Radiocephalic wrist arteriovenous fistulae (AVF) have been superior to other types of vascular access for hemodialysis (HD) [1]. Nevertheless, 23%-46% of all AVF have problems with early failure or failure to mature, resulting in a year patency of 60%-65% [2]. Early failure has been defined as an AVF that never develops adequately for HD (failure to mature) or fails within 3 months of starting HD [3]. Aggressive neointimal hyperplasia and the inability to dilate adequately are the factors playing the major roles in the setting of early AVF failure.

After the creation of the AVF, hemodynamic shear stress increases and results in the vascular dilatation which tends to return shear stress to normal. This flow-mediated arterial vasodilatation is primarily a result of the release of nitric oxide (NO). Thus we hypothesized that administration of long-acting nitrates, an exogenous source of NO, would be beneficial in the process of fistula maturation via vasodilation. We decided to give isosorbid-5-mononitrate to a group of end-stage renal disease (ESRD) patients before a radiocephalic AVF creation in order to prevent fistula failure.

Figure 1. Diagram showing the flow of the study.

ESRD patients undergoing first time AVF creation were enrolled in this study. All patients were examined by Doppler ultrasonography prior to operation. Those who had stenosis of the cephalic vein in the preoperative USG examination were excluded from this study. The study protocol was approved by the local ethics committee. All patients approved the study procedures and gave written informed consent. Fifty-five patients were assessed for eligibility. Four patients refused to start HD and were discharged from the hospital. Seven patients refused to participate in this study and vascular structure of 4 patients was not suitable for an AVF creation. In the end, 40 patients were included in the study and were randomly divided into 2 groups. The long-acting nitrate (isosorbid-5-mononitrate) 60 mg was given to Group 1 patients two days before the operation and continued 7 days after the operation. Group 2 patients were not admitted nitrates (Figure 1). All Group 1 patients tolerated the drug well. All patients were examined at the 7th and 30th day after the creation of AVF. During the follow-up, the occlusions and radiocephalic AVF unable to reach Dialysis Consortium Study (DAC)’ criteria were defined as non-functioning [4].

Prior to the operation, the upper-limb of each patient was assessed clinically by a surgeon for any sign of venous obstruction or ischemia. Pulses were palpated and an Allen test was performed.

All USG measurements were made in a dark room at room temperature by a single observer. Patients were told not to smoke any cigarette or drink coffee 4-6 hours before the procedure and vasoactive medications were withheld for 24 hours. The diameters of the arteries were measured at diastole and the averages of the three consecutive measurements were calculated. To take the measurements from the same place, the anatomic structures like vena and fascia were identified and marked on the arm which we planned to create the fistula. The diameter of the brachial artery on longitudinal plane was recorded 5 cm above the antecubital fossa. The arterial tree was assessed from the antecubital fossa down to the wrist. Vessel diameters and anatomical variations were noted.

Gray scale and Doppler USG was performed with Applio scanner (Toshiba, Tokyo, Japan) by an experienced radiologist using 7-12 MHz linear transducers. Ultrasonographic examinations were performed before the operation (0) and at the 7th day and 30th day after AVF creation in both groups. This consisted of a non-invasive duplex ultrasound scanning including measurement of blood flow through the radial and brachial artery and imaging of the cephalic vein, radial artery, and the brachial vein.

Brachial artery diameter, brachial artery blood flow, radial artery diameter, radial artery blood flow and cephalic vein diameter were measured for evaluation of fistula maturation. Area under curve (AUC) was calculated between 0 to the 7th day and between the 7th day to the 30th day.

All procedures were performed under local or regional anaesthesia with the use of antibiotic prophylaxis by the same vascular surgeon. AVF was created at the wrist and the anastomosis between radial artery and cephalic vein was constructed in end vein-to-side fashion. Systemic heparinization was used in all patients. First canulation was performed when the vessels maturated adequately, usually after 4-6 weeks.

SPSS 15.0 statistic software was used for the statistical analysis. The Kolmogorov-Smirnov test was used to determine normality of distributions of variables. Continuous variables with normal distribution were presented as mean ± standard deviation. Median value was used in variables without normal distribution. Statistical analysis for the parametric variables was performed using the Student’s t-test between two groups. The Mann-Whitney U test was used to compare nonparametric variables between two groups. The qualitative variables were given as percent and the correlation between categorical variables was investigated by the χ2 test. To evaluate fistula maturation in both groups, AUC, which was calculated by the trapezoidal method, was used for diameters and flows of brachial and radial arteries and diameter of cephalic vein. The differences between the AUC values of the groups were compared by the Mann-Whitney U test. P value of <0.05 was considered to be significant.

Forty patients with AVF were followed for 30 days. Mean age of the 40 patients was 61.8 ± 13.4 years; 24 of them were female. Baseline demographic, clinical, and laboratory parameters between the two groups are compared in Table 1.

Systolic and diastolic blood pressure values and albumin level were significantly lower in Group 1 than in Group 2 (p: 0.010, 0.021, and 0.032, respectively). On the other hand, there were no significant difference between the two groups with respect to age, gender, presence of hypertension, diabetes mellitus, and coronary artery disease, anti-hypertensive drug, body mass index, and other laboratory parameters, including serum creatinine, lipids, glucose, hemoglobin, white blood cell count, and C-reactive protein (p >0.05).

Figure 2. Diameter and flow of brachial artery before the operation (0) and at the 7th day and the 30th day after AVF creation and AUC values between 0 to the 7th day and between the 7th day to the 30th day.

Table 2 shows comparison of the diameters and flows of the brachial and radial arteries and diameter of cephalic vein. There is no significant difference between two groups in terms of all the diameters and flows (p >0.05).

There are no significant differences between two groups with regard to AUC values for diameter and flow of brachial artery between 0 to the 7th day and between the 7th day to the 30th day (Figure 2). Similarly, there are no significant differences between two groups with regard to AUC values for diameter and flow of radial artery during the two periods (Figure 3). Furthermore, there is no significant difference between two groups with regard to AUC values for diameter of cephalic vein (Figure 4).

Figure 3. Diameter and flow of radial artery before the operation (0) and at the 7th day and the 30th day after AVF creation and AUC values between 0 to the 7th day and between the 7th day to the 30th day.

Autogenous radiocephalic AVFs have been regarded as the best choice of vascular access in HD patients. Nevertheless, in some fistulas, thrombosis develops after the operation or the fistulas fail to mature. It appeared that 8-10% of the patients, who were judged to have adequate vessels, still developed non-functioning AVFs [2]. Selecting patients who would benefit from autogenous AVFs is a problem and there are no objective criteria. Doppler USG-derived preoperative parameters may predict the risk of fistulae failure or dysmaturation.

AVF maturation is a complex and multifactorial process and there are some risk factors for AVF failure. In previous studies, increasing age, female gender, presence of diabetes mellitus and the presence of peripheral and coronary vascular disease were predictive of early failures [5, 6]. Oral systemic agents, including angiotensin converting enzyme (ACE) inhibitors [7], dipyridamole [8], fish oil [9], sirolimus [10], rosiglitazone [11], klopidogrel [12], have been tried to correct vascular access dysfunction. However, the role of these agents in clinical use is unknown at present.

Figure 4. Diameter of cephalic vein before the operation (0) and at the 7th day and the 30th day after AVF creation and AUC values between 0 to the 7th day and between the 7th day to the 30th day.

After anastomosis of an artery and vein, there is a rapid increase in vein pressure and the shear stress increases. Afterwards, vessels try to reduce shear stress back to a normal level by dilating. Early phase of venous dilation is largely mediated by increased NO production and late dilation depends on metalloproteinase activity, which is also in part mediated by NO activity [13, 14]. Experimental and clinical studies have showed that NO plays a crucial role in early fistula maturation and late access patency.

NO, named as endothelium-derived relaxing factor (EDRF), is produced by vascular endothelium [15] and induces endothelium-independent smooth muscle relaxation. Exogenous organic nitrates enter vascular smooth muscle vessels and likely bind to guanylate cyclase. This leads to an increase in cyclic guanosine monophosphate and facilitates the generation of NO [16]. Endothelial dysfunction occurs in chronic kidney diseases, leading to impaired endothelium-mediated release of NO and impaired arterial dilation in response to an increased flow rate [17].

Non-maturation depends on the size of the vessels; therefore, we hypothesized that long-acting nitrates could help the vessels to dilate and increase blood flow soon after the anastomosis and, as a consequence, increase fistulae patency. We administered nitrates two days before AVF creation to obtain a constant plasma level and continued to administer till the end of the 7th day in order to keep the bioconversion to NO remain unaltered at the time of the AVF operation.

In one study, the successful AVFs had a preoperatively measured radial artery diameter of 2.7 mm [18] and in another one, primary failure was observed with a radial artery diameter of < 1.6 mm [19]. In our study, the preoperative mean radial artery diameters of Group 1 and 2 were 2.55 ± 0.58 mm and 2.29 ± 0.36 mm, respectivelyl thus preoperative radial artery diameters were sufficient for fistulae patency according to previous studies.

The most frequent cause of an AVF to mature is neointimal hyperplasia which typically occurs in the juxta-anastomotic vein during the first post-operative month. We administered nitrates for 10 days, but not any longer, and looked for any discrepancy in vessel diameters between the two groups. None of our patients started HD with vascular access till the end of the 7th day to rule out any confounding effect of HD-related injury on our results.

In our study, the systolic and diastolic blood pressures were significantly lower in patients in Group 1 than that in the other group, but none of 40 patients were lower than 90/60 mmHg. Hypotension has been shown to have an adverse effect on fistula maturation. Insufficient augmentation of blood flow because of hypotension may occur in our patients and, perhaps this is one of the factors that we could not find any positive effect of nitrates on the fistula patency in early phase of AVF maturation.

Exogenous NO source, isosorbid-5-mononitrate treatment, produced an insignificant increase in forearm vasodilatation compared with a control group and nitrates were found no effective on early maturation of the AVF. The attenuated vasodilatation response may be associated with a potential defect in smooth muscle function or nitrate tolerance may have occurred. This may explain why we could not find a positive effect of nitrates on fistula patency.

The authors declare that there is no conflict of interest.