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      Vitamin E tocotrienol supplementation improves lipid profiles in chronic hemodialysis patients

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          Abstract

          Purpose

          Chronic hemodialysis patients experience accelerated atherosclerosis contributed to by dyslipidemia, inflammation, and an impaired antioxidant system. Vitamin E tocotrienols possess anti-inflammatory and antioxidant properties. However, the impact of dietary intervention with Vitamin E tocotrienols is unknown in this population.

          Patients and methods

          A randomized, double-blind, placebo-controlled, parallel trial was conducted in 81 patients undergoing chronic hemodialysis. Subjects were provided daily with capsules containing either vitamin E tocotrienol-rich fraction (TRF) (180 mg tocotrienols, 40 mg tocopherols) or placebo (0.48 mg tocotrienols, 0.88 mg tocopherols). Endpoints included measurements of inflammatory markers (C-reactive protein and interleukin 6), oxidative status (total antioxidant power and malondialdehyde), lipid profiles (plasma total cholesterol, triacylglycerols, and high-density lipoprotein cholesterol), as well as cholesteryl-ester transfer protein activity and apolipoprotein A1.

          Results

          TRF supplementation did not impact any nutritional, inflammatory, or oxidative status biomarkers over time when compared with the baseline within the group (one-way repeated measures analysis of variance) or when compared with the placebo group at a particular time point (independent t-test). However, the TRF supplemented group showed improvement in lipid profiles after 12 and 16 weeks of intervention when compared with placebo at the respective time points. Normalized plasma triacylglycerols (cf baseline) in the TRF group were reduced by 33 mg/dL ( P=0.032) and 36 mg/dL ( P=0.072) after 12 and 16 weeks of intervention but no significant improvement was seen in the placebo group. Similarly, normalized plasma high-density lipoprotein cholesterol was higher ( P<0.05) in the TRF group as compared with placebo at both week 12 and week 16. The changes in the TRF group at week 12 and week 16 were associated with higher plasma apolipoprotein A1 concentration ( P<0.02) and lower cholesteryl-ester transfer protein activity ( P<0.001).

          Conclusion

          TRF supplementation improved lipid profiles in this study of maintenance hemodialysis patients. A multi-centered trial is warranted to confirm these observations.

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          Most cited references59

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          Chronic kidney disease: effects on the cardiovascular system.

          Accelerated cardiovascular disease is a frequent complication of renal disease. Chronic kidney disease promotes hypertension and dyslipidemia, which in turn can contribute to the progression of renal failure. Furthermore, diabetic nephropathy is the leading cause of renal failure in developed countries. Together, hypertension, dyslipidemia, and diabetes are major risk factors for the development of endothelial dysfunction and progression of atherosclerosis. Inflammatory mediators are often elevated and the renin-angiotensin system is frequently activated in chronic kidney disease, which likely contributes through enhanced production of reactive oxygen species to the accelerated atherosclerosis observed in chronic kidney disease. Promoters of calcification are increased and inhibitors of calcification are reduced, which favors metastatic vascular calcification, an important participant in vascular injury associated with end-stage renal disease. Accelerated atherosclerosis will then lead to increased prevalence of coronary artery disease, heart failure, stroke, and peripheral arterial disease. Consequently, subjects with chronic renal failure are exposed to increased morbidity and mortality as a result of cardiovascular events. Prevention and treatment of cardiovascular disease are major considerations in the management of individuals with chronic kidney disease.
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            Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure.

            Atherosclerotic cardiovascular disease and malnutrition are widely recognized as leading causes of the increased morbidity and mortality observed in uremic patients. C-reactive protein (CRP), an acute-phase protein, is a predictor of cardiovascular mortality in nonrenal patient populations. In chronic renal failure (CRF), the prevalence of an acute-phase response has been associated with an increased mortality. One hundred and nine predialysis patients (age 52 +/- 1 years) with terminal CRF (glomerular filtration rate 7 +/- 1 ml/min) were studied. By using noninvasive B-mode ultrasonography, the cross-sectional carotid intima-media area was calculated, and the presence or absence of carotid plaques was determined. Nutritional status was assessed by subjective global assessment (SGA), dual-energy x-ray absorptiometry (DXA), serum albumin, serum creatinine, serum urea, and 24-hour urine urea excretion. The presence of an inflammatory reaction was assessed by CRP, fibrinogen (N = 46), and tumor necrosis factor-alpha (TNF-alpha; N = 87). Lipid parameters, including Lp(a) and apo(a)-isoforms, as well as markers of oxidative stress (autoantibodies against oxidized low-density lipoprotein and vitamin E), were also determined. Compared with healthy controls, CRF patients had an increased mean carotid intima-media area (18.3 +/- 0.6 vs. 13.2 +/- 0.7 mm2, P or = 10 mg/liter). Malnourished patients had higher CRP levels (23 +/- 3 vs. 13 +/- 2 mg/liter, P < 0.01), elevated calculated intima-media area (20.2 +/- 0.8 vs. 16.9 +/- 0.7 mm2, P < 0.01) and a higher prevalence of carotid plaques (90 vs. 60%, P < 0.0001) compared with well-nourished patients. During stepwise multivariate analysis adjusting for age and gender, vitamin E (P < 0.05) and CRP (P < 0.05) remained associated with an increased intima-media area. The presence of carotid plaques was significantly associated with age (P < 0.001), log oxidized low-density lipoprotein (oxLDL; P < 0.01), and small apo(a) isoform size (P < 0.05) in a multivariate logistic regression model. These results indicate that the rapidly developing atherosclerosis in advanced CRF appears to be caused by a synergism of different mechanisms, such as malnutrition, inflammation, oxidative stress, and genetic components. Apart from classic risk factors, low vitamin E levels and elevated CRP levels are associated with an increased intima-media area, whereas small molecular weight apo(a) isoforms and increased levels of oxLDL are associated with the presence of carotid plaques.
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              The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia.

              Cardiovascular disease is the leading cause of mortality in uremic patients. In large cross-sectional studies of dialysis patients, traditional cardiovascular risk factors such as hypertension and hypercholesterolemia have been found to have low predictive power, while markers of inflammation and malnutrition are highly correlated with cardiovascular mortality. However, the pathophysiology of the disease process that links uremia, inflammation, and malnutrition with increased cardiovascular complications is not well understood. We hereby propose the hypothesis that increased oxidative stress and its sequalae is a major contributor to increased atherosclerosis and cardiovascular morbidity and mortality found in uremia. This hypothesis is based on studies that conclusively demonstrate an increased oxidative burden in uremic patients, before and particularly after renal replacement therapies, as evidenced by higher concentrations of multiple biomarkers of oxidative stress. This hypothesis also provides a framework to explain the link that activated phagocytes provide between oxidative stress and inflammation (from infectious and non-infections causes) and the synergistic role that malnutrition (as reflected by low concentrations of albumin and/or antioxidants) contributes to the increased burden of cardiovascular disease in uremia. We further propose that retained uremic solutes such as beta-2 microglobulin, advanced glycosylated end products (AGE), cysteine, and homocysteine, which are substrates for oxidative injury, further contribute to the pro-atherogenic milieu of uremia. Dialytic therapy, which acts to reduce the concentration of oxidized substrates, improves the redox balance. However, processes related to dialytic therapy, such as the prolonged use of catheters for vascular access and the use of bioincompatible dialysis membranes, can contribute to a pro-inflammatory and pro-oxidative state and thus to a pro-atherogenic state. Anti-oxidative therapeutic strategies for patients with uremia are in their very early stages; nonetheless, early studies demonstrate the potential for significant efficacy in reducing cardiovascular complications.
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                Author and article information

                Journal
                Vasc Health Risk Manag
                Vasc Health Risk Manag
                Vascular Health and Risk Management
                Vascular Health and Risk Management
                Dove Medical Press
                1176-6344
                1178-2048
                2013
                2013
                28 November 2013
                : 9
                : 747-761
                Affiliations
                [1 ]Department of Nutrition and Food Science, Wayne State University, Detroit, MI, USA
                [2 ]Great Lake Dialysis Clinic, LLC, Detroit, MI, USA
                Author notes
                Correspondence: Pramod Khosla, 3002 Science Hall, Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA, Tel +1 313 577 0448, Email aa0987@ 123456wayne.edu
                Article
                vhrm-9-747
                10.2147/VHRM.S51710
                3849001
                24348043
                22c0fe66-e336-400c-8575-beaedcf30879
                © 2013 Daud et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Original Research

                Cardiovascular Medicine
                vitamin,end-stage renal disease,tocotrienol-rich fraction,nutrition intervention,lipid profiles,hemodialysis

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