Effects of vitamin E-coated dialysis membranes on anemia, nutrition and dyslipidemia status in hemodialysis patients: a meta-analysis

Abstract

Background: This was controversial whether vitamin E-coated dialyzer therapy was beneficial for the complications associated with hemodialysis. Therefore, we performed this systematic review to evaluate the effects of vitamin E-coated dialyzer. Methods: Related trials were searched from multiple electronic databases. We conducted meta-analysis to assess changes in the predefined outcomes using RevMan 5.3 software. Results: Meta-analysis showed vitamin E-coated dialyzer therapy could decrease erythropoietin (EPO) resistance index (SMD, −0.24; 95% CI, −0.47 to −0.01; p = 0.04). However, pooled-analysis showed vitamin E-coated dialyzer therapy could not decrease weekly EPO dose (SMD, −0.11; 95% CI, −0.32 to 0.09; p = 0.28) and intima–media thickness (IMT) of the carotid artery (MD, −0.09; 95% CI, −0.2 to 0.01; p = 0.09), and vitamin E-coated dialyzer therapy did not improve the serum hemoglobin (MD, −0.03; 95% CI, −0.18 to 0.13; p = 0.74), albumin levels (SMD, −0.64; 95% CI, −1.62 to 0.34; p = 0.2), in addition, there was no significant difference in serum cholesterol (SMD, −0.07; 95% CI, −0.45 to 0.31; p = 0.71), triglycerides (MD, −2.77; 95% CI, −32.42 to 26.87; p = 0.85), high density lipoprotein (HDL) (SMD, 0.24; 95% CI, −0.14 to 0.62; p = 0.22) and low density lipoprotein (LDL) (SMD, 0.00; 95% CI, −0.38 to 0.37; p = 0.98) levels. Conclusions: Vitamin E-coated dialyzer may reduce the EPO resistance, but there is no conclusive evidence that vitamin E-coated dialyzer can improve the renal anemia, malnutrition, dyslipidemia and atherosclerosis status in hemodialysis (HD) patients. However, high-quality trials with hard clinical endpoints are required to fully elucidate the clinical value of vitamin E-coated dialyzer therapy.

• Dialyzer
• hemodialysis
• meta-analysis
• vitamin E

Introduction

A status of excessive oxidative stress is highly prevalent in patients undergoing maintenance hemodialysis (HD), in part because of an increased free radicals production due to the interaction of blood with the dialyzer membranes during extracorporeal circulation,1 and net losses of many soluble antioxidants.2 The reactive oxygen species (ROS) can impair neighboring cells and evoke an inflammatory response,3 which is increased in HD patients not only because of their uremic status per se, but also due to HD-related factors such as the chemical and biological quality of the dialysate, and the bio-incompatibility of dialysis membranes.4 In addition, the circulating biomarkers of oxidative stress and chronic inflammatory cytokines such as malondialdehyde (MDA), C-reactive protein (CRP) or interleukin-6 (IL-6) are significantly elevated in maintenance HD patients.5^,6 There is increasing evidence that increased oxidative stress and inflammatory cytokines play a key role in the pathogenesis of malnutrition,7 resistance to erythropoietin,8 dyslipidemia9 and atherosclerosis10 related with hemodialysis.

Consequently, all these observations suggest that the direct scavenging of oxygen free radicals through the use of antioxidants (e.g., vitamin E) may be an attractive therapeutic strategy for anemia or malnutrition in HD patients. This can be achieved by taking oral vitamin E supplementation or specifically binding vitamin E to the dialysis membrane site. Recently two system reviews have concluded that vitamin E-coated dialyzer treatment could reduce the oxidative stress and inflammatory status in HD patients.11^,12 In this regard, some encouraging results have been obtained with vitamin E-modified membrane dialyzer could improve renal anemia, erythropoietin (EPO) consumption and atherosclerosis.8^,13^,14 However, there was controversy about these effects of vitamin E-coated dialyzer.15^,16. Therefore, we undertook the present meta-analysis mainly to reconcile the various strands within the dispute about the effects of vitamin E-coated dialyzer on renal anemia, resistance to EPO, malnutrition, dyslipidemia and atherosclerosis in HD patients.

Materials and methods

Inclusion criteria

Types of studies: Published reports of randomized controlled trials (RCTs) and quasi-RCTs comparing vitamin E-coated HD membranes with conventional unmodified dialyzer (polysulfone or cellulose and so on) in English with available data for our prescribed outcomes.

Type of participants: The studies were restricted to any patients with end stage renal disease (ESRD) requiring HD therapy stability.

Type of interventions: Studies comparing conventional dialyzer (unmodified cellulose-derived membranes or synthetic membranes dialyzers) with vitamin E-coated dialyzer for chronic HD patients.

Type of outcome measures: Anemia parameters: hemoglobin (HB), weekly EPO dose, EPO resistance index; nutrition parameters: serum albumin (Alb); lipid parameters: serum triglycerides, cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL) levels; atherosclerosis parameters: the intima–media thickness (IMT) of the carotid artery; dialysis adequacy: fractional clearance of urea (Kt/V).

Data sources and search strategy

We searched the medical literature for clinical studies examining the effect of vitamin E-coated dialyzer. Four English electronic databases were initially searched: SCOPUS, MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CCRCT) (all to October 2014). Article search terms included: hemodialysis, dialysis, renal replacement therapy, dialyzer, vitamins, vitamin E, tocopherol, alpha-tocopherol, beta-tocopherol, anemia, nutrition, lipid, atherosclerosis, hemoglobin, erythropoietin, erythropoietin resistance index, albumin, cholesterol, triglyceride, HDL, LDL, IMT, etc. In order to identify further potentially relevant studies, we also searched various network databases such as Google Scholar (http://scholar.google.com/), and the reference lists of included studies were manually checked.

Study selection and data extraction

Two authors (B.Y. and J.H.) independently screened the titles and abstracts of identified studies. Only parallel RCTs or quasi-RCTs and the first period of crossover RCTs or quasi-RCTs on examining the effects of vitamin E-coated dialyzer on markers of anemia, nutrition, lipid, atherosclerosis were included. The full-text articles were retrieved for comprehensive review and rescreened independently. Data extraction was performed by two authors (B.Y. and J.H.) using the standard data extraction forms.

Study quality assessment

The method quality of each study was evaluated by two authors (J.H. and A.M.L.) independently using the Cochrane risk of bias tool,17 this included six evaluation criterias: random sequence generation (selection bias), allocation sequence concealment (selection bias), blinding (performance and detection bias), selective outcome reporting (reporting bias), incomplete outcome data (attrition bias) and other potential sources of bias. The judgment for each criterion was indicating as “low risk of bias”, “high risk of biases”, or “unclear risk of biases”.

Data synthesis and statistical analysis

The extracted outcome from studies was continuous data, so treatment effects were summarized using the mean difference (MD) and 95% confidence interval (CI) was also calculated. As different units of some parameters (e.g., weekly EPO dose, EPO resistance index, serum Alb, cholesterol levels) were used in different trials, so we used standardized mean (SMD) to report, the Cochrane Review Manager (RevMan 5.3, Cochrane Collaboration, Oxford, UK) software was used for all the pooled analyses.18

Assessment of heterogeneity and subgroup analysis

Existence of statistical heterogeneity among effect sizes was analyzed using the Q statistic (p < 0.1 indicating significant) and the I² statistic (I² value of >50% correspond to high heterogeneity).19 If heterogeneity was not present, we performed a fixed-effect meta-analysis to assess net changes in the same outcome variables. If there was significant statistical heterogeneity, the random-effects model was performed. Subgroup analyses were conducted to explore potential sources of heterogeneity according to the controlled dialyzer type (biocompatible membranes dialyzer and bio-incompatible membranes dialyzer) and study duration (<6 months, 6 months and >6 months). Funnel plots were used to assess publication bias.20

Results

Selection and identification of studies

Our electronic search yielded 1189 studies, of which 948 studies were irrelevant to the study question. The remaining 241 articles were retrieved for detailed evaluation. Among them, duplicate records, non-RCTs or quasi-RCTs, review and letter, article not in English, other intervention and concerning other outcome were excluded. After the progressive selection process, 14 eligibility studies1^,8^,13–16^,21–28 including five crossover and nine parallel-arm trials were included in this meta-analysis (Figure 1).

Figure 1. Flow diagram of study selection.

Characteristics of studies

The main characteristics of included studies are summarized in Table 1. The studies varied in sample size (16–305 patients). These 14 studies enrolled a total of 975 HD patients, among them, 473 were treated with vitamin E-coated dialyzer and 502 were treated with conventional dialyzer. Of these 14 included studies, seven of the 14 included studies compared vitamin E-coated dialyzer with polysulfone dialyzer8^,14–16^,22^,25^,28 while four studies compared with cellulose membrane dialyzer.1^,13^,21^,26 Mean age of study participants ranged from 51.9 to 72.3 years, with follow-up ranged from 1 to 12 months.

Table 1. Characteristic of included studies.

Author, year, country	Study design	No. of patients	Mean age (years)	Gender (M/F)	Dialytic age (years)	Study duration (months)	Intervention	Results
Andrulli, 2010, Italy22	Not blind, Parallel	E: 10^a	E: 67 (58–76)^b	E: 5/5	E: 3.5(2.0–9.7)^b	8	E: Vit E-coated PSM dialyzer	No effect on HB level and weekly EPO does
		C: 10	C: 72 (59–74)^b	C: 5/5	C: 3.3(1.8–6.1)^b		C: PSM dialyzer
Al-Jondeby, 2003,  Saudi Arabia	Not blind, Crossover	E: 34	E: 61.52	E: 20/14	E: 62.11 months	1	E: Vit E-bonded dialyzers	No effect on HB level
		C: 41	C: 51.97	C: 22/19	C: 63.17 months		C: PSM dialyzer
Baragetti, 2006, Italy21	Not blind, Parallel	E: 8	E: 68.25 ± 1.76	E: 4/4	E: 53 ± 17.2 months	42 weeks	E: Vit E-coated dialyzer	No effect on EPO resistance
		C: 8	C: 68 ± 1.77	C: 5/3	C: 50 ± 15.8 months		C: CLSM dialyzer
Bufano, 2004, Italy	Not blind, Parallel	E: 16	E: 59.2 ± 6.8	NR	E: 29.9 ± 7.8 months	6	E: Vit E-coated dialyzer	Decrease endothelial cells damage
		C: 16	C: 58.0 ± 7.3		C: 30.4 ± 9.6 months		C: CLSM dialyzer
Clermont, 2001, France23	Not blind, Crossover	E: 6	61.6 ± 4.0	11/5	NR	1	E: Vit E-coated dialyzer	No effect on HB level
		C: 10					C: Synthetic hollow fiber dialyzer
Kirmizis, 2011, Greece24	Not blind, Parallel	E: 37^c	E: 55.0 ± 16.0	E: 19/16	E: 84 ± 58 months	6	E: Vit E-coated dialyzer	No effect on dyslipidemia and malnutrition
		C: 25	C: 62.0 ± 13.0	C: 12/13	C: 65 ± 41 months		C: CLSM, PSM, hemophage membrane dialyzer
Kobayashi, 2003,  Japan13	Not blind, Parallel	E: 17	E: 60.9 ± 13.0	E: 10/7	E: 4.4 ± 2.6	12	E: Vit E-bonded cellulose dialyzer	Decrease atherosclerosis and EPO does
		C: 17	C: 63.2 ± 10.7	C: 9/8	C: 4.4 ± 2.7		C: CLSM dialyzer
Lines, 2014,  United Kingdom16	Not blind, Parallel	E: 123^d1	E: 62.6 ± 1.5	E: 76/47	E: 3.2(1.2–6.6)	12	E: Vit E-coated PSM dialyzer	No effect on EPO resistance
		C: 137^d2	C: 64.0 ± 1.3	C: 80/57	C: 3.9(1.8–7.6)		C: PSM dialyzer
Mandolfo, 2012, Italy14	Not blind, Crossover	E: 8	72.3 ± 8.9	NR	45.5 ± 40.8 months	6	E: Vit E-bonded PSM dialyzer	Decrease EPO resistance
		C: 8					C: PSM dialyzer
Morimoto, 2005, Japan25	Not blind, Crossover	E: 16	E: 69.4 ± 10.6	E: 8/8	E: 77.8 ± 65.1 months	6	E: Vit E-coated PSM dialyzer	Decrease weekly EPO does
		C: 15	C: 69.0 ± 12.2	C: 7/8	C: 73.9 ± 58.3 months		C: PSM dialyzer
Nakamura, 2003, Japan26	Not blind, Parallel	E: 7	E: 54.0 ± 5.2	E: 5/2	E: 5.0 ± 2.2	10 weeks	E: Vit E-coated dialyzer	Decrease atherosclerosis
		C: 12	C: 54.5 ± 5.0	C: 8/4	C: 4.5 ± 2.0		C: CLSM dialyzer
Panichi, 2011, Italy	Single blind, Crossover	E: 31	E: 68 ± 13	E: 16/15	48 ± 27 months	6	E: Vit E-coated PSM dialyzer	Decrease weekly EPO does
		C: 31	C: 63 ± 11	C: 18/13			C: PSM dialyzer
Sanaka, 2013, Japan15	Not blind, Parallel	E1: 95^e1	E1: 64.6 ± 11.4	NR	E1: 80.4 ± 67.3 months	12	E: Vit E-coated PSM dialyzer	No effect on EPO resistance
		C1: 99^e2	C1: 61.5 ± 12.2		C1: 73.5 ± 74.1 months		C: PSM dialyzer
		E2: 56^e3	E2: 57.4 ± 13.7		E2: 92.3 ± 79.8 months
		C2: 55^e4	C2: 62.8 ± 12.5		C2: 84.1 ± 72.5 months
Usberti, 2002, Italy27	Not blind, Parallel	E: 9	E: 63.0 ± 11.0	NR	E: 90 ± 75 months	3	E: Vit E-coated dialyzer	Improve anemia
		C: 18	C: 64.0 ± 15.0		C: 99 ± 86 months		C: CLSM and PSM dialyzer

Notes: PSM: polysulfone membrane; CLSM: cellulose membrane; Vit: Vitamin; NR: not reported; E: vitamin E-coated dialyzer group; C: conventional dialyzer group; EPO: erythropoietin; HB: hemoglobin.

^aNine patients in vitamin E-coated dialyzer treatment group completed the study.

^bValues were reported as median (range).

^cThirty five patients in vitamin E-coated dialyzer treatment group completed the study.

^d1Hundered and four patients in vitamin E-coated dialyzer treatment group completed the study.

^d2Hundred and sixteen patients in control group completed the study.

^e1Seventy four patients in vitamin E-coated dialyzer treatment group completed the study (10 ≤ Hb ≤ 11).

^e2Sixty seven patients in control group completed the study (10 ≤ Hb ≤ 11).

^e3Fourty patients in vitamin E-coated dialyzer treatment group completed the study (11 ≤ Hb ≤ 12).

^e4Thirty two patients in control group completed the study (11 ≤ Hb ≤ 12).

Quality assessment of included studies

Allocation: Randomization was unclear in 12 studies. Some randomized methods such as computer-generated randomization table and drawing random numbers were applied in two studies.8^,22 None of the included trials clearly described the allocation concealment ways.

Blinding: Only one study performed by Panichi et al. was single blinded,8 while other studies were not blinded designed.

Incomplete outcome data: Four studies reported withdrawals,15^,16^,22^,24 but the results were not analyzed on an intention-to-treat basis. Ten trials were assessed to be low risk of attrition bias.

Selective reporting: None of the 14 included studies reported all expected outcomes.

Other potential sources of bias: Other potential bias was unable to be assessed due to insufficient information in the included trials. The summaries of the risk of bias findings are shown in Figure 2.

Figure 2. Risk of bias graph and bias summary: review authors’ judgements about each risk of bias item presented as percentages across all included studies and review authors’ judgements about each risk of bias item for each included study.

Effects on renal anemia

The effect of vitamin E-coated dialyzer on HB level was assessed in six trials,8^,14^,15^,21^,23^,25 this meta-analysis showed a nonsignificant increase in HB level compared with that of control (MD, −0.03; 95% CI, −0.18 to 0.13; p = 0.74; Figure 3), with significant heterogeneity between studies (p = 0.06; I² = 50%). Six studies reported the EPO dose as mean and standard deviation,8^,13–15^,23^,25 the fixed model was performed for meta-analysis. The pooled analysis showed that vitamin E-coated dialyzer therapy did not result in a significant decrease in EPO dose (SMD, −0.11; 95% CI, −0.32 to 0.09; p = 0.28, Figure 4A). In the study performed by Andrulli et al.,22 HB and weekly EPO dose were reported as median and range, in line with our pooled analysis, the result showed that vitamin E-coated dialyzer was not associated with a significant improvement in HB level and weekly EPO dose (p = 0.859, p = 0.362 respectively).22

Figure 3. Forest plot of studies comparing the effect of vitamin E-coated dialyzer versus conventional dialyzer on HB level in hemodialysis patients.

Figure 4. Forest plot of studies comparing the effect of vitamin E-coated dialyzer versus conventional dialyzer on EPO dose and EPO resistance index in hemodialysis patients.

Three studies reported on EPO resistance index (n = 291), and the pooled analyzed were performed under a fixed-effects mode,8^,14^,15 the analysis showed that vitamin E-coated dialyzer therapy resulted in a significant reduction in EPO resistance index (SMD, −0.24; 95% CI, −0.47 to −0.01; p = 0.04; Figure 4B), with acceptable heterogeneity (p = 0.21; I² = 35%). In the study performed by Lines et al.,16 EPO resistance index data was reported as median and range, in contrast with our pooled analysis, the result showed that vitamin E-coated dialyzer was not associated with a significant decrease in EPO resistance index at the end of 12 months’ treatment (p = 0.2).16

Effects on nutrition markers

As shown in Figure 5(A), the changes in serum Alb were evaluated in four trials (n = 108).14^,21^,23^,24 When the meta-analysis was performed, no significant effect was found after conversion from conventional dialyzer to vitamin E-coated dialyzer (SMD, −0.64; 95% CI, −1.62 to 0.34; p = 0.2), with evidence of heterogeneity (p = 0.004; I² = 78%).

Figure 5. Forest plot of studies comparing the effect of vitamin E-coated dialyzer versus conventional dialyzer on serum Alb, IMT of the carotid artery and Kt/V levels in hemodialysis patients.

Effects on serum lipid parameters

As seen in Figure 6, serum cholesterol was compared between patients receiving vitamin E-coated dialyzer and those receiving conventional dialyzer in three trials involving 111 patients.1^,24^,26 The meta-analysis showed that there was no statistically significant change in serum cholesterol in the vitamin E-coated dialyzer groups (SMD, −0.07; 95% CI, −0.45 to 0.31; p = 0.71), with minimal heterogeneity (p = 0.46; I² = 0%).

Figure 6. Forest plot of studies comparing the effect of vitamin E-coated dialyzer versus conventional dialyzer on lipid parameters in hemodialysis patients.

The changes in serum triglycerides fractions were analyzed from two trials.24^,26 Again, there was no significant change of triglycerides in the vitamin E-coated dialyzer groups (MD, −2.77; 95% CI, −32.42 to 26.87; p = 0.85; Figure 6). In addition, the pooled analysis showed that vitamin E-coated dialyzer therapy could not change serum HDL and LDL levels (SMD, 0.24; 95% CI, −0.14 to 0.62, p = 0.22; SMD, −0.00; 95% CI, −0.38 to 0.37, p = 0.98, respectively).

Effects on atherosclerosis

It has been suggested that vitamin E-coated dialyzer may exert its favorable therapeutic effects on atherosclerosis. Two studies involving 53 patients were analyzed under a fixed model.13^,26 However, no significant effect on IMT of the carotid artery was found in the vitamin E-coated dialyzer groups (MD, −0.09; 95% CI, −0.2 to 0.01; p = 0.09; Figure 5B).

Effects on dialysis adequacy

Four studies involving 79 patients reported fractional clearance of urea (Kt/V) index as a measure of dialysis adequacy. In line with the research performed by Yang et al.,12 our pooled analysis result showed that conversion from vitamin E-coated dialyzer to conventional dialyzer did not result in increase in Kt/V index (MD, −0.07; 95% CI, −0.14 to 0.00; p = 0.06), with minimal heterogeneity (p = 0.85; I² = 0%; Figure 5C).

Investigations of heterogeneity

We performed subgroup analysis to explore mean change in HB and weekly EPO dose in trials, stratified by dialyzer membranes biocompatibility and study duration. In brief, there was no significant effect on HB level using different biocompatible membranes dialyzer, but the use of vitamin E-coated dialyzer resulted in a significant decrease in weekly EPO dose compared with studies using bio-incompatible membranes (cellulose membrane) dialyzer (MD, −0.87; 95% CI, −1.57 to −0.16; p = 0.02).13 In addition, use of vitamin E-coated dialyzer therapy resulted in a significant increase in HB level in trials of 6 months duration (MD, 0.36; 95% CI, 0.07 to 0.65; p = 0.01),8^,14^,25 while there was no effect on HB level in those of >6 months duration (MD, −0.12; 95% CI, −0.37 to 0.12; p = 0.32).15^,21 We used funnel plots to assess the publication bias, as shown in Table 2, most funnel plots of the outcomes such as EPO dose, HB, TG, HDL, LDL were symmetric. However, there were some key outcomes such as Alb and Kt/V was asymmetric, which suggested that there might be publication bias among these studies.

Table 2. Summary effect of vitamin E-coated dialyzer on maintenance hemodialysis patients.

					Assessment of	Publication bias
Outcome variables	No. studies	No. patients	Mean net change (95% CI)	p-Value	heterogeneity I^2 index(%)	Q-statistic p-Value	Funnel plots
Anemia parameters
EPO (total)	6	372	−0.11 (−0.32, 0.09)	0.28	27	0.23	Symmetric
EPO (study duration <6 months)	1	16	0.85 (−0.22, 1.92)	0.12	–	–	–
EPO (study duration = 6 months)	3	109	−0.12 (−0.50, 0.25)	0.53	0	0.77	–
EPO (study duration >6 months)	2	247	−0.16 (−0.41, 0.09)	0.21	54	0.11	–
EPO (VEM dialyzer vs. BCM dialyzer)1	5	338	−0.04 (−0.26, 0.17)	0.69	0	0.64	–
EPO (VEM dialyzer vs. BICM dialyzer)2	1	34	−0.87 (−1.57, −0.16)	0.02	–	–	–
HB (total)	6	354	−0.03 (−0.18, 0.13)	0.74	50	0.06	Symmetric
HB (VEM dialyzer vs. BCM dialyzer)1	5	338	−0.02 (−0.17, 0.14)	0.85	53	0.06	–
HB (VEM dialyzer vs. BICM dialyzer)2	1	16	−0.8 (−2.13, 0.53)	0.24	–	–	–
HB (study duration <6 months)	1	16	−0.30 (−0.60, 0.00)	0.05	–	–	–
HB (study duration = 6 months)	3	109	0.36 (0.07, 0.65)	0.01	0	0.86	–
HB (study duration >6 months)	3	229	−0.12 (−0.37, 0.12)	0.32	0	0.60	–
EPO resistance index	3	291	−0.24 (−0.47, −0.01)	0.04	35%	0.21	Asymmetric
Nutritional marker
ALB (total)	4	108	−0.64 (−1.62, 0.34)	0.2	78	0.004	Asymmetric
Lipidemia parameters
Tchol	3	111	−0.07 (−0.45, 0.31)	0.71	0	0.46	Symmetric
TG	2	79	−2.77 (−32.42, 26.87)	0.85	0	0.95	Symmetric
HDL	3	111	0.24 (−0.14, 0.62)	0.22	0	0.56	Symmetric
LDL	3	111	0.00 (−0.38, 0.37)	0.98	0	0.74	Symmetric
Atherosclerosis parameters
IMT	2	53	−0.09 (−0.2, 0.01)	0.09	0	0.58	Asymmetric
Dialysis adequacy markers
Kt/V	4	79	−0.07 (−0.14, 0.00)	0.06	0	0.85	Asymmetric

Notes: EPO: erythropoietin, HB: hemoglobin, Alb: albumin, Tchol: total cholesterol, TG: triglyceride, HDL: high density lipoprotein, LDL: low density lipoprotein, IMT: intima–media thickness, Kt/V: fractional clearance of urea.

Discussion

The main finding based on this system review is that vitamin E-coated dialyzer may reduce the EPO resistance, but there is no conclusive evidence that vitamin E-coated dialyzer can improve the renal anemia, malnutrition and atherosclerosis status in HD patients. As these there is no specific defined hypothesis before this exploratory meta-analysis. The pooled analysis results can only suggest vitamin E-coated dialyzer therapy effects but dose not demonstrate them.

As a consequence of the low biocompatibility of conventional hemodialysis membrane dialyzer (e.g., cellulose-derived dialysis membranes), these materials can activate the oxidative metabolism of polymorphonuclear cells and macrophages1 in HD patients who require an increasing number of repeated extracorporeal circulations, then resulting in a series of cytotoxic effects commonly described as “oxidative stress”.29^,30 This condition has been demonstrated to contribute to the pathogenesis of various complications such as cardiovascular diseases, beta-2 microglobulin-amyloidosis and protein malnutrition. To cope with this problem, dialyzers have been evolved into more biofriendly devices. In the 1990s, a cellulosic hollow-fiber dialyzers coated with vitamin E on the blood surface was developed by the Terumo Corporation with triple goals of better filtration, an improvement in biocompatibility and antioxidant bioactivity.31 Soon afterward, vitamin E-coated polysulfone dialyzer was developed,32 which has such excellent properties as good biocompatibility, clearance, permeability, and is easy to process. In addition, a number of clinical studies and meta-analysis have demonstrated that the anti-inflammatory and antioxidative effects of these vitamin E modified dialyzers reflected by the decreasing of circulating biomarkers (e.g., CRP, IL-6 and oxLDL levels).11^,12

Oxidative and inflammatory events triggered by the extracorporeal treatments are believed to influence the entire uremic comorbidity. Beside cardiovascular disease, oxidative stress contributes importantly to uremic anemia.21 In HD patients, due to impairment in defense mechanisms against oxidative stress,33 the erythrocytes become a preferential target for HD-induced ROS overproduction, oxidative stress induces increased lipid peroxidation of the erythrocyte membrane then resulting in the resistance to erythropoietin and the shorter erythrocyte lifespan. Thus, using vitamin E modified membrane dialyzer was anticipated to decrease oxidation of the erythrocytes’ membrane lipids, improve abnormal erythrocyte morphology and prolong erythrocyte lifespan. In line with this, our pooled analysis showed that vitamin E coated dialyzer treatment did result in a decrease in EPO resistance index level (SMD, −0.24; 95% CI, −0.47 to −0.01; p = 0.04). However, in this meta-analysis, we were not able to find any significant effect of vitamin E-coated dialyzer therapy on EPO dose and HB levels in maintenance HD patients (p = 0.28; p = 0.74, respectively). It indicating that renal anemia associated with HD cannot be explained solely by the presence of inflammation and oxidative stress. In addition, some studies suggested that the improvements in EPO resistance after vitamin E-coated dialyzer therapy were not due to a reduction in systemic inflammation.8^,16 On the other hand, previous studies have been suggested that supplementation of vitamin E also has a pro-oxidant action under special conditions such as other antioxidants (e.g. vitamin C) are deprived in HD patients,34 it indicated that future larger and long-term randomized clinical trials are required to fully elucidate the clinical value of vitamin E-coated dialyzer plus appropriate replacement of ascorbic acid et al. lost during dialysis on renal anemia for HD patients.

Despite remarkable technological advances that dialysis treatment has achieved, there still exists many problems associated with prolonged HD such as protein malnutrition, atherosclerosis and accelerated cardiovascular disease.35 It is reported that about 20–80% of the HD patients have a mildly to moderately malnourished status.36^,37 In an inflammatory status like what we see in HD patients, inflammatory cytokines induced by bio-incompatible dialyzer membranes and dialysate bacterial contaminants can trigger an acute-phase reaction by the liver resulting in a decrease in serum albumin levels,38 and the results of some cohort studies has also demonstrated the interaction of malnutrition and inflammation.39^,40 As vitamin E-coated dialyzer treatment has been shown to decrease oxidative stress and inflammation status,11^,12 it is proposed that vitamin E-coated dialyzer is likely to improve nutritional status by reducing inflammation status. And some clinical trials indicate vitamin E supplement can improve the malnutrition status in HD patients.37 However, our pooled-analysis showed that vitamin E-coated dialyzer therapy did not result in a significant increase in serum albumin level (SMD, −0.64; 95% CI, −1.62 to 0.34; p = 0.20), it indicating that the hypoalbuminemia status not only induced by the presence of inflammation, but also related with the considerable losses of amino acids and/or protein during hemodialysis therapy.

About 40% of deaths of maintained hemodialysis patients have been attributable to atherosclerosis and consequent increased cardiovascular diseases,41 although it still remains unclear whether HD per se affects the progression of the atherosclerosis, the patients undergoing maintained HD therapy tend to have more serious cardiovascular complications. It may be owing to severe oxidative stress induced by extracorporeal circulation and bioincompatible dialyzer membrane.13 Many studies have confirmed that vitamin E-bonded hemodialyzer could significantly decrease oxidative stress status and improve the endothelial dysfunction,13 therefore vitamin E-bonded dialyzer may be able to retrieve abnormality of atherosclerosis and lipid metabolism. But in this meta-analysis, we were not able to find significant effect of vitamin E-bonded dialyzer therapy on the IMT of the carotid artery (p = 0.09), which was a good indicator of atherosclerosis. In addition, the pooled analysis showed that vitamin E-coated dialyzer therapy had no effect on serum cholesterol and triglycerides (p = 0.71; p = 0.85 respectively). This result suggested that vitamin E-bonded dialyzer therapy might not be efficacious for controlling the HD-induced atherosclerosis and dyslipidemia, particularly when compared with other approved lipid-lowering drugs.42

Several important potential study limitations to this systematic review should be acknowledged. Firstly, mostly included studies were of low quality and small-size, only two studies explained the randomization method, and most of studies were not blinded designed. In addition, some funnel plots for the key outcomes were asymmetric (Table 2), which suggested there was publication bias among these studies. Secondly, there were a few heterogeneities of baseline clinical features in these included RCTs or quasi-RCTs, such as different study duration and different types of conventional dialyzer, we should acknowledge that the accuracy of the pooled analytical results might be influenced. Thirdly, most included researches reported short-term (less than 1 year) outcomes of vitamin E-coated dialyzer treatment, and there were controversial in the subgroup-analysis whether vitamin E-coated dialyzer was beneficial for renal anemia and EPO resistance. So this result needed to be confirmed by more larger and long-term randomized clinical trials. Finally, although we observed some surrogate endpoints (HB and EPO dose et al.), while the studies did not examine hard clinical endpoints such as morbidity or mortality, thereby limiting the clinical relevance of our findings.

In summary, this meta-analysis indicates vitamin E-coated dialyzer may reduce the EPO resistance, but there is no conclusive evidence suggest a significant advantage in renal anemia, malnutrition, dyslipidemia and atherosclerosis status conferred by the use of vitamin E-coated dialyzer versus conventional dialyzers. As this report is merely an exploratory system review, future high-quality RCTs aimed at assessing the effects of vitamin E-coated dialyzer are warranted.

Declaration of interest

None of the authors is in any condition that may represent a potential conflict of interest.

This study was in part supported by the Natural Science Foundation of Hunan Province (NO. 13JJ3033), and the Scientific and Technological Project of Hunan Province (NO. 2011FJ3217).