Abstract
Introduction:
Arteriovenous fistulae mature less frequently in women than in men, leading to inferior patency and decreased fistula utilization in women. We hypothesized that both anatomic and physiologic sex differences explain reduced maturation.
Methods:
The electronic medical records of patients who had a primary arteriovenous fistula created from 2016 to 2021 at a single center were reviewed; sample size was determined using a power calculation. Post-operative ultrasound and labs were obtained at least 4 weeks after fistula creation. Primary unassisted fistula maturation was determined up to 4 years post-procedure.
Results:
28 women and 28 men with a brachial-cephalic fistula were analyzed. Inflow brachial artery diameter was smaller in women than men, both pre-operatively (4.2±0.9 vs 4.9±1.0 mm, p=0.008) and post-operatively (4.8±0.8 vs 5.3±0.9 mm, p=0.039). Despite similar pre-operative brachial artery peak systolic velocity, women had significantly lower post-operative arterial velocity (p=0.027). Fistula flow was reduced in women, particularly in the mid-humerus (747.0±570.4 vs 1117.1±471.3 cc/min, p=0.003). Percentages of neutrophils and lymphocytes were similar among women and men 6 weeks after fistula creation. However, women had reduced monocytes (8.5 ± 2.0 vs 10.0 ± 2.6%, p=0.0168). Among men, 24/28 (85.7%) achieved unassisted maturation, whereas only 15/28 (53.6%) women had fistulae that matured without intervention. Secondary analysis through logistic regression suggested that post-operative arterial diameter was associated with maturation in men while post-operative monocyte percentage was associated with in maturation in women.
Conclusion:
Sex differences during arteriovenous fistula maturation are present in arterial diameter and velocity, suggesting that both anatomic and physiologic differences in arterial inflow contribute to sex differences in fistula maturation. In men, post-operative arterial diameter is correlated with maturation, whereas in women the significantly lower proportion of circulating monocytes suggests a role for the immune response in fistula maturation.
Keywords: arteriovenous fistula, sex differences, hemodynamics, immunity
Introduction
Arteriovenous fistulae (AVF) are the preferred access for hemodialysis to treat end-stage renal disease (ESRD).1,2 AVF have superior long term results compared with prosthetic grafts and catheters,1,3,4 yet still have high failure rates.1,5 AVF fail to mature in ~30–50% of cases, requiring adjunctive interventions.1,6–9 Female patients have worse rates of AVF maturation compared with men4 and reduced AVF usage.10,11 These poor clinical results increase patient morbidity, expenditure of healthcare dollars, and use of medical resources.
To improve clinical outcomes, vessel diameters and pre-operative hemodynamics have evaluated factors that predict AVF maturation.10–21 The Hemodialysis Maturation Study reported that AVF blood flow, diameter, and depth predicted maturation.12 Other studies suggested pre-operative venous diameter,13 arterial diameter,14 or venous blood flow15 as predictors of successful maturation; however, they did not report sex differences (Supplemental Tables I and II). Furthermore, studies specifically examining sex differences in AVF maturation reached differing conclusions. For example, one reported no differences between female and male vessels at baseline.16 Others reported significant differences in vessel diameters and hemodynamics but found that these did not impact maturation.10,11,17,18 Conversely, others concluded that preoperative differences explained sex differences in maturation.19–20 However, no study comprehensively reported pre- and post-operative data. In addition, data suggest that immune cells influence fistula remodeling. As immune responses between women and men are different, this may also contribute to sex-based differences in AVF patency.22, 23 T cells and monocytes play a role in early fistula maturation,22 and women have different levels of these immune cell subtypes24, suggesting that the specific cells of the immune response contribute to sex differences in AVF maturation.
Some studies suggest the ability of the vein to adapt to increased flow may better predict fistula success,11,17,20,21 although it is not clear which characteristics would be most associated with maturation. We hypothesized that a combination of factors, such as inadequate inflow, low outflow, and reduced venous expansion, driven by smaller pre-operative arterial diameters and reduced immune system activation in women, contribute to sex differences in maturation. We examined how sex differences among pre- and post-operative values correlated with trends in early AVF maturation.
Methods
Literature Review and Power Calculation
Pub-Med was queried for articles that reported sex differences in AVF maturation, including papers reporting vessel diameter and hemodynamics. Keywords searched included “arteriovenous fistula”, “sex difference”, “female”, “hemodynamics”, and “women”. Papers reporting mean brachial artery diameter separately for women and men were used to calculate the sample size needed to detect a significant difference in mean brachial artery diameter between women and men in our study with 80% power.17, 25, 26 Sample size calculations were performed using Stata 17 (StataCorp, College Station, TX).
Patient Selection
The electronic medical records of patients who underwent AVF creation at Yale New Haven Hospital were reviewed. Sequential patients were selected in reverse chronological order of date of surgery starting in December 2021 to achieve the predetermined sample size. Male and female patients were selected separately to achieve equal numbers in the sample. Patients who had arteriovenous grafts, brachial-basilic fistulae, and redo procedures were excluded. Patient demographics, comorbidities, pre-operative ultrasound values, and follow-up values were recorded. This study was approved by the Institutional Review Board of Yale University (Study #2000032112) and complies with the Declaration of Helsinki on research ethics. The IRB waived the requirement for patient consent for this study.
Hemodynamic Measurements
Data were obtained from vein mapping closest to the operative date. Pre-operative cephalic venous diameter and brachial arterial peak systolic velocity were manually measured by radiologists using inner wall-to-inner wall measurements; arterial diameter was confirmed using the VISAGE ruler tool set (Visage® 7 Enterprise Imaging Platform, Pro Medicus Limited, San Diego, CA) by two authors and averaged. Post-operative data was obtained from the first follow-up ultrasound study at least 4 weeks after fistula creation. In addition, we noted patients that had radial-cephalic fistula creation and collected the same pre-operative and post-operative information.
Immune System Measurements
Since women have different immune responses compared with men,22 and immune cells play a role in fistula remodeling,23 we examined populations of circulating immune cells. The complete blood count (CBC) closest in date to post-operative ultrasound was used to determine percentages of white blood cells, neutrophils, lymphocytes, and monocytes, as this data is readily available.
Fistula Maturation
Patients’ records were reviewed to assess initial AVF maturation. AVF were characterized as ‘mature’ or ‘failure to mature’ based on having a palpable thrill on physical exam with the most recent ultrasound exam indicating fistula flow > 600 cc/min. AVF with primary unassisted maturation were categorized as ‘mature’, whereas fistulae that failed or required interventions such as balloon angioplasty to assist maturation were categorized as ‘failure to mature’.
Statistical Analysis
Demographics were analyzed using Chi-Square test for variables with sample size greater than 5 and Fischer’s Exact test for variables with a smaller sample size using GraphPad Prism (San Diego, CA). Hemodynamic values were analyzed for normality using the Shapiro-Wilk test (GraphPad Prism). Normally distributed continuous variables were analyzed using Student’s Ttest and non-normally distributed variables were analyzed using the Mann-Whitney U test (GraphPad Prism). P-values <0.05 were considered significant.
Incidence of unassisted maturation for men and women were calculated, and cumulative incidence over time after surgery was graphed by sex. The relationship between unassisted maturation and pre- and post-operative measurements was assessed by examining differences in mean values by maturation status for women and men separately. Odds of AVF maturation by post-operative brachial artery diameter and by percentage of circulating monocytes were assessed using logistic regression.
Results
Literature Review and Sample Size
A review of the literature revealed a heterogenous group of papers. Based on the limited amount of published data, a power calculation was performed using pooled results in studies reporting brachial artery diameter (Persic (2009), Wilmink (2018), Zonnebeld (2008)). We calculated a pooled mean of 4.427 ± 0.735 mm for men and 3.908 ± 0.615 mm for women. Using an alpha of 0.05 and power of 80%, we calculated a required sample size of 28 men and 28 women to detect a significant difference in mean diameter at least as large as the difference in the pooled means.
We reviewed our institution’s data and retrieved records of 28 consecutive men that had a primary brachial-cephalic AVF performed between 2019 and 2021; 28 consecutive women had a primary brachial-cephalic AVF performed between 2016 and 2021, consistent with fewer women having AVF performed. Mean patient age was 65.5 ± 17.1 years with no difference between female and male age or comorbidities (Table I). In the arterial inflow, pre-operative brachial artery diameter was significantly smaller in women than men (4.2 ± 0.9 vs 4.9 ± 1.0 mm, p=0.008). This difference persisted after fistula creation (5.0 ± 0.9 vs 5.3 ± 0.9 mm, p=0.039). Pre-operative brachial artery velocity was not significantly different between women and men (p=0.403); however, post-operative brachial artery velocity was significantly lower in women (219.4 ± 70.9 vs 262.6 ± 71.2 cm/sec, p=0.027; Table I). This suggests that arterial inflow may play a role in the sex differences during fistula maturation.
Table I:
Comparison of Patient Characteristics and Hemodynamic Data in Men and Women with Brachial-cephalic Fistulae
| Brachial-cephalic Fistula | Total | Men | Women | P-Value |
|---|---|---|---|---|
| N | 56 | 28 | 28 | |
| Age | 65.5 ± 17.1 | 65.1 ± 19.0 | 65.9 ± 15.2 | 0.871 |
| Hypertension | 55 (98.2%) | 27 (96.4%) | 28 (100%) | 0.893 |
| Coronary Artery Disease | 15 (26.8%) | 10 (35.7%) | 5 (17.9%) | 0.197 |
| Peripheral Arterial Disease | 7 (12.5%) | 4 (14.3%) | 3 (10.7%) | 0.705 |
| Diabetes | 34 (60.7%) | 15 (53.6%) | 19 (67.9%) | 0.493 |
| Hyperlipidemia | 33 (58.9%) | 15 (53.6%) | 18 (64.3%) | 0.602 |
| Antiplatelet Drug | 29 (51.8%) | 15 (53.6%) | 14 (50%) | 0.853 |
| Anticoagulation | 13 (23.2%) | 9 (28.6%) | 5 (17.9%) | 0.405 |
| Statin | 32 (57.1%) | 15 (53.6%) | 17 (60.7%) | 0.724 |
| Antihypertensive | 53 (94.6%) | 25 (89.3%) | 28 (100%) | 0.680 |
| Smoking | 0.561 | |||
| Current | 9 (16.1%) | 5 (17.9%) | 4 (14.3%) | |
| Former | 21 (37.5%) | 12 (42.9%) | 9 (32.1%) | |
| Never | 26 (46.4%) | 11 (29.3%) | 15 (53.6%) | |
| Arterial | ||||
| Pre-Op Brachial Artery Diameter (mm) | 4.6 ± 1.0 | 4.9 ± 1.0 | 4.2 ± 0.9 | 0.008 |
| Velocity (cm/sec) | 89.1 ± 28.0 | 92.2 ± 30.4 | 85.7 ± 25.2 | 0.403 |
| Post-Op Brachial Artery Diameter (mm) | 5.0 ± 0.9 | 5.3 ± 0.9 | 4.8 ± 0.8 | 0.039 |
| Velocity (cm/sec) | 241.0 ± 73.7 | 262.6 ± 71.2 | 219.4 ± 70.9 | 0.027 |
| Venous | ||||
| Pre-Op Cephalic Vein Diameter (mm) | ||||
| Antecubital Fossa | 3.9 ± 1.1 | 4.1 ± 1.2 | 3.6 ± 0.9 | 0.030 |
| Low Humerus | 3.6 ± 1.2 | 3.7 ± 1.2 | 3.5 ± 1.2 | 0.562 |
| Mid Humerus | 3.5 ± 1.2 | 3.7 ± 1.5 | 3.3 ± 1.0 | 0.727 |
| Upper Humerus | 3.6 ± 1.1 | 3.8 ± 1.2 | 3.5 ± 1.0 | 0.502 |
| Post-Op Cephalic Vein Diameter (mm) | ||||
| Antecubital Fossa | 7.3 ± 2.7 | 7.2 ± 3.2 | 7.5 ± 0.4 | 0.859 |
| Low Humerus | 6.9 ± 2.0 | 7.1 ± 1.7 | 6.7 ± 2.2 | 0.449 |
| Mid Humerus | 6.6 ± 1.5 | 6.8 ± 1.7 | 6.4 ± 1.3 | 0.823 |
| Upper Humerus | 6.5 ± 1.7 | 5.9 ± 1.1 | 7.2 ± 2.0 | 0.142 |
| % Increase in Cephalic Vein | ||||
| Antecubital Fossa | 104.8 ± 106.2 | 75.2 ± 95.2 | 183.9 ± 108.5 | 0.137 |
| Low Humerus | 97.5 ± 67.2 | 91.0 ± 63.9 | 103.7 ± 71.3 | 0.561 |
| Mid Humerus | 116.7 ± 94.8 | 113.4 ± 105.1 | 119.3 ± 88.7 | 0.861 |
| Upper Humerus | 95.1 ± 75.1 | 69.4 ± 66.9 | 117.6 ± 78.8 | 0.228 |
| Fistula Velocity (cm/sec) | ||||
| Anastomosis | 155.1 ± 80.2 | 170.4 ± 79.3 | 139.7 ± 79.5 | 0.859 |
| Antecubital Fossa | 439.9 ± 227.5 | 441.0 ± 215.0 | 438.8 ± 248.2 | 0.981 |
| Low Humerus | 264.7 ± 160.9 | 252.1 ± 160.0 | 277.3 ± 163.8 | 0.364 |
| Mid Humerus | 169.2 ± 102.7 | 170.7 ± 94.4 | 167.9 ± 111.4 | 0.558 |
| Upper Humerus | 138.6 ± 51.7 | 151.5 ± 55.6 | 127.4 ± 46.3 | 0.129 |
| Fistula Flow (cc/min) | ||||
| Low Humerus | 1045.3 ± 591.3 | 1064.3 ± 411.5 | 1022.9 ± 761.6 | 0.319 |
| Mid Humerus | 927.9 ± 551.1 | 1117.1 ± 471.3 | 747.0 ± 570.4 | 0.003 |
| Upper Humerus | 867.3 ± 594.0 | 1122.5 ± 758.1 | 681.7 ± 377.8 | 0.112 |
Pre-operative venous diameter was not significantly different among women and men at all levels of the cephalic vein except for the antecubital fossa, which was smaller in women (3.6 ± 0.0 vs 4.1 ± 1.2 mm, p=0.030). Post-operative venous diameter was not different between women and men; similarly, relative change in vein diameter after fistula creation was not significantly different. Although post-operative fistula velocity was not significantly different, flow within the fistula was lower among women and significant in the mid-humerus (747.0 ± 570.4 vs 1117.1 ± 471.3 cc/min, p=0.003; Table I).
As most literature reported on radial-cephalic fistulae, we also observed radial-cephalic fistulae created at our institution. During the study period, only 7 women and 7 men had primary radial-cephalic fistulae (Supplemental Table III). There was a trend towards reduced baseline radial artery diameter in women than men (2.2 ± 0.7 vs 3.0 ± 1.0 mm, p=0.146). Further, post-operative venous diameters were higher in women (Supplemental Table III). As these results were not observed in brachial-cephalic fistulae, sex differences in fistula maturation may vary depending on the type of fistula.
Since women have increased immune responses compared with men,22 and immune cells play a role in fistula remodeling,23 we examined populations of circulating immune cells in the 56 patients with brachial-cephalic fistulae. No differences were detected in total white cells, neutrophils, and lymphocytes. However, women had a lower percentage of monocytes (8.5 ± 2.0 vs 10.0 ± 2.6%, p=0.0168; Table II). Since monocytes play a role in early fistula maturation, lower circulating monocytes following fistula creation may contribute to fistula failure in women in addition to differences in hemodynamics.
Table II:
Post-Operative Complete Blood Count in Men and Women with Brachial-cephalic Fistulae
| Post-Fistula CBC | Total | Men | Women | P-Value |
|---|---|---|---|---|
| N | 56 | 28 | 28 | |
| WBC | 7.6 ± 3.2 | 7.7 ± 3.8 | 7.5 ± 2.5 | 0.837 |
| Neutrophils | 67.0 ± 10.6 | 65.5 ± 11.9 | 68.3 ± 9.2 | 0.335 |
| Lymphocytes | 20.3 ± 9.1 | 20.9 ± 9.4 | 19.7 ± 9.0 | 0.626 |
| Monocytes | 9.2 ± 2.4 | 10.0 ± 2.6 | 8.5 ± 2.0 | 0.017 |
To validate our data, we compared our values for brachial-cephalic fistulae to available data in the literature. All 6 papers reporting pre-operative brachial artery diameter were pooled, and all 6 papers reporting pre-operative cephalic vein diameter were pooled.10, 11, 16, 17, 25, 26 Pooled brachial artery diameter values for men (n=611) did not differ significantly from the means found in our study (p=0.950), as did the values for women (p=0.964; Figure 1A). Similarly, pooled cephalic vein diameters for men (n=620) did not differ from our means (p=0.992), as did women (n=499; p = 0.941; Figure 1B). These findings suggest that our population is representative of the general patient population.
Figure 1.
Validation of data. (A) Comparison of brachial artery pre-operative diameters to the literature. (B) Comparison of cephalic vein pre-operative diameter to the literature.
Primary unassisted maturation of the AVF was observed in 24/28 (85.7%) male and 15/28 (53.6%) female patients (p<0.001). Cumulative incidence of maturation over time differed significantly for men and women; the time to 50% of the AVF achieving maturation was 82 days for men and 182 days for women (p=0.009; Figure 2).27
Figure 2.
Sex differences in cumulative incidence of maturation over time. Women show delayed maturation compared to men (182 vs. 82 days; p=0.009; Gray’s test).
We examined pre- and post-operative measurements to determine associations with early AVF maturation. Significant associations by sex were found among post-operative arterial diameter and monocyte percentage (Table III). There was an overall significant difference in mean postoperative brachial artery size by maturation status, with mature AVF having larger arterial diameter (matured: 5.2 ± 0.8 mm, failed: 4.6 ± 0.8 mm; p=0.006). However, this differed by sex, with increased diameter in mature AVF only in men (Table III; Figure 3A). Similarly, there was a significant difference in mean post-operative percentage of monocytes, with mature AVF having greater percentages of monocytes (matured: 9.7 ± 2.3, failed: 8.1 ± 2.5%; p=0.026). However, these associations differed by sex, with increased monocyte percentages in mature AVF only in women (Table III; Figure 3B). These data suggest arterial remodeling impacts AVF maturation in men whereas the immune response impacts maturation in women.
Table III:
Relationship between Unassisted Maturation and Patient Measurements by Sex
| Maturation | Failure to Mature | Overall | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| N | Mean | SD | N | Mean | SD | N | Mean | SD | p-value | |
| Pre-op vein (ACF) diameter (mm) | ||||||||||
| All patients | 38 | 3.8 | 1.1 | 17 | 4.0 | 1.0 | 55 | 3.9 | 1.1 | 0.629 |
| Women | 15 | 3.5 | 0.8 | 13 | 3.7 | 1.0 | 28 | 3.6 | 0.9 | 0.492 |
| Men | 23 | 4.0 | 1.2 | 4 | 4.8 | 0.5 | 27 | 4.1 | 1.2 | 0.262 |
| Pre-op brachial artery diameter (mm) | ||||||||||
| All patients | 39 | 4.7 | 1.0 | 17 | 4.3 | 0.9 | 56 | 4.6 | 1.0 | 0.266 |
| Women | 15 | 4.3 | 1.0 | 13 | 4.2 | 0.8 | 28 | 4.2 | 0.9 | 0.754 |
| Men | 24 | 4.9 | 1.0 | 4 | 4.9 | 1.1 | 28 | 4.9 | 1.0 | 0.969 |
| Post-op brachial artery diameter (mm) | ||||||||||
| All patients | 39 | 5.2 | 0.8 | 17 | 4.6 | 0.8 | 56 | 5.0 | 0.9 | 0.006* |
| Women | 15 | 4.9 | 0.7 | 13 | 4.6 | 0.9 | 28 | 4.8 | 0.8 | 0.253 |
| Men | 24 | 5.4 | 0.8 | 4 | 4.5 | 0.6 | 28 | 5.3 | 0.9 | 0.045* |
| Pre-op brachial artery velocity (cm/sec) | ||||||||||
| All patients | 37 | 92.5 | 30.8 | 17 | 81.6 | 19.1 | 54 | 89.1 | 28.0 | 0.185 |
| Women | 13 | 88.4 | 30.6 | 13 | 83.1 | 19.4 | 26 | 85.7 | 25.2 | 0.601 |
| Men | 24 | 94.7 | 31.4 | 4 | 76.8 | 19.9 | 28 | 92.2 | 30.4 | 0.282 |
| Post-op brachial artery velocity (cm/sec) | ||||||||||
| All patients | 39 | 253.3 | 71.0 | 17 | 212.8 | 74.0 | 56 | 241.0 | 73.7 | 0.058 |
| Women | 15 | 229.9 | 68.0 | 13 | 207.2 | 74.9 | 28 | 219.4 | 70.9 | 0.410 |
| Men | 24 | 267.9 | 70.3 | 4 | 230.8 | 78.7 | 28 | 262.6 | 71.2 | 0.344 |
| Post-op Monocytes (%) | ||||||||||
| All patients | 38 | 9.7 | 2.3 | 17 | 8.1 | 2.5 | 55 | 9.2 | 2.4 | 0.026* |
| Women | 15 | 9.2 | 2.1 | 13 | 7.6 | 1.4 | 28 | 8.5 | 2.0 | 0.028* |
| Men | 23 | 10.0 | 2.4 | 4 | 9.9 | 4.3 | 27 | 10.0 | 2.6 | 0.920 |
Figure 3.
Distribution of brachial artery diameters and percentages of monocytes for men and women based on maturation status. (A) Among men, mean diameter differed significantly among those who achieved maturation and those who did not (5.4 ± 0.8 vs 4.5 ± 0.6 mm; p=0.045) (B) Among women, there was substantial overlap in artery diameter among those who did and did not achieve maturation (4.9 ± 0.7 vs 4.6 ± 0.9 mm; p = 0.253). (C) Among men, percentages of monocytes did not differ significantly among those who achieved maturation and those who did not (10.0 ± 2.4 vs 9.9 ± 4.3%, p = 0.920). (D) Among women, percentages of monocytes differed significantly among those who achieved maturation and those who did not (9.2 ± 2.1 vs 7.6 ± 1.4%; p = 0.028).
To quantify the independent impact of sex and brachial artery diameter on AVF maturation, we performed logistic regression to calculate odds of maturation. Among men, every 1 mm increase in post-operative brachial artery diameter was associated with a trend toward increased odds of maturation (aOR=8.24, 95% CI: 0.95–71.75; p=0.056). However, for women, each 1 mm increase was not associated with increased odds (aOR=1.79, 95% CI: 0.67–4.82; p=0.246). This additionally suggest that arterial diameter influences maturation in men but not in women.
To quantify the independent impact of sex and percentage of monocytes on AVF maturation, we performed a second logistic regression. Among women, every 1% increase in monocytes was associated with 1.7 times increased odds of AVF maturation (aOR=1.71, 95% CI: 1.01 – 2.87; p=0.044). However, for men, monocyte percentage was not associated with increased odds of maturation (aOR=1.02, 95% CI: 0.67–1.55; p=0.916). This suggests that the percentage of circulating monocytes influence AVF maturation but only in women.
Discussion
We show significant sex differences in pre- and post-operative vascular measurements in patients undergoing AVF creation. Women with brachial-cephalic fistulae had smaller pre- and post-operative brachial arterial diameter, as well as lower peak systolic velocity than men. Significant differences in baseline venous diameter and flow were not observed, but reduced flow in the fistula was noted post-operatively in women. Furthermore, women had reduced circulating monocytes. Logistic regression suggested that arterial diameter played a larger role in fistula maturation in men while monocyte percentage was more important in women. In total, this suggests that arterial inflow and systemic immune response could explain sex differences in maturation among brachial-cephalic fistulae.
Several published studies analyzed vessel diameters and hemodynamics in the pre-operative, post-operative, and intra-operative period to determine what was predictive for AVF maturation.10–21 The Hemodialysis Maturation Study reported that post-operative arterial flow (518–1473 mL/min), AVF blood flow (414–1407 mL/min), and vein diameter (4.48–7.15 cm) partially predicted maturation.12 Others suggested pre-operative venous13 or arterial diameter14 as predictors of maturation. Lauvao et al showed that vein diameter >4 mm helped maturation,13 while Farrington reported that for each 1 mm increase in arterial size, odds of fistula maturation increased by 1.5.14 Saucy et al found that intraoperative venous blood flow predicted maturation.15 These studies cumulatively showed that measures recorded before, during, and after fistula creation were each predictive for maturation.
Some studies correlated diameter differences with sex differences in AVF maturation. In our logistic regression models examining odds of maturation stratified by post-operative arterial diameter, a trend towards a positive association between increasing post-operative brachial artery diameter and odds of achieving maturation was observed in men but not women. Miller et al and Wilmink et al reported that men have larger arterial diameter than women, but this was not significant after adjusting for maturation.11,17 Similarly, Peterson et al reported that women had diminished upper arm arterial diameter than men (4.8 ± 1.2 vs. 5.4 ± 1.0 mm; p=0.001); however, arterial diameters were similar among women whose fistulae failed to mature and those with successful fistulae (5.0 ± 1.0 vs. 5.1 ± 1.4 mm, p=0.86).10 On the other hand, Korten et al reported that radial artery diameter did impact AVF primary patency.20 While these studies showed sex differences in arterial diameter, they did not agree if these anatomical differences could explain patency differences; however, we believe that avoiding radial artery-based AVF in women does not appear to be supported by these studies.
Another factor that could impact AVF maturation is sex differences in hemodynamics. Lockhart et al measured change in arterial peak systolic velocity and showed that this was lower in women. However, this change did not predict fistula adequacy.18 Gjorgjievski et al showed that fistula flow was lower in women than men (375.12 vs 576.03 mL/min, p=0.004), and fewer women had fistulae with adequate blood flow (12% vs 63.2%, p=0.001); in addition, flow was significantly higher in arteries with larger pre-operative diameters, suggesting that the preoperative arterial diameter difference was the fundamental factor responsible for flow differences.19 Our data is similar to that of Gjorgjievski et al, with a trend to lower flow in female fistulae, which they believe was driven by the arterial diameter differences that we also observed. In total, our data and that of others lead us to conclude that diameter alone may not directly influence AVF maturation but may impact post-operative fistula velocity and flow, which in turn influence AVF maturation.
Whereas vessel diameters and hemodynamics influence AVF maturation, other mechanisms may also be contributing to sex differences in maturation. Although human studies have not yet determined a role for the immune system in AVF maturation, mouse models have suggested that the immune system regulates venous remodeling. Matsubara et al showed that T cells and macrophages are critical regulators of early maturation,23 and T cells may be critical regulators of the macrophages.28 Since women have increased measures of innate as well as adaptive immunity, with higher inflammation as well as increased T cell and macrophage populations,29–33 it is possible that sex differences in the immune system may be another factor influencing sex differences during AVF maturation. Our data shows a significantly lower percentage of circulating monocytes in women, a cell population thought to influence wall thickening and dilation during early fistula remodeling. In addition, this population was lower in women whose fistulae failed to mature compared with those that successfully matured, suggesting that in addition to sex differences in arterial inflow, sex differences in the immune response such as differing amounts of macrophages may also play a role in sex differences observed during AVF maturation. Thus, our data suggests that modulating the immune system might be another strategy to increase the rate of AVF maturation in women.
This study has both strengths and limitations. First, our data did not exactly match any single study’s data that reported vessel diameters or hemodynamics; however, we believe that our data is representative of our patient population as it very closely matches the pooled mean of over 500 arterial and venous diameters from multiple papers. (Figure 1) Second, data for radial-cephalic fistulae are reported frequently in the literature; however, we found relatively fewer patients with radial-cephalic fistulae at our institution from 2016–2021. In addition, patients at our institution frequently have subsequent care elsewhere, beyond the peri-operative period, preventing us from tracking fistula patency and failure rates over the long term. Thus, we cannot correlate preoperative and early post-operative hemodynamic differences with long-term patency; we therefore focused on early hemodynamics and early primary maturation. Similarly, the relatively low numbers of patients reflect inclusion of cases only at the main hospital and not in network or outpatient facilities, as well as exclusion of basilic vein transpositions, grafts and repeat or staged procedures; as such, the surgeon volumes of access procedures are significantly higher than included in this report. Additionally, our study was powered to examine differences in brachial artery size between men and women as our primary analysis goal; since maturation was a secondary analysis, this study was not powered to examine difference in maturation or failure between men and women. This is highlighted by the small numbers (n=4) of men that experienced failure to mature. Therefore, our examination of the relationships between AVF maturation and brachial artery diameter and percentages of monocytes must be interpreted cautiously. Lastly, the effects of hemodialysis on the cell populations in the complete blood count are not completely understood and thus require additional analysis; however, these data were collected at the time of dialysis, e.g., using uniform timing and methodology, and should be reliable. We are also unable to determine the specific subsets of cell types within the complete blood count data.
Conclusion
There are sex differences among multiple pre- and post-operative variables, suggesting that sex differences during AVF maturation cannot be explained by a single variable. Significantly reduced arterial diameter and peak systolic velocity as well as reduced fistula flow in women suggest that arterial inflow may impact downstream hemodynamics. The interaction between several factors, including fistula type, pre-operative hemodynamics, post-operative hemodynamics, and the immune response, ultimately drive fistula maturation. We suggest the value of a long-term, multi-institution study to determine sex differences in these multiple factors on fistula maturation.
Supplementary Material
Highlights.
Among 56 patients, brachial artery diameter and velocity were smaller in women
Women had lower circulating monocytes during maturation than men
Arterial inflow and the immune system drive sex differences during AVF maturation
Acknowledgments
This work was supported by the US National Institutes of Health grants R01-HL144476 and R01-HL162580.
Footnotes
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The Authors declare that there is no conflict of interest
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