arterial elasticity was estimated in a subset of randomly selected 15 patients. The arterial strain was calculated from the change in intima-media thickness between end systole and end diastole, and arterial stress was estimated from the pulse pressure. The arterial elastic modulus in the radial direction was then estimated as the ratio of arterial stress to strain (11). In general, increased arterial stiffness is associated with reduced vascular compliance (distensibility).

Postoperative AVF Outcomes

The 6-week postoperative ultrasound measured AVF diameter and blood flow in 98 patients (12). The postoperative AVF measurements were imputed for an additional 13 patients, in whom the AVF was patent at 6 weeks but the ultrasound was not performed. Clinical AVF maturation was defined as successful AVF use for dialysis with two needles and a dialysis blood flow ≥300 ml/min on six or more dialysis sessions during a 1-month period within 6 months of AVF creation (12). If the patient had not yet started dialysis, AVF maturation was assessed in the first month after initiation of dialysis.

Statistical Analyses

The study cohort included a total of 125 patients, of whom 40 patients had at least one missing value in one of the following variables: postoperative AVF diameter (n=28), postoperative AVF blood flow (n=27), venous medial fibrosis (n=12), and preoperative vein diameter (n=7). Multiple imputation was performed to impute the indicated missing values using the Markov chain Monte Carlo method under the assumption that the variables with missing data followed a multivariate normal distribution. In total, 10 imputed datasets were created. The imputation model included the following variables: arterial medial fibrosis, age, sex, race, diabetes, hypertension, congestive heart failure (CHF), cerebrovascular disease (CVD), coronary artery disease (CAD), and peripheral vascular disease (PVD). The imputed postoperative AVF diameters and blood flows were set to missing after imputation if they were missing because of early AVF thrombosis (within 6 weeks of creation), because they were viewed as structurally missing. Missing medial collagen patterns were categorized as damaged, because these samples were too small to allow for determination of the medial pattern.

Linear regressions were performed to investigate the association of postoperative AVF diameter with medial fibrosis and medial collagen patterns. Because the postoperative AVF flow had a skewed distribution, gamma regressions were performed to investigate the association of postoperative AVF flow with medial fibrosis and medial collagen patterns. Logistic regressions were performed to investigate the association of AVF nonmaturation with medial fibrosis and medial collagen patterns. Separate models were performed for artery and vein without adjustment and with adjustment for age, sex, race, diabetes, hypertension, CAD, CVD, PVD, CHF, and preoperative vein diameter.

Data were analyzed using appropriate procedures in Stata 13 (StataCorp. 2013; Stata Statistical Software: Release 13; StataCorp., College Station, TX). P values were two sided, with P<0.05 considered significant.

Results

Clinical, Sonographic, and Histological Features of the Study Population

We studied 125 patients who underwent AVF creation between October of 2008 and April of 2012 who had vascular specimens obtained at AVF surgery and in whom clinical AVF maturation could be assessed. The clinical characteristics are summarized in Table 1. Nearly one half of the patients were women, and two thirds were black. Diabetes was present in 51%; hypertension was present in 90%; CHF was present in 17%; and coronary, peripheral, and cerebral vascular disease were each present in approximately 10%. The median preoperative vascular diameters (3.7 mm for artery and 3.5 mm for vein) were well above the thresholds recommended for AVF creation (2.0 mm for artery and 2.5 mm for vein). A 6-week postoperative ultrasound was obtained in 98 patients (14 patients experienced early AVF thrombosis, and 13 missed their scheduled ultrasound). The median values of AVF diameter and blood flow rate are listed in Table 1.

Table 1.

Clinical and vascular sonographic features of the study population

Parameter	Value
No. of patients	125
Patient demographics and comorbidities
Age, yr, mean ±SD	52.9±14.3
Women, N (%)	57 (45.6%)
Black race, N (%)	84 (67.2%)
Diabetes, N (%)	64 (51.2%)
History of hypertension, N (%)	113 (90.4%)
History of congestive heart failure, N (%)	21 (16.8%)
History of coronary artery disease, N (%)	16 (12.8%)
History of peripheral vascular disease, N (%)	13 (10.4%)
History of cerebrovascular disease, N (%)	12 (9.6%)
Ultrasound measurementsa
Preoperative arterial diameter, mm, median [IQR]	3.7 [2.8–4.7]
Preoperative venous diameter, mm, median [IQR]	3.5 [2.8–4.7]
Postoperative AVF venous diameter, mm, median [IQR]	4.8 [3.7–6.8]
Postoperative AVF blood flow rate, ml/min, median [IQR]	796 [413–1036]

IQR, interquartile range; AVF, arteriovenous fistula.

^aPostoperative ultrasound measurements were performed in 98 patients and imputed in an additional 13 patients, in whom the AVF was patent 6 weeks postoperatively but the ultrasound was not performed.

The surgeons obtained vascular tissue specimens in 125 patients. There was a broad range of medial fibrosis in the arterial (32%–96%) and venous (33%–94%) samples (Figure 1). In contrast, elastin staining was minimal in the medial layers of all samples. Representative trichrome and elastin stain images from two arterial samples, one with mild medial fibrosis and the other with severe medial fibrosis, are shown in Figure 2.

Figure 1.

Distribution of medial fibrosis. Distribution among samples of the (A) arteries and (B) veins used to create arteriovenous fistulas.

Figure 2.

Collagen and elastin in samples of the arteries used to create arteriovenous fistulas. Masson’s trichrome stain shows (A) an artery with mild medial fibrosis (49%) and (B) an artery with significant medial fibrosis (95%). (C and D) Elastic van Gieson stain of these two samples shows that both arteries have little elastin in their respective medial layers. Collagen appears blue and smooth muscle cells appear red in Masson’s trichrome stain. Elastic lamellae appear black in elastic van Gieson stain.

The vascular SHG images were classified into distinct collagen patterns (Figure 3, Table 2). The arterial samples exhibited seven types of fiber orientation: parallel to the lumen, perpendicular to the lumen, microperpendicular with macroparallel, railroad track, random, honeycomb, and a mixed pattern. The vein samples exhibited five patterns, including parallel to the lumen, microperpendicular with macroparallel, railroad track, random, and a mixed pattern. The honeycomb, random, and perpendicular patterns were most common in arteries, whereas the railroad track, parallel, and mixed patterns were most common in veins.

Figure 3.

Representative second harmonic generation images of the different patterns of medial collagen fiber orientation. (A) Parallel to lumen, (B) Perpendicular to lumen, (C) Random, (D) Railroad track, (E) Honeycomb, and (F) Mixed patterns. The relative frequency of each pattern is summarized in Table 2. The microperpendicular with macroparallel pattern, which accounted for very few samples, is not displayed.

Table 2.

Vascular histological features of the study population

Parameter	Value
Vascular medial fibrosis, n=125
Arterial medial fibrosis, %, mean±SD	69±14
Venous medial fibrosis, %, mean±SD	63±12
Arterial medial pattern, n=107a
Parallel to lumen	16 (15.0%)
Perpendicular to lumen	25 (23.4%)
Microperpendicular with macroparallel	1 (0.9%)
Railroad track	2 (1.9%)
Honeycomb	33 (30.8%)
Random	28 (26.2%)
Mixed	2 (1.9%)
Venous medial pattern, n=112a
Parallel to lumen	30 (26.8%)
Microperpendicular with macroparallel	6 (5.4%)
Railroad track	37 (33.0%)
Random	11 (9.8%)
Mixed	28 (25.0%)

^aThe samples were too small to allow for determination of the medial pattern in 18 arteries and 13 veins.

Association of Vascular Medial Fibrosis and Fiber Patterns with Postoperative AVF Outcomes

The preoperative arterial medial fibrosis was positively associated with both the 6-week postoperative AVF diameter and blood flow after controlling for patient age, sex, race, CHF, CAD, PVD, CVD, hypertension, diabetes, and the preoperative vein diameter (Table 3). Each absolute 10% greater arterial medial fibrosis was associated with a 0.58-mm greater AVF diameter and a 85-ml/min greater AVF blood flow rate. The shape of the relationship between arterial medial fibrosis and the 6-week AVF diameter and blood flow is depicted in Figure 4. In contrast, there was no significant association between venous medial fibrosis and AVF diameter or blood flow rate. Likewise, neither the arterial nor the venous collagen fiber pattern (nonparallel versus parallel) was associated with the postoperative AVF diameter or blood flow rate.

Table 3.

Association of vascular medial fibrosis amount and collagen fiber pattern with postoperative arteriovenous fistula diameter and blood flow rate

Predictor and AVF Outcome	Unadjusted		Adjusteda
	Difference in Diameter or Blood Flow (95% Confidence Interval)	P Value	Difference in Diameter or Blood Flow (95% Confidence Interval)	P Value
Arterial medial fibrosis (per 10% greater)
AVF diameter, mm	0.46 (0.13 to 0.79)	<0.01	0.58 (0.27 to 0.89)	<0.001
AVF blood flow, ml/min	50 (−24 to 124)	0.19	85 (19 to 150)	0.01
Venous medial fibrosis (per 10% greater)
AVF diameter, mm	−0.04 (−0.45 to 0.37)	0.85	−0.03 (−0.42 to 0.36)	0.88
AVF blood flow, ml/min	16 (78 to 111)	0.74	18 (−67 to 103)	0.67
Arterial fiber orientation (nonparallel versus parallel)
AVF diameter, mm	1.56 (0.13 to 2.98)	0.03	0.98 (−0.49 to 2.45)	0.18
AVF blood flow, ml/min	197 (−127 to 522)	0.23	25 (−278 to 329)	0.87
Venous fiber orientation (nonparallel versus parallel)
AVF diameter, mm	0.01 (−1.16 to 1.17)	0.99	−0.05 (−1.19 to 1.10)	0.94
AVF blood flow, ml/min	80 (−183 to 343)	0.55	−11 (−243 to 222)	0.93

AVF, arteriovenous fistula.

^aAdjusted for age, sex, race, congestive heart failure, coronary artery disease, peripheral vascular disease, cerebrovascular disease, hypertension, diabetes, and preoperative vein diameter.

Figure 4.

Association of arterial medial fibrosis with 6-week arteriovenous fistula (AVF) diameter and blood flow. (A) The y coordinate of the red curve provides the difference between the adjusted mean 6-week AVF diameter at the indicated arterial fibrosis and the adjusted mean 6-week AVF diameter at the median arterial fibrosis, which is used as the reference. (B) The y coordinate provides the ratio of the adjusted geometric mean 6-week AVF blood flow rate at the indicated arterial fibrosis to the adjusted geometric mean 6-week AVF blood flow rate at the median arterial fibrosis reference. Analyses were adjusted for preoperative vein diameter and baseline case mix covariates. Multiple imputation was performed to impute missing arterial fibrosis and ultrasound measurements. The shaded regions indicate pointwise 95% confidence intervals.

AVF nonmaturation occurred in 37 of the 125 patients or 30% of the study cohort. AVF nonmaturation was significantly lower in patients with a greater degree of arterial medial fibrosis (odds ratio, 0.71; 95% confidence interval, 0.51 to 0.99; P=0.04 per 10% absolute increase in percentage of fibrosis). In contrast, venous medial fibrosis was not associated with AVF nonmaturation (odds ratio, 1.29; 95% confidence interval, 0.90 to 1.86; P=0.17). Diabetes did not affect the association of arterial or venous medial fibrosis with the 6-week AVF diameter or blood flow (data not shown).

Fourteen patients experienced early AVF thrombosis. Patients with and without early AVF thrombosis had a similar magnitude of arterial (63%±10% versus 70%±14%; P=0.09) and venous medial fibrosis (62%±13% versus 63%±12%; P=0.80). Similarly, neither the arterial collagen pattern (P=0.18) nor the venous collagen pattern (P=0.46) was associated with early AVF thrombosis.

Among the 88 matured AVFs, the median time from AVF creation to successful use was 90 days. Arterial medial fibrosis was similar for AVFs that matured within 90 days of creation versus those that matured 91–180 days after creation (70%±14% versus 73%±14%; P=0.53). The 6-week AVF blood flow was also similar between AVFs that matured in ≤90 days versus those that matured in 91–180 days (876±452 versus 981±645 ml/min; P=0.45). Finally, 51 of the 88 (58%) matured AVFs required intervention before successful use. The magnitude of arterial medial fibrosis did not differ between patients whose AVF matured with or without an intervention (72%±14% versus 67%±12%; P=0.09). Similarly, the arterial collagen pattern was not associated with intervention before AVF maturation (P=0.79).

No Association between Vascular Medial Fibrosis and Elasticity

We hypothesized that arteries with greater medial fibrosis would be stiffer (less elastic). We evaluated this hypothesis in 15 patients whose arterial medial fibrosis ranged from 50% to 90% and arterial elastic modulus ranged from 50 to 300 kPa (Figure 5). The linear regression analysis showed no association between arterial medial fibrosis and elastic modulus (Δelastic modulus =0.14 kPa per 10% greater medial fibrosis; 95% confidence interval, −0.58 to 0.30; P=0.52).

Figure 5.

No association between arterial medial fibrosis and the arterial elastic modulus (a measure of arterial stiffness). The regression coefficient for a linear regression is −0.14 (95% confidence interval, −0.58 to 0.30) per 10% absolute difference in medial fibrosis (P=0.52).

Discussion

Prior research on AVF nonmaturation has focused primarily on the role of aggressive venous intimal hyperplasia that leads to flow-limiting stenosis near the arteriovenous anastomosis (inward vascular remodeling). However, many AVFs mature despite significant juxta–anastomotic stenosis (13), suggesting that additional factors contribute to AVF nonmaturation. Sustained, irreversible increases in the AVF diameter and blood flow rate (outward vascular remodeling) may be affected by preexisting structural vascular abnormalities. We hypothesized that medial fibrosis would lead to stiffer vessels with decreased capacity to dilate and impaired AVF maturation. In a pilot study (50 patients), we observed a nonsignificant trend of higher clinical AVF maturation in patients with greater preexisting arterial medial fibrosis (12). However, that study was underpowered, examined arteries but not veins, and did not adjust for baseline covariates. In addition, it evaluated only clinical AVF maturation, an end point that may be confounded by processes of care unrelated to the physiologic changes that occur early after AVF creation. To overcome the limitations of the pilot study, this investigation enrolled more (125) patients, used the 6-week postoperative AVF ultrasound measurements as the primary outcome, adjusted for baseline demographics and comorbidities in the statistical analysis, and obtained both arterial and venous tissue samples.

Contrary to our original hypothesis, we observed that greater arterial medial fibrosis was associated with greater 6-week AVF diameter and blood flow and a lower likelihood of AVF nonmaturation. Clearly, our findings are not compatible with the concept that medial fibrosis directly impairs vascular reactivity. In fact, we found no statistically significant association between medial fibrosis and the elastic modulus, a measure of arterial stiffness, in a small subset of the patients (Figure 5). What are some potential explanations for this surprising finding of a positive association between arterial medial fibrosis and AVF outcomes? First, nitric oxide stimulates collagen synthesis in cultured fibroblasts and tendon cells (14,15). Thus, greater endogenous nitric oxide production may be the common denominator that stimulates both medial fibrosis and AVF dilation. Second, collagen may regulate vascular smooth muscle cells (SMCs) through integrin-dependent and -independent mechanisms. Fibrillar collagen type 1 promotes the contractile phenotype of SMCs, whereas monomeric collagen type 1 activates SMC proliferation (16), hence linking SMC phenotype with collagen fiber composition. Third, greater arterial medial fibrosis is associated with a reciprocal decrease in the density of smooth muscle, which may, in turn, improve passive dilation after AVF creation (17). Fourth, increased arterial fibrosis may lead to more steady flow, diminishing the potentially detrimental effects of the diastolic to systolic flow difference or the oscillatory flow. Regardless of the precise mechanism by which arterial medial collagen is associated with AVF maturation, our results suggest that it could be used as a predictor of AVF outcome. Several noninvasive or minimally invasive techniques for quantifying collagen (18,19) preoperatively could potentially be used to predict AVF development preoperatively.

In contrast to the association of arterial medial fibrosis with greater increases in AVF diameter and blood flow, venous medial fibrosis did not correlate with either postoperative AVF measurement. A potential explanation is that vein dilation after AVF creation is a more passive process responding to the high arterial pressure, given the relatively thin medial layer. The vein tissue has no prestress in the circumferential direction. In contrast, the arterial tissue has prestress in the circumferential direction (20), and arterial tone is more tightly regulated.

We identified and coined several distinct patterns of medial collagen fiber organization by state of the art SHG microscopy. In healthy blood vessels, medial collagen fibers orient circumferentially with small crimps (6). These crimps extend and straighten in the circumferential direction when the blood vessel wall dilates, thereby allowing the wall to distend but preventing overstretching (6). These observations led us to hypothesize that an orientation of fibers parallel to the vascular lumen would maximize the capacity of vessels to dilate and be associated with greater AVF diameter and blood flow. Our results did not support this hypothesis. However, we observed that the parallel fiber bundles in our CKD population had no or minimal crimps. In another words, these fibers were already prestretched nearly fully in the circumferential direction. The degree of collagen fiber orientation may be directly related to the stiffness of the arterial tissue, and increased tissue stiffness is caused by an increased alignment of collagen fibers in the load direction (21). This could potentially explain our finding that the parallel pattern in patients with CKD did not translate into greater AVF diameter or blood flow.

The strengths of this study include the prospective data collection, the availability of both arterial and venous tissue samples, and the exploration of both collagen amount and pattern. Our study also has some limitations. First, it was a single-center study, and the results may not be generalizable to some dialysis centers. Second, we did not obtain direct measurements of arterial function (such as flow-mediated dilation and nitroglycerin-mediated dilation) before AVF creation. However, our elasticity findings (Figure 5) suggest that arterial medial fibrosis does not lead to stiffer arteries. Third, we did not characterize the type of collagen present in the vascular media or the dynamics of collagen microstructure when collagen is subject to mechanical loading as a result of increased BP after AVF creation. Fourth, the small vascular samples obtained in this study may not be representative of the entire vessel of interest. Fifth, our results do not exclude the concept of neointimal hyperplasia as a mechanism of AVF maturation failure.

In summary, this study showed an unexpected positive association between the amount of medial fibrosis in the arterial but not venous samples obtained at the time of AVF creation and postoperative AVF diameter and blood flow rate. Regardless of the precise mechanism by which arterial medial collagen is associated with AVF maturation, our results suggest that it could be used as a preoperative predictor of AVF outcome. Future investigations are needed to define the mechanisms underlying this association.

Disclosures

A.K.C. is a member of the Data and Safety Monitoring Board for “A Phase I Study for the Evaluation of Safety and Efficacy of Humacyte’s Human Acellular Vascular Graft for Use as a Vascular Prosthesis for Hemodialysis Access in Patients with End-Stage Renal Disease” (Humacyte, Inc.) and “Novel Endovascular Access Trial (NEAT)” (TVA Medical). M.A. is a consultant for CorMedix and W.L. Gore Associates.