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. 2023 Jun 19;14(2):48–53. doi: 10.4103/2045-9912.378880

Therapeutic effect of hydrogen and its mechanisms in kidney disease treatment

Jin Cheng 2, Minmin Shi 2, Xuejun Sun 1,3, Hongtao Lu 1,*
PMCID: PMC10715323  PMID: 37929507

Abstract

Hydrogen is a simple, colorless, and biologically active small molecule gas that can react with reactive oxygen species. Recent research suggests that hydrogen possesses several biological effects, including antioxidant, anti-inflammatory, and anti-apoptotic effects, while exhibiting an extremely high level of safety. Hydrogen application has shown promise in treating a range of acute and chronic diseases, both benign and malignant. Importantly, an increasing number of clinical studies on hydrogen have demonstrated its efficacy and safety in treating various diseases. This review highlights the beneficial effects of hydrogen in kidney diseases, summarizes potential mechanisms by which hydrogen may act in these diseases, and proposes several promising avenues for future research.

Keywords: acute kidney injury, anti-apoptosis, anti-inflammation, anti-oxidation, chronic kidney disease, end-stage renal disease, hydrogen, therapeutic effect

INTRODUCTION

In 2007, Professor Shigeo Ohta discovered that hydrogen (H2) can selectively scavenge hydroxyl radical (-OH) and nitrite anion free radical (ONOO-) to alleviate oxidative damage caused by middle cerebral artery ischemia/reperfusion (I/R) in rats.1 Since then, H2 has emerged as a promising area of research in medical gas therapy.2 As the simplest and colorless small molecule gas, H2 has been studied for over a decade and has shown various physiological regulatory activities and signal transduction functions. In the field of medicine, animal model studies and clinical trials have shown that H2 has anti-inflammatory, anti-apoptotic, and anti-oxidative effects, but the main molecular targets have yet to be identified.

In recent years, H2 has been suggested as a potential therapeutic and preventive treatment for various kidney diseases (Table 1).3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 According to epidemiological data, the incidence of chronic kidney disease (CKD) in the Chinese population is estimated to be 11–13%, resulting in over 100 million CKD patients in China.22 Due to the complex physiological function and special tissue structure of the kidney, it is particularly vulnerable to damage in many cases. Kidney disease has become a major chronic illness that not only increases medical expenses, but also leads to a decline in the quality of life for affected individuals, particularly the elderly. Oxidative stress and inflammation are important mechanisms in the progression of kidney disease. As a new type of antioxidant, H2 has shown promise in the treatment of kidney diseases.

Table 1.

Application of hydrogen in kidney diseases

Kidney disease Mechanism
 Signal pathway The intake of hydrogen Animals Hydrogen concentration Reference
Anti-oxidation Anti-inflammation Anti-apoptosis Anti-fibrosis Other
CsA-induced nephrotoxicity ROS, MDA, GSH, SOD Keap1/Nrf2 HR-water Adult male Sprague- Dawley rats ≥ 0.6 ppm Lu et al.3
PD-related peritoneal fibrosis ROS (in vitro) FN, α-SMA, MMP1, E-cadherin, vimentin ROS-PTEN- AKT-mTOR IP-HR- solution Male C57B/L6 mice (21–25 g) Lu et al.4
Sepsis-related AKI IL-6, TNF-α, IL-4, IL-13, IL-10, TGF-β, CD16, CD206 Promote M2 macrophage polarization Inhalation of a HR solution Male C57B/L6 mice (20–25 g) > 0.6 mM Yao et al.5
I/R-AKI α-SMA, collagen-1 Klotho, Beclin-1, LC3-II Klotho/ Beclin-1, LC3-II/ autophapy IP-HR-saline Male C57BL/6 mice (8-wk-old) 0.6 mM Chen et al.6
UUO α-SMA, fibronection, E-cadherin, Smad2, Sirt1, TGF-β1 TGF-β1/ SMAD/Sirt1 HR-water Male Balb/c mice (25±3 g) 0.6 MPa dissolve in water for 2 h Xing et al.7
I/R-AKI IL-6, TNF-α Bcl-2, Bax, Caspase3, Caspase9, Caspase8 IP-HR- solution Sprague-Dawley rats (250–300 g) 0.6 mM Li et al.8
AKI after OLT MDA, SOD Caspase3, Cyt-C Beclin-1, LC3- II, P62, LAMP2, p-P53 P53/DRAM/ Beclin-1, LC3-II/ autophapy Inject-HR- saline Male Sprague- Dawley rats (220±10 g) 0.6 mM Du et al.9
Severe burn- induced early AKI MDA, SOD, CAT, GSH-Px IL-6, TNF-α, IL-1β, IL- 10, ICAM-1, NF-κB, ERK, p-ERK JNK, p-JNK, AKT, p-AKT, P38, p-P38 MARK/ AKT/NF-κB IP-HR saline Male Sprague- Dawley rats (220–250 g) > 0.6 mM Guo et al.10
Severe AP-induced early AKI MDA, SOD IL-6, TNF-α, IL-1β, IL-10, NF-κB, MPO, IκBa IκBa/NF-κB Inject -HR- saline Male Wistar rats (200–250 g) > 0.6 mM Shi et al.11
Renal injury in spontaneously HT MDA, TAC, ROS, O2-, OONO-, SOD, GPx, catalase, GST, NADPH oxidase IκKBa/NF-κB HR-water Male spontaneously hypertensive rats; male Wistar-Kyoto rats (8-wk-old) > 0.8 mg/L Xin et al.12
Rhabdomyolysis induced AKI ROS, MDA, SOD, GSH-Px, 8-OH-dG TNF-α, IL-6 IP-HR-saline Male Wistar rats (180–200 g) 0.6 nM Gu et al.13
Ferric NTA- induced nephrotoxicity HO-1, HO-2, MDA, OONO-, catalase, NADPH oxidase, xanthine oxidase IL-6, MCP-1, NF-κB JAK/STAT/ PCNA HR-water Male Wistar rats (200–230 g) > 0.8 mg/L Li et al.14
Renal injury induced by UUO MDA, SOD ED1 Apoptotic tubular cells were determined by TUNEL-positive staining Interstitial fibrotic area IP-HR-saline Male Sprague- Dawley rats (180–200 g) 0.4 MPa dissolve in saline for 4 h Xu et al.15
T2DM and MS ROS, MDA HR-water Male stroke-prone spontaneously hypertensive rats (5-wk-old) 0.3-0.4 ppm Katakura et al.16
Renal cold I/R injury in kidney transplantation MDA, 8-OH-dG, iNOS, HO-1 ED1, IFN-γ, IL-6, TNF-α, CCL2, IL-1β Apoptotic tubular cells were determined by TUNEL-positive staining Kidney grafts were preserved in HRUW solution Inbred male Lewis (LEW) rats (250–350 g) 1.61 mg/L Abe et al.17
Gentamicin- induced nephrotoxicity Na+-K+- ATPase HR-water Male Sprague- Dawley rats (284±23 g) 1.2±0.1 mg/L Matsushita et al.18
Cisplatin-induced nephrotoxicity Na+-K+- ATPase HR-water Male Sprague- Dawley rats (284±4 g) 1.2±0.1 mg/L Kitamuta et al.19
Renal I/R injury MDA, 8-OH-dG, SOD, CAT IL-6, TNF-α, IL-1β, MPO Apoptotic tubular cells were determined by TUNEL-positive staining IP-HR-saline Male Sprague- Dawley rats (200–220 g) > 0.6 nM Wang et al.20
Renal I/R injury 8-OH-dG Inject-HR- saline Male Wistar rats (250–300 g) 640 μM Shingu et al.21
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Note: 8-OH-dG: 8-Hydroxy-2'-deoxyguanosine; AKI: acute kidney injury; AKT: AKT serine/threonine kinase 1; AP: acute pancreatitis; ATPase: adenosine triphosphatase; CAT: catalase; CCL2: chemokine (C-C motif) ligand 2; CsA: cyclosporine A; Cyt-C: cytochrome-C; DRAM: DNA damage regulated autophagy modulator; ED1: ectodysplasin A; ERK: extracellular signal-regulated kinase; FN: fibronectin 1; GSH: glutathione; GSH-Px: glutathione peroxidase; GST: glutathione S-transferase; HO: hemeoxygenase; HR: hydrogen-rich; HRUW: Hydrogen-Rich University of Wisconsin; HT: hypertension; ICAM-1: intercellular adhesion molecule 1; IL: interleukin; IP: prostacyclin; I/R: ischemia/reperfusion; IκBa: NF-κB inhibitor alpha; JAK: Janus kinase; LAMP2: lysosomal associated membrane protein 2; LC3-II: microtubule associated protein 1 light chain 3-II; MARK: microtubule-affinity regulating kinase; MDA: malondialdehyde; MMP1: matrix metallopeptidase 1; MPO: myeloperoxidase; MS: metabolic syndrome; mTOR: mechanistic target of rapamycin kinase; NF-κB: nuclear factor kappa-B; NADPH: nicotinamide adenine dinucleotide phosphate; NTA: nitrilotriacetate; O2-: superoxide anion; OLT: orthotropic liver transplantation; OONO-: peroxynitrite; p-ERK: phosphorylated ERK; p-P53: phosphorylated p53; PCNA: proliferating cell nuclear antigen; PD: peritoneal dialysis; PTEN:phosphatase and tensin homolog; ROS: reactive oxygen species; Sirt1: sirtuin 1; SOD: superoxide dismutase; STAT: signal transducer and activator of transcription; T2DM: type 2 diabetes mellitus; TAC: total antioxidant capacity; TGF-β: transforming growth factor-β; TNF-α: tumour necrosis factor-α; TUNEL: terminal deoxynucleotide transferase-mediated dUTP nick end labeling; UUO: unilateral ureteral obstruction; α-SMA: alpha-smooth muscle actin.

To analyze the application of H2 in kidney disease, 20 related articles in the past 10 years were analyzed using VOS Viewer software (v.1.6.15.0, Centre for Science and Technology Studies, Leiden University, Leiden, the Netherlands). A co-occurrence analysis of terms that appear twice or more in the article title and abstract was conducted (Figure 1). Each cluster, represented by a different color, is centered on a specific subject. The red Cluster 1, containing 36 items, is primarily focused on animal experiments, where hydrogen-rich (HR) water pretreatment was found to reduce cytokine production in acute kidney injury (AKI) models and improve kidney fibrosis in unilateral ureteral obstruction models. The top ten items in this cluster are mice, roles, antioxidants, cells, cytokines, data, AKI, development, fibrosis, and survival. The green Cluster 2, containing 25 items, is centered on H2 treatment pathways for kidney disease. The blue Cluster 3 is focused on molecular hydrogen's ability to reduce renal I/R injury through anti-oxidation and anti-apoptosis. Cluster 4 is centered on the role of HR water in organ preservation. The results are presented in four clusters, highlighting the therapeutic effects and potential mechanisms of H2 in the kidney disease.

Figure 1.

Figure 1

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Social network diagram on keywords about the hydrogen application in kidney disease in the past 10 years.

Note: The red Cluster 1 is primarily focused on animal experiments. The green Cluster 2 is centered around hydrogen treatment pathways for kidney disease. The blue Cluster 3 is focused on molecular hydrogen's ability to reduce renal I/R injury through anti-oxidation and anti-apoptosis. Cluster 4 is centered on the role of hydrogen-rich water in organ preservation. I/R: Ischemia/reperfusion.

HYDROGEN PROTECTIONS IN DIFFERENT KINDS OF KIDNEY DISEASES

Application of hydrogen in renal I/R injury

AKI is a prevalent and costly disease with high morbidity and mortality rates, particularly among the elderly population. Renal I/R injury is a significant contributor to AKI and is inevitable in various clinical scenarios such as kidney transplantation, partial nephrectomy, and treatment of renal aortic aneurysm.23,24,25 Although the mechanism of renal I/R injury may involve oxygen free radicals, inflammation, apoptosis, adhesion factors between endothelial cells, and calcium overload, the exact mechanism of renal injury is still unclear.26 Recent studies have demonstrated that H2 can protect renal tissue from I/R-induced oxidative damage, primarily due to the anti-inflammatory and anti-apoptotic effects of H2 and selective reduction of cytotoxic reactive oxygen species, particularly -OH and ONOO-.8,20 Furthermore, it has been reported that H2 can also mitigate I/R damage to other organs such as the heart,27,28 lungs,29 liver,30 and intestines.31,32,33

Application of hydrogen in renal transplantation

Renal transplantation remains the most effective treatment for end-stage renal disease (ESRD). However, kidney I/R injury is an inevitable consequence of renal transplantation, and the duration of cold ischemia time is a potential risk factor for the survival of donor kidney transplantation. In a study conducted by Japanese scholar Abe et al.,17 a H2 dissolving device from Miz Company was used to electrolyze circulating water between a water tank and an electrolyzer. H2 was produced continuously, which allowed the concentration of H2 in the water to reach 1.61 mg/L at 20°C. They then prepared hydrogen-rich University of Wisconsin organ protection solution (HRUW) by immersing 50 mL centrifuge tubes containing University of Wisconsin solution (ViaSpan; DuPont, Wilmington, DE, USA) into MiZ hydrogen-saturated water for 48 hours. It was found that after 24 hours of refrigeration, there was no significant difference in the survival rate between the UW group and the HRUW group. However, HRUW treatment significantly improved renal function, reduced renal tubular damage, and inhibited the development of renal tubular cell apoptosis and interstitial fibrosis. The possible mechanism for this is that H2 protects cells by reducing oxidative damage to DNA, lipids, and proteins. Compared with UW preservation solution, the level of malondialdehyde in renal tissue was significantly reduced, indicating that HRUW treatment reduced the level of reactive oxygen species. Additionally, this study showed that HRUW treatment inhibited the expression of inducible nitric oxide synthase, which is responsible for producing nitric oxide. The reaction of nitric oxide with superoxide anion radical (O2) forms another highly active peroxynitrite ion (ONOO-), which causes oxidation/nitration modification of biomolecules and regulates physiological and pathophysiological processes. Several studies have shown that inhibiting inducible nitric oxide synthase can reduce I/R injury,34,35,36 indicating that inducible nitric oxide synthase plays an important role in this process.

Application of hydrogen in hemodialysis and peritoneal dialysis

The number of ESRD patients worldwide is increasing annually. In China, the prevalence of CKD is as high as 10.8%, and 1% of CKD patients will develop ESRD.37 Hemodialysis (HD) and peritoneal dialysis (PD) are the main alternative therapies for ESRD, with renal transplantation being the most ideal treatment option. However, due to the scarcity of kidney resources and patient physical and economic conditions, HD and PD remain the most common treatment methods. Both of these dialysis methods use a large amount of dialysate during the process, which allows H2 to enter the body as a carrier. As the smallest molecule in nature, H2 has the characteristics of strong penetration and rapid diffusion and can enter the blood and body through free diffusion. In recent years, more and more studies have focused on H2-containing dialysate. It has been found that HR dialysate (with an average H2 concentration of 50 ppb) can effectively reduce oxidative stress levels in the dialyzer, improve the nutritional status of dialysis patients, and reduce the incidence of cardiovascular disease.38,39 H2-containing dialysate does not reduce biocompatibility or increase the risk of infection, making it a possible clinical application for HR dialysate.40,41

Patients with HD who have elevated levels of oxidative stress are more likely to have severe cardiovascular disease. The contact between blood and the dialysis membrane increases the level of oxidative stress during HD. Japanese scholar Nakayama and his team developed a new HD system that delivers HR dialysate (with a H2 concentration range of 30–80 ppb) through water electrolysis. After more than three years of observation, the study shows that HR HD can reduce the incidence of end-point events, such as all-cause mortality and non-fatal cardiovascular and cerebrovascular events (such as heart disease, stroke, and limb amputation caused by peripheral artery disease) compared to conventional HD patients, improving the prognosis of long-term HD patients.40,41 As an alternative therapy for ESRD patients, PD has the advantage of better protecting residual renal function and stabilizing hemodynamics. However, the long-term use of peritoneal dialysate can lead to peritoneal fibrosis and peritoneal failure, resulting in the discontinuation of PD. Scholar Nakayama and his team40,41 produced H2 in peritoneal dialysate by electrolyzing water. The H2-containing peritoneal dialysate can improve apoptosis, proliferation, and fibrosis of peritoneal surface cells. Animal experiments have shown that H2-containing peritoneal dialysate has a certain protective effect on mesothelial cells and the integrity of the peritoneum.40,41 H2 has also been used in clinical cases. Encapsulated peritoneal sclerosis (EPS), the most serious and life-threatening complication of PD, has a high mortality rate. Recent reports show that the mortality rate of EPS is 14–84%. Extensive peritoneal fibrosis in patients with EPS can lead to malnutrition and intestinal obstruction. Inflammation, angiogenesis, and fibrosis of the peritoneum are the key factors, while peritoneal fibrosis and adhesion are the core elements.42,43 Although drug interventions (such as tamoxifen, steroids, and new immunosuppressive agents) can delay the progression of EPS, the effect is still poor, and the side effects are significant.44 Adverse reactions such as ischemic stroke and pulmonary embolism are related to tamoxifen, and opportunistic infections are related to corticosteroids. In contrast, H2 has been tested in deep water diving, and no toxicity has been found even at high concentrations. This case study shows that the delivery of H2 through HD and peritoneal lavage, in addition to giving oral prednisolone treatment, can improve EPS. Therefore, H2 is expected to become a new alternative drug therapy for EPS.45

Application of hydrogen in other kidney diseases

Cisplatin is a highly effective chemotherapeutic drug that has a broad anti-cancer spectrum and a strong synergistic effect with a variety of other anti-tumor drugs. However, the efficacy of cisplatin is dose-dependent, and its significant risk of nephrotoxicity often hinders the use of higher doses, thereby limiting its anti-tumor effect. Accumulation of reactive oxygen species at high concentrations plays a crucial role in cisplatin-induced nephrotoxicity.46 Studies have shown that inhalation of H2 and oral intake of HR water can reduce cisplatin-induced nephrotoxicity without affecting its anti-tumor activity.47 Furthermore, H2 has shown to be effective in reducing kidney injury caused by other factors such as nephrotoxicity caused by nitrogenous ferric acetate,14 unilateral ureteral obstruction,15 septic shock,48 acute pancreatitis,11 and burns.10 HR water supplementation has also been confirmed to be effective in treating interstitial cystitis/painful bladder syndrome, with the results indicating significant improvement in bladder pain scores in 11% of patients.49 However, further research with an extended observation period and a larger number of clinical cases are necessary. In addition, H2 has demonstrated advantages in interfering with various chronic diseases related to kidney diseases, such as diabetes, arteriosclerosis, hypertension, and others that significantly threaten human health. An intervention study in 2008 demonstrated the effect of drinking HR water on patients with type 2 diabetes. The results showed a decrease in the levels of oxidized low-density lipoprotein and free fatty acid in serum, while the level of plasma adiponectin and extracellular superoxide dismutase increased in patients who consumed HR water daily. Among the six patients with impaired glucose tolerance, four patients recovered their normal glucose tolerance test by consuming HR water, indicating its potential in preventing type 2 diabetes and insulin resistance.50 Furthermore, a double-blind, randomized, placebo-controlled trial by domestic scholars showed that the intake of HR water reduced plasma low-density lipoprotein cholesterol levels in patients with metabolic syndrome. H2 activates the A1-dependent efflux of ATP-binding transporter and enhances the anti-atherosclerotic function of high-density lipoprotein.51 These findings suggest that H2 has the potential to prevent atherosclerosis.

SUMMARY AND PERSPECTIVE

H2 medicine is rapidly advancing and has unique advantages compared to hydrogen sulfide and other cytotoxic antioxidants. H2 is safe and has strong diffusion ability, making it an attractive treatment method. Recent studies have shown that H2 has anti-oxidant, anti-inflammatory, and anti-apoptotic effects, making it an effective treatment for a variety of diseases. Despite numerous studies confirming the preventive and therapeutic effects of H2, the specific mechanisms of H2 on human diseases remain unclear, especially in the field of urinary system research. However, the safety and accessibility of H2 offer excellent opportunities for extensive research in this area. Overall, H2 shows great potential as a promising new treatment for various urinary system diseases.

Author contributions

Study design: HL and XS; paper drafting: JC and MS. All the authors approved the final version of the manuscript.

Conflicts of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. Editor note: Xuejun Sun is an Editorial Board member of Medical Gas Research. He was blinded from reviewing or making decisions on the manuscript. The article was subject to the journal's standard procedures, with peer review handled independently of this Editorial Board member and his research group.

Data availability statement

No additional data are available.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

Funding Statement

Funding: This work was supported by Foundation of Naval Medical University, No. 2019QH001, Foundation of Center of Hydrogen Science, No. WF510105001, Shanghai Rising-Star Program, No. 20YF1458200, Foundation of Qingdao Special Food Research Institute, No. 66120002, Key Specialty Construction Project of Changning District of Shanghai, No. 20191005, and Health Service Key Project of Naval Medical Center of PLA, No. 22M3201.

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