CKD: Micronutrients: Vitamins E and A Supplementation (2020)
Click here to see the explanation of recommendation ratings (Strong, Fair, Weak, Consensus, Insufficient Evidence) and labels (Imperative or Conditional). To see more detail on the evidence from which the following recommendations were drawn, use the hyperlinks in the Supporting Evidence Section below.
CKD: Vitamins E and A Supplementation and Toxicity
In adults with CKD 5D on MHD or CKD 5D on PD, it is reasonable to not routinely supplement Vitamin A or E because of the potential for vitamin toxicity. However, if supplementation is warranted, care should be taken to avoid excessive doses, and patients should be monitored for toxicity (OPINION).
Risks/Harms of Implementing This Recommendation
There is a potential for toxicity in those patients who are being supplemented. High doses of vitamin E supplementation has the potential to increase risk of hemorrhagic stroke and impair platelet aggregation. Vitamin E interacts with anticoagulant and antiplatelet medications and therefore caution is advised on vitamin E supplementation for CKD patients already receiving these medications. The potential of vitamin A toxicity with supplementation is also a concern.
Conditions of Application
As a result of the limited number of high quality studies, (see study selection criteria) and the variability in the outcomes reported in these trials, there is insufficient evidence to make recommendations on vitamin E intake for CKD patients. The nutritional requirements or Recommended Dietary Intake of vitamin E for individuals with CKD 1-5, those undergoing chronic dialysis and post-transplant are unknown. Dose response studies identifying the relation between Vitamin E intake and serum levels of vitamin E are not available. The prevalence of vitamin E deficiency in CKD population is unclear. The potential of vitamin E toxicity with supplementation is a concern for this fat-soluble vitamin.
There is a potential for toxicity in those patients who are being supplemented. High doses of vitamin E supplementation has the potential to increase risk of hemorrhagic stroke and impair platelet aggregation. Vitamin E interacts with anticoagulant and antiplatelet medications and therefore caution is advised on vitamin E supplementation for CKD patients already receiving these medications.
Vitamin A was investigated in this SR, however there were no trials examining dietary intake of vitamin A, and supplementation trials included IV vitamin A, which the WG determined qualified it as a medication vs a nutritional supplement. However, the same concerns regarding toxicity of vitamin E supplementation apply to vitamin A supplementation.
Recommendations cannot be made with regard to vitamins A or E supplementation in CKD population. An individualized approach is required in considering the need to supplement vitamins A or E supplementation or terminate supplementation in adult CKD population and there is also a need to monitor for toxicity with supplementation.
- Suggested vitamin intake should be based on recommendations for the general population (ex: Recommended Dietary Allowance) unless there are specific considerations requiring modification.
- Vitamin E supplementation dose should consider individual patient’s nutritional status, dietary intake, concomitant medications, co-morbid conditions particularly with regard to baseline cardiovascular disease, and lipid levels.
- Oral doses >= 400 IU of vitamin E are not recommended without at least intermittent monitoring of serum vitamin E levels.
Monitoring and Evaluation
Platelet count should be monitored as should any changes in medical status, medications, and nutritional status.
Potential Costs Associated with Application
The cost of nutrition supplements should be considered before recommending to a patient.
Vitamin E is a fat-soluble nutrient recognized for antioxidant properties. There are eight known naturally occurring forms of vitamin E (IOM et al 2000), but alpha-tocopherol is the only known form of vitamin E that meets human requirements and is the form found in plasma. Therefore, Dietary Reference Intake (DRI) for vitamin E is only available for alpha-tocopherol. The RDA for vitamin E was determined by identifying serum levels of vitamin E that provided protection to erythrocyte survival when exposed to hydrogen peroxide.
While vitamin E supplements are typically provided as alpha-tocopherol, products containing other tocopherols and tocotrienols have been reported.The potency of synthetic alpha-tocopherol (RRR-alpha-tocopherol, labeled as D or d) is not identical to the natural form. This is because synthetic alpha-tocopherol contains eight stereoisomers of which only 4 are found in tissues and serum. Synthetic alpha-tocopherol: all rac-alpha-tocopherol, labeled as dl or DL is therefore only half as active as the natural form, therefore requiring 50% more IU to receive a dose equivalent to the natural source. Most supplements provide vitamin E as alpha-tocopherol in a 100-400mg dose (IOM 2000).
Vitamin E is a fat-soluble vitamin. The potential risk of vitamin E toxicity is primarily related to the use of supplements (IOM 2000, Miller et al 2005). High doses of vitamin E supplements in the form of alpha-tocopherol have been reported to cause bleeding and/or disrupt blood coagulation in vivo and there are some in vivo data that suggest alpha-tocopherol inhibits platelet aggregation (Miller et al 2005). The RDA for vitamin E for normal adult men and woman is 15mg per day (22.4 IU). The Food and Nutrition Board has defined an upper level of intake for vitamin E in the form of alpha-tocopherol and the stereoisomer forms in synthetic vitamin E supplements as 1500 IU and 1100 IU/day respectively. While not definitive, these level of intake appear to be the safety limit with regard to the potential of vitamin E to confer bleeding risk.
Several studies evaluated the effects of Vitamin E coated dialyzer membranes on biocompatibility, blood pressure during dialysis and oxidative stress (Takouli et al 2010, Zweiger et al 2013). However, results were inconclusive. Data regarding the effect of vitamin E coated dialyzers on hemoglobin, lipid profile and nutritional status were inconclusive and study design for these trials and the meta-analyses were of low quality (Huang et al 2015).
Studies examining daily vitamin A requirements for individuals with various stages of CKD are lacking. Optimal serum levels of vitamin E are not defined for this population. Daily vitamin E required to maintain nutritional health, reverse deficiency, and to avoid toxicity in CKD population are unclear. Vitamin A was initially investigated in the systematic review, but there were no dietary trials available, only trials in which vitamin A was delivered intraveneously, which was considered beyond the scope of this guideline.
The eight studies included for this review examined the effect of oral vitamin E supplementation in adults with CKD on serum indices and health outcomes (Ahmadi et al 2003, Boaz et al 2000, Daud et al 2013, Himmelfarb et al 2014, Mann et al 2004 and Ramos et al 2011, Hodkova et al 2006 and Khajehdehi et al 2000). In three of these studies, vitamin E supplementation was combined with α-lipoic acid supplementation (ALA) (Ahmadi et al 2013, Himmelfarb et al 2014, Ramos et al 2011). All studies examined MHD patients as the target population, except for Ramos et al, who examined Stages 3-5 CKD subjects. Subjects in Hodkova, et al. were vitamin E repleted, but baseline vitamin E status was not reported for any of the other studies.
All- Cause Mortality and Cardiovascular Disease Outcomes
Participants with CKD (serum creatinine ≥1.4 to 2.3 mg/dL) and high risk for cardiovascular events were given 400 IU daily oral vitamin E for a median of 4.5 years (Mann et al 2004). Compared to the placebo group, there was no difference in total mortality between groups. Additionally, there was no difference in the relative risk of myocardial infarction (MI), stroke, death from CV causes, unstable angina, heart failure hospitalizations, heart failure, TIA or composite or MI, stroke, or death from cardiovascular causes between groups.
Serum Vitamin E Levels
Two RCTs examined the effect of daily oral vitamin E supplementation on vitamin E levels (Boaz et al 2011, Hodkova et al 2006). Both studies included MHD patients. Hodkova et al found that serum vitamin E levels increased in the vitamin E supplemented group (α-tocopherol 400 mg/888 IU) after 5 weeks, but no change in the control. Between group differences were not reported. Boaz, et al. found that the vitamin E supplemented group had significantly higher vitamin E levels compared to the placebo group when MHD participants with pre-existing CVD were supplemented with 800 IU oral vitamin E/day for a median of 519 days, but between group differences were not reported. In pooled analysis of the two RCTs that examined vitamin E supplementation alone, there was no significant effect of supplementation compared to the placebo/control group. Therefore, available evidence indicates that vitamin E supplementation alone does not affect vitamin E levels.
Daily oral vitamin E supplementation of 110 mg for four months (Daud et al 2013) and 200 mg for three months (Khajehdehi et al.) did not change serum triglyceride, total cholesterol or LDL (low density lipoprotein) levels but demonstrated efficacy of increasing HDL-C levels.
Recommendation Strength Rationale
The recommendation regarding supplementation of vitamins E and A is based on Consensus/expert opinion, since there was no literature to suggest a benefit of dietary or oral supplementation.
- Risks/Harms of Implementing This Recommendation
The recommendations were created from the evidence analysis on the following questions. To see detail of the evidence analysis, click the blue hyperlinks below (recommendations rated consensus will not have supporting evidence linked).
What is the effect of vitamin E supplementation on all-cause mortality in adults with CKD 1-5D and post-transplant?
What is the effect of vitamin E supplementation on CVD outcome in adults with CKD 1-5D and post-transplant?
What is the effect of vitamin E supplementation on lipid profile in adults with CKD 1-5D and post-transplant?
What is the effect of vitamin E supplementation on vitamin E levels in adults with CKD 1-5D and post-transplant?
What is the effect of vitamin E supplementation on CRP levels in adults with CKD 1-5D and post-transplant?
What is the effect of vitamin E supplementation on IL-6 levels in adults with CKD 1-5D and post-transplant?
What is the effect of vitamin E supplementation on SGA score in adults with CKD 1-5D and post-transplant?
Boaz M, Smetana S, Weinstein T, Matas Z, Gafter U, Iaina A, Knecht A, Weissgarten Y, Brunner D, Fainaru M, Green M. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet (London, England) 2000; 356:1213-8
Mann J, Lonn E, Yi Q, Gerstein H, Hoogwerf B, Pogue J, Bosch J, Dagenais G, Yusuf S. Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficiency: results of the HOPE study. Kidney International 2004; 65:1375-80
Daud Z, Tubie B, Sheyman M, Osia R, Adams J, Tubie S, Khosla P. Vitamin E tocotrienol supplementation improves lipid profiles in chronic hemodialysis patients. Vascular Health and Risk Management 2013; 9:747-61
Khajehdehi P. Effect of vitamins on the lipid profile of patients on regular hemodialysis. Scandinavian Journal of Urology and Nephrology 2000; 34:62-6
Hodkova M, Dusilova-Sulkova S, Kalousova M, Soukupova J, Zima T, Mikova D, Malbohan I, Bartunkova J. Influence of oral vitamin E therapy on micro-inflammation and cardiovascular disease markers in chronic hemodialysis patients. Renal Failure 2006; 28:395-9
Ahmadi A, Mazooji N, Roozbeh J, Mazloom Z, Hasanzade J. Effect of alpha-lipoic acid and vitamin E supplementation on oxidative stress, inflammation, and malnutrition in hemodialysis patients. Iranian Journal of Kidney Diseases 2013; 7:461-7
Ramos L, Kane J, McMonagle E, Le P, Wu P, Shintani A, Ikizler T, Himmelfarb J. Effects of combination tocopherols and alpha lipoic acid therapy on oxidative stress and inflammatory biomarkers in chronic kidney disease. Journal of Renal Nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation 2011; 21:211-8
Himmelfarb J, Ikizler T, Ellis C, Wu P, Shintani A, Dalal S, Kaplan M, Chonchol M, Hakim R. Provision of antioxidant therapy in hemodialysis (PATH): a randomized clinical trial. Journal of the American Society of Nephrology 2014; 25:623-33
References not graded in Academy of Nutrition and Dietetics Evidence Analysis Process
Huang J, Yi B, Li AM, Zhang H. Effects of vitamin E-coated dialysis membranes on anemia, nutrition and dyslipidemia status in hemodialysis patients: a meta-analysis. Ren Failure. 2015;37(3):398-407. PMID: 25585953
IOM. Food and Nutrition Board. Dietary Reference Intakes: Vitamin C, Vitamin E, Selenium and Carotenoids. In: Washington, DC: National Academy Press; 2000: https://www.nap.edu/catalog/9810/dietary-reference-intakes-for-vitamin-c-vitamin-e-selenium-and-carotenoids.
Miller ER, 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142(1):37-46. PMID: 15537682
Takouli L, Hadjiyannakos D, Metaxaki P, et al. Vitamin E-coated cellulose acetate dialysis membrane: long-term effect on inflammation and oxidative stress. Renal failure. 2010;32(3):287-93. PMID: 20370442
Zweiger C NM, Storr M et al. Chapter 2: Progress in the development of membranes for kidney -replacement therapy. In: Drioli E GL, ed. Comprehen MembrSci Engineer. United Kingdom: Elsevier; 2013:351-387.