INTRODUCTION

Chronic kidney disease (CKD) is a progressive and irreversible loss of kidney function, causing accumulation of substances such as urea and creatinine in the blood. In its most advanced phase (chronic renal failure), the kidneys cannot maintain the normality of the patient's internal environment, requiring adherence to treatment with renal replacement therapies, such as hemodialysis (HD)^1,2,3.

HD can compensate for renal dysfunction in these patients, improving their quality of life. However, it has been associated with an increase in the inflammatory process and oxidative stress, as it removes nutrients and enzymes with antioxidant action, in addition to increasing the formation of reactive oxygen species (ROS) and inflammatory cytokines^4,5,6.

Oxidative stress in these patients is considered one of the main mechanisms responsible for changes in the endothelium and nitric oxide dysfunction, with consequently greater susceptibility to atherosclerosis⁷. Nowak et al. (2018)⁸ point out that elevation of inflammatory markers in these patients is associated with adverse clinical outcomes, including all-cause mortality, cardiovascular events, and progression of kidney disease. It is estimated that more than 50% of hemodialysis deaths are associated with cardiovascular disease (CVD)⁹.

Studies emphasizes that HD patients have limited dietary intake and disturbances in Vitamin E metabolism, which consequently favors the reduction of its blood concentrations^10,11. This vitamin refers to eight structurally similar compounds, α-, β-, γ- and δ-tocopherol and α-, β-, γ- and δ-tocotrienol, whose main function is to protect polyunsaturated fatty acids against oxidative stress. In addition, it interferes with smooth muscle cell proliferation, platelet aggregation, monocyte adhesion, uptake of oxidized LDL, and cytokine production^12,13,14. In this context, Vitamin E supplementation is indicated as a strategy to combat the deficiency of this nutrient and thus assist in reducing oxidative and inflammatory processes. It is worth noting that the effectiveness of this supplementation depends on the time of intervention and the dose administered¹⁵. However, it is still not well elucidated in the literature whether this treatment can be implemented in clinical practice. Thus, this systematic review aims to present the most recent data on the effect of Vitamin E supplementation on inflammatory biomarkers and oxidative stress in CKD patients on HD therapy.

METHODS

This is a systematic review study conducted between April and May 2021, using the methodology for systematic reviews and meta-analyses (PRISMA)¹⁶. The guiding question of the study was defined as: “Is Vitamin E supplementation able to attenuate inflammation and oxidative stress in patients with chronic kidney disease on hemodialysis?” The PICO strategy was used to establish Patients (Adults with CKD), Intervention (Vitamin E supplementation), Comparison (Adults without Vitamin E supplementation) and Outcome (Improvement of oxidative and inflammatory parameters).

After formulation of the guiding question, the review protocol was prepared and registered on International Prospective Register of Systematic Reviews (PROSPERO).

The research was carried out by three authors (DJMS, LLCS and COB), independently, retrieving publications in English, Spanish or Portuguese from the last 15 years, indexed in Pubmed, Cochrane Library, Scopus or Web of Science. The search strategies were adapted to each database, in order to retrieve the largest number of articles on the subject, being developed based on the DeCS (Health Sciences Descriptors) vocabulary: Hemodialysis, Vitamin E, Alpha-tocopherol.

The eligibility criteria included clinical trials, conducted in humans aged ≥ 18 years, of both sexes, that investigated the effect of vitamin E supplementation on improving inflammatory biomarkers or oxidative stress in patients with chronic kidney disease on hemodialysis therapy. Observational studies, review articles and experimental studies were excluded.

The articles were identified by applying filters such as document type, source type and language. Then, the recruited studies were distributed in a spreadsheet to identify duplicates. Initially, the titles and abstracts were read and, finally, the reading in full made it possible to identify the eligibility criteria and define the inclusion or exclusion of the articles.

The studies were compared, and equivalence verified in article selection and analyze. All divergences, such as the decision to include or exclude, were identified, discussed, and resolved by consensus between the authors (DJMS, LLCS and COB).

The risk of bias of included studies was independently assessed by two reviewers (DJMS and LLCS), using the Cochrane Risk of Bias Tool¹⁷, which is composed of seven domains named: random sequence generation, allocation concealment, blinding of participants and professionals, blinding of outcome assessors, incomplete results, selective outcome reporting and other sources of bias. The judgment of each domain was classified into the following categories: high risk of bias, low risk of bias and uncertain risk of bias. Differences in the assessment of bias were resolved by consensus between the authors (DJMS and LLCS).

RESULTS

A total of 1362 studies were identified in PubMed (n = 460), Cochrane Library (n = 214), Scopus (n = 297) and Web of Science (n = 391). After selecting and removing duplicate articles, 31 articles were identified as eligible. After reading the texts in full and applying a 15-year time cutoff to obtain the most current studies, 12 articles were included in this review. The details of the selection are shown in Figure 1.

Figure 1 Flowchart of study selection. 

The following data were extracted for analysis: authors and year of the study, place where the study was conducted, objectives, biomarkers evaluated, sample, dose/time of supplementation, and outcomes (Table 1).

The studies included in this review were developed between the years 2006 to 2020. Half of the studies were conducted in Iran (n = 6) and the rest were conducted in different countries: United States, Brazil, Spain, India, Greece, and the Czech Republic.

Among the included articles, 11 used vitamin E doses ranging from 400 IU to 888 IU and 1 study used 500 mg supplementation. Regarding the route of administration, all took the oral route. The duration of supplementation ranged from 2 weeks to 12 months, it is worth noting that 9 of the studies implemented the intervention for a period of 2 months or more.

Regarding risk of bias, 5 studies were classified with low risk of bias in domain 1 (random sequence generation), while in domain 2 (allocation concealment) the studies were equally distributed among the three classification categories. In domain 3 (blinding of professional participants) and domain 4 (blinding of outcome assessors) a good portion of the studies showed uncertain risk of bias (n = 7; n =6, respectively). In domain 5 (incomplete results) there was a predominance of low risk of bias (n =9) and in domain 6 (selective results reporting) 9 was found to have uncertain risk of bias. Finally, in domain 7 (other sources of bias), 9 were found to have low risk of bias (Figure 2).

Figure 2 Evaluation of the risk of bias of the analyzed studies. D1: Random sequence generation; D2: Allocation concealment; D3: Blinding of participants and professionals; D4: Blinding of outcome assessors; D5: Incomplete results; D6: Selective outcome reporting; D7: Other sources of bias. 

Of the 12 included articles, 3 looked at the effect of supplementation on inflammatory biomarkers, 6 on oxidative stress biomarkers, and 3 addressed these parameters simultaneously. Positive effects of supplementation on inflammation were observed in 1, on oxidative stress in 3, and the articles (n = 3) that analyzed the effect on both aspects showed positive results. Vitamin E supplementation on inflammatory biomarkers showed a positive effect in the study by Pirhadi-Tavanshti et al. (2020)⁹ (600 IU for ten weeks), in which a significant reduction in serum concentrations of the following vascular inflammatory markers was observed: intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1); and in the study by Castilla et al. (2008)¹⁸ (800 IU for two weeks) who found a reduction in ICAM-1 levels.

In the studies by Ahmadi et al. (2013)14 (400 IU for two months) and Sohrabi et al. (2016)¹⁹ (600 IU for eight weeks) there was a significant decrease in Interleukin 6 (IL-6) levels after supplementation. In contrast, Jafari et al. (2020)²⁰ (400 IU for eight weeks) and Hodkova et al. (2006)²¹ (888 IU for five weeks) who evaluated biomarkers such as C Reactive Protein (CRP), Tumor Necrosis Factor Alpha (TNF-α), pregnancy-associated Plasma Protein A (PAPP-A), IL-6, ICAM-1, VCAM-1 and E-selectin, did not obtain significant results.

Regarding the effect of supplementation on biomarkers of oxidative stress, Roozbeh et al. (2011)²² (400 IU for three weeks) showed that the intervention promoted an increase in the erythrocyte concentration of Glutathione Peroxidase (GPx); and Bhogade et al. (2008)²³ (400 IU for two months) found an increase in the erythrocyte concentration of the Superoxide Dismutase (SOD) enzyme. Different from that found by Antoniadi et al. (2008)²⁴ (500 mg for 12 months) who observed that GPx level remained unchanged, while erythrocyte SOD had significant reduction.

Castilla et al. (2008)¹⁸ (800 IU for two weeks) observed a positive role of this vitamin in relation to Low-Density Lipoprotein (LDL) oxidation, however Jafari et al. (2020)⁴ (400 IU for eight weeks) and Lu et al. (2007)²⁵ (800 IU for six months) found no beneficial effect of supplementation on reducing lipid peroxidation.

Bhogade et al. (2008)²³ (400 IU for two months) found that supplementation had a beneficial effect in reducing serum Malondialdehyde (MDA) levels, in contrast Roozbeh et al (2011)²² (400 IU for three weeks) did not obtain a significant decrease in plasma MDA levels.

Two other studies found that this treatment was positive at reducing levels of Electronegative Low-Density Lipoprotein [LDL (-)] and NADPH oxidase activity^26,18.

DISCUSSION

This systematic review indicates that Vitamin E supplementation may influence inflammatory and oxidative stress markers in patients with chronic kidney disease on hemodialysis therapy, in a predominantly positive way.

Vitamin E has weak O – H bonds that make it a powerful hydrogen donor and free radical scavenger, protecting cell membranes against oxidative stress. The antioxidant activity of this nutrient supports its anti-inflammatory properties²⁰.

Some in vivo and in vitro studies have shown that this vitamin can suppress protein kinase C (PKC) in vascular smooth muscle cells. When active, PKC can induce NADPH oxidase phosphorylation, resulting in production of free radicals. In addition, Vitamin E can also activate the Activator Protein 1 (AP1), which dephosphorylates PKC, inhibiting the release of reactive oxygen species from monocytes, and thus reducing inflammation⁹.

Inflammation in patients with CKD on HD exacerbates endothelial dysfunction and oxidative stress, which in turn are associated with increased risk of cardiovascular diseases, one of the leading causes of death in these patients^27,28.

In the studies of Pirhadi-Tavandashti et al (2020)9 and Castilla et al. (2008)¹⁸ it was observed that the Vitamin E supplementation reduced vascular inflammatory biomarkers (ICAM-1 and VCAM-1; and ICAM-1, respectively) in patients on hemodialysis, highlighting that the possible mechanism would be by combating oxidative stress in endothelial cells that can reduce ICAM-1 and VCAM-1 gene expression. On other hand, Jafari et al. (2020)²⁰ did not observe significant effects with Vitamin E supplementation on inflammatory biomarkers, however the authors highlighted that the conditions of the participants did not allow the use of a dose greater than 400 IU/ day of Vitamin E. In addition, the intervention time was short, which may have contributed to the lack of effect of supplementation.

Hodkova et al. (2006)²¹ verified that the serum concentrations of PAPP-A, CRP, ICAM-1 and E-selectin remained unchanged after Vitamin E supplementation. The authors justify this by the short time of therapy, and furthermore believe that the beneficial effect of supplementation on serum CRP may have been masked by the frequent fluctuation of CRP levels in HD patients due to infections, although none of the participants showed any signs of acute inflammation during the study. Another explanation for this result is that in vivo antioxidants can only operate effectively, if all components of the antioxidant system are in balanced concentrations, then it is possible that the effect of Vitamin E was also masked by the general imbalance of the antioxidant system. It is worth noting that this was the only study that used a higher dose than recommended by the European Renal Nutrition Best Practice Guidelines (400-800 IU) which may have contributed to the pro-oxidant effect obtained¹⁰.

Other studies^15,19 have observed that the supplementation significantly reduced IL-6. According to the authors, Vitamin E decreases the transfer of monocytes to inflammatory sites, which reduces the expression of factors such as VCAM-1 and nuclear factor kappa B, promoting lower production of inflammatory cytokines such as IL-6.

Castilla et al. (2008)¹⁸ found that Vitamin E promoted a reduction in oxidized LDL concentration (LDL-ox) and the acidity of NADPH oxidase, an enzyme complex known to be the main source of superoxide radicals, which promote LDL oxidation.

Increased LDL-ox levels induce endothelial cell dysfunction and the expression of many pro-inflammatory genes, including monocyte chemoattractant protein of endothelial cells 1 (MCP-1), VCAM-1 and ICAM-1. This process leads to the recruitment of monocytes in the intima, which differentiate into macrophages that capture LDL-ox and become foam cells, producing more pro-inflammatory cytokines^15,29,30.

Huang et al. (2012)³⁰ highlighted that the antioxidant capacity of Vitamin E is responsible for the decreased expression of cytokines and ROS in foam cells, resulting in lower LDL-ox uptake by these cells.

Mafra et al. (2020)²⁶ found that the supplementation promoted a significant decrease in LDL (-), because alpha-tecopherol acts as a scavenger of lipid peroxyl radicals in lipoproteins, protecting them against oxidation and preventing the generation of LDL-ox. It is worth mentioning that LDL (-) is involved in atherogenesis by inducing cytotoxicity, apoptosis and the production of cytokines and chemokines, such as interleukin 8 (IL-8), MCP-1 and VCAM-1.

In the studies by Antoniadi et al. (2008)²⁴ and Lu et al. (2007)²⁵ no improvements in the antioxidant status of patients were obtained with the administration of alpha-tocopherol. The authors point out that under special conditions, Vitamin E can act as a pro-oxidant. This occurs in vitro when there are sufficient amounts of Vitamin E, but with concomitant depletion of other antioxidants that are necessary for the reduction of this vitamin, such as ascorbate. Also, increased concentrations of alpha-tocopherol may cause decreased levels of gamma-tocopherol, which in turn is also important in modulating inflammatory pathways and is even better able to combat myeloperoxidase-mediated oxidation. According to Pirhadi-Tavandashti et al. (2020)⁹, γ-tocopherol can have its levels reduced by competition for the hepatic transporter (α-TTP), which has more affinity for alpha-tocopherol, resulting in less transfer of γ-tocopherol from liver to serum.

The present review was conducted with clinical trials only, and consisted of a good number of studies, including studies from different countries. As limiting points, one can highlight the lack of blinding of some studies and the lack of equivalence of sample sizes.

CONCLUSIONS

This research has provided evidence indicating that Vitamin E supplementation may be a good strategy to increase the quality of life of chronic kidney disease patients on hemodialysis treatment, since most of the included studies found a positive effect in reducing inflammatory biomarkers and oxidative stress. However, it is worth mentioning that the effectiveness of this therapy depends on the dosage and timing of the supplementation. Adding to that, it is essential to keep a nutritional monitoring so that the intervention occurs in a secure and efficient manner.