Antioxidant therapy in hemodialysis patients: a systematic review
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Kidney International (2012) 81, 233–246
報告者: Fellow 1 陳筱惠指導醫師:尤俊成醫師
Antioxidant therapy in hemodialysis patients: a
systematic review
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Oxidative stress:Pro-oxidants overwhelm antioxidant defenses.
Pro-oxidants: reactive oxygen species and reactive nitrogen speciesConsist of free radicalsMost common reactive nitrogen: nitric oxide
Antioxidants: synergistic relationshipsEndogenousExogenous
Dietary: vitamin E (a-tocopherol), vitamin C (ascorbic acid), and b-carotene
Therapeutic: N-acetylcysteine and bardoxolone
BACKGROUND
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The markers of oxidative stress:F2-isoprostanes,lipid hydroperoxides, oxidized
anti-LDL antibodies, the oxidizability of LDL, free sulfhydryl groups, carbonyl groups, 3-chlorotyrosine, and advanced oxidation protein products
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Oxidative stress in HD patients:HD patients have elevated oxidative stress
compared with healthy matched controls.Contribute to the high levels of CVD morbidity
and mortality in these individualsPlasma levels of vitamin E are decreased
during HD.
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decreasing uptake ofdietary antioxidants
HD activate immune cells and increases production of reactive oxygen species
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Cardiovascular disease (CVD): 10~20 fold increased risk, cause of death in
~34% of hemodialysis (HD) patientsInterventions aimed at improving CVD
outcomes in HD patients:Lipid-lowering therapyIncreased dialysis doseAbout the timing of dialysis initiationAntioxidant therapy positive effect
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Beneficial effects in following studies:Observational studies:
World Health Organization’s MONICA (MONitoring trends and determinants In CArdiovascular disease) Study
The Nurses Health StudyThe US Physicians study
Randomized controlled clinical trials: CHAOS (Cambridge Heart AntiOxidant Study)
Large trials ??HOPE (Heart Outcomes Prevention Evaluation) trial1The Heart Protection Study
Antioxidants and cardiovascular disease
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PubMedSearch terms: dialysis and
Aantioxidants, vitamin E, tocopherol, vitamin C, ascorbic acid, selenium, acetylcysteine, vitamin A, beta-carotene, coenzyme Q10
Limits: humans and clinical trials that investigate effects of oral antioxidant therapy on a marker/s of oxidative stress or a CVD outcome measure in patients undergoing HD
56/298 articles:53 studies the effects of antioxidant therapy on a
biomarker or biomarkers of oxidative stress3 studies the effects of antioxidants on CVD end points
SYSTEMATIC REVIEW -- Methods
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The timing of blood collection for oxidative stress biochemical measures35/53 studies Comparing predialysis data: blood
samples shortly after initiation of the HD session, before and after the therapeutic period
9/53 studies Comparing changes from pre- to postdialysis: change in the measures before and after the dialysis session, before and after the therapeutic period
4/9 studies Comparing postdialysis: changes in oxidative stress from postdialysis, before and after therapy
SYSTEMATIC REVIEW -- General considerations
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Substrates with oxidative damage: 20 oxidative stress biomarkers
Lipids (44 studies):1st: Malondialdehyde (MDA), 27 studies2nd: LDL cholesterol, 10 studies3rd: isoprostanes, 4 studies; protein carbonyls,
4 studies)4th: lipid hydroperoxides, 3 studies
Proteins (7 studies) and DNA (1 study)
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37/53 studies: a decrease in biomarkers of oxidative stress following antioxidant therapy (20/37 a-tocopherol)
15/53 studies: no effect8/53 studies: an increase
FINDINGS
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25 studies investigating the effects of a-tocopherol on oxidative stress in HD patient
20/25 studies: decrease oxidative stressThe mean dose: 500 mg/day (15~1200 IU/day)
5/25 studies showing that a-tocopherol had no effect:The doses: 200 mg/day, 800 IU/day
a-Tocopherol
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The form of a-tocopherol: natural or synthetic??The majority of studies did not specify the form
administered.Duration:
No differences in the median duration of therapeutic periods in the studies showing that a-tocopherol decreased oxidative stress compared with those reporting no effect
8 weeks
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3/25 studies: RCT design, 95 patientsEffects of atorvastatin and vitamin E on
lipoproteins and oxidative stress in dialysis patients: a randomised-controlled trial. J Intern Med 2005; 257: 438–445a-tocopherol (800 IU/day) + atorvastatin (40
mg/day), 12 weeksNo effect of a-tocopherol on plasma-oxidized
LDL
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Effect of vitamin E therapy on oxidative stress and erythrocyte osmotic fragility in patients on peritoneal dialysis and hemodialysis. J Nephrol 2006; 19: 739–745800 IU/day, 6 monthsNo effect on oxidative protein products
Serum vitamin E and oxidative protein modification in hemodialysis: a randomized clinical trial. Am J Kidney Dis 2007; 50: 305–313300 mg/day, 20 weeksDecreased erythrocyte osmotic fragility and plasma
MDA
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11 studies, 371 patients, 9 with RCT design4/11 studies: decrease oxidative stress
250 mg 12 weeks, 1g/day 1 year, orally300 mg~1 g/day 8 weeks, intravenously
3/11 studies: increase oxidative stress2/3 studies: a single intravenous dose
Vitamin C with metal ions that may exacerbate oxidative stress (may occur after single dose). Over time, there are adjustments to defenses that eventually result in a more pronounced antioxidant effect.
Vitamin C
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1/3 studies: 200mg~1 g/day, 3 monthsThe increased dose may have a similar effect as the
single dose, with insufficient time to enable other antioxidant defenses to compensate.
4/11 studies: no significant effect250mg/day, 4~12 weeks, ineffectual period and
dose
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Increase the endogenous antioxidant glutathione by contributing cysteine
Facilitate the production and action of nitric oxide, leading to improved vasodilation
4 studies. 172 patients, 3 with RCT designAll studies: decrease oxidative stress
1.2, 2, 5 g/dayOne-off dose, 3 weeks
N-acetylcysteine
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Essential trace element that functions as a cofactor for the reduction of antioxidant enzymes such as glutathione peroxidase, but toxic in large doses
3 studies, 40 patients2/3 studies: decrease biomarkers of oxidative
stress1/3: no effect25ug orally, 400mg intravenously, 8~20 weeks
Selenium
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r-tocopherolDocosahexaenoic acida-lipoic acidCoenzyme Q10
Other antioxidants
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7 studies, 1 with RCT design4/7 studies: decrease oxidative stress2/7 studies: no effect1/7 studies: a decrease in one biomarker, but
no change in another6/7 studies with a-tocopherol, 5/6 studies
with vitamin C
Antioxidant combinations
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3 trialsThe effect of vitamin C supplementation and
withdrawal on the mortality and morbidity of regular hemodialysis patients. Clin Nephrol 1989; 31: 31–34The 1st clinical outcome trial in HD patientsNoncontrolled, 61 patients500 mg/day of vitamin C, 2 yearsNo difference in morbidity or mortality rates
Clinical outcome trials
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SPACE (Secondary Prevention with Antioxidants of Cardiovascular disease in End-stage renal disease) trialThis most cited oneRandomized, double-blind, placebo-controlled
trial97 patients, 800 IU a-tocopherol/day, 500 days99 patients, placebo54% reduction in cardiovascular risk
(P=0.014), 40% reduction in composite CVD end points, 70% reduction in total myocardial infarction (P=0.014 and 0.016, respectively)
Lack of a healthy control group??
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The antioxidant acetylcysteine reduces cardiovascular events in patients with end-stage renal failure: a controlled trial. Circulation 2003; 107: 992–99564 patients, 1.2 g/day orally, 14 months70 patients with placeboReduced rates of CVD events, but no
differences in secondary end points (total mortality and CVD mortality)
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The presence of oxidative stress was not an inclusion criterion for 3 trials.Patients were potentially not in a biochemical
state that would benefit from additional antioxidant defenses.
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Lack of a clinically accepted and validated oxidative stress biomarker
FUTURE STUDIES
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Thanks for your listening