Part Ⅱ Hydrogen: A Novel Treatment Strategy in Kidney Disease
May 23, 2023
The Role of Kidney Diseases
The effects of H2 in kidney diseases are shown in Table 1.
1. Drug-Induced Nephrotoxicity
Drug-induced nephrotoxicity is becoming increasingly common today. A common cause of renal toxicity can be drugs, such as antibiotics or antitumor drugs. Cisplatin, a widely used cancer chemotherapy agent, is effective against many solid tumors, including lung, ovary, and breast cancer. Nephrotoxicity is the main dose-limiting toxicity of cisplatin. Despite saline hydration and diuresis, the incidence of nephrotoxicity is in the range of 20–30% [33]. Cisplatin has a high affinity for SH (sulfhydryl) groups, in addition to DNA, it's the primary target [34]. The interaction between cisplatin and SH groups leads to GSH depletion, resulting in the reduction of the cellular antioxidant system and accumulation of ROS and its products [34]. Cisplatin is mainly accumulated in the kidney as it is excreted mostly through this organ [35]. The accumulation of cisplatin and the generation of ROS in the kidney may be attributed to cisplatin-induced nephrotoxicity. Nakashima-Kamimura et al. [36] showed that the inhalation of hydrogen gas has a protective effect against cisplatin. For acute and strong OS induced by I/R, 1% of hydrogen gas provides sufficient protection, while the inhalation of 1% or 2% hydrogen gas may be applicable for short-term treatments. In addition to hydrogen gas, this study demonstrated that drinking hydrogen water ad libitum was also effective in obtaining a significant protective effect. Subsequently, some researchers confirmed that hydrogen-rich water (HW) ameliorates renal dysfunction caused by cisplatin-induced nephrotoxicity in rats, using dynamic contrast-enhanced CT and blood oxygenation level-dependent magnetic resonance imaging [37, 38]. Also, HW restored the redox equilibrium, suppressed OS damage, and improved kidney function induced by cyclosporine A via activation of the Keap1/Nrf2 signaling pathway [39]. The findings above [36–39] confirm that HW can be a promising therapeutic strategy for treating renal diseases and preventing clinical chronic allograft nephrotoxicity following organ transplantation.
2. Renal Fibrosis
Renal fibrosis, characterized by the accumulation of scars within the parenchyma, represents a common final pathway of chronic and progressive nephropathy. Renal fibrosis affects half of adults over the age of 70 and 10% of the world’s population [40]. Therefore, actively exploring the pathogenesis and defense measures of renal fibrosis is important to improve the prognosis of kidney disease. Xing et al. [41] used HW to treat a Balb/C mouse model of renal fibrosis constructed by unilateral ureteral obstruction. Their study showed that HW alleviated unilateral ureteral obstruction-induced renal fibrosis. In the cell model, HW prevented the HK-2 cells from transforming to epithelial to mesenchymal transition induced by TGF-β1, in which Sirt1 other than TGF-β1/Smad2 pathway was involved. The study implies a therapeutic potential of hydrogen against fibrosis, with Sirt1 being a latent target for the treatment and diagnosis of fibrosis. Chen et al. [42] found that hydrogen-rich saline (HRS) showed a protective effect in the prevention of renal injury and could inhibit renal fibrosis after an IR injury in mice. HRS might be exerted via retaining Klotho expression and activating autophagy in the kidney. Future research should aim to find out a non-invasive method for treating renal fibrosis.
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3. Ischemia-Reperfusion Injury
IRI, which is unavoidable in organ transplantation, is severely detrimental to renal graft function and survival. One of the major events in ischemia-reperfusion is the generation of cytotoxic oxygen radicals, which lead to cellular injury by inducing DNA damage, protein oxidation, lipid peroxidation, and apoptosis [43]. In 2001, Noiri et al. [44] demonstrated that the generation of ROS and NO in IRI can result in the formation of a cytotoxic metabolite, peroxynitrite (ONOO−), which can cause lipid peroxidation and DNA damage. A rapid transition from an ischemic condition to reperfusion causes OS damage [45]. To mimic ischemia, Ohsawa et al. [2] subjected neocortical cells to oxygen-glucose deprivation (OGD) under nitrogen or hydrogen gas for 60 min, followed by reperfusion with a medium containing O2 and glucose. HPF fluorescence showed that 10 min after the completion of OGD followed by reperfusion, •OH levels notably increased in the absence of H2 but diminished when H2 was present. At 24 h after OGD and reperfusion, H2 increased neuron survival and vitality, indicating that H2 protected neurons against OS-induced cell death. In addition, 8-OHdG and malondialdehyde are the main forms of DNA and lipid damage-induced ROS, respectively [43]. Given that H2 molecules can mitigate IRI by selectively removing ROS that leads to oxidative damage to DNA, lipids, and proteins, Kawamura et al. [43] evaluated OS by monitoring urinary 8-OHdG and serum malondialdehyde levels. 8-OHdG and malondialdehyde, which are peroxidation products of DNA and lipids, respectively, are widely used as OS markers [46–48]. The treatment with nano-Si led to a reduction in the increased urinary 8-OHdG and malondialdehyde levels due to IRI. To sum up, •OH and ONOO− are the major ROS that contributes to IRI, while 8-OHdG and malondialdehyde can be used as main OS markers to IRI. Since the discovery of the selective antioxidant properties of molecular hydrogen (H2) in 2007, several studies have shown that hydrogen has beneficial effects in a variety of animal models of OS in vivo [2, 49, 50]. H2 treatment has been shown to abrogate IRI following warm and cold ischemia, and thus, it has been identified as a potential therapy to improve kidney transplantation outcomes [8]. Li et al. [51] induced a rat model of renal IRI and found that the treatment with HRS solution (HRSS) significantly reduced interstitial congestion, edema, and hemorrhage compared with saline treatment. HRSS could promote renal function recovery after IRI in rats by inhibiting the inflammatory TNF-α/IL-6 pathway, increasing the Bcl- 2/Bax ratio, and attenuating kidney cell apoptosis. Another study [52] reported that HRS improved the renal response to I/R in aged rats, possibly by reducing OS and upregulating HO-1 gene expression. In addition, Nishida et al. [53] conducted a study to evaluate the effects of a mixture of H2 gas and CO gas (dual gas) in comparison with hydrogen gas (H2: 2%) alone on I/R renal injury. They observed the cytoprotective effects of dual treatment in comparison with H2 treatment and I/R renal injury in terms of superoxide radical scavenging activity and histochemical features. Rats given dual treatment showed a significant reduction in both blood urea nitrogen and the expression of several inflammatory cytokines (IL-6, TNF- α, ICAM-1, HIF-1α, NF-κB, and HO- 1). Although the mechanism of the protective effect of hydrogen remains unclear, the application of hydrogen therapy may be a simple, safe, economical, and effective new method for protecting against kidney injury.
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4. Renal Calculi
Kidney stones, caused by the abnormal accumulation of crystalline substances (calcium oxalate – CaOx – being the most common), are one of the most common diseases of the urinary system. To evaluate the protective effect and underlying mechanism of hydrogen gas (H2) in glyoxylate-induced renal CaOx crystal deposition in mice, Peng et al. [54] established a rodent renal CaOx crystal deposition model by intra-abdominal injection of glyoxylate (precursor of oxalate) for 5 days. According to the results of the levels of urine calcium excretion, renal calcium deposition, serum excretion of kidney injury molecule-1 (KIM-1) assay, and TUNEL assay, the inhalation of H2 successfully decreased the crystallization of CaOx and protected against renal injury. Crystal deposition in the kidneys is associated with OS. OS leads to apoptosis and necrosis of renal tubular epithelial cells. This is a key element for renal tubular epithelial cell damage [55] and contributes to the renal crystal deposition and occurrence of renal stones [56], due to the production of ROS [57]. ROS are considered to be cytotoxic and can damage a variety of macromolecules [58]. Serum metabolomics studies in mice [55] showed that H2 protects against renal injury caused by the crystallization of CaOx, which may be related to changes in fatty acid metabolism, phospholipid metabolism, and amino acid metabolism. More research, however, is needed to gain a better understanding of the molecular mechanisms of CaOxinduced renal injury and the therapeutic effects of hydrogen gas.
5. Hemodialysis
Increased OS is associated with severe cardiovascular disease and premature death in patients treated with hemodialysis (HD). During HD, the exposure of the dialysis membrane to blood can enhance the production of OS [59]. In a clinical study [59], 8 patients with regular hemodialysis were alternately treated with standard dialysate and dialysate dissolved with a high concentration of hydrogen, and the results showed that dialysate containing hydrogen could reduce the level of OS in hemodialysis patients, which may reduce the incidence of cardiovascular diseases. Thus, dialysate containing hydrogen can provide a new treatment for the control of uremia. In another study [60], Nakayama et al. [60] developed a novel hemodialysis (E-HD) system delivering an H2 (30–80 ppb)-enriched dialysis solution by water electrolysis and conducted a nonrandomized, nonblinded, prospective observational study exploring its clinical impact. It was concluded that E-HD was an independent significant factor in reducing the risk of the primary events of all-cause mortality and development of nonlethal cardio-cerebrovascular events. Thus, the application of H2-enriched solutions may ameliorate OS during HD, although more research is needed to determine its clinical impact.
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6. Chronic Allograft Nephropathy
Chronic allograft nephropathy (CAN), also called interstitial fibrosis and tubular atrophy of unknown etiology (IF/TA), remains one of the most vexing clinical entities for renal transplant physicians to treat, as it is resistant to current treatment modalities and is a major cause of long-term graft loss [61]. Therefore, potential new approaches to the treatment of CAN such as the one described by Cardinal et al. [62] are of great interest. The addition of hydrogen to drinking water reduced the severity of CAN and increased graft survival, indicating that the mechanism may be due to a reduction in ROS. Therefore, oral HW is an effective antioxidant and anti-inflammatory agent that prevented CAN, improved the survival rate of rat allograft kidney transplantation, and may have therapeutic value in transplantation.
7. Sepsis-Related AKI
AKI is common in the early stages of sepsis, with an incidence of 55–73% [62], independently associated with mortality [63]. Approximately 70% of septic AKI cases are fatal. Thus, kidney protection is critical for these patients’ survival [64]. Excessive inflammatory response and OS are considered to be the main mechanisms of septic AKI [65]. Recently, it has been discovered that reducing inflammation is critical in sepsis therapy, suggesting a new therapeutic concept for preventing septic AKI [66]. Yao et al. [67] explored the renal protective effects of aerosol inhalation of a hydrogen-rich solution in a mouse model of septic AKI. Septic AKI was induced by an 18-h cecal ligation and puncture. AKI occurred during the early stage of sepsis and was characterized by increased blood urea nitrogen and serum creatinine levels, pathological changes, renal fibrosis and renal tubular epithelial cell apoptosis, macrophage infiltration, and M1 macrophage-associated pro-inflammatory cytokine (IL- 6 and TNF-α) generation in renal tissues. Aerosol inhalation of the HRS increased anti-inflammatory cytokine (IL-4 and IL-13) mRNA levels in renal tissues and promoted macrophage polarization to the M2 type, which generated additional anti-inflammatory cytokines (IL-10 and TGF-β). Ultimately, aerosol inhalation of HRS protected the kidneys and increased survival among septic mice. Thus, HRS aerosol inhalation appears to be highly beneficial for renal protection and inflammation reduction in septic AKI.
8. Other Functions
Xin et al. [68] investigated the protective effect of HW on renal injury in spontaneously hypertensive rats (SHR). The 8-week-old male SHR and age-matched Wistar-Kyoto rats were randomized into HW-treated and vehicle-treated groups. Although HW had no significant effect on blood pressure, it significantly ameliorated renal injury, reducing the formation of ROS, suppressing NADPH oxidase activity, and upregulating the activities of superoxide GSH peroxidase, dismutase, GSH-S-epoxide transferase, and catalase. Treatment with HW in SHR-depressed expression of pro-inflammatory cytokines such as IL-6, IL-1b, TNF-a, and macrophage chemoattractant protein 1, which may be mediated by inhibiting the activation of the nuclear factor-κB. Furthermore, HW treatment had a protective effect on mitochondrial function including adenosine triphosphate formation and membrane integrity in SHR. To sum up, HW is a promising strategy for reducing renal injury when used in conjunction with anti-hypertensive therapy.
Guan et al. [23] reveal that H2 can ameliorate CIHinduced kidney injury by decreasing ER stress and activating autophagy through inhibiting OS-dependent p38 and JNK MAPK activation. Increased expression of renal transferrin receptor and divalent metal transporter-1 expression, as well as reduced ceruloplasmin expression, may be possible causes for iron accumulation in the proximal tubule epithelial cells of rats after CIH treatment. Inhalation of H2 could prevent renal injury induced by CIH via inhibition of iron overload in renal epithelial cells, which is involved in the mechanism of OS-mediated injury [69].
In addition, Shi et al. [70] demonstrated that HRS could attenuate acute renal injury in a sodium taurocholate-induced severe acute pancreatitis rat model. By inhibiting NF-κB activation and scavenging ROS, HRS prevented the development of an inflammatory cascade and eased renal oxidative damage. Homma et al. [71] found that contrast-induced AKI in rats was carried on using an intravenous injection of a contrast medium, lovers. During the injection of these reagents, the rats inhaled H2 gas or control gas. The inhalation of H2 was effective in ameliorating the severity of contrast-induced AKI in rats by reducing renal cell apoptosis and OS.
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Conclusion
At present, there have been few reports of hydrogen causing adverse reactions in cells. Hydrogen has been studied for its mutagenicity, genotoxicity, and subchronic toxicity. Saitoh et al. [72] investigated the toxic and side effects of neutral-pH hydrogen-enriched electrolyzed water on rats (20 mL/kg/day, lasting for 28 days). No toxicity was related to drinking hydrogen-rich electrolytic water in terms of clinical symptoms, hematology, and histopathology. Nakao et al. [73] conducted an open-label pilot study of drinking HW, which showed that drinking HW down-regulated aspartate aminotransferase and alanine aminotransferase while increasing gamma-GSH transferase and total bilirubin. However, the changes in these parameters were limited to one gender, and the mean values of these parameters were within the normal acceptable reference range for both male and female subjects. So far, no studies have shown that hydrogen has a clear adverse impact on the treatment of renal disease.
To sum up, hydrogen plays a unique role in anti-oxidation, anti-inflammation, anti-apoptosis, and cell death. Several animal studies have now confirmed the therapeutic effect of hydrogen in kidney diseases, such as renal calculi, renal fibrosis, and drug-induced nephrotoxicity. The specific molecular mechanisms behind the therapeutic effect of hydrogen remain unknown. Future research should focus on the negative effects of hydrogen and its specific mechanisms of action in kidney disease. Largescale clinical trials will be needed to demonstrate the effectiveness and cost-efficiency of hydrogen as a therapy against kidney disease.
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Bo Wang a Zhuoshu Li b, c Longfei Maod Mingyi Zhaob Bingchang Yange Xiaowu Taoa Yuxiang Lia Guangming Yina
a Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, China;
bDepartment of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China;
c Xiangya School of Medicine, Central South University, Changsha, China;
d Bioinformatics Center, College of Biology, Hunan University, Changsha, China;
e Department of Critical Care Medicine, Central South University, Changsha, China
