Kidney International (2012) 81, 233–246
報告者：Fellow 1 陳筱惠
指導醫師：尤俊成醫師
 Oxidative stress:
 Pro-oxidants overwhelm antioxidant defenses.
 Pro-oxidants: reactive oxygen species and reactive
nitrogen species
 Consist of free radicals
 Most common reactive nitrogen: nitric oxide
 Antioxidants: synergistic relationships
 Endogenous
 Exogenous
 Dietary: vitamin E (a-tocopherol), vitamin C (ascorbic acid),
and b-carotene
 Therapeutic: N-acetylcysteine and bardoxolone
 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
 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 individuals
 Plasma levels of vitamin E are decreased during HD.
decreasing uptake of
dietary antioxidants
HD activate immune cells
and increases production
of reactive oxygen species
 Cardiovascular disease (CVD):
 10~20 fold increased risk, cause of death in ~34% of
hemodialysis (HD) patients
 Interventions aimed at improving CVD outcomes in
HD patients:
 Lipid-lowering therapy
 Increased dialysis dose
 About the timing of dialysis initiation
 Antioxidant therapy  positive effect
 Beneficial effects in following studies:
 Observational studies:
 World Health Organization’s MONICA (MONitoring trends
and determinants In CArdiovascular disease) Study
 The Nurses Health Study
 The US Physicians study
 Randomized controlled clinical trials: CHAOS
(Cambridge Heart AntiOxidant Study)
 Large trials ??
 HOPE (Heart Outcomes Prevention Evaluation) trial1
 The Heart Protection Study
 PubMed
 Search 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 stress
 3 studies  the effects of antioxidants on CVD end points
 The timing of blood collection for oxidative stress
biochemical measures
 35/53 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
 Substrates with oxidative damage: 20 oxidative stress
biomarkers
 Lipids (44 studies):
 1st: Malondialdehyde (MDA), 27 studies
 2nd: LDL cholesterol, 10 studies
 3rd: isoprostanes, 4 studies; protein carbonyls, 4 studies)
 4th: lipid hydroperoxides, 3 studies
 Proteins (7 studies) and DNA (1 study)
 37/53 studies: a decrease in biomarkers of oxidative
stress following antioxidant therapy (20/37  atocopherol)
 15/53 studies: no effect
 8/53 studies: an increase
 25 studies investigating the effects of a-tocopherol on
oxidative stress in HD patient
 20/25 studies: decrease oxidative stress
 The 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
 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
 3/25 studies: RCT design, 95 patients
 Effects of atorvastatin and vitamin E on lipoproteins
and oxidative stress in dialysis patients: a randomisedcontrolled trial. J Intern Med 2005; 257: 438–445
 a-tocopherol (800 IU/day) + atorvastatin (40 mg/day),
12 weeks
 No effect of a-tocopherol on plasma-oxidized LDL
 Effect of vitamin E therapy on oxidative stress and
erythrocyte osmotic fragility in patients on peritoneal
dialysis and hemodialysis. J Nephrol 2006; 19: 739–745
 800 IU/day, 6 months
 No effect on oxidative protein products
 Serum vitamin E and oxidative protein modification in
hemodialysis: a randomized clinical trial. Am J Kidney
Dis 2007; 50: 305–313
 300 mg/day, 20 weeks
 Decreased erythrocyte osmotic fragility and plasma
MDA
 11 studies, 371 patients, 9 with RCT design
 4/11 studies: decrease oxidative stress
 250 mg 12 weeks, 1g/day 1 year, orally
 300 mg~1 g/day 8 weeks, intravenously
 3/11 studies: increase oxidative stress
 2/3 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.
 1/3 studies: 200mg~1 g/day, 3 months
 The 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 effect
 250mg/day, 4~12 weeks, ineffectual period and dose
 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 design
 All studies: decrease oxidative stress
 1.2, 2, 5 g/day
 One-off dose, 3 weeks
 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 patients
 2/3 studies: decrease biomarkers of oxidative stress
 1/3: no effect
 25ug orally, 400mg intravenously, 8~20 weeks
 r-tocopherol
 Docosahexaenoic acid
 a-lipoic acid
 Coenzyme Q10
 7 studies, 1 with RCT design
 4/7 studies: decrease oxidative stress
 2/7 studies: no effect
 1/7 studies: a decrease in one biomarker, but no change
in another
 6/7 studies with a-tocopherol, 5/6 studies with vitamin
C
 3 trials
 The effect of vitamin C supplementation and
withdrawal on the mortality and morbidity of regular
hemodialysis patients. Clin Nephrol 1989; 31: 31–34
 The 1st clinical outcome trial in HD patients
 Noncontrolled, 61 patients
 500 mg/day of vitamin C, 2 years
 No difference in morbidity or mortality rates
 SPACE (Secondary Prevention with Antioxidants of
Cardiovascular disease in End-stage renal disease) trial
 This most cited one
 Randomized, double-blind, placebo-controlled trial
 97 patients, 800 IU a-tocopherol/day, 500 days
 99 patients, placebo
 54% 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??
 The antioxidant acetylcysteine reduces cardiovascular
events in patients with end-stage renal failure: a
controlled trial. Circulation 2003; 107: 992–995
 64 patients, 1.2 g/day orally, 14 months
 70 patients with placebo
 Reduced rates of CVD events, but no differences in
secondary end points (total mortality and CVD
mortality)
 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.
 Lack of a clinically accepted and validated oxidative
stress biomarker