Effect of transcutaneous vagus nerve stimulation in hemodialysis patients: A randomized controlled trial

Abstract

Introduction

Transcutaneous auricular vagus nerve stimulation (tVNS) has shown potential in neurological, autoimmune, and cardiovascular disorders, but its effects on HD patients remain unclear. This study aimed to evaluate the efficacy and safety of tVNS in HD patients.

Methods

We conducted a randomized controlled clinical trial on patients receiving HD ≥6 months. The tVNS group received stimulation for 1 h during the first 2 h of HD sessions, three times weekly for 8 weeks, while the control group received standard care. The primary outcomes were dialysis efficiency (Single‐pool Kt/V, Sp Kt/V) and dialysis‐related symptoms (Dialysis Symptom Index, DSI), assessed every 4 weeks. Secondary outcomes included pain and fatigue scores, physical performance, Hemodialysis Comfort Scale, hemoglobin levels, Mini‐Mental State Examination, and anxiety and depression scores, measured at baseline and 8 weeks after intervention.

Results

A total of 63 patients were enrolled in the study, with 32 patients assigned to the tVNS group and 31 patients to the control group. At 8 weeks, the tVNS group showed significant improvements in Sp Kt/V (1.31 ± 0.11 vs. 1.25 ± 0.10, p = 0.02), and DSI (12.09 ± 5.84 vs. 16.26 ± 5.27, p = 0.004), as well as reductions in pain and fatigue, and increases in physical function, comfort, and hemoglobin. However, there were no statistically significant changes observed in cognitive function, anxiety, or depression.

Conclusions

tVNS could improve dialysis efficiency, symptoms, and physical function in HD patients, indicating it may have a role as a complementary therapy.

1. INTRODUCTION

CKD is a prevalent condition, affecting over 10% of the global population, and represents a major public health challenge, ranking as the tenth leading cause of mortality worldwide [1]. HD is a cornerstone of renal replacement therapy for patients with ESRD, and is widely utilized to prolong survival and improve outcomes [2]. However, despite its life‐sustaining benefits, HD is often accompanied by a spectrum of distressing symptoms, including pain, fatigue, anxiety, and depression, which significantly diminish patients' quality of life and contribute to an overall decline in physical, emotional, and psychological well‐being [3, 4, 5]. Current management strategies predominantly rely on pharmacological interventions, which, while effective to some extent, are limited by side effects and can compromise patient adherence. Thus, there is an urgent need for novel, non‐pharmacological approaches to alleviate these burdensome symptoms in HD patients.

The vagus nerve constitutes the principal nerve of the parasympathetic system, regulating pain, mood, and the neuroendocrine‐immune axis [6]. Vagus nerve stimulation (VNS) has been established as an effective non‐pharmacological treatment for several conditions, including refractory epilepsy, migraine, and depression [7, 8]. More recently, transcutaneous VNS (tVNS), a non‐invasive variant of this technique, has gained attention for its ability to reduce inflammatory pain in autoimmune diseases [9, 10, 11] and offer therapeutic benefits in cardiovascular disorders and post‐stroke recovery [12, 13, 14]. The mechanisms underlying these effects are believed to involve the activation of the cholinergic anti‐inflammatory pathway, modulation of cytokine profiles, and enhancement of neuroplasticity [14, 15]. Moreover, the anti‐inflammatory and pain‐relieving effects of tVNS are thought to be mediated through its influence on the parasympathetic branch of the autonomic nervous system [16].

Despite the growing body of evidence supporting the efficacy of tVNS in various clinical contexts, its potential applications in HD patients have not yet been thoroughly investigated. Given the significant symptom burden in this population, this study aims to rigorously evaluate the efficacy and safety of tVNS in HD patients, with a particular focus on its ability to improve dialysis adequacy, reduce dialysis‐related symptoms, enhance muscle strength, and increase overall patient comfort. By exploring these aspects, the study seeks to determine whether tVNS can serve as a viable complementary therapy to improve the clinical outcomes and quality of life in HD patients.

2. METHODS

2.1. Trial design and participants

This study was a randomized, controlled clinical trial conducted at the Third Clinical Medical College of China Three Gorges University, located in Hubei Province.

Inclusion Criteria: Eligible participants were required to meet the following criteria: (1) Adults (aged 18 years or older) with a diagnosis of stable ESRD. (2) For patients aged over 65 years, a standardized Mini‐Mental State Examination (MMSE) score of 24 or higher was necessary to ensure cognitive ability to consent and comply with the study protocol. (3) Females of childbearing potential were required to have a negative pregnancy test, and all participants were required to be non‐pregnant. (4) A history of receiving HD for at least 6 months, ensuring patient stability and familiarity with HD procedures. (5) A treatment regimen of HD three times per week and a willingness to participate voluntarily, confirmed through written informed consent.

Exclusion Criteria: Participants were excluded if they met any of the following criteria: (1) Pregnancy or planning to become pregnant during the study period. (2) Presence of significant cardiovascular abnormalities, including electrocardiogram (ECG) irregularities, use of beta‐blocker medications, or dependence on cardiac pacemakers. (3) A history of symptomatic orthostatic hypotension or recurrent vagal syncope, as these conditions could be exacerbated by VNS. (4) Recent hospitalization within the past 3 months, which might indicate acute illness or instability. (5) Presence of any active infections that could interfere with the intervention or outcomes. (6) A history of psychiatric illness, which could affect compliance with the study protocol or interfere with the accurate assessment of outcomes.

2.2. Randomization

Patients meeting the inclusion criteria were randomly assigned to the intervention or control group using a computer‐generated randomization sequence, created by an investigator who was not involved in administering the intervention or assessing the outcomes. To maintain allocation concealment, assignments were placed in consecutively numbered, opaque, tamper‐evident envelopes. These envelopes were opened by the study coordinator immediately before applying the blinded study intervention, ensuring that both participants and study personnel remained unaware of group assignments throughout the trial.

2.3. Interventions

All patients underwent standardized dialysis conditions, including a dialysate flow rate of 500 mL/min, a blood flow rate of 250–300 mL/min, a 4‐h treatment duration, and FX80 dialyzers, consistent with those used before the intervention. Treatment protocols followed standardized principles for managing anemia, hypertension, and other complications, with individualized medication regimens tailored to each patient. Treatment plans, including medications, dosages, or anticoagulants, were not adjusted during the intervention period unless deemed necessary. Additionally, patients maintained a standardized protein intake of 1.2–1.4 g/kg/day throughout the study. Prior to the administration of tVNS, all patients underwent baseline assessments, including an ECG and evaluation for orthostatic hypotension, to ensure safety and eligibility. The tVNS procedure involved placing an auricular electrode at the cymbal concha of the left ear, where the anode electrode, coated with a conductive gel, was positioned without prior disinfection and connected to the stimulation device.

For patients in the intervention group, tVNS was administered for 1 h during the first 2 h of each HD session, three times per week for 8 weeks. The stimulation parameters were initiated at a frequency of 25 Hz with a pulse width of 50 μs. The stimulation intensity started at a low level and was gradually increased to a maximum of 15 mA or reduced if the patient reported discomfort, such as tingling or mild pain in the stimulation area. The intensity was adjustable and required configuration by clinical staff during each session to maintain patient comfort. In contrast, patients in the control group had the tVNS device turned “OFF” throughout the study period to maintain blinding. The specific tVNS parameters selected for this study were based on evidence from previous clinical studies on tVNS applications [17, 18] and were further refined by preliminary experimental findings.

To ensure adherence to the intervention protocol, the device automatically recorded the history of stimulations, monitoring the percentage of effective stimulation based on proper electrode‐skin contact. A compliance threshold of at least 85% of the total prescribed stimulation time was required for a participant's data to be included in the final analysis.

2.4. Outcomes

The primary outcomes of this study were HD efficiency, measured by Sp Kt/V, and the Dialysis Symptom Index (DSI). Sp Kt/V is a well‐established, dimensionless parameter used to assess the adequacy of HD by quantifying serum urea clearance. For this trial, Sp Kt/V was measured using Fresenius 4008‐S HD machines equipped with On‐Line Clearance Monitors (Fresenius, Bad Homburg, Germany). The Sp Kt/V value was calculated as the average of three sessions conducted each week for patients undergoing HD thrice weekly. Treatments involving hemofiltration or hemoperfusion were excluded from Sp Kt/V calculations due to differing clearance dynamics. We also collected data on pre‐ and post‐dialysis BUN, ultrafiltration volume (UF), and dry weight (DW), and manually calculated Sp Kt/V using the Daugirdas formula. The results were compared between the two groups. The DSI, initially developed by Weisbord et al. (2004), was employed to assess the physical and emotional symptom burden in HD patients [19]. The DSI evaluates 30 symptoms over the previous 7 days, with each symptom receiving a “yes” or “no” response. A 5‐point Likert scale was used to rate the severity of symptoms for “yes” responses, ranging from 1 (none) to 5 (very much), with total scores ranging from 0 to 150. Higher DSI scores indicate a greater impact of dialysis‐related symptoms. Both Sp Kt/V and DSI were assessed at baseline and then every 4 weeks for both the intervention and control groups.

Secondary outcomes included pain, fatigue, physical performance, patient comfort, hemoglobin levels, cognitive function, anxiety, and depression. Pain and fatigue were quantified using a Visual Analog Scale (VAS), a widely accepted tool for subjective symptom measurement. Patient comfort during HD was assessed using the Hemodialysis Comfort Scale (HCS), a validated scale specifically developed in 2017 to measure comfort in HD patients undergoing treatment for at least 6 months [20]. Physical function was evaluated using the 6‐min walk test (6MWT) to assess endurance and the grip strength test (GST) to measure muscle strength. Hemoglobin levels were regularly monitored as an indicator of anemia management. Cognitive function was measured using the MMSE. Anxiety and depression were evaluated with the Self‐rating Anxiety/Depression Scale. All secondary outcomes were assessed at baseline and at the end of the 8‐week intervention period.

2.5. Statistical analysis

Data were expressed as mean ± SD for continuous variables or as counts and percentages for categorical variables. Group comparisons for continuous data were performed using independent‐sample t‐tests, while categorical data were analyzed using Chi‐Square Test or Fisher's exact test. All statistical tests were two‐tailed, with a p‐value of less than 0.05 considered statistically significant. Data analysis was conducted using GraphPad Prism software (version 10.1.2, GraphPad Software Inc., San Diego, California) and SPSS (version 27, IBM Corp., Armonk, NY).

3. RESULTS

3.1. Study population

Between September 2023 and December 2023, a total of 63 patients undergoing HD treatment were enrolled in the study. Patients were randomly assigned to either the tVNS group (n = 32) or the control group (n = 31). All participants successfully completed the 8‐week study period. Baseline characteristics, including demographic data, causes of ESRD, duration of HD, type of vascular access, and education level, were well balanced between the two groups, with no statistically significant differences observed (Table 1). Additionally, baseline values for both primary and secondary outcomes were comparable, demonstrating homogeneity between the groups at the start of the trial (p > 0.05 for all comparisons).

TABLE 1.

Baseline characteristics of control and tVNS groups.

	Control (n = 31)	tVNS (n = 32)	t/χ2	p
Age (years)	65.61 ± 12.14	65.28 ± 12.77	0.106	0.916
Sex (No)			0.24	0.877
Male	19 (61.3%)	19 (59.4%)
Female	12 (38.7%)	13 (40.6%)
Causes of ESRD (No)
Hypertension	5	4
DM	4	5
APCKD	2	2
GN	7	10
Unknown origin	9	8
Others	4	3
Vascular access (No)
AV fistula	25 (80.6%)	27 (84.4%)
Tunneled catheter	6 (19.4%)	5 (15.6%)
Duration of HD (months)	66.45 ± 52.99	67.38 ± 44.14	−0.075	0.940
Education level (years)	8.45 ± 2.87	8.38 ± 3.36	0.097	0.923
Sp Kt/V	1.25 ± 0.13	1.25 ± 0.12	−0.018	0.986
Sp Kt/V‐D	1.24 ± 0.12	1.23 ± 0.09	0.399	0.691
UF (L)	2.28 ± 0.54	2.28 ± 0.53	−0.027	0.978
DW (kg)	62.97 ± 8.68	63.25 ± 9.23	−0.126	0.900
BUN‐pre (mmol/L)	23.08 ± 5.11	24.01 ± 4.22	−0.783	0.437
BNU‐post (mmol/L)	7.22 ± 2.45	7.00 ± 2.02	0.379	0.706
DSI	15.10 ± 6.13	15.47 ± 7.04	−0.223	0.824
Pain VAS	2.84 ± 2.03	2.81 ± 1.44	0.059	0.953
Fatigue VAS	3.29 ± 1.32	3.44 ± 1.52	−0.409	0.684
6MWT (m)	516.58 ± 76.43	517.31 ± 78.89	−0.037	0.970
GST (kg)	28.11 ± 5.90	27.80 ± 6.84	0.190	0.850
HCS	100.87 ± 11.42	100.63 ± 10.92	0.087	0.931
Hemoglobin (g/L)	117.61 ± 14.76	117.63 ± 11.58	−0.004	0.997
MMSE score	26.10 ± 1.79	26.16 ± 1.86	−0.129	0.898
Anxiety score	30.97 ± 5.98	30.66 ± 5.85	0.209	0.835
Depression score	33.97 ± 7.34	33.72 ± 7.25	0.135	0.893

Note: Data were expressed as mean ± SD or counts.

Abbreviations: tVNS, transcutaneous auricular vagus nerve stimulation; APCKD, adult polycystic kidney disease; GN, glomerulonephritis; Sp Kt/V, single‐pool Kt/V; Sp Kt/V‐D, single‐pool Kt/V‐Daugirdas; UF, ultrafiltration volume; DW, dry weight; BUN‐pre, pre‐dialysis BUN; BNU‐post, postdialysis BUN; DSI, Dialysis Symptom Index; VAS, Visual Analog Scale; 6MWT, 6‐minute walk test; GST, grip strength test; HCS: Hemodialysis Comfort Scale; MMSE, Mini‐Mental State Examination.

3.2. Primary outcomes

At 8 weeks, the tVNS group demonstrated a statistically significant improvement in HD efficiency compared to the control group, as measured by Sp Kt/V. The mean Sp Kt/V in the tVNS group was significantly higher than that of the control group (1.31 ± 0.11 vs. 1.25 ± 0.10; p = 0.02). An upward trend in Sp Kt/V was observed as early as week 4 in the tVNS group (1.30 ± 0.11 vs. 1.24 ± 0.12; p = 0.069), though this difference did not reach statistical significance at that time (Table 2, Figure 1A).

TABLE 2.

Comparison of Sp Kt/V, UF, DW, BUN, and DSI between groups at weeks 4 and 8.

Variables	Week 4		t	p	Week 8		t	p
	Control (n = 31)	tVNS (n = 32)			Control (n = 31)	tVNS (n = 32)
Sp Kt/V	1.24 ± 0.12	1.30 ± 0.11	−1.853	0.069	1.25 ± 0.10	1.31 ± 0.11	−2.399	0.020
Sp Kt/V‐D	1.23 ± 0.11	1.29 ± 0.10	−1.991	0.051	1.24 ± 0.10	1.30 ± 0.11	−2.425	0.018
UF (L)	2.37 ± 0.54	2.27 ± 0.53	0.773	0.442	2.29 ± 0.56	2.31 ± 0.64	−0.124	0.902
DW (kg)	62.11 ± 7.62	63.48 ± 7.55	−0.712	0.239	63.68 ± 7.83	64.88 ± 9.58	−0.545	0.294
BUN‐pre (mmol/L)	23.14 ± 5.55	23.80 ± 4.91	−0.503	0.617	23.87 ± 5.53	22.40 ± 5.03	1.104	0.274
BNU‐post (mmol/L)	7.09 ± 2.18	6.86 ± 1.98	0.442	0.660	7.09 ± 1.98	5.96 ± 1.77	2.382	0.020
DSI	15.06 ± 6.14	12.16 ± 4.65	2.122	0.038	16.26 ± 5.27	12.09 ± 5.84	2.967	0.004

Note: Data were expressed as mean ± SD.

Abbreviations: BUN‐pre: pre‐dialysis blood urea nitrogen, BNU‐post: post‐dialysis blood urea nitrogen, DSI: Dialysis Symptom Index, DW: Dry Weight, Sp Kt/V: Single‐pool Kt/V, Sp Kt/V‐D: Single‐pool Kt/V‐Daugirdas, UF: Ultrafiltration volume.

FIGURE 1.

Effect of tVNS on Sp Kt/V and DSI. (A) Comparison of Sp Kt/V between the tVNS and control groups. (B) Comparison of DSI between the tVNS and control groups. *p < 0.05. tVNS, transcutaneous auricular vagus nerve stimulation; DSI, Dialysis Symptom Index.

Additionally, the Sp Kt/V values calculated manually (Sp Kt/V‐D) were closely aligned with those obtained from the Fresenius machine at both week 4 and week 8. For instance, at week 8, the Sp Kt/V‐D value in the tVNS group was significantly higher than that of the control group (1.30 ± 0.11 vs. 1.24 ± 0.10; p = 0.018), consistent with the Sp Kt/V values obtained from the Fresenius machine, further supporting the validity of the automated measurements (Table 2). Moreover, comparisons of other key variables, including UF, DW, and BUN levels, which are closely related to Sp Kt/V‐D, revealed no significant differences between the tVNS and control groups. UF values were comparable between groups at both week 4 and week 8 (p > 0.05), as were the DW and pre‐BUN levels (p > 0.05 for both parameters) (Table 2).

Furthermore, there was a significant reduction in DSI scores in the tVNS group at both week 4 and week 8 compared to the control group. At week 4, we found that the tVNS group had a lower DSI score than the control group (12.16 ± 4.65 vs. 15.06 ± 6.14; p = 0.038). This improvement was more pronounced by week 8 (12.09 ± 5.84 vs. 16.26 ± 5.27; p = 0.004) (Table 2, Figure 1B).

3.3. Secondary outcomes

Patients in the tVNS group experienced significant reductions in pain and fatigue scores at the end of the study period. The mean pain score, measured using the VAS, was significantly lower in the tVNS group compared to the control group (2.16 ± 1.11 vs. 2.97 ± 1.70; p = 0.028). Similarly, the fatigue VAS score was significantly reduced in the tVNS group (2.25 ± 1.68 vs. 3.23 ± 1.68; p = 0.025) (Table 3, Figure 2A,B).

TABLE 3.

Secondary outcomes in control and tVNS groups at week 8.

Variables	Control (n = 31)	tVNS (n = 32)	t	p
Pain VAS	2.97 ± 1.70	2.16 ± 1.11	2.248	0.028
Fatigue VAS	3.23 ± 1.68	2.25 ± 1.68	2.296	0.025
6MWT (m)	504.71 ± 76.81	543.84 ± 75.61	−2.038	0.046
GST (kg)	26.86 ± 5.00	30.12 ± 6.22	−2.285	0.026
HCS	100.13 ± 9.22	105.06 ± 8.45	−2.214	0.031
Hemoglobin (g/L)	115.13 ± 13.07	122.38 ± 12.30	−2.266	0.027
MMSE score	26.03 ± 1.77	26.09 ± 2.10	−0.125	0.901
Anxiety score	30.87 ± 5.74	31.47 ± 5.21	−0.433	0.667
Depression score	34.35 ± 7.34	33.13 ± 6.16	0.721	0.474

Data were expressed as mean ± SD.

Abbreviations: tVNS, transcutaneous auricular vagus nerve stimulation; VAS, Visual Analog Scale; 6MWT, 6‐minute walk test; GST, grip strength test; HCS: Hemodialysis Comfort Scale; MMSE, Mini‐Mental State Examination.

FIGURE 2.

Effect of tVNS on various outcomes in HD patients. (A) Pain VAS, (B) Fatigue VAS, (C) 6MWT, (D) GST, (E) HCS, (F) Hemoglobin levels, (G) MMSE score, (H) Anxiety score, (I) Depression score. *p < 0.05. tVNS, transcutaneous auricular vagus nerve stimulation; VAS, Visual Analog Scale; 6MWT, 6‐minute walk test; GST, grip strength test; HCS, Hemodialysis Comfort Scale; MMSE, Mini‐Mental State Examination.

Physical function, as assessed by the 6MWT and GST, showed significant improvements in the tVNS group. The 6MWT distance was significantly greater in the tVNS group compared to the control group (543.84 ± 75.61 meters vs. 504.71 ± 76.81 meters; p = 0.046), indicating enhanced exercise capacity. Grip strength was also significantly higher in the tVNS group than in the control group (30.12 ± 6.22 kg vs. 26.86 ± 5.00 kg; p = 0.026) (Table 3, Figure 2C,D). The HCS score, which measures patient comfort during HD, was significantly better in the tVNS group compared to the control group (105.06 ± 8.45 vs. 100.13 ± 9.22; p = 0.031) (Table 3, Figure 2E). The mean hemoglobin level was significantly higher in the tVNS group compared to the control group at the end of the 8 weeks (122.38 ± 12.30 g/L vs. 115.13 ± 13.07 g/L; p = 0.027), suggesting improved management of anemia in patients receiving tVNS (Table 3, Figure 2F).

No significant differences were found between the groups in cognitive function, as measured by MMSE (26.09 ± 2.10 in the tVNS group vs. 26.03 ± 1.77 in the control group; p = 0.901). Similarly, there were no significant differences in anxiety and depression scores at week 8 (anxiety: 31.47 ± 5.21 in the tVNS group vs. 30.87 ± 5.74 in the control group, p = 0.667; depression: 33.13 ± 6.16 in the tVNS group vs. 34.35 ± 7.34 in the control group, p = 0.474) (Table 3, Figure 2G to I).

3.4. Safety

Table 4 summarizes the adverse events reported during the entire intervention period. In the tVNS group, the most frequently observed adverse events were headache (2 cases, p = 1.000) and local tingling (1 case, p = 0.613), with no statistically significant differences compared to the control group. One patient in the tVNS group experienced a cardiovascular reaction (device‐induced tingling), which resulted in transient tachycardia and elevated blood pressure; however, this event did not necessitate the discontinuation of dialysis (p = 1.000). Additionally, dizziness was reported in 1 case (p = 1.000), and no cases of fatigue were documented (p = 0.492). Across all adverse events, no statistically significant differences were noted between the tVNS and control groups. Overall, tVNS was well tolerated, with no serious adverse reactions observed during the study period.

TABLE 4.

Reported adverse events of the tVNS in both groups.

Adverse events	Control (n = 31)	tVNS (n = 32)	p
Local tingling	2	1	0.613
Headache	1	2	1.000
Cardiovascular reactions	0	1	1.000
Dizziness	1	1	1.000
Fatigue	1	0	0.492

Note: Data were expressed as counts.

Abbreviation: tVNS, transcutaneous auricular vagus nerve stimulation.

4. DISCUSSION AND CONCLUSIONS

4.1. Discussion

This study demonstrates that tVNS significantly improves dialysis efficiency, as indicated by Sp Kt/V, and reduces dialysis symptoms, measured by the DSI, in HD patients. Additionally, tVNS led to reductions in pain and fatigue and improvements in physical performance (6MWT and grip strength), patient comfort (HCS), and hemoglobin levels. However, tVNS did not significantly affect cognitive function, anxiety, or depression scores over the 8‐week study period.

Dialysis adequacy and symptom management are central concerns in the care of HD patients, as these factors are interdependent and have a significant impact on patient outcomes [21]. Sp Kt/V is a widely accepted quantitative measure of dialysis adequacy, reflecting the efficacy of urea clearance during HD sessions. Clinical practice guidelines recommend maintaining Sp Kt/V within the range of 1.2–1.4 per session for patients undergoing HD three times per week to ensure optimal clearance of uremic toxins [22]. Adequate dialysis, as measured by Sp Kt/V, has been consistently associated with reduced uremic complications, fewer symptoms, lower morbidity, and improved survival in HD patients [23, 24]. Although variables such as interdialytic weight gain, UF, and BUN levels can influence Sp Kt/V, our study controlled for these factors to isolate the effect of tVNS on dialysis efficiency. Comparisons of these variables showed no significant differences between the tVNS and control groups at both week 4 and week 8, indicating that the improvement in Sp Kt/V was primarily due to the tVNS intervention. Dietary protein intake was also standardized at 1.2–1.4 g/kg/day to minimize the impact of dietary variations on BUN levels and Sp Kt/V outcomes. Stricter dietary controls in future studies may further clarify the interaction between diet and dialysis adequacy.

Although the precise mechanisms contributing to symptomatology in HD patients remain unclear, it is hypothesized that the accumulation of uremic toxins plays a key role in the development of symptoms such as fatigue, pain, and discomfort [21]. In our study, tVNS led to significant improvements in both Sp Kt/V and the DSI, suggesting a dual benefit of enhancing dialysis adequacy and reducing the symptom burden. Several mechanisms may explain how tVNS improves both Sp Kt/V and DSI. First, tVNS may enhance tissue perfusion and vascular regulation [25], improving urea and solute clearance during dialysis and thus enhancing Sp Kt/V. Improved vascular function and perfusion may also alleviate symptoms like fatigue and pain associated with poor oxygenation and toxin buildup. Second, tVNS may modulate inflammatory pathways by inhibiting pro‐inflammatory cytokines [9, 12], which not only reduces systemic inflammation but also alleviates inflammation‐related symptoms in HD patients. Finally, tVNS may regulate autonomic nervous system activity [9, 18], attenuating the physiological stress response during dialysis, which could contribute to improvements in both dialysis efficiency and reductions in stress‐related symptoms, such as discomfort or fatigue. These combined effects enhance both Sp Kt/V and reduce the symptom burden, ultimately leading to better dialysis outcomes.

Pain and fatigue are prevalent and debilitating symptoms experienced by HD patients, often contributing to poor adherence to treatment and decreased quality of life [21]. Previous studies have highlighted the role of VNS as a non‐pharmacological intervention for pain and fatigue management [10, 26, 27]. The vagus nerve projects to multiple brain regions involved in pain processing, which can be affected by VNS [6]. In addition to neural regulation, the anti‐inflammatory property of VNS may also enhance its pain‐inhibitory effects [18]. In this study, patients in the tVNS group reported significant reductions in fatigue, consistent with previous findings [10, 27]. Beyond pain and fatigue, pruritus, dry mouth, and other symptoms were also significantly reduced, as reflected in lower DSI scores and improved HCS ratings. These findings suggest that tVNS may contribute to better symptom control and enhance the overall prognosis for HD patients.

Anemia is a common complication in ESRD, driven by factors such as uremic toxin accumulation, chronic inflammation, and oxidative stress [28]. Adequate dialysis can enhance toxin clearance, and it has been reported that patients with optimal HD adequacy respond better to erythropoiesis‐stimulating agents [29]. In this study, hemoglobin levels significantly increased in patients treated with tVNS, likely due to improved dialysis adequacy and the potential anti‐inflammatory and antioxidant effects of tVNS, which may enhance the efficacy of erythropoietin and promote hemoglobin production.

This study also demonstrated that tVNS significantly improved physical performance, as measured by the 6MWT and grip strength. These findings suggest that tVNS may have therapeutic potential in enhancing exercise capacity and slowing muscle strength decline in ESRD patients. This result aligns with prior studies on the use of VNS in stroke rehabilitation, where VNS was shown to enhance motor function [30, 31]. Given the high burden of physical impairment in HD patients, this therapeutic effect of tVNS could have important implications for improving patient mobility and quality of life.

VNS has been shown to have positive effects on mood disorders, and it is approved for the treatment of epilepsy and depression in Europe [32, 33]. The stimulation of afferent fibers linked to limbic system structures is believed to underlie the mood‐improving effects of VNS [34]. VNS has also been shown to modulate neurotransmitter levels, mimicking the effects of pharmacological treatments for anxiety and depression [35]. However, these benefits typically require extended treatment periods (12–24 months) to manifest. In this study, no significant improvements in anxiety or depression were observed, potentially due to the short follow‐up period and limited sample size. Future studies with longer follow‐up durations are needed to validate the potential mood benefits of tVNS in HD patients.

Regarding cognitive function, the evidence supporting the efficacy of VNS is limited, with only a few studies reporting improvements [34, 36]. In this study, cognitive function was assessed using the MMSE, which, although widely used, may lack sensitivity, especially for detecting mild cognitive impairment. Additionally, cognitive improvement is typically a slow process, and the 8‐week duration of this study may have been insufficient to capture significant changes. Longer‐term studies with more sensitive cognitive assessment tools are necessary to fully understand the impact of tVNS on cognitive outcomes in HD patients.

This study has several limitations. First, it was conducted at a single center, with a relatively small sample size and a short follow‐up period, which may have limited the statistical power to detect significant changes. Second, there is currently no established gold standard for tVNS parameters, and future studies should explore a range of stimulation parameters to optimize efficacy. Additionally, the intermittent delivery of tVNS, as opposed to daily stimulation, may have influenced the overall outcomes of the study.

4.2. Conclusions

In conclusion, this study indicates that an 8‐week course of tVNS can improve dialysis efficiency, alleviate symptoms such as pain and fatigue, and enhance physical function, comfort, and hemoglobin levels in HD patients. However, no significant effects were observed on cognitive function, anxiety, or depression. tVNS presents a promising complementary approach for managing complications in HD patients; however, further research is needed to validate these findings and assess long‐term outcomes.

FUNDING INFORMATION

This study was supported by the National Natural Science Foundation of China (81801068).

CONFLICT OF INTEREST STATEMENT

The authors have no conflicts of interest to declare.

ETHICS STATEMENT

This study protocol was reviewed and approved by the Ethics Committee of Sinopharm Gezhouba Central Hospital. The research was conducted in accordance with the ethical standards outlined in the World Medical Association Declaration of Helsinki.

PATIENT CONSENT STATEMENT

Written informed consent was obtained from all participants.

PERMISSION TO REPRODUCE MATERIAL FROM OTHER SOURCES

No material from other sources is reproduced in this work.

Zhang Q, Dou J, Ao H, Guo D, Yang X, Li M. Effect of transcutaneous vagus nerve stimulation in hemodialysis patients: A randomized controlled trial. Ther Apher Dial. 2026;30(5):739–748. 10.1111/1744-9987.14243

DATA AVAILABILITY STATEMENT

The raw data supporting the conclusions of this article will be made available by the authors upon reasonable request, without any undue restrictions.