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

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

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 individualsPlasma levels of vitamin E are decreased

during HD.

decreasing uptake ofdietary 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) patientsInterventions aimed at improving CVD

outcomes in HD patients:Lipid-lowering therapyIncreased dialysis doseAbout the timing of dialysis initiationAntioxidant 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 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

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

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

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)

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

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

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 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

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

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

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

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

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

r-tocopherolDocosahexaenoic acida-lipoic acidCoenzyme Q10

Other antioxidants

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

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

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??

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)

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

FUTURE STUDIES

Thanks for your listening