Effect of far infrared therapy on arteriovenous fistula maturation, survival and stenosis in hemodialysis patients, a randomized, controlled clinical trial: the FAITH on fistula trial

Worldwide, the number of patients with end stage kidney disease in need of hemodialysis therapy increases [1]. In order to receive an efficient hemodialysis treatment, the patient needs a well-functioning and stable vascular access. Currently, there are 3 options: an arteriovenous fistula (AVF), an arteriovenous graft (AVG) and a central venous catheter (CVC) [2, 3]. CVCs are associated with an increased risk of stenosis of the central thoracic vessels, thrombosis in a present AVF, local and systemic infections and death [4‐7]. In a multivariate analysis performed by Bray et al., patients with a tunneled CVC almost had a 7 fold increased risk of death from septicemia compared with patients with an AVF [4].

AVGs are associated with increased risk of infection, stenosis in the AVG and loss of access [6, 8, 9]. A study by Almasri et al. [9] showed the need of an intervention (defined as both surgical and endovascular) during 2 years of observation to be 60% in the AVG group compared to 45% in the AVF group. Conclusively, the AVF is the preferred vascular access. However, the AVF is not without complications. Following the creation of an AVF there is a 20–50% risk of maturation failure and consequently, the AVF cannot be used [10, 11]. Furthermore, up to 45–67% of the AVFs will develop a stenosis, that needs an intervention within 1 year [9, 10]. During the period with a malfunctioning AVF, the patient may need a CVC as an alternative vascular access which leads to an increased risk of infection, more hospital days and death [6]. The poor AVF maturation and patency is due to many factors. High age, female sex, anatomic location of the AVF (primarily radio-cephalic), small vein diameter, comorbidity, surgeon experience and perhaps arterial stiffness, are all risk factors that influence the AVF survival [10, 12‐15].

Studies investigating possible therapies that improves the AVF maturation and AVF survival are scarce as stated in the vascular access guidelines by European Renal Best Practice and European Society for Vascular Surgery [2, 3]. Furthermore, it is not well established, what causes the neo-intimal hyperplasia in the AVF leading to stenosis and loss of the vascular access [16, 17]. This makes it even more difficult to clarify potential treatments.

Far Infrared therapy (FIR) is a new treatment modality modestly suggested by the European Renal Best Practice to improve AVF maturation and patency [18]. Although suggested, they also call for further studies of FIR, which should be multicentre, preferably blinded and non-industry supported.

FIR is an electromagnetic radiation (heat therapy), that is given directly on the skin above the AVF. The infrared light has in various animal models shown to have a thermal effect, which leads to vasodilatation and angiogenesis [19]. In the clinical setting, FIR is used for wound healing and peripheral ischemia, where it has shown beneficial effect [20]. FIR also promotes a non-thermal effect, where it inhibits vascular endothelial inflammation via induction of anti-inflammatory and vasodilating factors, such as Heme-oxygenase and Nitric oxide [19, 21]. The non-thermal effect is sparsely investigated and understood, especially in hemodialysis patients.

The effect of FIR on the AVF maturation and survival has been explored in a few studies [22‐25]. Lin et al. [22, 23] showed a significant improvement in the maturation (90% vs 76% at 3 months) in patients with a newly placed AVF. In patients with a well-functioning AVF with no prior interventions, a lower incidence of AVF malfunction during 12 months of treatment with FIR compared with a control group was found (13% vs. 30%). Lai et al. [24] compared patients in a FIR group with a control group with more than 2 previous interventions on the AVF or AVG. They found a significantly improved unassisted patency rate for the AVGs (16% vs 2%), but not for AVFs (25% vs. 18%). All these studies were randomized, but not blinded. They were performed in one single dialysis department in Taiwan and has not been reproduced or confirmed in other dialysis units and populations.

A study by Choi et al. [25] designed to examine the effect of FIR on cannulation pain and access flow, found no difference in the AVF survival in the FIR treatment group compared to a control group during 12 months of intervention. However, the study was not powered to address this issue. Interestingly, the study showed a significant decrease in the cannulation pain. In conclusion, FIR appears as a promising treatment for AVF maturation and perhaps AVF survival, but the data is inconsistent. There is an urgent need for further investigations of the possible effects of FIR.

The present paper describes the design and rationale of a randomized, controlled, open-labeled multicenter trial of the effect of FIR on AVF maturation and on number of AVFs without intervention still functioning after 1 year. Changes in anti-inflammatory and vasodilating factors during FIR treatment will be explored and arterial stiffness as a marker of AVF maturation and survival will be examined.

Previous studies have shown very few side effects of the FIR treatment, such as burning and/or itching sensation. All the data collection will be performed during the patient’s regular hemodialysis treatment, thus there is no extra time for the participant to spend in the department due to the study. Blood samples will be drawn from the dialysis machine, so no extra needling of the patient is needed. Every third month the incidence of side effects will be evaluated. If there is a significant increased incidence in the intervention group (due to FIR) the study will be terminated and the participants will be informed.

Recruitment begun in October 2019. We expect to have completed recruitment in March 2021 for the group with prevalent AVF and in October 2022 for the group with incident AVF with the final data collection in April 2024.

The present study will examine the effect of FIR treatment on AVF maturation and overall patency rate through a randomized, multicenter, open-labelled trial. Furthermore, the acute effects of FIR in terms of changes in anti-inflammatory and vasodilating factors during FIR treatment will be explored and arterial stiffness as a marker for AVF maturation and patency will also be investigated.

After placement of an AVF there is a high risk of maturation failure and need of assisted patency [9, 10, 14]. Approximately 22 to 37% of created AVFs fails and will never be used. By 1 year, 40% of all AVFs fails or have required at least one intervention [10]. Maturation of the AVF depends on several patient related, but also surgically related factors. Factors such as comorbidity (diabetes mellitus, peripheral vascular disease), female sex, length of ESKD, anatomy of the vessel, surveillance after AVF placement, anatomic placement of the AVF and the surgically procedure itself have all been shown to have an influence on the AVF maturation [12, 13, 15, 28, 29].

Studies investigating possible therapies that improves the AVF maturation and survival are scarce. Since the dialysis population is getting older, they present with more comorbidities, and thereby an increased risk of AVF maturation failure. Therefore, there is a need of new interventions that may improve the AVF maturation. FIR is a suggested treatment modality with promising results in the presently available studies [22‐24]. There is an urgent need of further studies to explore this treatment. Cannulation of the AVF is by several guidelines suggested to be between 28 to 56 days [2, 3]. However, a huge difference between countries is seen. Early cannulation of the AVF has in studies shown not to reduce the AVF survival [14, 30]. In the largest dialysis center in Zealand, Denmark we found a median time to cannulation of 100 days (SD ± 46) suggesting a poor maturation rate. Lin et al. [22] found a significant improvement in maturation within 1 year (defined in successful cannulation in 8 out of 12 dialysis treatments of a 30 day period) in the FIR treated group compared to the control group (82% vs 60%). The primary endpoint for incident AVFs chosen in our study is therefore time to successful cannulation after AVF placement. Since the FIR treatment is supposed to have a thermal effect increasing blood flow and angiogenesis, we also wish to explore the change of access flow, diameter of the AVF and possible change in cardiac output (perhaps due to the increased access flow in the FIR treatment group). A difference in 1 year patency rate is also examined, since FIR treatment also has shown to decrease the incidence of interventions [22, 23].

After placement of the AVF the patency rates are poor. Al-jaishi et al. and Almasri et al. [9, 10] found a primary patency rate after 1 year of 60–65%. The stenosis in the AVF emerges from an endothelial dysfunction, inflammation and smooth muscle cell proliferation leading to intimal hyperplasia and in the end stenosis [16, 17]. The molecular mechanism that are responsible for the intimal hyperplasia is not well established [16, 28, 31]. Factors, such as Nitric Oxide, Heme-Oxygenase, TNF-alpha and MCP-1 are all factors, that are suggested to be of importance to the AVF maturation and stenosis [16, 31].

There is a need for studies that investigate possible treatments, that may prevent the development of the stenosis and improve the patency of the AVF. Previous studies [18, 32] have explored the effect of different antiplatelet medications, fish oil and prednisolone on the AVF maturation and patency with disappointing results. FIR is suggested by ERBP to be a possible new beneficial treatment for both AVF maturation and patency, but the results of the present studies of the effect of FIR on AVF malfunction is divergent. The studies are also from only one research group and one dialysis unit. Therefore, we designed the present randomized controlled trial to examine the influence of FIR on AVF patency in a Danish population in multiple dialysis units. The primary endpoint for prevalent AVFs is therefore improvement in patency rate in the two groups.

Since peripheral vascular disease is a risk factor for non AVF maturation and AVF survival one can speculate, that arterial stiffness, measured by pulse wave velocity can be used as a prognostic marker for AVF maturation and survival. This has only been explored in a few studies [33‐35]. In the studies there were no correlation between arterial stiffness measured by pulse wave velocity and AVF maturation. The follow up time were 6–8 weeks, thus primarily examining the primary failure and maturation of the AVF. Arterial stiffness at baseline as a predictor for long term AVF survival has not previously been explored. This will be clarified in the present study.

The possible mechanisms behind FIR is unraveled. The theory is both a direct vasodilatory effect and a release of various anti-inflammatory and vasodilating factors [20, 21]. FIR has shown positive effects on wound healing and phantom pain in the lower extremities suggesting an increased blood flow and angiogenesis [20]. FIRs effect on a few of the molecular factors involved in the AVF stenosis, have been studied in vitro by Lin et al. [21]. They found a stimulation of heme-oxygenase 1 in endothelial cells (a molecule involved in the relaxation of the smooth muscle cells in the endothelium of the vessels). A decrease of several anti-inflammatory factors, such as tumor necrosis factor and interleukin 8 was also found. There are no studies exploring the acute effect of FIR treatment on these biochemical markers in vivo in a hemodialysis population. This will be explored in the present study.

A large limitation in this study is, that it is not blinded either by investigator, patient or dialysis nurse. Unfortunately, this is not possible due to the size of the FIR emitter and the feeling of the FIR treatment (warm sensation). The majority of the participants enrolled will be of Caucasian origin, and thus the results may not be applicable in other ethnicities. The company, that produces the FIR machine advise, that the FIR treatment can be given during the whole dialysis treatment, except for the last hour (due to risk of prolonged time to hemostasis). In this study the patients will receive the FIR treatment in different time slots during a hemodialysis treatment. If this affects the results is unknown. The optimal timeslot for the FIR treatment during the dialysis session has not previously been investigated. Accessflow on the incident AVFs to determine AVF maturation and time to cannulation is not performed, since this is not standard procedure in the included dialysis units in the study. Other standard criteria’s according to a guideline is used, as described in the Methods and design section.

This project is designed to fill an unmet need regarding methods to investigate factors affecting AVF maturation and patency in an investigator initiated and driven study.