Fatigue is a pervasive and debilitating symptom in patients undergoing hemodialysis (HD) and is associated with an increased risk of adverse outcomes including death, cardiovascular disease, and depression; the contributing factors of fatigue in HD patients include anemia, fluid and electrolyte imbalances, and stress induced by the procedure.1 Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) initiative, aimed at advancing clinical research in nephrology, recognizes fatigue as a core outcome, along with cardiovascular disease, vascular access function, and mortality.2 The median country-specific use of HD was 298.4 per million population and the prevalence of fatigue ranges from 60% to 97% in HD patients.3
The specific causes of fatigue in patients undergoing HD are unclear. Based on the pathophysiology of chronic fatigue syndrome, the chronic activation of sustained oxidative stress, inflammation, and secondary mitochondrial dysfunction in the central nervous system could be implicated in fatigue experienced by patients undergoing HD.4,5
Given the limitations of previous interventions and the multifactorial nature of fatigue in patients undergoing HD, innovative approaches to address the underlying causes of fatigue are crucial. Molecular hydrogen (H2) has antioxidant properties, which may help reduce oxidative stress by scavenging excess hydroxyl radicals, potentially improving well-being and alleviating fatigue. A recent 8-week study on electrolyzed water hemodialysis showed fatigue amelioration in patients undergoing HD despite suboptimal dialysate H2 levels averaging 154 ppb.6 This suggests that a higher concentration of H2 is necessary to achieve further improvements in fatigue. Therefore, we conducted this case study to test this hypothesis by examining the efficacy of combining H2 gas inhalation with higher H2-enriched dialysate in two HD patients with fatigue. We herein present male patients who have successfully responded to this combined therapy.
Case 1: A 64-year-old male with end-stage renal disease due to nephrosclerosis, comorbidities including coronary artery bypass grafting, aortic valve replacement, and carpal tunnel syndrome. He had been on dialysis for 23 years at our clinic, primarily using HD or hemodiafiltration (HDF). Maximum fatigue and cognitive fog occurred after 3 hours of dialysis initiation and persisted for 18 hours. The patient transitioned from electrolyzed water online hemodiafiltration (EW-OL-HDF) monotherapy for 45 months to combined therapy with H2 gas inhalation for 3 months. Antiplatelet drugs, anticoagulants, statin, beta-blockers, and phosphate binders have been used. No antihypertensive agents have been prescribed.
Case 2: A 53-year-old male with end-stage renal disease due to chronic glomerulonephritis, comorbidities including sleep apnea syndrome, atrial radiofrequency ablation, and carpal tunnel syndrome. He had undergone dialysis for 30 years at our clinic, primarily using HD or HDF. Maximum fatigue, impaired thinking, and headache occurred after 4 hours of dialysis initiation and persisted for 16 hours. The patient switched from EW-OL-HDF monotherapy for 76 months to combined therapy with H2 gas inhalation for 3 months. Vitamin B12, proton pump inhibitor, and phosphate binders have been used. No antihypertensive agents have been prescribed.
The medication did not affect these two patients’ fatigue.
EW-OL-HDF: The novel HD system, electrolyzed water hemodialysis, employed electrolyzed water with H2 as the dialysate prepared by reverse osmosis. The personal use model (Trim Medical Institute, Osaka, Japan; EW-SP11-HD) delivered H2-dissolved dialysate through water electrolysis, with an average H2 concentration of 300 ppb. In EW-OL-HDF with pre-dilution mode, acetate-free dialysate (Carbostar-L®; AY Pharmaceuticals Co., Ltd., Tokyo, Japan), and low-molecular-weight heparin were used.
H2 gas inhalation: The experimental setup involves a nasal cannula connected to the H2JI1 gas generator (Doctors Man Co., Ltd., Yokohama, Japan), generating 99.99% pure H2 gas at 250 mL/min.7 Both patients inhaled 2.5% H2 gas for 4–5 hours, three times weekly, only during HD therapy.
This study investigated the effects of our 3-month combined therapy in patients undergoing EW-OL-HDF. Serum citrullinated histone H3 (CitH3) levels were determined using an enzyme-linked immunosorbent assay kit (Cayman Chemical, Ann Arbor, MI, USA) according to the manufacturer’s instructions. Dialysate H2 levels were measured using a dissolved hydrogen meter (DH-35A, TOA DKK, Tokyo, Japan), and blood H2 concentrations were determined using gas chromatography with a semiconductor detector (TRIlizer mBA-3000, TAIYO Instruments INC, Osaka, Japan). The SONG-HD Fatigue measure comprises three items that assess the effect of fatigue on life participation, tiredness, and energy levels, on a scale ranging from 0 (no fatigue) to 9 (maximum fatigue).1 The Euro-Qol (EQ) Visual Analog Scale (VAS) ranges from 0 (“worst imaginable health”) to 100 (“best imaginable health”).8 Our findings revealed decreased serum CitH3 levels and other oxidative stress markers such as human nonmercaptalbumin,9 toxic advanced glycation end-products,10 and flow-mediated dilation11 after therapy. Furthermore, patient-reported outcomes, including SONG-HD fatigue and EQ-VAS scores, showed remarkable improvements (Table 1 and Figure 1). The median SONG-HD fatigue scores for conventional HDF, EW-OL-HDF, and combined therapy were 9, 3, and 0 in both patients, respectively. Furthermore, the median EQ-VAS scores were 0, 30, and 100 in case 1, and 0, 35, and 100 in case 2, respectively. Following the transition to conventional HDF, we observed a remarkable change in both the SONG-HD fatigue score and the EQ-VAS score. Specifically, the median SONG-HD fatigue score returned to 9, and the median EQ-VAS score returned to 0.
Table 1.
Laboratory findings and patient-reported outcomes of the combined therapy after 3 months
| Case 1 | Case 2 | ||||
|---|---|---|---|---|---|
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| Parameters | EW-OL-HDF | EW-OL-HDF+H2 gas | EW-OL-HDF | EW-OL-HDF+H2 gas | Control |
| CitH3 (ng/mL) (pre/post) | 0.2/8.48 | 0.2/1.58 | 0.2/6.71 | 0.25/4.32 | |
| HNA (%) (pre/post) | 38.62/26.01 | 29.43/26.34 | 45.02/27.06 | 39.85/23.58 | 25.1±3.0 |
| TAGE (U/mL) | 8.52 | 7.15 | 7.86 | 7.85 | 6.96±2.36 |
| FMD (%) | 1.8 | 2.0 | 1.9 | 2.6 | > 6.0 |
| SONG-HD Fatigue | 3 | 0 | 3 | 0 | 0 |
| EQ-VAS | 30 | 100 | 35 | 100 | 100 |
| DH in blood (ppb) (inlet/outlet) | 0.23/240.33 | 22.8/373.51 | 0.33/312.23 | 24.0/308.23 | 0 |
CitH3: Citrullinated histone H3; DH: dissolved hydrogen; EQ-VAS: EuroQol Visual Analog Scale; EW-OL-HDF: electrolyzed water on-line hemodiafiltration; FMD: flow-medi-ated dilation; HNA: human nonmercaptalbumin; inlet/outlet: blood obtained from the inlet and outlet of hemodiafilter at the end of EW-OL-HDF; pre/post: serum levels at the start and end of EW-OL-HDF; SONG-HD Fatigue: standardized outcomes in nephrology-hemodialysis fatigue; TAGE: toxic advanced glycation end-products.
Figure 1.
Changes in patients based on the EQ-VAS during various therapies.
Conv.HD: Conventional hemodialysis; EQ-VAS: Euro-Qol Visual Analog Scale; EW-OL-HDF: Electrolyzed water online hemodiafiltration; H2 gas: H2 gas inhalation.
In this case study, we examined the efficacy of combined therapy of H2 gas inhalation together with H2-enriched dialysate in two cases in HD patients. We emphasize two important clinical issues in this report. First, combined therapy was associated with disappeared fatigue compared to EW-OL-HDF alone. Recent studies on electrolyzed water hemodialysis have shown improvements in fatigue in patients undergoing HD during an 8-week observation period.6 However, the degree of improvement was mild and not substantial.6 Second, the combined therapy showed a reduction in post-dialysis serum levels of CitH3 compared with EW-OL-HDF alone. Reactive oxygen species play a central role in neutrophil extracellular trap (NET) formation12 and CitH3 has been identified as a specific NET biomarker.13,14 Neutrophil activation during HD contributes to endothelial inflammation and damage.15 In patients undergoing HD, several factors can induce NET formation, including organ ischemia such as cerebral ischemia and/or myocardial stunning,16 inflammatory cytokines, endogenous “sterile” triggers, heparin, and uremic toxins.17,18 Heparin directly stimulates NET formation and induces both lytic and vital NETs. Low-molecular-weight heparin was found to have significantly lower NET-inducing activity than unfractionated heparin.19
H2 exhibits selective anti-oxidative, and anti-inflammatory activities, impacting the mitochondria, immune system, and endoplasmic reticulum stress, and plays a role in cell death, such as anti-apoptosis and regulation of autophagy, ferroptosis, and pyroptosis.20 A recent study showed that H2 gas suppresses NET production and alleviates inflammation.21 Fe-porphyrin (hematin), a redox-related biocatalyst/biosensor of H2, also plays a role in this process.22
In conclusion, the results of this case study suggest that our combined therapy can alleviate fatigue in patients undergoing HD. As a limitation, we report a case study involving a small number of patients. Nevertheless, combined therapy is associated with the disappearance of fatigue compared to EW-OL-HDF alone and with a decrease in the formation of NETs. Our report shows that adding gas inhalation to EW-OL-HDF is associated with managing fatigue and inflammation in HD patients. Therefore, further studies with larger cohorts including age, sex, oxidative stress, and inflammation-related parameters with a longer follow-up period are warranted to validate these findings.
Ethical approval was waived for this study because it is not a research study. Written informed consent was obtained from the subjects for the publication of data included in this article.
The authors would like to thank Sou Hashimoto and Yasuyo Aoyama (Doctors Man Co., Ltd.), Masayoshi Takeuchi (Kanazawa Medical University), and Tatsuo Shimosawa (International University of Health and Welfare) for their assistance with this research.
References
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