REVIEW

Therapeutic effect of hydrogen and its mechanisms in

kidney disease treatment
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Jin Cheng2, Minmin Shi2, Xuejun Sun1, 3, Hongtao Lu1, *

1 Department of Naval Medicine, Naval Medical University, Shanghai, China
2 Naval Medical Center, Naval Medical University, Shanghai, China 3 Center of Hydrogen Science, Shanghai Jiao Tong University, Shanghai, China
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*Correspondence to: Hongtao Lu, PhD, hongtao_lu1990@163.com.

orcid: 0000-0002-0414-5798 (Hongtao Lu)

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.

Key words: acute kidney injury; anti-apoptosis; anti-inflammation; anti-oxidation; chronic kidney disease; end-stage renal disease; hydrogen;
therapeutic effect

doi: 10.4103/2045-9912.378880
How to cite this article: Cheng J, Shi M, Sun X, Lu H. Therapeutic effect of hydrogen and its mechanisms in kidney disease treatment. Med
Gas Res. 2024;14(2):48-53.
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.

INTRODUCTION software (v.1.6.15.0, Centre for Science and Technology

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).3-21 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.
To analyze the application of H2 in kidney disease, 20 related
articles in the past 10 years were analyzed using VOS Viewer
48
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.
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 trans-
plantation, partial nephrectomy, and treatment of renal aortic
aneurysm.23-25 Although the mechanism of renal I/R injury may
© 2023 Medical Gas Research | Published by Wolters Kluwer - Medknow
 Cheng et al. / Med Gas Res www.medgasres.com

Table 1: Application of hydrogen in kidney diseases

Mechanism

Anti- Signal The intake Hydrogen

Kidney disease Anti-oxidation inflammation Anti-apoptosis Anti-fibrosis Other pathway of hydrogen Animals concentration Reference
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CsA-induced ROS, MDA, Keap1/Nrf2 HR-water Adult male Sprague- ≥ 0.6 ppm Lu et al.3
nephrotoxicity GSH, SOD Dawley rats
PD-related ROS (in vitro) FN, α-SMA, ROS-PTEN- IP-HR- Male C57B/L6 mice Lu et al.4
peritoneal fibrosis MMP1, AKT-mTOR solution (21–25 g)
E-cadherin,
vimentin
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Sepsis-related AKI IL-6, TNF-α, Promote M2 Inhalation of Male C57B/L6 mice > 0.6 mM Yao et al.5
IL-4, IL-13, macrophage a HR solution (20–25 g)
IL-10, TGF-β, polarization
CD16, CD206
I/R-AKI α-SMA, Klotho, Klotho/ IP-HR-saline Male C57BL/6 mice 0.6 mM Chen et al.6
collagen-1 Beclin-1, Beclin-1, (8-wk-old)
LC3-II LC3-II/
autophapy
UUO α-SMA, TGF-β1/ HR-water Male Balb/c mice 0.6 MPa Xing et al.7
fibronection, SMAD/Sirt1 (25±3 g) dissolve in
E-cadherin, water for 2 h
Smad2, Sirt1,
TGF-β1
I/R-AKI IL-6, TNF-α Bcl-2, Bax, IP-HR- Sprague-Dawley rats 0.6 mM Li et al.8
Caspase3, Caspase9, solution (250–300 g)
Caspase8
AKI after OLT MDA, SOD Caspase3, Cyt-C Beclin-1, P53/DRAM/ Inject-HR- Male Sprague- 0.6 mM Du et al.9
LC3- Beclin-1, saline Dawley rats
II, P62, LC3-II/ (220±10 g)
LAMP2, autophapy
p-P53
Severe burn- MDA, SOD, IL-6, TNF-α, JNK, p-JNK, AKT, MARK/ IP-HR saline Male Sprague- > 0.6 mM Guo et al.10
induced early AKI CAT, GSH-Px IL-1β, IL- p-AKT, P38, p-P38 AKT/NF-κB Dawley rats
10, ICAM-1, (220–250 g)
NF-κB, ERK,
p-ERK
Severe AP-induced MDA, SOD IL-6, TNF-α, IκBa/NF-κB Inject -HR- Male Wistar rats > 0.6 mM Shi et al.11
early AKI IL-1β, IL-10, saline (200–250 g)
NF-κB, MPO,
IκBa
Renal injury in MDA, TAC, IκBa/NF-κB HR-water Male spontaneously > 0.8 mg/L Xin et al.12
spontaneously HT ROS, O2–, hypertensive rats;
OONO-, SOD, male Wistar-Kyoto
GPx, catalase, rats (8-wk-old)
GST, NADPH
oxidase
Rhabdomyolysis ROS, MDA, TNF-α, IL-6 IP-HR-saline Male Wistar rats 0.6 nM Gu et al.13
induced AKI SOD, GSH-Px, (180–200 g)
8-OH-dG
Ferric NTA- HO-1, HO-2, IL-6, MCP-1, JAK/STAT/ HR-water Male Wistar rats > 0.8 mg/L Li et al.14
induced MDA, OONO-, NF-κB PCNA (200–230 g)
nephrotoxicity catalase,
NADPH oxidase,
xanthine oxidase
Renal injury MDA, SOD ED1 Apoptotic tubular Interstitial IP-HR-saline Male Sprague- 0.4 MPa Xu et al.15
induced by UUO cells were fibrotic area Dawley rats dissolve in
determined by (180–200 g) saline for 4 h
TUNEL-positive
staining
T2DM and MS ROS, MDA HR-water Male stroke-prone 0.3-0.4 ppm Katakura et
spontaneously al.16
hypertensive rats
(5-wk-old)
Renal cold I/R MDA, 8-OH-dG, ED1, IFN-γ, Apoptotic tubular Kidney Inbred male Lewis 1.61 mg/L Abe et al.17
injury in kidney iNOS, HO-1 IL-6, TNF-α, cells were grafts were (LEW) rats
transplantation CCL2, IL-1β determined by preserved (250–350 g)
TUNEL-positive in HRUW
staining solution
Gentamicin- Na+-K+- HR-water Male Sprague- 1.2±0.1 mg/L Matsushita
induced ATPase Dawley rats et al.18
nephrotoxicity (284±23 g)
Cisplatin-induced Na+-K+- HR-water Male Sprague- 1.2±0.1 mg/L Kitamuta et
nephrotoxicity ATPase Dawley rats al.19
(284±4 g)
Renal I/R injury MDA, 8-OH-dG, IL-6, TNF-α, Apoptotic tubular IP-HR-saline Male Sprague- > 0.6 nM Wang et
SOD, CAT IL-1β, MPO cells were Dawley rats al.20
determined by (200–220 g)
TUNEL-positive
staining
Renal I/R injury 8-OH-dG Inject-HR- Male Wistar rats 640 µM Shingu et
saline (250–300 g) al.21

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.

Medical Gas Research ¦ June ¦ Volume 14 ¦ Issue 2 49

 Cheng et al. / Med Gas Res
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involve oxygen free radicals, inflammation, apoptosis, adhe-
sion 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.31-33
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 be-
tween a water tank and an electrolyzer. H2 was produced con-
tinuously, 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 re-
50
www.medgasres.com
Figure 1: 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.
duced, 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 ox-
ide. 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 ox-
ide synthase can reduce I/R injury,34-36 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 an-
nually. 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 con-
centration 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
Medical Gas Research ¦ June ¦ Volume 14 ¦ Issue 2
 Cheng et al. / Med Gas Res
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 in-
creases the level of oxidative stress during HD. Japanese
scholar Nakayama and his team developed a new HD system
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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 mortal-
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ity and non-fatal cardiovascular and cerebrovascular events
(such as heart disease, stroke, and limb amputation caused by
peripheral artery disease) compared to conventional HD pa-
tients, improving the prognosis of long-term HD patients.40,41
As an alternative therapy for ESRD patients, PD has the ad-
vantage of better protecting residual renal function and stabiliz-
ing 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 electrolyz-
ing 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 isch-
emic 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 reac-
tive 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
Medical Gas Research ¦ June ¦ Volume 14 ¦ Issue 2
www.medgasres.com
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, arterio-
sclerosis, 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, random-
ized, 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 antioxi-
dants. 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 dis-
eases. 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 accessibil-
ity 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.
51
 Cheng et al. / Med Gas Res
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Date of submission: December 12, 2021
Date of decision: January 24, 2022
Date of acceptance: February 25, 2023
Date of web publication: June 19, 2023
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