Category Archives: [:en] ionized water [:ro] apa ionizata

AlkaViva EmcoTech/Jupiter alkaline ionized water as cancer treatment -clinical case , integrative oncology

AlkaViva EmcoTech/Jupiter alkaline ionized water as cancer treatment -clinical case , integrative oncology

Abstract

The present article describes the ongoing (partial) remission of a female patient (41 years old) from estrogen receptor (ER)-positive/progesterone receptor (PR)-negative metastatic breast cancer in response to a combination treatment directed towards the revitalization of the mitochondrial respiratory chain (oxidative phosphorylation), the suppression of NF-kappaB as a factor triggering the inflammatory response, and chemotherapy with capecitabine. The reduction of tumor mass was evidenced by a continuing decline of CA15-3 and CEA tumor marker serum levels and 18FDG-PET-CT plus magnetic resonance (MR) imaging. It is concluded that such combination treatment might be a useful option for treating already formed metastases and for providing protection against the formation of metastases in ER positive breast cancer. The findings need to be corroborated by clinical trials. Whether similar results can be expected for other malignant tumor phenotypes relying on glycolysis as the main energy source remains to be elucidated.

1. Introduction

Since Richard Nixon declared war on cancer about 30 years ago, much efforts have been made in order to overcome this dreadful disease. Enormous financial resources have been invested in cancer research in the last three decades, yet most metastasized solid malignant tumors are still considered incurable. Chemotherapy has been shown to be a potent (long lasting) treatment option against only a few solid cancers including testis cancer. The overall contribution of curative and adjuvant cytotoxic chemotherapy was assessed to be 2.3% in Australia and 2.1% in the United States of America with a five-year survival in adults based on data for 1998 []. Under chemotherapy, cancer cells can gradually develop drug resistance that is acquired, for instance, by overexpression of transporter proteins (e.g., those belonging to the ATP-binding cassette type) [,] and fractionation of the cancerous stem cells [] (which are less sensitive to exposure to cytostatics than more differentiated cancer cells), plus AKT [,] and NF-kappaB [,] overexpression as a compensatory response to administered cytotoxic drugs. Likewise, induced hypoxia may act as protective shield against tumor eradication by chemotherapeutics and radiation due to alterations of gene expression profiles related to hypoxia, which result in the inhibition of apoptosis [].

On the other hand, a plethora of “alternative” cancer therapies have been developed and applied in the past. Here, we report on a combination treatment, including chemotherapy, bisphosphonates, and complementary measures, aiming at the normalization of the cellular metabolism, vascular angiogenesis, cell life cycle, and cell proliferation activity.

2. Experimental

2.1. Chemicals/Dietary Supplements

Super Ubiquinol CoQ10, Life Extension, article nr. 01426, USA: www.lefeurope.com

Vitamin B2, tablets, 10 mg, Jenapharm®, Mibe GmbH, Germany

Vitamin B3, capsules, 54 mg, Allpharm, Germany, PZN 6605862

5-Loxin®capsules, 75 mg, (std. for acetyl-11-keto-β-boswellic acid (AKBA), minimum 30% on dry basis), Life Extension, article nr. 00939, USA, www.lefeurope.com

Linseed oil, Linosan Leinöl, Heirler Cenovis GmbH, D-78303 Radolfzell, Germany

Bio-Kefir, Andechser Natur, 1,5% fat, containing L(+) dextrorotatory lactic acid, Andechser Molkerei Scheitz GmbH, D-82346 Andechs, Germany, www.andechser-molkerei.de

Bio-Yoghurt, Andechser Natur, 0,1% fat, containing L. acidophilus and B. bifidus, Andechser Molkerei Scheitz GmbH, D-82346 Andechs, Germany, www.andechser-molkerei.de

Flaxseed, freshly ground

EPA/DHA: Mega EPA/DHA, capsules, Life Extension, article nr. 00625

Sodium selenite, Selenase®200 XXL, 200 μg selenium, biosyn Arzneimittel GmbH, D-70734 Fellbach, Germany

L-Carnitine: Multinorm® L-Carnitin aktiv, 250 mg L-carnitin plus 3 μg Vitamin B12, Sankt Pirmin® Naturprodukte GmbH, D-55218 Ingelheim, Germany

L-Carnitine, 300 mg capsules: Altapharma, Germany

Zinc, Unizink® 50, 50 mg zinc-bis(hydrogen-DL-aspartat), Kohler Pharma GmbH, D-64665 Alsbach-Hähnlein, Germany, PZN-3441621

Ibandronat Bondronat®, 6 mg/6 mL concentrate, Roche Pharma AG, D-79639 Grenzach-Wyhlen, Germany

Capecitabine, Xeloda®, Roche Pharma AG, D-79639 Grenzach-Wyhlen, Germany

Drinking water ion exchanger and filter, pHresh, EMCO TECH Co. Ltd., Korea

Vitamin D and vitamin A were sporadically taken.

2.2. Procedure

The mentioned chemicals/dietary supplements have been taken as follows:

Alkalized drinking water was prepared ad lib by using water ion exchanger and filter. The filtered water was boiled prior to use.

Capecitabine was taken orally at 3.65 g Xeloda®/70 kg body weight per day. Two weeks of treatment were followed by one week of therapy pause per cycle.

“Budwig diet”: the following items were mixed for preparing a full batch using a blender: 1 kg Bio-Yoghurt, 0.1% fat, 0.25 kg Bio-Kefir, 1.5% fat, 6 table spoons of linseed oil, 4 table spoons of linseed, to be freshly milled: A part of this full batch may be prepared daily (the daily dose per person was about 250 grams).

Taken together around noon: 400 mg of Ubiquinol CoQ10 (4 capsules à 100 mg), 10 mg vitamin B2 (Riboflavin), 50 mg vitamin B3 (Niacin)

Taken three times daily: 2 softgels of MEGA EPA/DHA (eicosapentaenoic acid/docosahexaenoic acid), including 720 mg of EPA and 480 mg of DHA per 2 capsules.

One capsule of 5-Loxin®, one dose of Multinorm® L-Carnitin aktiv (taken only during chemotherapy pause; during the chemotherapy 300 mg pure L-carnitine not containing vitamin B12 was ingested), one tablet of Unizink® 50, and one tablet of Selenase®200 XXL were taken daily. EPA/DHA are COX-2 inhibitors. Therefore, the heart and vascular functions should be checked by a physician on a regular basis (it has been found that members of synthetic COX-2 inhibitors have been found to increase thrombosis, stroke, and heart attack risk under certain conditions). Moreover, Q10/B2/B3 were not taken in combination with radiation (the antioxidant Q10 potentially quenches the oxidative damage caused by radiation). EPA and DHA have potentially blood thinning effect.

3. Results

3.1. Applied Methodology and Methods

It has been hypothesized by the author that a multi-factorial approach towards breast cancer treatment would result in a synergetic response and reduced likelihood of development of resistance to treatment. Accordingly, it was sought to combine complementary, non-antagonistic treatments, which have the theoretical potential to suppress tumorigenesis and proliferation, with a “conventional” treatment. The envisaged therapy modules were Budwig diet and normalization of the fatty acid dietary balance, alkaline therapy, suppression of the inflammatory signaling chain, revitalization of the mitochondrial respiratory chain, bone protection against osteoclast-effected resorption by bisphosphonates and AKBA, and finally chemotherapy in the form of the prodrug capecitabine as 5-fluorouracil precursor []. The latter has been the recommended treatment by the medical tumor board in charge.

The described efforts have concretely been undertaken for suppressing refractory breast cancer stage IV in a female patient (body mass index 24–26, 41 years old), having developed a ductal carcinoma in situ in 2007. After biopsy revealed an estrogen receptor positive and progesterone receptor negative breast cancer, followed by surgical resection of the invaded sentinel lymph nodes, a neoadjuvant chemotherapy (four cycles Epirubicin/Cyclophosphamide, followed by four cycles of Taxotere®) was applied. However, the tumor showed little response (the tumor regression grade according to Sinn was only 1). Thus, the first and second axillary lymph node levels were resected in the following, and the affected breast was ablated. No suspicious tumor marker levels have been observed after ablation. The resection area was furthermore treated with radiation (gamma rays). The post-operational therapy included firstly tamoxifen, clodronate (a bisphosphonate), and a GNRH analogue (Enantone-Gyn®).

However, in September 2008, the patient – alerted by pain in the spinal cord – underwent MRI imaging, which revealed multiple bone metastases, including in the spinal cord.

As a consequence, the medication was altered as follows by the medical board in charge: Letrozol (aromatase inhibitor, 2.5 mg/d) and Ibandronat (6 mg intravenous infusion per month) as bisphosphonate. However, the disease progressed and a staging (18FDG-PET-CT and MRI) in March 2009 revealed the formation of various liver metastases. Therefore, the medication was changed to capecitabine chemotherapy instead of anti-hormonal therapy, accompanied by continuation of administration of Ibandronat.

Together with this therapy change, the author recommended the complimentary ingestion of the following substances: “Budwig diet” (linseed oil, flaxseed, and yoghurt), EPA/DHA concentrate in the form of distilled fish oil, ubiquinol (Q10 in reduced form), and vitamins B2 and B3, later on also 5-Loxin®(AKBA). See above for further dosage and substance specifications.

3.2. Results

After about three months (June 2009) of continued intake of the above mentioned substances (besides 5-Loxin®), PET-CT showed no metabolic activity of the liver metastases any longer and reduced activity of the bone metastases under 18F-deoxyglucose as tracer in the PET. Concurrently, a decline of the tumor markers’ (CA 15-3 and CEA) serum concentration was observed.

At this time, as a further element, 5-Loxin® (AKBA) was introduced into the supplementation scheme for the reasons mentioned.

Nine months later, the MRI showed that three out of six initial liver metastases could no longer be imaged, and that the largest lesion had decreased from about 15 mm to about 7 mm. A further small liver metastasis remained unchanged in size. This situation is depicted in Figure 1. Again, no metabolic activity in 18FDG-PET-CT was detected for any of the liver metastases.

An external file that holds a picture, illustration, etc. Object name is cancers-03-01454f1.jpg

Diffusion-weighted MRI of the liver showing two metastases in the right lobe in (a) June 2009, and (b) February 2010. One metastasis (arrow) decreased from 15 mm in diameter to 7 mm, while the other remained unchanged (courtesy of Prof. Dr. E. Rummeny, Klinikum Rechts der Isar, Technische Universität München, Technical University of Munich, Germany).

Moreover, the PET-CT (18F-deoxyglucose as PET tracer) showed, in addition, a reduction of the size and metabolic activity of bone metastases, accompanied by re-calcification of the lesions. The response to treatment correlated with markedly decreased tumor marker serum levels, with CEA concentration being close to the significance threshold of 4 ng/mL. The development of the tumor marker levels over time is displayed in Table 1 below. The decline of tumor marker concentrations has been found to correlate with cancer remission in clinical studies on breast cancer patients [,]. In addition, the initial concentration of CEA has been associated with the clinical disease outcome in breast cancer patients.

Table 1.

Development of the CEA and CA 15-3 serum concentrations over time; cut-off values were 4 ng/mL for CEA and 27 U/mL for CA15-3.

Date/Months after Therapy Start CA 15-3 (U/mL) Excess over Cut-off Value [%] CEA (ng/mL) Excess over Cut-off Value [%]
29 June 2009/3 49.3 82.6 31.4 684
13 September 2009/7 46.2 71.1 8.4 110
11 January 2010/10 37 37.0 4.1 2.5
19 April 2010/13 38.3 41.9 3.6 -10.8
12 July 2010/16 35.7 32.3 4.1 1.5

The latest 18FDG-PET-CT of August 2010 showed ongoing sclerosis of at least some of the bone lesions and stable disease.

4. Discussion and Conclusions

A plethora of complementary cancer treatments have been reported. Firstly, the intake of polysaccharides and proteoglucans, such as mushroom and yeast glucans [  ,  ], mistletoe lectins [,] and nerium oleander extracts, the latter also in combination with sutherlandia frutescens extracts [,], have been described. The activation of the immune system against cancer cells has been ascribed to all of these compounds.

Another approach employed against the proliferation of cancer is alkaline therapy, which addresses the cellular acid-base balance. It has been found that extracellular/interstitial cancer tissue is more acidic than healthy tissue due to excessive production of lactic acid stemming from the glycolysis of glucose []. Otto Warburg already suggested in the last century that (as a consequence of hypoxia often encountered in tumor tissues) cancer cells undergo excessive glycolysis instead of relying on the energetically by far more effective oxidative phosphorylation [,], a fact which could recently also be verified by biopsy analysis in breast cancer patients, revealing a marked decrease in β-F1-ATPase/HSP60 expression ratio during disease progression []. Lately, it has been suggested that the initiation of glycolysis could be triggered by AKT activation during tumor development [] and that the resulting acidification of the extra-cellular cancer tissue brings about survival advantages for cancer cells [,]. It has been found recently that T-cell development is markedly suppressed in acidified cancer tissue []. Alternative alkaline therapies applied for cancer treatment included the intake of sodium bicarbonate [], cesium chloride [], or alkaline diet, which is based on fruit and vegetables having high potassium content. A further approach was the ingestion of alkaline drinking water obtained from ion exchangers.

Another avenue towards cancer suppression has been established by the supplementation of (essential) polyunsaturated fatty acids, aiming at re-establishing cellular membrane functionality [] and fluidity []. In addition, the polyunsaturated omega-3 fatty acids eicosapentaenoic (EPA) and docosapentaenoic acid (DHA) have been found to have a direct bearing on gene expression level by e.g., deactivation of NF-kappaB and AKT by EPA and DHA in a mouse model []. Polyunsaturated omega-3 fatty acids have also been shown to possess anti-inflammatory properties, for instance. by suppression of NF-KappaB and cyclooxygenases [], or caused by the reduction of prostaglandin E2 biosynthesis via arachidonic acid due to a shift in the omega-6 fatty acid/omega-3 FA level towards omega-3 species (omega-6 fatty acids form the pool for the endogenous biosynthesis of E2 prostaglandin) [,].

In addition, a direct positive correlation between cytotoxic drug efficacy and DHA level in breast adipose tissue of patients has been observed [  ]. Also, recent clinical studies suggested that EPA/DHA supplementation may suppress cancer-related cachexia []. Whereas severe side effects have been reported for the prolonged administration of some synthetic COX-II inhibitors, including increased thrombosis, stroke, and heart attack risk, to our best knowledge no comparably grave effects have been reported for the prolonged intake of EPA/DHA (e.g. in the form of fish oil) in clinical studies. The side effects of fish oil therapy, including blood thinning, have recently been discussed, e.g., by Farooqui et al.[].

Likewise, Johanna Budwig established a cancer diet (the so-called “Budwig diet”), which includes inter alia the daily intake of linseed oil as a potent source of alpha-linolenic acid as essential omega-3 fatty acid []. Anecdotal cases of complete cancer remissions after continued Budwig diet have been reported []. To our best knowledge, no randomized clinical trials exploring the efficacy of the Budwig diet have been launched to date. The consequence of a continued Budwig diet is said to be an optimization of the dietary balance of omega-6/omega-3 fatty acids and reconstitution of physiologically intact cellular membrane composition by enhanced administration of polyunsaturated fatty acids as a substitute for peroxidized and saturated fatty acids in cellular membranes, thus increasing membrane fluidity. Furthermore, it has been hypothesized that polyunsaturated fatty acids may act as oxygen carriers []. The present-day Western diet results in an adverse ratio of about 15:1 of omega-6/omega-3 fatty acids, whereas a ratio of about 1:1 has been reported as paleolithic reference value for humans []. As a consequence, the endogenous high level of omega-6 fatty acids in humans fosters the increased biosynthesis of pro-inflammatory arachidonic acid from e.g., linoleic acid. Moreover, it has been hypothesized that cottage cheese, quark or yoghurt as second constituent of the Budwig diet refills the pool of sulfhydryl amino acids (which are essential for glutathione biosynthesis).

Warburg considered the glycolytic switch as being a final event in cancer formation, accompanied by irreversible genetic changes and the inactivation of the mitochondrial respiratory chain in cells, giving rise to their dedifferentiation []. However, recent studies suggest that this may not be the case: Dichloroacetate has been shown to be a potent inhibitor of pyruvate dehydrogenase kinase, thereby suppressing, as other agents, the glycolytic switch and thus fostering oxidative phosphorylation [,,]. As a consequence of such an apparent normalization of the cellular energy production, cancer remissions in animal trials and anecdotal reports of healing of malignant tumors in human patients have been reported lately [].

Moreover, investigations involving the administration of coenzyme Q10 directed towards the revitalization of the mitochondrial respiratory chain suggest that, indeed, the inhibition of the respiratory chain (Q10 is present in various complexes thereof) can be reversed or at least be halted: Folkers et al. reported that breast cancer patients taking 90 mg per day Q10 stayed in a state of constant disease, and did not develop new metastases. No patient in the group died, although about 20% (6/32) deaths were statistically expected in the observation period. When the dose of Q10 was augmented to 390 mg daily, five patients who already showed remission under 90 mg of Q10 per day went into apparently complete remission, including the eradication of liver metastases [,]. Cases of complete remission in response to high doses of Q10 for other cancer types, such as small cell bronchogenic carcinoma, have also been published by Folkers et al.[].

Likewise, Sachdanandam et al. recently reported on tumor control and remission caused by a combination treatment by coenzyme Q10, vitamins B2 and B3 (all of which are essential for the cellular energy generation) and tamoxifen in animal trials []. As a result, markedly lower levels of lipid peroxidation and cachexia over the tumor-induced non-treated control group was observed. Orienting clinical trials of Premkumar et al., involving 84 breast cancer patients, affirmed the anti-tumor action of said agent combination []. Inter alia, a decrease of the plasma concentration of urokinase plasminogen activator (UPA) by about 50% was observed, and the level of adhesion factors such as E-selectin and pro-angiogenic proteinase MMP-9 were found to be drastically decreased after only 90 days of treatment. Moreover, significantly reduced tumor marker levels (CA-15-3 and CEA) have been measured after 90 days of coenzyme Q10, vitamins B2 and B3 plus tamoxifen combination treatment []. UPA expression level was determined as correlating with the clinical outcome of breast cancer, and UPA inhibition has therefore been made the target of extensive research [].

Another approach addressing the stabilization of the course of breast cancer is the administration of bisphosphonates [] such as ibandronate, which stabilize the bone matrix and thus impede osteoclast-mediated bone lysis. In addition, certain bisphosphonates, such as the latter compound, have been shown to possess direct anti-tumor action in vitro and in vivo [,].

Finally, a further route towards the suppression of cancers is the suppression of nuclear factor kappa B (a gene transcription promoter involved in the inflammatory chain and in a tumor’s capability to invade, metastasize and evade apoptosis) []. NF-kappaB stimulates the expression of various pro-inflammatory genes [,], also in breast cancer []. Consequently, a number of approaches have been divulged lately which are concerned with inhibition of this factor. The different compounds, which hinder the activation of NF-kappaB, are e.g., EPA (see above), and 11-keto-17-hydroxy boswellic acid (AKBA) [], a compound which has been shown to abrogate the osteoclastogenesis by inhibition of NF-kappaB activation in vitro. AKBA was also shown to hinder the enzyme 5-lipoxygenase [], which plays a pivotal role in the biosynthesis of pro-inflammatory leucotrienes. Remarkably, it has been shown that NF-kappaB inhibitors effectively inhibited MCF-7 breast cancer stem-like cells [].

In the present case, refractory breast cancer, which had not or has poorly responded to initial chemo- and anti-hormonal therapy, showed drastic and ongoing response to a combination treatment including capecitabine and complementary treatment components; the latter include NF-kappaB blockers, and other inhibitors of the inflammatory chain, respiratory chain stimulants, plus alkaline therapy. The rationale for employing these agents has been explained in the preceding paragraphs. No resistance to the therapy was observed after 17 months, and the decrease of tumor marker levels correlated with imaging results. The obtained results are significant in view of the initial heavy disease progress and lack of relevant response to all preceding therapies.

The incremental contributions of each individual treatment element remain unclear. However, it is hypothesized that a synergetic action of the measures takes place. These have been selected by theoretical considerations in order to avoid potential antagonistic interferences, which could annihilate action. It should also be noted that concerns about the simultaneous intake of chemotherapeutics and antioxidants have been raised in the literature, especially in the context of cytostatics that have free radical formation as their believed primary mechanism of action. To our best knowledge, the primary mechanism of action of capecitabine, however, is not via free radicals but DNA synthesis and thymidylate synthase inhibition []. No antagonistic interaction with the remaining measures “base therapy” (addressing the immune suppression observed in the acidic tumor environment due to the purported suppression of T-cell development in the acidic tissue adjacent to tumors) and bone stabilization by bisphosphonates has been expected. On the contrary, the reported suppression of NF-kappaB expression by e.g. AKBA should reduce the RANKL-induced osteoclastogenesis, which is triggered by the transcription factor NF-kappaB [].

Whether all measures contribute to the observed results remains speculative. The progression-free interval of 17 months observed so far is encouraging in view of a median time to progression from 3–9 months reported for the first line treatment of metastatic breast cancer by capecitabine []. Randomized clinical trials appear to be indicated in view of the promising orienting results.

Note that ER positive/PR negative breast cancer constitutes a rather limited high risk subset within the broader patient collective suffering from luminal breast cancer. Lately, it has been hypothesized in the literature that the expression of progesterone receptor (genes) in breast cancer has a positive bearing on the disease malignity and outcome, correlating with a less aggressive phenotype, and that the expression of progesterone receptor genes may be hindered by AP-1 [,,]. AP-1 and NF-kappaB have been shown to bind to UPA promoter sequence and to cooperatively foster UPA expression. Consequently, it has been directly or indirectly suggested to therapeutically inhibit NF-kappaB in order to improve efficacy of antiestrogen treatment of patients associated to high risk hormone-dependent breast cancer [,].

Moreover, the reduced UPA expression mediated by Q10 described in the literature could also be a sign of a reduced activity of the transcription factor AP-1. At the same time, reduction of AP-1 activity could lead to a reversal of the blockage of the progesterone receptor expression caused by the inhibitory action of AP-1 and a consequent sensitization of ER-positive/PR-negative breast cancers to anti-estrogenic treatment by tamoxifen (compare to references [,]).

It is further hypothesized that the obtained orienting results hint (as already observed for DCA) at a revitalization of the mitochondrial respiratory chain at the expense of a pathologic increase of glycolysis. The reduction of glucose metabolism of the metastases was corroborated by reduced signal intensity in 18FDG-PET-CT scans during the treatment. Hence, the results are interpreted as a pointer towards the (at least partial) reversibility of the glycolytic switch and the associated changes in gene profile expression.

 

SEE ALL WATER IONIZERS – MOLECULAR HYDROGEN GENERATORS

Logo of cancers

Link to Publisher's site
. 2011 Mar; 3(1): 1454–1466.
Published online 2011 Mar 17. doi: 10.3390/cancers3011454
PMCID: PMC3756422
PMID: 24212668

Clinical Response of Metastatic Breast Cancer to Multi-targeted Therapeutic Approach: A Single Case Report

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).

Acknowledgements

Thanks are due to E. Rummeny and J. Gaa, both Department of Radiology, Klinikum Rechts der Isar, Technische Universitat Munchen, for kindly providing the MRI images and the image analysis.

Disclaimer

The author does not suggest that breast cancer can be healed by applying the described measures. Moreover, the author disclaims all responsibilities and liabilities as consequence of a potential application of the described treatment steps, either taken separately or in any combination by patients, third parties, institutions, or other persons, and for the correctness of the provided information. Questions concerning the disclosed treatment will be answered to physicians and clinical academia in general, only.

References

1. Morgan G., Ward R., Barton M. The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies. Clin. Oncol. 2004;16:549–560. [PubMed[]
2. Coley H. Mechanisms and strategies to overcome chemotherapy resistance in metastatic breast cancer. Cancer Treat. Rev. 2008;34:378–390. [PubMed[]
3. Ozben T. Mechanisms and strategies to overcome multiple drug resistance in cancer. FEBS Lett. 2006;580:2903–2909. [PubMed[]
4. Morrison B., Schmidt C., Lakhani S., Reynolds B., Lopez J. Breast cancer stem cells: Implications for therapy of breast cancer. Breast Cancer Res. 2008:10–210. [PMC free article] [PubMed[]
5. Clark A., West K., Streicher S., Dennis P. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol. Cancer Ther. 2002;1:707–717.[PubMed[]
6. Dillon R., White D., Muller W. The phosphatidyl inositol 3-kinase signaling network: Implications for human breast cancer. Oncogene. 2007;26:1338–1345. [PubMed[]
7. Garg A., Aggarwal B. Nuclear transcription factor-κB as a target for cancer drug development. Leukemia. 2002;16:1053–1068. [PubMed[]
8. Li F., Sethi G. Targeting transcription factor NF-κB to overcome chemoresistance and radioresistance in cancer therapy. Biochim. Biophys. Acta. 2010;1805:167–180. [PubMed[]
9. Marignol L., Coffey M., Lawler M., Hollywood D. Hypoxia in prostate cancer: A powerful shield against tumour destruction? Cancer Treat. Rev. 2008;34:313–327. [PubMed[]
10. Walko C.M., Lindley C. Capecitabine: A review. Clin. Ther. 2005;27:23–44. [PubMed[]
11. Kallioniemi O., Oksa H., Aaran R., Hietanen T., Lehtinen M., Koivula T. Serum CA 15-3 assay in the diagnosis and follow-up of breast cancer. Br. J. Cancer. 1988;58:213–215. [PMC free article] [PubMed[]
12. Lässig D. Dissertation. Ludwigs-Maximilians-Universität; München, Germany: 2007. pp. 70–92. []
13. Moradali M., Mostafavi H., Ghods S., Hedjaroude G. Immunomodulating and anticancer agents in the realm of macromycetes fungi (macrofungi) Int. Immunopharmacol. 2007;7:701–724. [PubMed[]
14. Bohn J., BeMiller J. (1-3)Beta-D-Glucans as biological response modifiers: A review of structure-functional activity relationships. Carbohyd. Polym. 1995;28:3–14. []
15. Grossarth-Maticek R., Kiene H., Baumgartner S., Ziegler R. Use of Iscador, an extract of European Mistletoe (Viscum album) in cancer treatment: prospective nonrandomized and randomized matched-pair studies nested within a cohort study. Altern. Ther. Health M. 2001;7:57–78. [PubMed[]
16. Timoshenko A., Lan Y., Gabius H., Lala P. Immunotherapy of C3H/HeJ mammary adenocarcinoma with interleukin-2, mistletoe lectin or their combination. effects on tumour growth, capillary leakage and nitric oxide (NO) production. Eur. J. Cancer. 2001;37:1910–1920. [PubMed[]
17. Caribik I., Baser K., Özel H., Ergun B., Wagner W. Immunologically Active Polysaccharides from the Aqueous Extract of Nerium Oleander. Planta Med. 1990;56:668. []
18. Swanepoel Marc. Sutherlandia OPC Website. Available online: http://www.sutherlandiaopc.com/(accessed on 16 March 2011)
19. Harguindey S., Orive G., Luis Pedraz J., Paradiso A., Reshkin S.J. The role of pH dynamics and the Na+/H+ antiporter in the etiopathogenesis and treatment of cancer. Two faces of the same coin–one single nature. Biochim. Biophys. Acta. 2005;1756:1–24. [PubMed[]
20. Warburg O. The Prime Cause and Prevention of Cancer—Part 1 with two prefaces on prevention, Revised lecture at the meeting of the Nobel-Laureates; Lindau, Lake Constance, Germany. 30 June 1966. []
21. Warburg O. On the origin of cancer cells. Science. 1956;123:309–314. [PubMed[]
22. Isidoro A., Casado E., Redondo A., Acebo P., Espinosa E., Alonso A.M., Cejas P., Hardisson D., Fresno Vara J.A., Belda-Iniesta C., González-Barón M., Cuezva J.M. Breast Carcinomas Fulfill the WARBURG Hypothesis and Provide Metabolic Markers of Cancer Prognosis. Carcinogenesis. 2005;26:2095–2104. [PubMed[]
23. Borzillo G.V. Akt and emerging models for tumor cell energetics. Drug Discov. Today Therap. Strateg. 2005;2:331–336. []
24. Pedersen P.L. The cancer cell’s “power plants” as promising therapeutic targets: An overview. J. Bioenerg. Biomembr. 2007;39:1–12. [PubMed[]
25. Robey I.F., Baggett B., Kirkpatrick N., Roe D., Dosescu J., Sloane B., Hashim A., Morse D., Raghunand N., Gatenby R., Gillies R. Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Res. 2009;69:2260–2268. [PMC free article] [PubMed[]
26. Sartori H.E. Cesium Therapy in Cancer Patients. Pharmacol. Biochem. Be. 1984;21(Suppl. 1):11–13.[PubMed[]
27. Peskin B.S., Carter M.J. Chronic cellular hypoxia as the prime cause of cancer: what is the de-oxygenating role of adulterated and improper ratios of polyunsaturated fatty acids when incorporated into cell membranes? Med. Hypo. 2008;70:298–304. [PubMed[]
28. Schmitz G., Ecker J. The opposing effects of n-3 and n-6 fatty acids. Prog. Lipid Res. 2008;47:147–155. [PubMed[]
29. Ghosh-Choudhury T., Mandal C., Woodruff K, St Clair P, Fernandes G, Choudhury G., Ghosh-Choudhury N. Fish oil targets PTEN to regulate NFkappaB for downregulation of anti-apoptotic genes in breast tumor growth. Breast Cancer Res. Treat. 2009;118:213–228. [PMC free article] [PubMed[]
30. Musiek E., Brooks J., Joo M., Brunoldi E., Porta A., Zanoni G., Vidari G., Blackwell T., Montine T., Milne G., McLaughlin B., Morrow J. Electrophilic cyclopentenone neuroprostanes are anti-inflammatory mediators formed from the peroxidation of the omega-3 polyunsaturated fatty acid docosahexaenoic acid. J. Biol. Chem. 2008;283:19927–19935. [PMC free article] [PubMed[]
31. Berquin I.M., Edwards I., Chen Y. Multi-targeted therapy of cancer by omega-3 fatty acids. Cancer Lett. 2008;269:363–377. [PMC free article] [PubMed[]
32. Manna S., Chakraborty T., Ghosh B., Chatterjee M., Panda A., Srivastava S., Rana A., Chatterjee M. Dietary fish oil associated with increased apoptosis and modulated expression of Bax and Bcl-2 during 7,12-dimethylbenz(α)anthracene-induced mammary carcinogenesis in rats. Prostag. Leukotr. Ess. 2008;79:5–14. [PubMed[]
33. Bougnoux P., Germain E., Chajès V., Hubert B., Lhuillery C., Le Floch O., Body G., Calais G. Cytotoxic drugs efficacy correlates with adipose tissue docosahexaenoic acid level in locally advanced breast carcinoma. Br. J. Cancer. 1999;79:1765–1769. [PMC free article] [PubMed[]
34. Farooqui A.A., Ong W.Y., Horrocks L.A., Chen P., Farooqui T. Comparison of biochemical effects of statins and fish oil in brain: the battle of the titans. Brain Res. Rev. 2007;56:443–471. text section 8.4. [PubMed[]
35. Budwig J. Öl-Eiweiss-Kost. 8th ed. Sensei Verlag; Kernen, Germany: 2007. []
36. Anonymous. A Tape Transcription by Clifford Beckwith (Budwig diet & advanced prostate cancer) Available online: http://www.whale.to/a/beckwith.html (accessed on 28 February 2011)
37. Bonnet S., Archer S.L., Allalunis-Turner J., Haromy A., Beaulieu C., Thompson R., Lee C.T., Lopaschuk G.D., Puttagunta L., Harry G., Hashimoto K., Porter C.J., Andrade M.A., Thebaud B., Michelakis E.D. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007;11:37–51. [PubMed[]
38. Sun R.C., Fadia M., Dahlstrom J.E., Parish C.R., Board P.G., Blackburn A.C. Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res. Treat. 2010;120:253–260. [PubMed[]
39. Xu R., Pelicano H., Zhou Y., Carew J.S., Feng L., Bhalla K.N., Keating M.J., Huang P. Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res. 2005;65:613–621. [PubMed[]
40. Anonymous. Updating you on DCA and cancer. Available online: http://www.thedcasite.com/and references cited therein (accessed on 28 February 2011)
41. Lockwood K., Moesgaard S., Folkers K. Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q10. Biochem. Biophys. Res. Commun. 1994;199:1504–1508. [PubMed[]
42. Lockwood K., Moesgaard S., Yamamoto T., Folkers K. Progress on therapy of breast cancer with vitamin Q10 and the regression of metastases. Biochem. Biophys. Res. Commun. 1995;212:172–177.[PubMed[]
43. Folkers K., Brown R., Judy W.V., Morita M. Survival of cancer patients on therapy with coenzyme Q10. Biochem. Biophys. Res. Commun. 1993;192:241–245. [PubMed[]
44. Perumal S.S., Shanti P., Sachdanandam P. Augmented efficacy of tamoxifen in rat breast tumorigenesis when gavaged along with riboflavin, niacin, and CoQ10: effects on lipid peroxidation and antioxidants in mitochondria. Chem. Biol. Interact. 2005;152:49–58. [PubMed[]
45. Premkumar V.G., Vuvaraj S., Sathish S., Shanti P., Sachdanandam P. Anti-angiogenic potential of Coenzyme Q10, riboflavin and niacin in breast cancer patients undergoing tamoxifen therapy. Vascul. Pharmacol. 2008;48:191–201. [PubMed[]
46. Premkumar V.G., Yuvaraj S., Vijayasarathy K., Gangadaran S.G., Sachdanandam P. Effect of coenzyme Q10, riboflavin and niacin on serum CEA and CA 15-3 levels in breast cancer patients undergoing tamoxifen therapy. Biol. Pharm. Bull. 2007;30:367–370. [PubMed[]
47. Muehlenweg B., Sperl S., Magdolen V., Schmitt M., Harbeck N. Interference with the urokinase plasminogen activator system: a promising therapy concept for solid tumours. Expert Opin. Biol. Ther. 2001;1:683–691. [PubMed[]
48. Diehl I.J. Antitumour effects of bisphosphonates: First evidence and possible mechanisms. Drugs. 2000;59:391–399. [PubMed[]
49. Bauss F., Bergstrom B. Preclinical and clinical efficacy of the bisphosphonate ibandronate in cancer treatment. Curr. Clin. Pharmacol. 2008;3:1–10. [PubMed[]
50. Clézardin P., Ebetino F.H., Fournier P.G. Bisphosphonates and cancer-induced bone disease: Beyond their antiresorptive activity. Cancer Res. 2005;65:4971–4974. [PubMed[]
51. Kawasaki B.T., Hurt E.M., Mistree T., Farrar W.L. Targeting cancer stem cells with phytochemicals. Mol. Interv. 2008;8:174–184. [PubMed[]
52. Sethi G., Sung B., Aggarwal B.B. Nuclear factor-kappaB activation: From bench to bedside. Exp. Biol. Med. 2008;233:21–31. [PubMed[]
53. Aggarwal B.B., Vijayalekshmi R.V., Sung B. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin. Cancer Res. 2009;15:425–430. [PubMed[]
54. Zhou Y., Eppenberger-Castori S., Marx C., Yau C., Scott G.K., Eppenberger U., Benz C.C. Activation of nuclear factor-κB (NFκB) identifies a high-risk subset of hormone-dependent breast cancers. Int. J. Biochem. Cell Biol. 2005;37:1130–1144. [PubMed[]
55. Takada Y., Ichikawa H., Badmaev V., Aggarwal B.B. Acetyl-11-keto-beta-boswellic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing NF-kappa B and NF-kappa B-regulated gene expression. J. Immunol. 2006;176:3127–3140. [PubMed[]
56. Safayhi H., Mack T., Sabieraj J., Anazodo M.I., Subramanian L.R., Ammon H.P. Boswellic acids: novel, specific, nonredox inhibitors of 5-lipoxygenase. J. Pharmacol. Exp. Therap. 1992;261:1143–1146.[PubMed[]
57. Zhou J., Zhang H., Gu P., Bai J., Margolick J.B., Zhang Y. NF-kappaB pathway inhibitors preferentially inhibit breast cancer stem-like cells. Breast Cancer Res. Treat. 2008;111:419–427.[PMC free article] [PubMed[]
58. Gelmon K., Chan A., Harbeck N. The Role of Capecitabine in First-Line Treatment for Patients with Metastatic Breast Cancer. Oncologist. 2006;11:42–51. [PubMed[]
59. Arpino G., Weiss H., Lee A.V., Schiff R., De Placido S, Osborne C.K., Elledge R.M. Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance. J. Natl. Cancer Inst. 2005;97:1254–1261. [PubMed[]
60. Loi S. Molecular analysis of hormone receptor positive (luminal) breast cancers: What have we learnt? Eur. J. Cancer. 2008;44:2813–2818. [PubMed[]
61. Wei B., Wang J., Bourne P., Yang Q., Hicks D, Bu H., Tang P. Bone metastasis is strongly associated with estrogen receptor-positive/progesterone receptor-negative breast carcinomas. Hum. Pathol. 2008;39:1809–1815. [PubMed[]
62. Nakshatri H., Bhat-Nakshatri P., Martin D.A., Goulet R.J., Jr., Sledge G.W., Jr. Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol. Cell. Biol. 1997;17:3629–3639. [PMC free article] [PubMed[]

Articles from Cancers are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

 

Novel HAEMODIALYSIS (HD) treatment employing molecular hydrogen (H2)-enriched dialysis solution improves prognosis of CHRONIC DIALYSIS chronic dialysis patients: A prospective observational study

Abstract

Recent studies have revealed unique biological characteristics of molecular hydrogen (H2) as an anti-inflammatory agent. We developed a novel haemodialysis (E-HD) system delivering an H2 (30–80 ppb)-enriched dialysis solution by water electrolysis, and conducted a non-randomized, non-blinded, prospective observational study exploring its clinical impact. Prevalent chronic HD patients were allocated to either the E-HD (n = 161) group or the conventional HD (C-HD: n = 148) group, and received the respective HD treatments during the study. The primary endpoint was a composite of all-cause mortality and development of non-lethal cardio-cerebrovascular events (cardiac disease, apoplexy, and leg amputation due to peripheral artery disease). During the 3.28-year mean observation period, there were no differences in dialysis parameters between the two groups; however, post-dialysis hypertension was ameliorated with significant reductions in antihypertensive agents in the E-HD patients. There were 91 events (50 in the C-HD group and 41 in the E-HD group). Multivariate analysis of the Cox proportional hazards model revealed E-HD as an independent significant factor for the primary endpoint (hazard ratio 0.59; [95% confidence interval: 0.38–0.92]) after adjusting for confounding factors (age, cardiovascular disease history, serum albumin, and C-reactive protein). HD applying an H2-dissolved HD solution could improve the prognosis of chronic HD patients.

Introduction

The combination of enhanced oxidative stress and inflammation in patients on chronic haemodialysis (HD) treatment plays a crucial role in the occurrence of excessive cardiovascular events and death,. The bio-incompatibility of the HD procedure is supposed to be involved with this pathology. HD may exaggerate leukocyte activation and injury, which enhance oxidative stress and inflammation. Therefore, we hypothesized that ameliorating the stress to leukocytes during HD may have a beneficial effect on patient outcomes.

Molecular hydrogen (H2) is an inert gas with no known side effects. Recent studies have shown that H2acts as an antioxidant and an anti-inflammatory agent, and ameliorates cellular and organ damage,. We therefore developed a novel HD system using highly dissolved H2 water rendered by the water electrolysis technique. Previous pilot studies, including ours, have reported that suppression of interleukin-6, high-sensitivity C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1)/chemokine (C-C motif) ligand 2 (CCL2), and myeloperoxidase (MPO), decrease oxidative injury of lymphocytes, improve the redox status of serum albumin, and ameliorate hypertension. In reference to these findings, we conducted a non-randomized, non-blinded, prospective observational study to compare the outcomes between patients receiving haemodialysis using an H2-enriched dialysis solution (E-HD group) and patients receiving conventional haemodialysis (C-HD group).

Results

Patient registration and characteristics

Patients were recruited during April 2011 and October 2012. Of the 327 prevalent chronic HD patients who were pre-registered, 18 were excluded because of the lack of data and withdrawal. Ultimately, 148 patients were allocated to the C-HD group and 161 patients were allocated to the E-HD group (Fig. 1). The patients’ characteristics in the two groups at baseline are shown in Table 1. All subjects were treated by the standard HD schedule (three sessions/week, 4–5 h/session), using high-performance biocompatible dialyzers with fixed blood flow rate (QB) (200 mL/min) and dialysate flow rate (QD) (500 mL/min). Patients who had been treated by a vitamin-E coated dialyzer were excluded from this study. At baseline, there was no statistical difference between the groups in the blood urea nitrogen (BUN) reduction rate by HD (69.7 ± 6.9% in the C-HD group and 70.3 ± 8.4% in the E-HD group; p = 0.485).

An external file that holds a picture, illustration, etc. Object name is 41598_2017_18537_Fig1_HTML.jpg

Flow chart from pre-registration to the end of observation. Abbreviations: C-HD, conventional haemodialysis; E-HD, electrolyzed water haemodialysis; KH, Kashima Hospital; GJC, Gumyoji Jin Clinic; TJC, Tateishi Jin Clinic; NH, Noboribetsu Hospital; NMH, Nikko Memorial Hospital; HMC, Higashi Muroran Clinic; HHC, Higashi Horai Clinic.

Table 1

Patient characteristics.

Characteristic C-HD E-HD P Value
N 148 161
Age (y) 67.4 ± 11.8 64.0 ± 11.9 <0.05
Gender, male (%) 92 (62.2) 85 (52.8) NS
Dialysis vintage (months) 60 (3, 263) 80 (2, 478) <0.01
Cause of renal failure (DM, (%)) 62 (41.9) 55 (34.2) NS
Patients with CVD history (%)) 36 (24.3) 53 (32.9) NS
with multiple CVDs (%) 5 (3.4) 10 (6.2) NS
with cardiac disease (%) 25 (16.9) 31 (19.3) NS
with apoplexy (%) 11 (7.4) 29 (18.0) <0.01
with PAD (%) 5 (3.4%) 3 (1.9%) NS
Body weight (pre HD, kg) 59.3 ± 12.0 58.9 ± 11.2 NS
Body weight (post HD, kg) 57.0 ± 11.7 56.3 ± 10.9 NS
CTR (%) 48.7 ± 6.0 48.7 ± 5.5 NS
Pre-dialysis SBP (mmHg) 154 ± 27 154 ± 25 NS
Pre-dialysis DBP (mmHg) 79 ± 15 80 ± 16 NS
Post-dialysis SBP (mmHg) 142 ± 24 135 ± 24 <0.05
Post-dialysis DBP (mmHg) 75 ± 14 73 ± 14 NS
Patients on Anti-hypertensive agents (%) 108 (73.0) 107 (66.5) NS
Patients with ESA (%) 124 (83.8) 140 (87.0) NS
Fatigue Grade 2.9 ± 1.0 2.9 ± 1.1 NS
Pruritis Intensity Grade 3.4 ± 0.9 3.2 ± 0.9 <0.05
Puriritis Frequency Grade 3.2 ± 1.0 3.0 ± 1.1 NS

C-HD, conventional haemodialysis; E-HD, electrolyzed water haemodialysis.

CVD, cardio-cerebrovascular disease; HD, haemodialysis; PAD, peripheral arterial disease; SBP, systolic blood pressure; DBP, diastolic blood pressure; ESA, erythropoiesis stimulating agents.

Changes in laboratory and subjective/objective parameters during the study

HD-related laboratory parameters at the time of the first HD session of the respective weeks are shown in Table 2. No differences were noted between the two groups during the study period. Regarding subjective symptoms, there was a significant difference in the grade of pruritus between the two groups at baseline (with more severe symptoms in the E-HD group); however, no differences were found during the course of the study. Small but significant differences were noted between the two groups in the fatigue grade (fewer symptoms in the E-HD group) at 48 weeks. No differences were observed in the time-course pre-dialysis blood pressures (BPs); however, post-dialysis BPs differed between the two groups. In sub-analysis of the post-dialysis systolic BP (SBP) levels at baseline, there were significant differences in post-dialysis SBP (6 months) and Defined Daily Dose of antihypertensive medication (6, 12, 18 months) in patients with post-dialysis SBP ≥ 140 mmH at baseline, while no statistical differences were found in those parameters in patients with post-dialysis SBP < 140 mmHg (Fig. 2).

Table 2

Dialysis-related and subjective/objective parameters in the two groups.

Months 0 m 6 m 12 m 18 m 24 m 30 m 36 m 42 m 48 m
WBC count (/µL) C-HD 5504 ± 1653 5597 ± 1840 5461 ± 1669 5321 ± 1778 5251 ± 1996 5404 ± 2093 5701 ± 2014 5543 ± 1840 5541 ± 1985
(n) 148 136 128 126 117 109 104 84 80
E-HD 5852 ± 1803 5865 ± 2091 5734 ± 2083 5648 ± 1851 5779 ± 1823 5584 ± 1751 5620 ± 1684 5637 ± 1759 5642 ± 1793
(n) 161 160 152 145 131 123 121 112 105
Hemoglobin (g/dL) C-HD 10.6 ± 1.1 10.6 ± 1.2 10.4 ± 1.3 10.7 ± 1.4 10.4 ± 1.3 10.5 ± 1.3 10.4 ± 1.3 10.6 ± 1.3 10.7 ± 1.3
(n) 148 136 128 126 117 109 104 83 80
E-HD 11.1 ± 1.2 11.0 ± 1.0 10.7 ± 1.2 10.9 ± 1.2 10.4 ± 1.3 11.1 ± 1.1 10.8 ± 1.1 10.9 ± 1.1 11.1 ± 1.3
(n) 161 159 152 145 131 123 121 112 105
BUN (mg/dL) C-HD 66.8 ± 15.1 63.7 ± 15.0 65.3 ± 13.9 56.1 ± 14.5 58.8 ± 14.3 56.3 ± 14.0 61.3 ± 13.1 57.0 ± 14.0 61.1 ± 13.7
(n) 148 136 128 126 117 109 103 84 80
E-HD 69.0 ± 15.8 67.5 ± 16.5 65.2 ± 15.5 62.9 ± 15.8 64.3 ± 14.5 61.0 ± 13.2 62.5 ± 15.1 63.0 ± 14.8 61.4 ± 13.4
(n) 161 160 152 145 131 123 121 112 105
creatinine (mg/dL) C-HD 10.8 ± 2.6 11.1 ± 2.5 10.9 ± 2.5 10.0 ± 2.3 10.3 ± 2.3 10.4 ± 2.5 10.9 ± 2.5 11.0 ± 2.4 10.8 ± 2.5
(n) 148 136 128 126 117 110 104 84 80
E-HD 10.6 ± 3.0 10.4 ± 2.8 10.7 ± 2.8 10.3 ± 2.8 10.6 ± 2.6 10.7 ± 2.6 10.4 ± 2.3 10.8 ± 2.2 10.6 ± 2.4
(n) 161 159 152 145 131 123 121 112 105
Ca (mg/dL) C-HD 8.8 ± 0.7 8.8 ± 0.8 8.8 ± 0.8 8.8 ± 0.6 8.8 ± 0.7 8.8 ± 0.7 8.8 ± 0.7 8.9 ± 0.8 8.6 ± 0.8
(n) 148 136 128 126 117 110 104 84 79
E-HD 8.8 ± 0.7 8.8 ± 0.6 8.7 ± 0.7 8.8 ± 0.6 8.7 ± 0.7 8.8 ± 0.6 8.8 ± 0.7 8.8 ± 0.6 8.8 ± 0.6
(n) 160 159 152 145 131 123 121 112 105
Pi (mg/dL) C-HD 5.5 ± 1.3 5.5 ± 1.4 5.6 ± 1.4 5.5 ± 1.3 5.6 ± 1.3 5.3 ± 1.3 5.7 ± 1.4 5.5 ± 1.6 5.8 ± 1.4
(n) 148 136 128 126 117 109 104 84 80
E-HD 5.6 ± 1.4 5.6 ± 1.5 5.4 ± 1.3 5.4 ± 1.3 5.4 ± 1.4 5.4 ± 1.1 5.4 ± 1.1 5.3 ± 1.3 5.2 ± 1.1
(n) 161 161 154 147 133 125 123 114 107
B2-microglobulin (mg/L) C-HD 27.7 ± 7.0 28.2 ± 6.6 27.5 ± 6.4 26.9 ± 5.8 26.6 ± 6.0 27.5 ± 5.3 29.9 ± 5.8 29.8 ± 5.7 29.1 ± 6.0
(n) 148 131 126 126 116 108 102 80 78
E-HD 26.9 ± 6.5 27.0 ± 6.9 27.6 ± 6.5 26.0 ± 5.9 26.9 ± 6.3 27.3 ± 5.6 28.4 ± 5.6 28.2 ± 5.7 28.6 ± 5.3
(n) 161 159 149 142 131 122 120 110 104
CRP (mg/dL) C-HD 0.32 ± 0.57 0.23 ± 0.34 0.41 ± 0.93 0.53 ± 2.24 0.26 ± 0.44 0.40 ± 0.95 0.45 ± 0.97 0.99 ± 5.12 0.82 ± 2.10
(n) 148 133 128 126 115 109 101 81 78
E-HD 0.39 ± 0.73 0.45 ± 1.03 0.66 ± 1.52 0.56 ± 1.87 0.57 ± 1.17 0.38 ± 0.88 0.41 ± 0.71 0.35 ± 0.67 0.62 ± 1.91
(n) 161 160 152 145 131 123 121 112 105
albumin (g/dL) C-HD 3.5 ± 0.3 3.6 ± 0.3 3.6 ± 0.4 3.5 ± 0.3 3.5 ± 0.3 3.5 ± 0.4 3.5 ± 0.3 3.5 ± 0.3 3.4 ± 0.3
(n) 148 136 126 124 116 109 103 83 79
E-HD 3.7 ± 0.3 3.6 ± 0.3 3.7 ± 0.4 3.5 ± 0.4 3.5 ± 0.3 3.6 ± 0.3 3.5 ± 0.3 3.6 ± 0.3 3.6 ± 0.3
(n) 161 159 152 145 131 123 121 112 107
Dry weight (kg) C-HD 56.6 ± 11.8 57.0 ± 11.6 57.6 ± 12.3 57.0 ± 11.6 56.9 ± 11.4 56.8 ± 11.1 56.6 ± 11.5 56.4 ± 12.6 56.4 ± 12.3
147 140 133 129 119 114 106 87 82
E-HD 56.4 ± 10.9 56.5 ± 11.0 56.5 ± 11.4 56.3 ± 11.5 56.9 ± 11.8 56.4 ± 11.3 56.5 ± 11.3 56.5 ± 11.6 58.3 ± 12.2
(n) 161 160 152 146 131 125 120 113 107
CTR (%) C-HD 48.7 ± 6.0 49.1 ± 4.2 49.0 ± 4.2 49.0 ± 4.4 49.9 ± 5.3 49.6 ± 5.2 49.7 ± 5.2 49.5 ± 5.8 49.1 ± 6.2
(n) 148 134 131 115 117 112 104 84 79
E-HD 48.7 ± 5.5 49.0 ± 5.4 49.3 ± 5.6 49.4 ± 5.4 49.2 ± 5.3 49.3 ± 5.4 49.5 ± 5.6 48.7 ± 5.4 49.0 ± 5.1
(n) 161 155 148 133 129 123 119 108 101
pre-dialysis MBP (mmHg) C-HD 104 ± 17 97 ± 16 104 ± 15 100 ± 14 100 ± 16 101 ± 17 104 ± 15 101 ± 18 101 ± 18
(n) 148 137 121 112 101 88 78 66 62
E-HD 103 ± 22 94 ± 19 103 ± 18 102 ± 19 103 ± 19 105 ± 15* 105 ± 15 104 ± 16 106 ± 18
(n) 161 163 152 146 131 125 120 115 105
post-dialysis MBP (mmHg) C-HD 97 ± 13 93 ± 18 96 ± 13 96 ± 15 96 ± 13 98 ± 14 98 ± 12 100 ± 12 95 ± 12
(n) 148 137 121 112 101 88 78 66 62
E-HD 93 ± 20 90 ± 18 94 ± 16 92 ± 16* 92 ± 15** 95 ± 16 95 ± 14* 96 ± 16 95 ± 13
(n) 161 162 152 146 131 125 120 115 105
DDD C-HD 1.04 1.03 1.00 1.00 1.22 1.36 1.34 1.12 1.00
(0, 2.34) (0, 2.53) (0, 2.05) (0, 2.00) (0, 2.83) (0.18, 2.33) (0, 2.50) (0, 2.05) (0.02, 2.71)
(n) 147 137 130 127 118 112 105 86 84
E-HD 0.57 0.57* 0.5** 0.50 0.76** 0.81* 1.07 0.86 0.62*
(0, 2.14) (0, 1.53) (0, 1.21) (0, 1.34) (0, 1.50) (0.03, 1.62) (0.06, 1.90) (0, 1.87) (0, 1.62)
(n) 159 159 151 145 130 124 120 115 104
Fatigue Grade C-HD 2.9 ± 1.0 2.8 ± 1.1 2.6 ± 1.1 3.0 ± 1.2 2.8 ± 1.2 2.7 ± 1.2 2.8 ± 1.2 2.9 ± 1.1 2.9 ± 1.1
(n) 148 136 124 123 111 112 103 79 74
E-HD 2.9 ± 1.1 3.0 ± 1.0 2.9 ± 1.2 2.9 ± 1.3 2.9 ± 1.3 3.1 ± 1.1* 2.9 ± 1.4 3.0 ± 1.3 3.2 ± 1.1
(n) 161 152 139 136 124 120 118 106 96
Pruritus Intensity Grade C-HD 3.4 ± 0.9 3.2 ± 0.9 3.1 ± 1.0 3.2 ± 1.0 3.1 ± 1.1 3.1 ± 1.0 3.1 ± 1.0 3.2 ± 0.9 3.0 ± 1.0
(n) 148 136 124 123 110 112 103 79 74
E-HD 3.2 ± 0.9* 3.2 ± 1.1 3.4 ± 0.9 3.5 ± 0.9 3.2 ± 1.0 3.4 ± 0.9 3.3 ± 1.0* 3.4 ± 0.9 3.3 ± 0.9*
(n) 161 152 139 136 124 120 118 106 96
Puriritus Frequency Grade C-HD 3.2 ± 1.0 2.9 ± 1.1 2.9 ± 1.1 2.9 ± 1.2 2.9 ± 1.2 2.9 ± 1.2 2.9 ± 1.1 3.1 ± 1.1 2.8 ± 1.2
(n) 148 135 124 123 111 112 103 79 74
E-HD 3.0 ± 1.1 3.1 ± 1.2 3.2 ± 1.1 3.3 ± 1.0 3.1 ± 1.1 3.3 ± 1.0 3.2 ± 1.1 3.3 ± 1.1 3.2 ± 1.1*
(n) 161 152 139 136 124 120 118 106 96

vs. C-HD; *p < 0.05, **p < 0.01

MBP, mean blood pressure; CTR, cardiothoracic ratio; DDD, defined daily dose of anti-hypertensive agents.

C-HD, conventional haemodialysis; E-HD, electrolyzed water haemodialysis; WBC, white blood cell; BUN, blood urea nitrogen; Ca, serum Calcium; Pi, serum phosphate; CRP, C-reactive protein.

An external file that holds a picture, illustration, etc. Object name is 41598_2017_18537_Fig2_HTML.jpg

Changes in post-dialysis systolic blood pressure, and prescription of antihypertensive agents during the study. Patients with post-dialysis SBP ≥ 140 mmHg (n = 139) at baseline (0 month): changes in post-dialysis SBP (a), and changes in DDD (b); Patients with post-dialysis SBP < 140 mmHg (n = 168) at baseline: changes in post-dialysis SBP (c), and changes in DDD (d). Abbreviations: C-HD, conventional haemodialysis; E-HD, electrolyzed water haemodialysis; SBP, systolic blood pressure; DDD, daily defined dose of antihypertensive agents. (a,c) There were significant differences in post-dialysis SBP (6 months; p < 0.05), and DDD (6, 12, 18 months; p < 0.05, respectively) between the two groups. (b,d) No differences were observed in post-dialysis SBP or DDD between the two groups.

Composite events summary and multivariate analysis of risk factors for events

During the mean observation period of 3.28 years, there were 91 events: 50 in the C-HD group and 41 in the E-HD group (Table 3). In Cox proportional hazards model analysis, possible risk factors for the primary endpoints, which were identified via p-values < 0.1, were depicted, e.g., E-HD dialysis modality, age, history of cardio-cerebrovascular disease (CVD), serum albumin, and CRP. Multivariate analysis after adjusting for these factors revealed E-HD as an independent significant factor for the primary event (hazard ratio [HR] 0.59 [95% confidence interval [CI]: 0.38–0.92]) (Fig. 3 and Table 4).

Table 3

Summary of events in the two groups.

C-HD E-HD
Observation vintage (patient⋅year) 467 544
Number of Primary events 50 41
(all causes of deaths and non-lethal CVD events)
 Cardiac events including death 29 20
  Congestive heart failure 11 8
  Ischemic heart disease 13 9
  Aortic aneurysm rupture 1 1
  Sudden cardiac arrest 4 2
 Apoplexy including death (bleeding/infarction) 6 (1/5) 10 (2/8)
 PAD including death 8 2
Primary events rate (1000 patients·year: 95%CI) 107.1 (81.2–141.1) 75.4 (55.6–102.2)
Number of deaths 17 20
Deaths rate (1000 patients·year: 95%CI) 36.4 (22.7–58.3) 36.8 (23.8–56.8)

C-HD, conventional haemodialysis; E-HD, electrolyzed water haemodialysis.

PAD, peripheral artery disease (with surgical procedure).

An external file that holds a picture, illustration, etc. Object name is 41598_2017_18537_Fig3_HTML.jpg

Cox proportional hazards model demonstrating events-free differences between patients on C-HD and those on E-HD. Treatment with E-HD was an independent predicting factor for events (hazard ratio:0.593; p < 0.05). Abbreviations: C-HD, conventional haemodialysis; E-HD, electrolyzed water haemodialysis.

Table 4

Cox proportional hazards model analysis for the composite primary endpoints.

Univariate HR 95%CI P value Multivariate HR 95%CI P value
E-HD 0.687 0.454-1.039 0.076 0.593 0.384–0.916 0.019
HD vintage 1.000 0.997–1.002 0.824
Age 1.036 1.017–1.055 0.000 1.014 0.993–1.036 0.183
Gender (female) 0.698 0.454–1.074 0.102
History of CVD 3.085 2.040–4.665 0.000 3.037 1.977–4.665 0.000
non DM 0.865 0.569–1.314 0.497
BMI 0.987 0.933–1.044 0.644
Pre SBP 0.999 0.990–1.007 0.783
Albumin 0.195 0.101–0.377 0.000 0.328 0.160–0.674 0.002
CRP 1.266 1.017–1.576 0.035 1.323 1.005–1.740 0.046
Hg 0.893 0.741–1.075 0.230

E-HD, electrolyzed water haemodialysis; HD, haemodialysis; CVD, cardio-cerebral vascular disease; DM, diabetes mellituss; BMI, body mass index; Pre SBP, pre-dialysis systolic blood pressure; CRP, C-reactive protein; Hg, hemoglobin.

Discussion

This prospective observational study primarily aimed to examine the clinical effects of the addition of H2to HD dialysate (an average of 30–80 ppb of H2), which was delivered continuously through the dialyzer membrane to the blood during treatment, as reported elsewhere. During the mean observation period of 3.28 years, the study results revealed E-HD as an independent significant factor for reducing the risk of the primary events of all-cause mortality and development of non-lethal cardio-cerebrovascular events. In the study, all HD systems employed an endotoxin-eliminating filter system. Thus, the different clinical profiles between the two groups, patients on E-HD and those on C-HD, reflects the influence of H2 during HD.

The mechanisms by which E-HD delivers clinical benefits remain to be elucidated, since there were no differences in dialysis-related clinically relevant parameters between the two groups during the study. However, we could speculate several possibilities. The observation that the amelioration of post-dialysis hypertension (SBP ≥ 140 mmHg) in E-HD patients may suggest an idea to elucidate the benefits of E-HD, because intra-dialysis systolic hypertension, as well as high SBP, are well-known risk factors for all-cause mortality in HD patients,. On the other hand, low SBP (<110 mmHg) has also been reported as a risk for excessive mortality. Interestingly enough, there were no differences during the course of the study in post-dialysis SBP levels among the patients with SBP < 140 mmHg at baseline (Fig. 2). Furthermore, there were no differences between the two groups in the proportion of patients with SBP < 110 mmHg (Supplementary Fig. S1). Thus, taken together the observations, the improved post-dialysis BP may have played a role, at least partially, for the better outcomes in patients with post-dialysis hypertension

Other possible mechanisms could be suggested in the previous studies, i.e., increased reduced albumin redox status by acute as well as long-term E-HD,, improved patients’ anti-oxidative capacity, amelioration of micro inflammation with reduction of pro-inflammatory cytokines,, and suppression of T-cell damage. These possible mechanisms need to be clarified in the context of patients’ clinical outcomes in the future.

The mitigating effect on elevated SBP, as observed in the present study and previous studies, is very unique. We speculate that the primary mechanism of BP reduction could not be attributed to changes in fluid volume, since there were no significant differences in body weight after HD. Rather, the primary mechanism of BP reduction might be related to vasodilation or to a reduction in vascular resistance. Recent studies in deoxycortisterone acetate (DOCA)-salt hypertension have revealed a crucial role of superoxide anion release from macrophages in mesenteric peri-arteries, due in part to impaired function of the Alpha 2-adrenergic autoreceptors, which provide negative feedback on the release of norepinephrine from the sympathetic nerves associated with the mesenteric arteries. The mesenteric arteries constitute a major resistance arterial bed for BP regulation. In addition, one fourth of the systemic blood volume is present in the splanchnic circulation. Therefore, an increase in arteriolar resistance will elevate the arterial BP, and an increase in the mesenteric venomotor tone will lead to an increase in the cardiac venous return and the cardiac load due to a decrease in the venous capacity,. The combination of these two pathological processes results in a severe cardiac load. Interestingly, a recent study showed that the chemokine (C-C motif) receptor type 2 blockade suppresses vascular macrophage infiltration and reduces blood pressure. Upon the observation that MCP-1 decreased in E-HD patients in the previous study, it is possible to speculate the possible action of E-HD on macrophage of patients. The question of whether the HD procedure activates the residential macrophages, or activates extrinsic macrophages to infiltrate the mesenteric vascular area, needs to be addressed.

There are several issues and limitations in this study. First, the observed results in the E-HD group were slightly complicated, i.e., the rate of the primary composite endpoint was lower in the E-HD group than in the C-HD group, although the rate of death was not different between the groups. In univariate analysis of the Cox proportional hazards model, E-HD was not a strong factor for the primary endpoint, although multivariate analysis showed E-HD to be a strong factor after adjusting for confounding factors. Regarding the reasons for this, we speculate that a potential bias existed in the patients who were allocated to the E-HD group in that these patients had a relatively higher incidence of CVD history. This may have influenced the results of the univariate-analysis, since the presence of a CVD history was the most influential risk factor for the occurrence of the primary endpoint. To clarify this point, we performed a sub-analysis on this profile according to the presence or absence of CVD history. And it was revealed that E-HD was a significant factor for reducing the risk of primary endpoint in patients without history of CVD (HR: 0.455; p = 0.010) by univariate as well as multivariate analysis (Supplementary Tables S1 and 2), which indicates the clinically significant impact of E-HD.

Second issue is the levels of H2 of HD solution. The H2 levels of the present dialysates were in the range of 30–80 ppb, and no adverse effects were observed with respect to an H2 load within this range. Upon the report that there are generation of H2 in average of 24 ml/min in healthy human (approximately over 15 mmol daily) in the colon, and that they are absorbed into body, the given H2 during the single session of HD, which we estimated approximately as much as 2.5 mmol, seemed to be within the physiological range. Therefore, it remains unknown whether the applied H2 levels were best in regards to provide clinical effects, and higher levels of H2 may offer additional clinical benefits without any adverse effects needs to be investigated.

Third, we could not conclude the influence of E-HD on clinical symptoms in this study. Of note is that during the clinical course, post-dialysis hypertension was ameliorated with significant reductions of anti-hypertensive agents in the patients on E-HD. However, patient selection in the present study was conducted according to the attending physician’s preference; therefore, the observed phenomena such as decrease in BP and improved subjective symptoms of fatigue and pruritus during the course, have remained speculative.

And lastly, there was a statistical difference in the age between the two groups in the present study, e.g. the E-HD group was 3.4 years younger than C-HD. Although we employed the age for multivariate analysis of Cox proportional hazards model analysis, this might have influenced the event rate in the real world. A randomized clinical study is critically needed to address these issues in the future.

H2 as biological gas has potentials in clinical medicine. However H2 volatile gas, is not easy to handle in the clinical setting. The technique of water electrolysis has made it possible to apply H2 very safe to generate H2 dissolved water for real HD therapy. We think that this innovative treatment could open a new therapeutic possibility beyond the conventional HD.

Method

Study design and participants

A non-randomized, non-blinded, prospective observational study was conducted to evaluate the clinical impact of the E-HD system (UMIN-ICDR Clinical Trial: Study Title: “Prospective observational study of the clinical effect of haemodialysis using electrolyzed water”; Unique ID issued by UMIN: UMIN000004857, Date of disclosure of the study information: 2011/01/11, Link to view the page (ICDR): https://upload.umin.ac.jp/cgi-bin/icdr_e/ctr_view.cgi?recptno = R000005491).

The primary composite endpoints included all-cause mortality, and concomitant disease such as cardiac disease (heart failure or myocardial infarction requiring hospitalization, coronary artery disease requiring invasive therapy), stroke (symptomatic cerebral hemorrhage or cerebral infarction confirmed by diagnostic imaging), and obstructive arteriosclerosis requiring leg amputation.

The study used a non-randomized design, and the candidate patients were selected by decision of the patient’s physician. In two centers (KH and NMH), candidates for the E-HD group were selected by chief physicians; subsequently, matched control patients in the C-HD group were selected from the rest of the patients in the respective centers in terms of demographic background such as age and sex. In two of the study centers (HMC and HHC), all patients were selected for the E-HD group since the centers were to employ a central E-HD system to completely replace the conventional HD system. In three study centers in which the E-HD system was not available (NH, TJC, GJC), more than one patient was selected as part of the matched control group to the E-HD group of the above four centers in terms of age and sex as much as possible. Patients who were receiving on-line hemodiafiltration or combination therapy with peritoneal dialysis, and potential subjects with serious disease at the time of enrollment, i.e., severe heart failure (New York Heart Association III/IV), severe liver disease, psychological problems, dementia, malignant disease within the previous 3 months, or an evidently poor systemic condition with an evidently poor short-term prognosis, were excluded from this study. History of CVD included cardiac disease, stroke (these definitions were comparable to those of the primary composite endpoints mentioned above), and symptomatic peripheral arterial disease requiring medical intervention.

The study was approved by the Ethics Committee of Fukushima Medical University (No. 1155: Supplementary file of study protocol), and the clinical investigation was conducted according to the principles expressed in the Declaration of Helsinki. Written informed consent was obtained from all patients registered.

Data collection

All patients were monitored for subjective symptoms and objective signs during the study period. Blood pressure was measured using a sphygmomanometer on the upper arm with the patient in a supine position just before starting each HD session, and data were recorded into the clinical record. Iron, erythropoiesis-stimulating agents (ESA) to correct anemia, and agents to control calcium and phosphate were administered according to the guidelines of the Japanese Society of Dialysis Treatment,. Antihypertensive agents and adjustment of body weight after HD (dry weight) were administered as needed by the attending physician. Quantities of antihypertensive agents were standardized using DDD. Regular monitoring of blood was performed at the first HD session of the week (Monday or Tuesday) at least once a month to monitor dialysis status. Patients were requested to fill out a self-assessment questionnaire every 6 months, which asked about the subjective symptoms of fatigue on the HD day and pruritus according to the following criteria: Fatigue (subjective level and daily activities)–Grade 1: Intense fatigue/Disturbed activity and required rest; Grade 2: Moderate fatigue/Reduced activity; Grade 3: Mild fatigue/Normal activity; Grade 4: Tireless/Normal activity; Grade 5: Inexhaustible/Active; Pruritus (subjective intensity and frequency)–Grade 1: Intense/Always; Grade 2: Moderate/Sometimes; Grade 3: Mild/Rarely; Grade 4: None/None. Levels of H2 were determined using the gas chromatograph with a semiconductor detector (TRIlizer mBA-3000, Taiyo Instruments Co., Osaka, Japan) according to the manufacturer’s instruction, as reported elsewhere.

All data generated or analysed during this study are included in this published article.

Statistical Methods

The target sample size of the original study (n = 70 < each) was based on an estimated event-free rate of 10% differences at 3 years between groups with 1:1 ratio between them, and calculated from the rationale that a statistical power of 90% and the alpha level 0.05, using a two-sided log-rank test.

All values are expressed as the mean ± standard deviation (SD) or median (interquartile range) as appropriate. For comparisons between the two groups, Student’s t-test or the Mann-Whitney U test was used for continuous variables and chi-square test or Fisher’s exact test was used for nominal variable, as appropriate. Values of p < 0.05 were considered statistically significant. Data were statistically analyzed using IBM SPSS Statistics version 22.0 for Windows (Chicago, IL, USA).

H2 delivery HD system

Figure 4 details of the system have been reported previously,. Briefly, test solutions were prepared as follows: pre-filtered water was processed using activated charcoal filtration and water softening to supply the HD-24K water electrolysis system (Nihon Trim, Osaka, Japan), where water was electrolyzed by direct current supply to the anode and cathode electrode plates. Water on the anode side was drained, and water from the cathode side (electrolyzed water) was collected to supply the reverse osmosis equipment (MH500CX; Japan Water System, Tokyo, Japan) at 500 mL/min. The intensity of electrolysis was adjusted to maintain a pH of 10.0. The reverse osmosis water produced by the water electrolysis system was supplied to prepare the HD solution. The composition of the inflow H2-HD solution was the same as the standard HD solution with the exception of the presence of dissolved H2 in the H2-HD, and there were no differences in terms of electrolytes levels and pH, as compared to the standard HD solution, as reported elsewhere,. Whereas regarding H2 levels of control group, dialysate and blood H2 levels were less than 1 ppb.

An external file that holds a picture, illustration, etc. Object name is 41598_2017_18537_Fig4_HTML.jpg

Manufacturing process of haemodialysis solution in the E-HD and H2 dynamics during treatment by E-HD. Abbreviations: E-HD, electrolyzed water haemodialysis; e-, electron; AVF, arterio-venous fistula.

The present E-HD system could deliver H2 (30–80 ppb)-enriched dialysis solution. H2 levels of inflow blood and HD solution reached an equivalent state in the dialyzer, and the H2 level of outflow blood from dialyzer showed approximately the same as that of inflow H2-HD solution under QB 200 ml/min and QD 500 ml/min. Therefore, H2 load to patient is determined by time of HD treatment and H2 levels of HD solution if QB and QD are fixed, i.e., it is estimated that about 1.2 mmol of H2 is loaded in case of 4 hour-treatment, and HD solution with 50 ppb H2. Regarding the H2 dynamics in the body, previous studies,revealed that no changes were found in H2 levels of inflow blood after 4-hour treatment, and there were increases of constant H2 levels in expired air of patients by treatment, and they soon returned to the basal levels by stop of treatment. Therefore, it is supposed that delivered H2 into blood during the HD treatment is mostly excreted from lung during the time on HD.

 

Electronic supplementary material

Logo of scirep

About Editorial Board For Authors Scientific Reports
. 2018; 8: 254.
Published online 2018 Jan 10. doi: 10.1038/s41598-017-18537-x
PMCID: PMC5762770
PMID: 29321509
Novel haemodialysis (HD) treatment employing molecular hydrogen (H2)-enriched dialysis solution improves prognosis of chronic dialysis patients: A prospective observational study
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

* product recommendations above are NOT part of the article

Author Contributions

M.N. wrote the main manuscript text and prepared all figures. M.N., N.I., S.K., R.N., M.M. and S.I. organized the study group. N.I., H.S., H.H., R.Y., K.T., N.O. and H.N. collected data. M.N. and Y.M. analyzed the data. M.N. and S.I. supervise the progress of research of all aspects.

Notes

Competing Interests

The authors declare that they have no competing interests.

Footnotes

Electronic supplementary material

Supplementary information accompanies this paper at 10.1038/s41598-017-18537-x.

Associated Data

Supplementary Materials

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

1. Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int. 1999;55:648–658. doi: 10.1046/j.1523-1755.1999.00273.x. [PubMed] [CrossRef[]
2. Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM. The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int. 2002;62:1524–1538. doi: 10.1046/j.1523-1755.2002.00600.x. [PubMed] [CrossRef[]
3. Takahashi T, Kubota M, Nakamura T, Ebihara I, Koide H. Interleukin-6 gene expression in peripheral mononuclear cells from patients undergoing haemodialysis or continuous ambulatory peritoneal dialysis. Ren Fail. 2000;22:345–354. doi: 10.1081/JDI-100100878. [PubMed] [CrossRef[]
4. Caglar K, et al. Inflammatory signals associated with hemodialysis. Kidney Int. 2002;62:1408–1416. doi: 10.1111/j.1523-1755.2002.kid556.x. [PubMed] [CrossRef[]
5. Yoon JW, Pahl MV, Vaziri ND. Spontaneous leukocyte activation and oxygen-free radical generation in end-stage renal disease. Kidney Int. 2007;71:167–172. doi: 10.1038/sj.ki.5002019. [PubMed] [CrossRef[]
6. Ohsawa I, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13:688–694. doi: 10.1038/nm1577. [PubMed] [CrossRef[]
7. Ichihara M, et al. Beneficial biological effects and the underlying mechanisms of molecular hydrogen – comprehensive review of 321 original articles. Med Gas Res. 2015;5:12. doi: 10.1186/s13618-015-0035-1.[PMC free article] [PubMed] [CrossRef[]
8. Nakayama M, et al. Less-oxidative hemodialysis solution rendered by cathode-side application of electrolyzed water. Hemodial Int. 2007;11:322–327. doi: 10.1111/j.1542-4758.2007.00187.x. [PubMed] [CrossRef[]
9. Nakayama M, et al. Biological effects of electrolyzed water in hemodialysis. Nephron Clin Pract 112. 2009;15:c9. doi: 10.1159/000210569. [PubMed] [CrossRef[]
10. Nakayama M, et al. A novel bioactive hemodialysis system using dissolved dihydrogen (H2) produced by water electrolysis: a clinical trial. Nephrol Dial Transplant. 2010;25:3026–3033. doi: 10.1093/ndt/gfq196. [PubMed] [CrossRef[]
11. Terawaki H, et al. Effect of a hydrogen (H2)-enriched solution on the albumin redox of hemodialysis patients. Hemodial Int. 2014;18:459–466. doi: 10.1111/hdi.12112. [PubMed] [CrossRef[]
12. Huang KC, Yang CC, Lee KT, Chien CT. Reduced hemodialysis-induced oxidative stress in end-stage renal disease patients by electrolyzed reduced water. Kidney Int. 2003;64:704–714. doi: 10.1046/j.1523-1755.2003.00118.x. [PubMed] [CrossRef[]
13. Huang KC, et al. Electrolyzed-reduced water reduced hemodialysis-induced erythrocyte impairment in end-stage renal disease patients. Kidney Int. 2006;70:391–398. doi: 10.1038/sj.ki.5001576. [PubMed] [CrossRef[]
14. Huang KC, et al. Electrolysed-reduced water dialysate improves T-cell damage in end-stage renal disease patients with chronic hemodialysis. Nephrol Dial Transplant. 2010;25:2730–2737. doi: 10.1093/ndt/gfq082. [PubMed] [CrossRef[]
15. WHO Collaborating Center for Drug Statistics Methodology. Guidelines for DDD 2nd ed, Oslo, 1–95 (1993) .
16. Park J, et al. A comparative effectiveness research study of the change in blood pressure during hemodialysis treatment and survival. Kidney Int. 2013;84:795–802. doi: 10.1038/ki.2013.237.[PMC free article] [PubMed] [CrossRef[]
17. Inaba M, et al. Association of blood pressure with all-cause mortality and stroke in Japanese hemodialysis patients: the Japan Dialysis Outcomes and Practice Pattern Study. Hemodial Int. 2014;18:607–615. doi: 10.1111/hdi.12156. [PubMed] [CrossRef[]
18. Zager PG, et al. “U” curve association of blood pressure and mortality in hemodialysis patients. Medical Directors of Dialysis Clinic, Inc. Kidney Int. 1998;54:561–569. doi: 10.1046/j.1523-1755.1998.00005.x. [PubMed] [CrossRef[]
19. Maeda K, et al. Improvement of the fraction of human mercaptalbumin on hemodialysis treatment using hydrogen-dissolved hemodialysis fluid: a prospective observational study. Renal Replacement Therapy. 2016;2:42. doi: 10.1186/s41100-016-0054-y. [CrossRef[]
20. Thang LV, et al. Macrophage depletion lowers blood pressure and restores sympathetic nerve α2-adrenergic receptor function in mesenteric arteries of DOCA-salt hypertensive rats. Am J Physiol Heart Circ Physiol. 2015;309:H1186–1197. doi: 10.1152/ajpheart.00283.2015. [PMC free article] [PubMed] [CrossRef[]
21. Averina VA, Othmer HG, Fink GD, Osborn JW. A new conceptual paradigm for the hemodynamics of salt-sensitive hypertension: a mathematical modelling approach. J Physiol. 2012;590:5975–5992. doi: 10.1113/jphysiol.2012.228619. [PMC free article] [PubMed] [CrossRef[]
22. Chan CT, et al. Reversal of vascular macrophage accumulation and hypertension by a CCR2 antagonist in deoxycorticosterone/salt-treated mice. Hypertension. 2012;60:1207–1212. doi: 10.1161/HYPERTENSIONAHA.112.201251. [PubMed] [CrossRef[]
23. Levitt MD. Volume and composition of human intestinal gas determined by means of an intestinal washout technic. N Engl J Med. 1971;284:1394–8. doi: 10.1056/NEJM197106242842502. [PubMed] [CrossRef[]
24. Tsubakihara Y, et al. Japanese Society for Dialysis Therapy: guidelines for renal anemia in chronic kidney disease. Ther Apher Dial. 2008;14(240–275):2010. [PubMed[]
25. Fukagawa M, et al. Clinical practice guideline for the management of chronic kidney disease-mineral and bone disorder. Ther Apher Dial. 2013;17:247–288. doi: 10.1111/1744-9987.12058. [PubMed] [CrossRef[]

Articles from Scientific Reports are provided here courtesy of Nature Publishing Group

HAEMODIALYSIS system using dissolved dihydrogen (H2) in water produced by electrolysis: a clinical trial

Abstract

BACKGROUND:

Chronic inflammation in haemodialysis (HD) patients indicates a poor prognosis. However, therapeutic approaches are limited. Molecular hydrogen gas (H(2)) ameliorates oxidative and inflammatory injuries to organs in animal models. We developed an HD system using a dialysis solution with high levels of dissolved molecular hydrogen H(2) and examined the clinical effects.

METHODS:

Dialysis solution with molecular hydrogen H(2) (average of 48 ppb) was produced by mixing dialysate concentrates and reverse osmosis water containing dissolved molecular hydrogen H(2) generated by a water electrolysis technique. Subjects comprised 21 stable patients on standard HD who were switched to the test HD for 6 months at three sessions a week.

RESULTS:

During the study period, no adverse clinical signs or symptoms were observed.

A significant decrease in systolic blood pressure (SBP) before and after dialysis was observed during the study, and a significant number of patients achieved SBP <140 mmHg after HD (baseline, 21%; 6 months, 62%; P < 0.05). Changes in dialysis parameters were minimal, while significant decreases in levels of plasma monocyte chemoattractant protein 1 (P < 0.01) and myeloperoxidase (P < 0.05) were identified.

CONCLUSIONS:

Adding molecular hydrogen H(2) to haemodialysis solutions ameliorated inflammatory reactions and improved BP control. This system could offer a novel therapeutic option for control of uraemia.

 2010 Sep;25(9):3026-33. doi: 10.1093/ndt/gfq196. Epub 2010 Apr 12.
A novel bioactive haemodialysis system using dissolved dihydrogen (H2) produced by water electrolysis: a clinical trial.
PMID:
20388631
DOI:
10.1093/ndt/gfq196

https://www.ncbi.nlm.nih.gov/pubmed/20388631

 

Alkaline Ionized Water/ Electrolyte Reduced Water treatment administration is effective in palliating hemodialysis

Alkaline Ionized Water/ Electrolyte Reduced Water/hydrogen water treatment administration is effective in palliating hemodialysis

Electrolyte Reduced Water treatment administration is effective in palliating hemodialysis -evoked oxidative stress as indicated by lipid peroxidation, hemolysis, and overexpression of proinflammatory cytokines in hemodialysis patients:

We explored whether alkaline ionized water/electrolyte-reduced water (ERW) could palliate chronic hemodialysis HD-evoked erythrocyte impairment and anemia.(Chronic hemodialysis (HD) patients increase erythrocyte susceptibility to hemolysis and impair cell survival).

43 patients undergoing chronic hemodialysis were enrolled and received alkaline ionized water/electrolyte-reduced water ERW administration for 6 month. We evaluated oxidative stress in blood and plasma, erythrocyte methemoglobin (metHb)/ferricyanide reductase activity, plasma metHb, and proinflammatory cytokines in the chronic hemodialysis  patients without treatment (n=15) or with vitamin C (VC)- (n=15), vitamin E (VE)-coated dialyzer (n=15), or alkaline ionized water/electrolyte-reduced water ERW treatment (n=15) during an  hemodialysis HD course.

The patients showed marked increases (15-fold) in blood reactive oxygen species, mostly H(2)O(2), after  hemodialysis without any treatment.  hemodialysis  resulted in decreased plasma Vitamin C, total antioxidant status, and erythrocyte metHb/ferricyanide reductase activity and increased erythrocyte levels of phosphatidylcholine hydroperoxide (PCOOH) and plasma metHb.

Antioxidants treatment significantly palliated single  hemodialysis course-induced oxidative stress, plasma and RBC PCOOH, and plasma metHb levels, and preserved erythrocyte metHb /ferricyanide reductase activity in an order Vitamin C>Electrolyte Reduced Water>Vitamin E-coated dialyzer.

However, Electrolyte Reduced Water had no side effects of oxalate accumulation easily induced by Vitamin C.

Six-month Electrolyte Reduced Water treatment increased hematocrit and attenuated proinflammatory cytokines profile in the hemodialysis patients.

In conclusion, Electrolyte Reduced Water treatment administration is effective in palliating hemodialysis-evoked oxidative stress, as indicated by lipid peroxidation, hemolysis, and overexpression of proinflammatory cytokines in hemodialysis patients.

PMID:16760903
DOI:10.1038/sj.ki.5001576
 2006 Jul;70(2):391-8. Epub 2006 Jun 7.
https://www.kidney-international.org/article/S0085-2538(15)51941-8/fulltext

Electrolyzed-reduced water reduced hemodialysis-induced erythrocyte impairment in end-stage renal disease patients.

Author information

1
Department of Family Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.