Matsumoto, S.; Ueda, T.; Kakizaki, H.
Source: Urology, Volume 81, Issue 2 (2013)

Objective:
To investigate the efficacy of hydrogen-rich water (HRW) supplementation in patients with interstitial cystitis/painful bladder syndrome (IC/PBS).

Methods:
A prospective, randomised, double-blind, placebo-controlled clinical trial was conducted to evaluate the effects of hydrogen-rich water in patients diagnosed with IC/PBS. Inclusion criteria were stable IC/PBS symptoms for ≥12 weeks following bladder hydrodistension, an Interstitial Cystitis Symptom Index (ICSI) score ≥7, and bladder pain intensity ≥4. Patients were randomised in a 2:1 ratio to receive either hydrogen-rich water or placebo water for a period of 8 weeks. Symptoms were assessed using the ICSI, Interstitial Cystitis Problem Index (ICPI), the Pelvic Pain and Urgency/Frequency (PUF) scale, Parsons’ pelvic pain score, bladder pain measured via a visual analogue scale (VAS), and a standardised 3-day voiding diary. The primary outcome was improvement in patient-reported symptoms post-treatment.

Results:
A total of 30 participants (29 women and 1 man, mean age 64.0 ± 14.8 years) were enrolled in the study; two female participants withdrew. Bladder pain scores significantly improved in both the hydrogen-rich water and placebo groups. However, no statistically significant difference was observed between the effects of HRW and placebo. Notably, 11% of patients in the HRW group experienced marked improvement in bladder pain scores, suggesting a potential benefit in a subset of patients.

Conclusion:
The findings of this study provide limited support for the use of hydrogen-rich water supplementation in the treatment of IC/PBS. While overall results did not show significant superiority over placebo, a subset of patients may benefit substantially.

Citation:
Matsumoto, S., Ueda, T., & Kakizaki, H. (2013). Effect of supplementation with hydrogen-rich water in patients with interstitial cystitis/painful bladder syndrome. Urology, 81(2), 226–230.
https://doi.org/10.1016/j.urology.2012.09.008

Mizutani, A.; Endo, A.; Saito, M.; Hara, T.; Nakagawa, M.; Sakuraya, K.; Murano, Y.; Nishizaki, N.; Hirano, D.; Fujinaga, S.
Source: Pediatric Research, Volume 91, Issue 7 (2022)

Background:
Congenital obstructive nephropathy (CKD) is a commonly implicated factor in the pathophysiology of chronic kidney disease affecting paediatric and adolescent populations. The release of reactive oxygen species (ROS) contributes significantly to the progression of renal fibrosis. Molecular hydrogen (H₂) has been shown to protect against tissue damage by reducing oxidative stress.

Objective:
To evaluate the efficacy of oral intake of hydrogen-rich water (HW) in preventing renal injury induced by unilateral ureteral obstruction (UUO) in rats.

Methods:
Male Sprague-Dawley rats subjected to UUO or sham-operated controls were administered either distilled water (DW) or hydrogen-rich water (HW) for two weeks post-surgery. Histopathological and immunohistochemical analyses of kidney tissue samples were conducted.

Results:
No histological changes were observed in sham-operated kidneys. However, kidneys from the UUO group exhibited expanded interstitial spaces and tubular dilatation. Compared to the UUO + DW group, HW administration significantly attenuated tubulointerstitial injury and reduced the interstitial fibrotic area. This was accompanied by a marked decrease in the frequency of α-SMA-, ED-1- and TGF-β1-positive cells in the UUO + HW group. Additionally, the downregulation of klotho mRNA expression was less pronounced in the UUO + HW group than in the UUO + DW group.

Conclusion:
Oral administration of hydrogen-rich water reduced oxidative stress and prevented interstitial fibrosis in UUO kidneys, potentially involving the klotho protein as part of the underlying mechanism. The oral intake of HW may suppress oxidative stress and interstitial fibrosis associated with unilateral ureteral obstruction-induced kidney damage in rats. This mechanism may involve klotho, known for its anti-ageing properties. While the relationship between molecular hydrogen and klotho in renal fibrosis is well documented, this is the first report demonstrating such an association in a unilateral ureteral obstruction model. Drinking hydrogen-rich water represents a safe and convenient treatment for oxidative stress-induced pathologies, with no known adverse effects. Its oral administration could offer a promising therapeutic strategy for improving renal fibrosis in congenital obstructive nephropathy.

Citation:
Mizutani, A., Endo, A., Saito, M. et al. Hydrogen-rich water reduced oxidative stress and renal fibrosis in rats with unilateral ureteral obstruction. Pediatr Res 91, 1695–1702 (2022).
https://doi.org/10.1038/s41390-021-01648-7

Si, Y.C.; Liu, L.L.; Cheng, J.; Zhao, T.T.; Zhou, Q.; Yu, J.P.; Chen, W.; Ding, J.R.; Sun, X.J.; Lu, H.T.; Guo, Z.Y.
Source: Frontiers in Medicine, Volume 8 (2021)

Objective:
To investigate the therapeutic effects and potential mechanisms of hydrogen-rich water (HRW) against oxalate-induced kidney injury.

Methods:
A murine model of calcium oxalate (CaOx) crystal-induced kidney damage was established by administering a soluble oxalate-enriched diet. Histological assessments were conducted to evaluate crystal deposition, tubular damage, fibrosis, and reactive oxygen species (ROS) production in renal tissue. Serum indices of kidney injury, inflammation, and oxidative stress were measured using commercial assay kits. RNA sequencing (RNA-seq) was performed to screen for potential molecular pathways, with the expression of key pathway-related molecules assessed via Western blotting and immunohistochemistry.

Results:
Oxalate-induced crystal deposition, tubular damage, fibrosis, and increased renal ROS production in mice were alleviated by HRW administration. Serum markers of kidney injury, inflammation, and oxidative stress were upregulated by the oxalate-rich diet but were significantly reduced with HRW treatment. RNA-seq identified 3,566 differentially expressed genes, which were further analysed through pathway enrichment. The PI3K/AKT, NF-κB, and TGF-β signalling pathways were selected for further validation. Expression levels of pathway-related molecules—PI3K, AKT, and phosphorylated AKT (p-AKT) for the PI3K/AKT pathway; NF-κB p65, phosphorylated NF-κB p65 (p-p65), NLRP3, and IL-1β for the NF-κB pathway; and TGF-β, TGF-β RI, TGF-β RII, p-Smad2, and p-Smad3 for the TGF-β pathway—were elevated in the oxalate-fed group and downregulated upon HRW administration.

Conclusion:
Hydrogen-rich water alleviates oxalate-induced kidney injury through its antioxidant, anti-inflammatory, and anti-fibrotic effects, mediated via inhibition of the PI3K/AKT, NF-κB, and TGF-β signalling pathways. Oral administration of HRW represents a promising therapeutic approach for oxalate-induced renal injury by mitigating oxidative stress, inflammation, and fibrosis.

Citation:
Si Y, Liu L, Cheng J, Zhao T, Zhou Q, Yu J, Chen W, Ding J, Sun X, Lu H, and Guo Z (2021). Oral Hydrogen-Rich Water Alleviates Oxalate-Induced Kidney Injury by Suppressing Oxidative Stress, Inflammation, and Fibrosis. Front. Med. 8:713536.
https://doi.org/10.3389/fmed.2021.713536

Matsushita, T.; Kusakabe, Y.; Kitamura, A.; Okada, S.; Murase, K.

Source: Magnetic Resonance in Medical Sciences, Volume 10, Issue 3 (2011)

Objective:

To evaluate intrarenal oxygenation in gentamicin-induced nephrotoxicity (GIN) and the protective effect of hydrogen-rich water (HW) against GIN using blood oxygenation level-dependent magnetic resonance (MR) imaging.

Methods:

T2*-weighted images (T2*WI) were obtained in 21 rats on days 0, 2, 4, and 7 using a 1.5-tesla MR imaging system. The rats were divided into three groups of seven animals each:

The control group had free access to standard water and received no gentamicin (GM) injection;

The GM group had free access to standard water and received daily subcutaneous injections of GM at 80 mg/kg for seven days;

The GM + HW group had free access to HW and received the same GM injections.

The R2* value (= 1/T2*) was estimated from the T2*WI data.

Results:

In the GM group, R2* values in the renal cortex were significantly decreased on days 2, 4, and 7 compared to day 0, indicating reduced oxygenation. In contrast, no significant changes in R2* values were observed in either the control or the GM + HW group. R2* values in the renal medulla remained unchanged across all groups.

Conclusion:

These findings suggest that gentamicin-induced nephrotoxicity is associated with impaired cortical oxygen utilisation. Oral intake of hydrogen-rich water exerted a protective effect, preserving cortical oxygenation and mitigating GIN-related damage.

Citation:

Matsushita, T., Kusakabe, Y., Kitamura, A., Okada, S., & Murase, K. (2011). Protective effect of hydrogen-rich water against gentamicin-induced nephrotoxicity in rats using blood oxygenation level-dependent MR imaging. Magnetic Resonance in Medical Sciences, 10(3), 169–176.

https://doi.org/10.2463/mrms.10.169

Xin, H.G.; Zhang, B.B.; Wu, Z.Q.; Hang, X.F.; Xu, W.S.; Ni, W.; Zhang, R.Q.; Miao, X.H.
Source: Molecular and Cellular Biochemistry, Volume 392, Issue 1–2 (2014)

Background:
In hypertensive animals and patients, oxidative stress is considered a primary risk factor contributing to the progression of kidney disease. Recent studies have demonstrated that hydrogen, as a novel antioxidant, can selectively neutralise hydroxyl radicals and peroxynitrite anions, thereby exerting therapeutic antioxidant effects.

Objective:
This study aimed to investigate the protective effects of hydrogen-rich water (HW) against renal injury in spontaneously hypertensive rats (SHR).

Methods:
Eight-week-old male SHR and age-matched Wistar-Kyoto rats were randomly assigned to groups treated with HW (1.3 ± 0.2 mg/L, administered as drinking water for 3 months) or with vehicle.

Results:
Although HW treatment did not significantly alter blood pressure, it markedly improved renal injury in SHR. HW administration reduced the generation of reactive oxygen species, upregulated the activity of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, glutathione S-transferase, and catalase, and inhibited NADPH oxidase activity. In SHR, HW treatment also suppressed the expression of pro-inflammatory cytokines such as TNF-α, IL-6, IL-1β, and monocyte chemoattractant protein-1, possibly mediated via inhibition of nuclear factor-kappa B activation. Additionally, HW treatment preserved mitochondrial function in SHR, including ATP production and membrane integrity.

Conclusion:
In conclusion, the consumption of hydrogen-rich water represents a promising adjunctive strategy to mitigate renal injury in the context of antihypertensive therapy.

Citation:
Xin, H.G., Zhang, B.B., Wu, Z.Q. et al. (2014). Consumption of hydrogen-rich water alleviates renal injury in spontaneous hypertensive rats. Molecular and Cellular Biochemistry, 392, 117–124.
https://doi.org/10.1007/s11010-014-2024-4