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): 1 st : Malondialdehyde (MDA), 27 studies 2 nd : LDL cholesterol, 10 studies 3 rd : isoprostanes, 4 studies; protein carbonyls, 4 studies) 4 th : 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 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 randomised- controlled 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– 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– 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 1 st 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– 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