Molecular hydrogen and kidney diseases: a scoping review based on scientometry and data analytics

Abstract

Acute kidney injury and chronic kidney disease impose substantial burdens on healthcare systems worldwide. Molecular hydrogen (H₂) has emerged as a potential therapy due to its selective antioxidant, anti-inflammatory, and antiapoptotic properties. The present study reviews evidence on H₂-based renal interventions, examining therapeutic mechanisms, bibliometric trends, and existing research gaps based on data analytics. This scoping review integrates quantitative bibliometric analysis with qualitative thematic synthesis. This integration, uncommon in conventional scoping reviews, reveals important gaps. Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines, 69 publications were identified through Scopus and Web of Science. These publications mostly originated from Asia, particularly China and Japan, with clear peaks of activity in 2019 and 2024, but international collaboration remains limited. H₂ consistently demonstrated protective effects against apoptosis, fibrosis, inflammation, and oxidative stress across acute kidney injury, nephrotoxicity, transplantation, and early chronic kidney disease models. Our findings suggest that hydrogen therapy holds promise for renoprotection in both acute kidney injury and chronic kidney disease. Nonetheless, more robust clinical trials and standardized research methodologies are imperative to facilitate its broader adoption into clinical nephrology practice.

Introduction

Scientific and medical interest in molecular hydrogen (H₂) dates back to the 1970s, when its potential as an antitumor agent was first explored under hyperbaric conditions.1 Initially, research primarily focused on cancer therapy, and broader medical implications remained relatively unexplored until 2007, when H₂ was recognized as a selective antioxidant capable of neutralizing highly reactive hydroxyl radicals and peroxynitrite, without disturbing essential cellular signaling molecules.2 This key discovery, originally demonstrated in cerebral ischemia-reperfusion (I/R) injury models, provided the foundation for exploring H₂-based therapies targeting diseases associated with oxidative stress and inflammation.

Kidney diseases, specifically acute kidney injury (AKI) and chronic kidney disease (CKD), represent major global health burdens.3,4 The pathophysiology of these renal diseases involves interconnected mechanisms, notably inflammation, fibrosis, and oxidative stress, with the excessive generation of reactive oxygen species playing a critical role in disease initiation and progression.5,6 Consequently, therapeutic strategies that modulate oxidative stress and associated redox-sensitive signaling pathways are increasingly relevant to nephrological research and clinical practice.

In this context, H₂ has emerged as a promising therapeutic candidate due to its unique antioxidant and anti-inflammatory properties. A landmark clinical trial published in 2010 demonstrated that H₂-enriched dialysis fluid reduced oxidative stress markers in patients undergoing hemodialysis.7 Subsequent research explored various administration methods—such as inhalation, H₂-rich drinking water, H₂-generating nanomaterials, and H₂-releasing solid-state compounds—across diverse experimental and clinical settings.8,9 Additionally, investigations have consistently confirmed that H₂ selectively targets harmful radicals, reduces inflammation, and beneficially modulates cellular signaling pathways implicated in cardiovascular, neurodegenerative, and renal disorders.10,11

Recent studies have observed the beneficial role of H₂ in renal disorders through mechanisms involving redox modulation and inflammatory response regulation.8,9,12,13,14,15 A recent review observed H₂ as a potential intervention in CKD, highlighting its modulation of oxidative stress-related pathways including: (i) the nuclear factor erythroid 2-related factor 2–Kelch-like ECH-associated protein 1 complex (Nrf2–Keap1); (ii) nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and hypoxia-inducible factor; as well as (iii) forkhead box O transcription factors.11

Experimental evidence supports these observations, showing H₂-rich saline ability to attenuate renal inflammation and preserve endothelial glycocalyx integrity in sepsis-induced AKI.12 Moreover, novel solid-state H₂ sources demonstrated efficacy against toxin-induced kidney injury by inhibiting critical inflammatory pathways.8 Additionally, high-concentration H₂ inhalation has been reported to reduce mitochondrial dysfunction in septic AKI models by promoting mitochondrial biogenesis and fusion processes.13

Beyond conventional delivery methods, advanced H₂-generating nanomaterials have been explored to achieve targeted reactive oxygen species modulation in renal conditions.9 Clinical case reports have shown improved renal function and reduced fatigue in diabetic nephropathy,14 while preclinical research also indicates protective effects in crush syndrome–associated AKI.15

Despite these promising results, the existing literature on H₂ therapies is marked by considerable methodological heterogeneity. Variations in experimental models, administration protocols, and outcome measures limit direct comparisons and hinder broader clinical translation.

A scoping review methodology is particularly suited to address such fragmented fields of research by systematically mapping the available evidence, identifying central concepts, delineating knowledge gaps, and establishing priorities for future research. Unlike systematic reviews or meta-analyses—which require a high level of methodological consistency and quantitative homogeneity—scoping reviews emphasize capturing the breadth and diversity of a research topic, so providing structured insights into emerging areas that may not yet be mature enough for quantitative synthesis.

To date, however, no comprehensive scoping review has specifically mapped the applications of H₂ within nephrology. Important questions remain unanswered, particularly regarding the therapeutic contexts, mechanisms of action, and research priorities for H₂-based interventions in renal diseases. Therefore, the present study has as objectives: (i) to provide a structured overview of H₂-based interventions across AKI and CKD; (ii) to elucidate the key molecular mechanisms underlying H₂ renoprotective effects; and (iii) to identify existing knowledge gaps, thereby highlighting areas requiring further investigation.

Methods

A comprehensive approach was applied to identify, screen, and select relevant studies on H₂ therapies for kidney-related conditions. The process was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines,16 ensuring transparency and reproducibility in the search, filtering, and inclusion of articles.

Search strategy

We conducted a systematic search in Web of Science and Scopus databases, chosen for their extensive multidisciplinary coverage and bibliometric capabilities. Our strategy combined terms related to H₂ therapies (“molecular hydrogen,” “hydrogen gas,” “hydrogen therapy,” “hydrogen-rich water,” and “hydrogen-rich saline”) with kidney-related terms (“kidney,” “renal,” “disease,” “injury,” “failure,” “dialysis,” “nephropathy,” “transplant,” “ischemia,” “reperfusion,” “fibrosis,” “CKD,” “AKI,” “ESRD” and “ischemia/reperfusion”). We opted to use some standard abbreviations (such as “CKD” and “AKI”) rather than full disease names to capture the widest set of relevant publications. No date or publication year restrictions were applied, and we searched all available records through February 12, 2025.

Inclusion and exclusion criteria

We included primary experimental and clinical studies explicitly addressing H₂-based therapies in kidney-related conditions. Eligible studies involved human or animal subjects experiencing kidney disease, injury, or risk thereof, utilizing H₂-based interventions (for example, inhalation, H₂-rich water/saline, or solid-state H₂ sources), and reporting renal outcomes (biomarkers, functional measures, or histopathology). Non-English publications and articles lacking direct relevance to renal conditions or H₂ therapy were excluded. Additionally, to maintain biomedical relevance, we omitted studies targeting non-medical contexts (such as “fuel cell,” “battery,” “combustion,” “photosynthesis,” and “plant”) identified during the search or screening process.

Dataset for bibliometric analyses

Initially, 235 articles were retrieved (123 from Web of Science and 112 from Scopus). After removing duplicates, 178 unique records remained. Screening by language criteria further narrowed the dataset to 140 articles. Titles and abstracts underwent independent screening by two authors, with discrepancies resolved by a third expert. Ultimately, 69 articles met the inclusion criteria and formed the final dataset for full-text evaluation (Figure 1).

Figure 1.

Flowchart of the identification, screening, and selection process following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines.

A total of 69 articles on H₂-based renal research included in this scoping review. H₂: Hydrogen; WoS: Web of Science.

Bibliometric and thematic analyses

Bibliometric and thematic analyses were conducted using scientometric methods to characterize the landscape of research on H₂-based renal therapies. The analysis involved three main steps as follows:

• First, publication trends were assessed by quantifying the annual number of publications, giving a chronology of research developments; and additionally, publications were categorized into original research articles, reviews, and conference proceedings to understand predominant document types.

• Second, the distribution of articles by journal was analyzed, revealing whether research was primarily concentrated in specialized nephrology journals or dispersed across multidisciplinary outlets.

• Third, international collaboration was examined using country-level co-authorship networks. A collaboration matrix was constructed based on author affiliations to identify interactions among countries. A clustering algorithm was applied to detect groups of countries frequently collaborating, visualizing geographic collaboration patterns, and identifying central contributors.17,18

The thematic analysis focused on keyword frequency and co-occurrence to identify major research topics. A keyword co-occurrence matrix was constructed, converted into a network, and analyzed with the same clustering approach to delineate thematic groups.17,18 Following established procedures for thematic mapping,19 each keyword cluster was positioned in a two-dimensional space defined by centrality—the extent to which a theme connects with other themes, indicating interdisciplinary relevance— and density—the internal cohesion among keywords within each theme, reflecting thematic maturity or specialization. Clusters with high centrality and density were identified as motor themes driving research progress, while clusters in other quadrants indicated emerging or specialized topics. All analyses were conducted in the R statistical software, primarily using the bibliometrix package for bibliometric analysis,17 the igraph library (https://igraph.org/) for network construction and clustering, and ggplot2 (https://ggplot2-book.org/) for data visualization.20 This integrated approach follows standard scientometric practices and employs widely accepted open-source tools.

Results

Publication trends over time

Research on H₂-based renal therapies began in 2009 but became more regular after 2010. From 2010 to 2015, the annual publication rate varied between two and five articles. Between 2016 and 2024, publication activity remained generally low, with slight increases observed in 2019 and 2024 (seven articles each), suggesting sporadic periods of greater research interest (Figure 2).

Figure 2.

The distribution of the number of publications on H₂-based renal research per year.

H₂: Hydrogen.

Document types

Most studies in the dataset had a distribution based on original research articles (63; 91%), with a small proportion comprising reviews (5; 7%) and a single conference proceeding (1; 1%). This distribution underscores the predominance of experimental and clinical investigations, whereas comprehensive syntheses and systematic reviews remain limited.

Journal distribution

Studies on H₂-based renal therapies appeared across various journals, although a few outlets published multiple relevant articles (Table 1). Journals hosting three articles each included PLoS One, Renal Replacement Therapy, Scientific Reports, and Shock. Several other journals published two articles each, reflecting medium specialization of publication venues yet underscoring the broad multidisciplinary interest in this research area.

Table 1.

Distribution of journals with at least two publications on H₂-based renal research

Journal	Number of publications	Relative frequency
PLoS One	3	0.0435
Renal Replacement Therapy	3	0.0435
Scientific Reports	3	0.0435
Shock	3	0.0435
Biological & Pharmaceutical Bulletin	2	0.029
Frontiers in Medicine	2	0.029
Frontiers in Pharmacology	2	0.029
International Immunopharmacology	2	0.029
Journal of Surgical Research	2	0.029
Transplantation	2	0.029

The “number of publications” column indicates how many articles each journal contributed to our final dataset, and the “relative frequency” column represents the proportion of articles relative to the total of articles. H₂: Hydrogen.

International collaboration network

To analyze international research collaborations, we constructed a co-authorship network based on country affiliations (Figure 3). China produced the highest number of publications (33 articles), followed closely by Japan (28 articles). However, international collaboration was notably limited for these countries. Specifically, China had only three multi-country publications (MCP ratio = 0.0909), and Japan had none (MCP ratio = 0.0000), indicating predominantly domestic research activities.

Figure 3.

The country collaboration network for H₂-based renal studies.

The node size indicates the total number of publications per country, and edges represent co-authorship connections between countries. H₂: Hydrogen.

In contrast, countries with few publications—such as Germany, Portugal, and Slovakia—found important international collaboration, each with an MCP ratio of 1.0 (Table 2). Although these findings are derived from a relatively small dataset, the MCP ratio (the proportion of articles involving international co-authors) clearly demonstrates that all publications from these countries involved multinational partnerships. The USA displayed moderate publication output (6 articles), with half resulting from international collaboration (MCP ratio = 0.50).

Table 2.

Metrics of country-level collaboration for H₂-based renal research

Country	Number of publications	SCP	MCP	MCP ratio	Relative frequency
China	33	30	3	0.0909	0.4783
Japan	28	28	0	0	0.4058
USA	6	3	3	0.5	0.0870
Germany	1	0	1	1	0.0145
Slovakia	1	0	1	1	0.0145
Portugal	1	0	1	1	0.0145
United Kingdom	1	1	0	0	0.0145
Turkey	1	1	0	0	0.0145
Ukraine	1	1	0	0	0.0145

The “number of publications” represents the total of articles from each country, “SCP” (single-country publications) denotes articles authored exclusively by researchers from one country; “MCP” includes articles co-authored by researchers from multiple countries; “MCP ratio” is calculated as MCP divided by the number of publications per country; and “relative frequency” represents the proportion of articles relative to the total of articles attributed to each country. H₂: Hydrogen.

Citation analysis

We further assessed the research impact by analyzing citation frequencies. Table 3 lists the five most-cited articles, each accumulating between 72 and 149 citations. As expected, earlier studies generally garnered more citations. The highest-cited publication in our dataset was an early study demonstrating H₂ protective effects against cisplatin-induced nephrotoxicity while preserving anticancer activity.21 Other influential articles included investigations on the use of H₂ in preventing chronic allograft nephropathy,22 mitigating renal I/R injury,23,24 and improving survival in generalized inflammation models.25

Table 3.

Top five most-cited articles on H₂-based renal research

Author	Year	Journal	Selected title/topic	Citations
Nakashima-Kamimura et al.21	2009	Cancer Chemotherapy and Pharmacology	Molecular hydrogen alleviates nephrotoxicity induced by an anti-cancer drug cisplatin without compromising anti-tumor activity in mice	149
Cardinal et al.22	2010	Kidney International	Oral hydrogen water prevents chronic allograft nephropathy in rats	148
Xie et al.25	2010	Shock	Hydrogen gas improves survival rate and organ damage in zymosan-induced generalized inflammation model	94
Wang et al.24	2011	Journal of Surgical Research	Hydrogen-rich saline protects against renal ischemia/reperfusion injury in rats	88
Shingu et al.23	2010	Journal of Anesthesia	Hydrogen-rich saline solution attenuates renal ischemia–reperfusion injury	72

H₂: Hydrogen.

Keyword frequency and co-occurrence analysis

A quantitative assessment of the most frequent author keywords provides insight into the dominant themes in H₂-based renal research. By aggregating keyword occurrences across all studies, we identified a set of core terms that recur throughout the literature. Figure 4 presents the top 20 keywords, highlighting the prevalence of concepts related to H₂ therapy (for example, H₂, H₂-rich water) and its principal mechanisms (such as oxidative stress, inflammation, apoptosis). The most frequently occurring keyword is oxidative stress (22 occurrences), followed closely by H₂ (18) and inflammation (13), underscoring the predominant focus on redox regulation and inflammatory modulation. H₂ (12) and AKI (8) reinforce this identification on cytoprotection, alongside related terms such as reactive oxygen species (6) and apoptosis (5). Less frequent keywords, such as fibrosis (3), H₂-rich saline (3), and nephrotoxicity (3), point to emerging or more specialized research niches.

Figure 4.

The distribution of the number of publications (frequency) for the top 20 most frequent keywords on H₂-based renal research.

H₂: Hydrogen.

While keyword frequency outlines the most prominent topics, it does not reveal how these terms interconnect. To explore the relationships among the most frequently used keywords, we constructed a co-occurrence network (Figure 5) focusing on the top 25 keywords.

Figure 5.

A co-occurrence network of the top 25 keywords in H₂-based renal research.

To enhance clarity and reduce visual clutter, weaker connections (low-frequency co-occurrences) were filtered out, where the nodes with a higher degree—namely, more connections—occupy central positions within the network. Each node represents a keyword, with its size proportional to the frequency of occurrence, whereas edges indicate the co-occurrence of keywords within the same article, and their thickness (weight) reflects the strength of these associations. H₂: Hydrogen.

Table 4 summarizes selected connectivity metrics, offering insight into each keyword relative importance and interlinkages within the network. For instance, “oxidative stress” (degree = 0.96) is near-ubiquitous, underlining its pivotal role in H₂-based renal interventions, whereas “hydrogen” (0.68) and “inflammation” (0.68) also exhibit high connectivity, bridging multiple research subdomains. By contrast, “acute kidney injury” (0.38) remains an important focus but is connected to fewer terms. Thus, this network analysis confirms that redox regulation and inflammation are dominant themes in H₂-related nephrology research, with H₂ intersecting multiple mechanistic and clinical areas.

Table 4.

Node degrees of selected keywords in the co-occurrence network on H₂-based renal research

Keyword	Degree	Interpretation
Oxidative stress	0.96	Highly connected, central to H2-mediated protective effects
Hydrogen	0.68	Bridges multiple domains (acute kidney injury, inflammation)
Inflammation	0.68	Strongly linked to oxidative stress and hydrogen
Molecular hydrogen	0.45	Key subdomain focusing on specific H2 formulations
Acute kidney injury	0.38	Major application context for H2 therapy

The degree” is the normalized node degree, which ranges from 0 to 1, with a higher degree indicating broader interlinkage and, therefore, greater centrality in the research landscape. H₂: Hydrogen.

Thematic map analysis

While the co-occurrence network illustrates how the top 25 keywords interrelate (Figure 5), it does not fully capture the overall thematic structure within this research domain. To address this, we constructed a thematic map (Figure 6) positioning keyword clusters according to centrality (connections with other topics) and density (internal cohesion). Clusters in the upper-right quadrant—characterized by both high centrality and high density—emerge as “motor themes,” exerting a pivotal influence on the research landscape.

Figure 6.

Thematic map of H₂-based renal research.

The centrality (horizontal axis) reflects the degree of interaction with other themes, density (vertical axis) indicates the internal cohesion of each theme, with each circle representing a cluster of related keywords, labeled by its most representative keyword or concept, while the circle size is proportional to the total frequency of keywords within each cluster, and colors (automatically assigned by the clustering algorithm) differentiate distinct thematic groups. H₂: Hydrogen.

Building on the co-occurrence network, we describe how keywords group into thematic clusters according to their centrality (connections with other topics) and density (internal cohesion). These clusters provide a broader overview of the field structure as follows:

• Core and transversal themes—The most interconnected cluster centers on oxidative stress, which demonstrates the highest centrality and is closely linked to inflammation, AKI, and H₂ therapy. Another highly central theme, H₂, spans multiple domains, bridging kidney disease, chronic intermittent hypoxia, and antioxidant mechanisms.

• Specialized research themes—Clusters such as H₂, chronic rejection/kidney transplantation, and sepsis exhibit higher internal density but lower centrality, indicating more self-contained lines of inquiry. Studies in these areas often focus on specific therapeutic applications of H₂ with fewer cross-links to other topics.

• Emerging or marginal themes—Keywords like CKD, renal function, and I/R injury show minimal connectivity, suggesting limited integration within the broader network. Likewise, cisplatin and hemodialysis appear relatively isolated, possibly due to low publication volume or specialized experimental designs.

Overall, the thematic map highlights oxidative stress and H₂ as pivotal organizing concepts, reflecting the dominant interest in H₂ antioxidant and anti-inflammatory mechanisms. Meanwhile, more narrowly focused niches—kidney transplantation, sepsis, nephrotoxicity—remain compartmentalized. This fragmentation suggests that stronger thematic integration could support broader translational applications of H₂-based therapies. A deeper understanding of how these research clusters align with the physiological and molecular effects of H₂ is essential to bridge the gap between experimental findings and clinical practice. Collectively, these bibliometric findings highlight the necessity of integrating thematic insights with the underlying physiological and molecular mechanisms responsible for renal protection. Consequently, the subsequent section transitions from a broad bibliometric perspective to a detailed examination of the mechanistic pathways and therapeutic contexts through which H₂ exerts its renoprotective effects.

Discussion

This part synthesizes current knowledge on H₂ therapy in nephrology, merging bibliometric trends with mechanistic insights to highlight both achievements and remaining challenges in the field.

Integrating bibliometric insights with mechanistic foundations

Our bibliometric analysis shows that research on H₂ in nephrology, though promising, has progressed irregularly since 2009, with modest publication peaks in 2019 and 2024.11,17 The field remains dominated by original research articles, whereas reviews and meta-analyses are relatively scarce,16 reflecting an emphasis on experimental or early clinical studies over comprehensive syntheses.

International collaboration also appears limited, particularly in East Asia (China, and Japan), where publication volume is high but multinational co-authorship is comparatively low.26 Conversely, countries such as Germany, Portugal, or Slovakia, despite fewer total publications, exhibit higher MCP ratios. Citation analyses point to pivotal early studies—like those demonstrating H₂ protective effects against cisplatin-induced nephrotoxicity2,21—as highly influential yet not always expanded upon. Furthermore, keyword clustering highlights “oxidative stress,” “inflammation,” and “hydrogen” as central themes, aligning with H₂ antioxidant and anti-inflammatory mechanisms. However, our thematic map shows that distinct application niches (for example, transplantation, sepsis, and dialysis) often develop in isolation, indicating opportunities for more unified research strategies.

These bibliometric observations align with mechanistic insights suggesting a strong foundation for H₂ renal protective capacity. Nevertheless, the existing literature remains fragmented, and greater coordination could further harness H₂ therapeutic potential in nephrology.

Mechanistic insights and protocol standardization

Initial studies on H₂-based renal therapies emphasized H₂ selective antioxidant properties: it scavenges hydroxyl radicals while preserving other reactive oxygen species involved in normal signaling.2,21 This duality underpins H₂ therapeutic potential, as it helps maintain endogenous antioxidants (such as catalase, superoxide dismutase) and inhibits proinflammatory cytokine release, thereby reducing apoptosis and tissue damage.21,22,23,24,25 Subsequent work broadened these findings to include anti-inflammatory and antifibrotic effects, with H₂ influencing key transcription factors, such as Nrf2, NF-κB, and sirtuin 1 (SIRT1), which modulate redox balance, fibrosis, and inflammation.9,11,27,28 Recent approaches, such as blood oxygen level–dependent magnetic resonance imaging and H₂-generating nanomaterials, suggest that H₂ renoprotection extends beyond radical scavenging, engaging multifaceted cellular networks critical for renal homeostasis.9,27,29

Despite these mechanistic advances, studies still employ diverse administration methods (inhalation, oral, dialysate) and outcome endpoints.7,9,11,30 Additionally, at the molecular level, H₂ targets inflammatory and apoptotic pathways, such as NF-κB and nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3), in AKI,8,9,12,13,23,31,32 and exhibits antifibrotic potential in CKD by downregulating transforming growth factor-beta 1 and supporting SIRT1.10,26,29,33,34,35

Clarifying whether short-term protection differs from longer-term antifibrotic effects is essential for guiding patient selection and dosing strategies. Next, we examine the renoprotective effects of H₂ in specific clinical contexts, beginning with AKI.

Hydrogen therapy in acute kidney injury

AKI arises from multiple etiologies, including nephrotoxic agents, I/R, and sepsis.31,36 Preclinical models consistently demonstrate H₂ protective effects. In drug-induced AKI (for example, cisplatin, gentamicin), H₂ therapy reduces oxidative stress markers (malondialdehyde, reactive oxygen species), preserves renal function (serum creatinine), and mitigates tissue injury.8,21,23,24,29,31,37 In I/R injury, H₂ helps protect tubular structures and partially prevents fibrosis, potentially via Klotho preservation and autophagy regulation.28,34,37,38

In sepsis-induced AKI, H₂ reduces proinflammatory mediators (for example, NF-κB, NLRP3 inflammasome) and improves survival in polymicrobial or endotoxin-based models.12,13,23,24,25,31 Novel formulations—such as magnesium hydride and H₂-generating nanomaterials—allow sustained or targeted release, expanding therapeutic options for rhabdomyolysis- and toxin-induced AKI.8,9,15,39

Although these findings are promising, differing protocols and routes of administration can complicate direct comparisons.21,23,29 Further clinical research will help clarify optimal dosing and delivery. Next, we discuss the potential of H₂ in CKD, where ongoing inflammation and fibrosis pose additional challenges.

Hydrogen therapy in chronic kidney disease

CKD is characterized by persistent inflammation, oxidative stress, and progressive fibrosis.3,4 Early experimental work in models such as unilateral ureteral obstruction indicates that H₂-rich saline attenuates fibrosis, oxidative biomarkers, and inflammatory cell infiltration.26,28,40,41 Mechanistically, H₂ appears to preserve key renal proteins (such as Klotho) and inhibit profibrotic pathways (including epithelial–mesenchymal transition and SIRT1).10,28,40,41 In hypertensive renal damage, H₂ reduces oxidative stress and structural injury, and can partially mitigate hypertension-related renal dysfunction.33,35 H₂ inhalation also lowered blood pressure in spontaneously hypertensive rats, suggesting a possible antihypertensive mechanism relevant to CKD progression.42 In diabetic kidney disease, H₂ therapy improved renal biomarkers and metabolic profiles,5,11,33,41 though efficacy may vary by etiology (for example, limited benefit in certain polycystic kidney disease models34,35,36). Clinically, H₂-enriched dialysis solutions correlate with reduced oxidative stress and inflammation, alongside improved patient-reported outcomes in end-stage renal disease.7,30,43,44,45,46,47 Recent technological developments, including real-time dialysate H₂ monitoring, may enhance clinical implementation,30,45 and preliminary work in peritoneal dialysis also suggests the preservation of membrane integrity.33,41 Given H₂ demonstrated renoprotective effects in chronic settings, next we explore its potential benefits in renal transplantation, which involves additional acute and chronic inflammatory challenges.

Hydrogen therapy in renal transplantation: efficacy and safety considerations

Efforts to introduce H₂ therapy into renal transplantation center on mitigating I/R injury and chronic allograft nephropathy. Early animal models suggest that oral H₂-enriched solutions

reduce proteinuria, histopathological damage, and oxidative markers.22 Further innovations in organ preservation indicate that H₂-containing solutions may improve graft outcomes compared to conventional fluids, diminishing tubular injury, apoptosis, and oxidative stress.38,41,48,49 However, some studies find minimal benefit from H₂ alone, highlighting the need for optimized delivery or combination strategies (such as with carbon monoxide).48,50,51 Preclinical data generally point to a favorable safety profile, yet certain ex vivo large-animal studies yield inconsistent results, suggesting that dosing refinements and synergistic therapies warrant further exploration.48,49,50 Additionally, few clinical trials focus on graft survival or long-term function as primary endpoints, underscoring the importance of investigating H₂ impact on chronic rejection, infection rates, and immunosuppression requirements. Standardized methods for documenting adverse events remain limited, complicating the identification of delayed or infrequent complications. Overall, current evidence supports H₂ safety and potential to enhance transplant outcomes, although rigorous human trials are needed to confirm clinical efficacy. Given that H₂-mediated renoprotection extends beyond transplantation and primary renal diseases, we now explore its role in additional specialized conditions involving renal impairment.

Other specialized contexts

Beyond common renal disorders, H₂ therapy shows promise in systemic or multifactorial conditions affecting the kidneys. In ferric nitrilotriacetate-induced renal carcinogenesis models, H₂-rich water reduced early tumor-promoting events by modulating oxidative and inflammatory pathways.52 Likewise, during high-stress surgeries such as orthotopic liver transplantation, H₂ helped preserve renal function by attenuating oxidative injury and apoptosis.38,40 In obstetric complications like preeclampsia, H₂ therapy lowered blood pressure, reduced oxidative damage, and improved pregnancy outcomes.53 Studies on chronic intermittent hypoxia and renal injury secondary to cardiac surgery further illustrate H₂ systemic cytoprotective potential.32,38 Nonetheless, outcome variability across these diverse scenarios points to the need for further inquiry into optimal dosing regimens, patient selection, and long-term safety.

Overview of administration methods

Successful clinical translation of H₂ therapy requires clarity regarding its delivery. Current approaches range from inhalation of H₂ and oral ingestion of H₂-rich water to H₂-enriched dialysate and H₂-generating nanomaterials or compounds.8,9,54,55 These methods differ in dose ranges and application frequencies, complicating cross-study comparisons.

H₂ physicochemical properties—such as low solubility and rapid diffusion—can also affect absorption and tissue distribution. Table 5 summarizes key administration strategies, including dosages, treatment frequencies, outcomes, and possible limitations. Establishing clear guidelines for these parameters will be crucial for designing reproducible preclinical and clinical trials that accurately gauge H₂ therapeutic efficacy in nephrology.

Table 5.

Summary of hydrogen administration protocols and representative models in H₂-based renal research

Administration method	Dose (concentration range)	Frequency/duration	Representative preclinical model	Representative clinical setting	Key observation	References
H2 inhalation	1-4%, up to 67% H2 in inhaled air	30 min to continuous exposure	AKI: Sepsis, rhabdomyolysis, I/R (rodents, pigs)	Limited AKI or dialysis studies	Reduced oxidative stress, inflammation, improved survival	13 15 32 33
H2-rich water (oral)	Typically 0.8–1.6 mg/L (~0.8–1.6 ppm)	Daily consumption (ad libitum/scheduled)	CKD (UUO, diabetic nephropathy), drug-induced AKI (cisplatin models)	Preliminary clinical case reports	Decreased oxidative markers, improved histology, metabolic profile improvements	21 22 26 27 29 33 36 52
H2-rich saline (IV/IP)	0.6–1.2 mM (saturation: 0.4–0.8 mM)	Single or multiple injections over days	AKI: I/R cisplatin/gentamicin nephrotoxicity, sepsis	Not widely tested clinically	Reduced inflammation, apoptosis, improved renal recovery	23 24 34 39 40 56
H2-enriched dialysate	47–154 ppb (up to ~300 ppb reported)	Per dialysis session (3–5 h/session)	Not typically used in standard rodent models (mostly ex vivo)	Hemodialysis in ESRD patients	Lower inflammation, oxidative stress, reduced fatigue	7 30 43 44 45
Solid-state H2 Sources	Magnesium hydride, H2- generating nanomaterials	Single-dose or repeated- dose regimens	Toxin-induced AKI (acetaminophen), ischemic injury	No routine clinical use yet	Sustained H2 release, reduced inflammation, fibrosis	8 9
H2-containing preservation solutions	Dissolved H2 in preservation solutions (such as University of Wisconsin solution)	Single administration (organ cold storage)	Kidney transplantation models (rats, pigs)	Experimental/ translational only	Improved graft function, reduced ischemic injury and chronic rejection markers	41 48 50

The concentrations in ppm are approximately equivalent to mg/L for aqueous solutions at standard conditions. AKI: Acute kidney injury; CKD: chronic kidney disease; ESRD: end-stage renal disease; H₂: hydrogen; IP: intraperitoneal; IV: intravenous; I/R: ischemia-reperfusion; ppm: parts per million; ppb: parts per billion; UUO: unilateral ureteral obstruction.

Clinical and experimental endpoints

Across experimental models—particularly in AKI—H₂ therapy consistently improves oxidative stress markers (for example, malondialdehyde, glutathione, superoxide dismutase), inflammatory cytokine levels, and histological injury scores.8,13,24,34,40,56 Interest also exists in H₂ ability to mitigate cisplatin-induced nephrotoxicity without reducing antitumor efficacy.21,37,57 Early clinical work, including small-scale dialysis studies, reports lowered fatigue and inflammation but insufficient data on long-term outcomes such as survival or progression to end-stage renal disease.7,30,43,44,46,47 While these findings strongly suggest multifaceted renoprotection—encompassing antioxidant, anti-inflammatory, and antifibrotic effects—further research is needed to refine clinical endpoints and confirm the full scope of H₂ therapeutic value. Addressing unresolved issues such as mechanistic specificity and broader validation will be critical, as discussed next.

Regulatory and practical considerations

Moving H₂ therapy toward routine clinical use hinges on regulatory guidance, delivery solutions, and cost-effectiveness. Currently, no unified standards exist for hospital-based generation, storage, or administration of H₂; available devices (for example, portable generators, and H₂-enriched dialysate systems) vary in quality and scalability. Key priorities include:

• Manufacturing standards—Ensuring purity, concentration, and consistent dosing;

• Regulatory approvals—Establishing safe guidelines for inhalation, oral intake, or dialysate use;

• Economic feasibility —Evaluating H₂ cost-effectiveness compared to standard therapies;

• Long-term safety —Monitoring for rare or delayed adverse events.

Addressing these considerations is essential for integrating H₂ therapy into nephrology practice. Further exploration of innovative delivery methods, data management, and trial optimization represents a vital next step in advancing H₂-based renal therapies.

Future directions

Novel technological methods in H₂ delivery, including nanomaterial-based systems and solid-state sources, show promise for achieving controlled release and targeted delivery.8,9,57 However, these emerging approaches require rigorous testing in human populations, guided by cost-effectiveness analyses. Blockchain and artificial intelligence applications could further optimize trial design, data governance, and real-time monitoring, enhancing transparency and efficiency in future research.58,59,60,61 Special attention to pediatric nephrology is also warranted, given the distinct pharmacokinetics and therapeutic requirements in children. While these future directions highlight the substantial promise of H₂ therapy, several current limitations must still be acknowledged and addressed to ensure meaningful clinical advancement.

Limitations

Despite the promising landscape, current findings on H₂ therapy face several notable limitations. First, much of the evidence originates from pre-clinical or small-scale clinical studies, often lacking standardized endpoints or robust randomization, which limits the generalizability of results. Second, the absence of unified dosing regimens and delivery protocols complicates cross-study comparisons and hinders meta-analytic efforts. Third, the long-term safety profile of H₂ therapy remains insufficiently characterized, particularly in vulnerable populations (such as pediatric or immuno-compromised patients). Lastly, although H₂-based interventions are approaching clinical viability, challenges related to regulatory frameworks, large-scale manufacturing standards, and cost-effectiveness analyses must be thoroughly addressed for broader adoption in nephrology.

Conclusions

This scoping review integrated a quantitative bibliometric analysis with a qualitative thematic synthesis to systematically map the current state and evolution of H₂ research in nephrology. By merging these methodologies, we not only provided an overview of therapeutic mechanisms and applications but also offered a comprehensive picture of publication trends, geographic distribution, and collaborative networks in this field. This combined approach—relatively uncommon in traditional scoping reviews—revealed important gaps, such as fragmented research efforts and insufficient international collaboration that must be rectified to advance the discipline.

Mechanistically, H₂ demonstrates considerable therapeutic versatility, with protective effects documented in AKI, chronic renal conditions, transplantation, and specialized clinical contexts. However, major challenges persist, particularly surrounding clinical translation. Crucial unanswered questions concern optimal dosing strategies, long-term safety, and the development of patient-tailored H₂-delivery technologies fit for routine clinical use. Overcoming these obstacles will require large-scale randomized controlled trials, standardized study designs, and exploration of innovative H₂-delivery methods supported by advanced data management solutions.58,59,60,61

Ultimately, cohesive and internationally integrated research frameworks—aligned with technological breakthroughs in targeted delivery and clinical trial management—are essential for fully realizing the therapeutic promise of H₂ in nephrology. By addressing the current limitations, harmonizing protocols, and deepening the evidence on safety and efficacy, H₂ therapy may evolve into a well-established treatment option in renal medicine.

Data availability statement:

No additional data are available.