Oxidative Stress, Renal Anemia, and Its [613856]

Oxidative Stress, Renal Anemia, and Its
Therapies: Is There a Link?
Cristina C /C21apusx/C21a, MD, PhD, and Gabriel Mircescu, MD, PhD
In chronic kidney disease, anemia and oxidative stress are common features and both are involved in increasing
morbidity and mortality. However, their relationship is still a matter of debate. This article is a review of published
data and our experience and is intended to debate the pro and contra arguments concerning renal anemia and its2 main therapeutic approaches, that are, erythropoietin and intravenous iron supplementation, as additional causesof oxidative stress in end-stage renal disease patients. To date, it seems more likely that renal anemia itself is the
main contributor, and intravenous iron further enhances oxidative stress associated with chronic kidney disease.
Future randomized prospective trials, with ‘‘hard’’ clinical end-points, are needed to establish the real effect ofbiochemical pro-oxidative changes on patient’s outcome.
/C2112010 by the National Kidney Foundation, Inc. All rights reserved.
MODERATE to severe chronic kidney dis-
ease (CKD) is frequently associated with
anemia. A strong correlation between the degree
of anemia and the high risk of morbidity and mor-tality from cardiovascular or other causes was re-ported in patients with CKD,
1a fact which
emphasizes the importance of anemia correction.
The understanding of renal anemia pathogenesis
provides the background for an optimal therapeuticapproach. The multifactorial pathogenesis of renalanemia is well known ( Fig. 1). Although erythropoi-
etin deficiency is the main mechanism of impairederythropoiesis, many other factors play importantroles. Among them, absolute or relative iron defi-ciency is the most common cause of a poor responseto erythropoietin therapy.
2,3Chronic inflammation,
malnutrition, and uremic toxins can also suppresserythropoiesis and contribute to the decreased redblood cells survival. Additionally, blood lossesbecause of repetitive sampling and hemodialysis(HD) procedure are involved.
Oxidative stress could also contribute to the
hypoproliferative normochromic normocytic renalanemia by shortening the red blood cell life spanand by impairing erythropoietin action.
4
Current management of renal anemia includes
the following: (1) hemoglobin assessment in all pa-tients with CKD, (2) exclusion of other possiblecauses, such as inflammation, nutritional defi-ciencies, severe hyperparathyroidism, dialysis in-adequacy, hereditary diseases or drug toxicities,
and evaluation of iron metabolism, (3) iron ther-
apy according to serum ferritin and transferrinsaturation, and (4) administration of erythropoie-tin, if iron deficiency is corrected and no othercause is identified.
2,3
Currently, the widely accepted evidence-based
renal anemia therapies are erythropoiesis-stimulating agents and intravenous (IV) iron. Other
adjuvants (folic acid, vitamin B12, L-carnitine)
have been proposed, but the lackof well-controlledstudies and the inconsistency of therapeutic trialshave till date not allowed their rational placementin the renal anemia therapeutic algorithm.
2,3
Recombinant human erythropoietin has been
shown to interfere with free radicals productionand antioxidant systems; but it is not yet clear
whether it can favor or reduce oxidative stress.
4
Moreover, IV iron was associated with both reactive
species generation and antioxidants impairment.5
Hypothetically, oxidative stress in HD patients
can result from uremia, comorbid conditions, aswell as from dialysis-related factors or additionaltherapies. However, uremia-related factors seemto be the most important contributors,
6both by
enhancing reactive species production throughchronic inflammation and uremic toxinsDepartment of Nephrology, ‘ ‘Dr. Carol Davila’’ Teaching Hospi-
tal of Nephrology, ‘ ‘Carol Davila’’ University of Medicine and
Pharmacy, Bucharest, Romania.
The authors have no known conflicts of interest.
Address reprint requests to Cristina C /C21apusx/C21a, ‘ ‘Dr. Carol Davila’’
Teaching Hospital of Nephrology, 4 Calea Grivit xei, sector 1,
010731 Bucharest, Romania. E-mail: ccalexandr@yahoo.com
(C. C /C21apusx/C21a.) or gmircescu@hotmail.com (G. Mircescu.)
/C2112010 by the National Kidney Foundation, Inc. All rights
reserved.
1051-2276/$36.00doi:10.1053/j.jrn.2010.06.005
Journal of Renal Nutrition, V ol 20, No 5S (September), 2010: pp S71–S76 S71

retention, and by impairment of the antioxidant
systems, because of reduced thiols pool, partially
accounted for by malnutrition, or decreased renalsynthesis of glutathione peroxidase. Dialysis alsocould enhance oxidative stress because of bioin-compatibility and antioxidant losses. Finally, adju-vant therapies including renal anemia therapycould be involved.
Accumulating evidence supports oxidative
stress, along with inflammation and malnutritionas predictors of outcome in patients with CKD,possibly linked to an immune connection. Al-though oxidative stress was proposed as anotheraccomplice to uremic toxicity, the precise contri-bution of each factor is still not defined.
7Oxida-
tive stress and inflammation could increase therisk of morbidity and mortality by promoting
endothelial dysfunction, hypertension, atheroscle-
rosis, and various other disorders. They could alsocause erythropoietin-resistant anemia by: (1)erythrocyte membrane phospholipids oxidationand depletion in redox capacity, with subsequenterythrocyte life span shortening; (2) increase inliver production of hepcidin which blocks bothintestinal absorption and mobilization of iron;
(3) reduction in transferrin levels with diminished
iron availability; and (4) resistance to erythropoie-tin actions.
8
The relationship between renal anemia and ox-
idative stress is quite complex ( Fig. 2 ). As noted
previously, oxidative stress could decrease redblood cells survival by membrane lipids peroxida-tion. In contrast, anemia itself could enhance tissue
reactive oxygen species generation by favoring an-
aerobic metabolism and could induce antioxidantdeficiency because of the diminished erythrocytepool resulting in a lower reduced glutathioneand antioxidant enzymes store. Routinely usedanemia therapies could influence the oxidativestatus in patients with CKD as well. On the basisof these considerations, we will try to review stud-ies concerning renal anemia itself, erythropoietintherapy, and IV iron administration as causes ofoxidative stress in CKD.
Is Renal Anemia Itself a Cause of
Oxidative Stress?
Observational studies suggested that higher
plasma lipid peroxidation might be related to theseverity of anemia. For instance, in a small studyon 14 nondiabetic, nonsmoking HD patients,a negative correlation between 4-hydroxynone-nal, a marker of lipid peroxidation, and serum he-moglobin was found.
9Similarly, in another group
of 107 consecutive HD patients, the lower the
hemoglobin, the higher were serum levels of 4-
hydroxynonenal, malondialdehyde, and proteincarbonyls. Conversely, the serum levels of aldehy-dic lipid peroxidation products were reduced afterlong-term appropriate correction of renal anemiaby epoetin.
10Moreover, Sommerburg et al. found
increased levels of 4-hydroxynonenal in HD pa-tients with hemoglobin below 10 g/dL as com-
pared with those with greater hemoglobin,
irrespective of erythropoietin administration, andconcluded that renal anemia itself is a cause ofaugmented oxidative stress.
11
Enhancement of oxidative stress was also dem-
onstrated in an experimental model of iron-deficient anemia.
12Feeding an iron-deficient
diet to mice for 5 to 9 weeks resulted in a moderate
to severe anemia and in an increased red cells oxi-
dative stress, as reflected by augmented autoxida-tion of partially oxygenated hemoglobin,producing methemoglobin and superoxide. Theoxidative stress started on the membrane,where it can both damage the red cell and release
Figure 2. The potential links between renal anemia
and oxidative stress.
Figure 1. The multifactorial pathogenesis of renal
anemia.C/C21APUS x/C21A AND MIRCESCU S72

reactive oxygen species to the vasculature and ad-
jacent tissues, contributing to anemia-associatedcomorbidities.
12
The precise mechanisms of exacerbated oxida-
tive stress in anemic patients are not fully under-stood, but a role of hypoxia and disturbances incatecholamine metabolism as pro-oxidative fac-
tors, as well as decreased availability of antioxidants
in states with low red blood cells pool were pro-posed.
13Under hypoxic conditions, increased
free radical production could occur because ofshifts in cellular metabolism, higher catecholaminemetabolism rates, and persistent leukocyte activa-tion, not counterbalanced by the anemia-weakened antioxidant system.
14
Erythropoietin Therapy: Induces or
Ameliorates Oxidative Stress?
In vitro and in vivo studies on relationship be-
tween erythropoietin administration and oxidativestress provided conflicting evidence. In a study on
endothelial cells in culture, addition of epoietin
beta and darbepoietin alpha in concentrations cor-responding to therapeutic plasma levels in patientswith CKD increased the endothelial production ofasymmetric dimethylarginine by impairing itsdegradation enzyme activity in a dose-dependentmanner. Furthermore, epoietin-induced accumu-lation of asymmetric dimethylarginine was ac-
companied by a significant reduction of nitric
oxide synthesis and an increase in oxidativestress.
15Moreover, a crossover study on a small
number of HD patients concluded that IVepoietinand iron in doses commonly used to treat anemiaacutely generate significant but transient oxidativestress, which is blunted by pre-therapy withmelatonin.
16
In contrast, epoietin therapy could exert antiox-
idative effects.17,18In a hemoglobin-independent
manner (direct action), epoietin could reduce in-tracellular oxidative stress by inducing hemeoxygenase-1 and some antioxidant enzymes,such as superoxide dismutase, catalase, and gluta-thione peroxidase.
17Further strengthening of the
antioxidative defense systems could indirectly re-
sult from the increased number of circulating
young red blood cells, which are highly effectivefree radical scavengers, and from depletion ofiron stores.
17,18
Supporting these observations, an association of
epoietin beta with anemia correction, decreasedlevels of oxidized-low-density lipoprotein anti-bodies, and increased serum paraoxonase-1 activitywas reported in predialysis patients. Interestingly,inhibition of lipoprotein oxidation was observeddespite concomitant iron treatment.
19
Similarly, a recent randomized controlled study
on 30 anemic patients with chronic heart failure
and serum creatinine ,2.5 mg/dL reported a de-
crease in serum malondialdehyde and protein car-
bonyls, along with an increase in antioxidativeglutathione after darbepoetin alpha treatment ascompared with placebo-treated patients.
20
However, in our personal experience, epoietin
administration had no influence on HD patientspro-oxidant state.
21Stable nondiabetic HD pa-
tients, treated for at least 2 months with a steadydose of epoietinum (n 514; mean dose 597.7
619.1 U/kg/week) or not (n 515), none of
them on iron therapy, and 13 matched healthycontrols were investigated. An increase in markersof reactive species generation was found in HDgroups as compared with controls, irrespective ofepoietin therapy. Plasma and erythrocyte antioxi-
dant parameters were not different between the
2 HD groups. Hence, we concluded that erythro-poietin did not influence the oxidative stress ofHD patients in respect to both, reactive speciesgeneration and antioxidant systems, at least inthe absence of iron supplementation and atsimilar hemoglobin levels. Our data seem to high-light the essential contribution of renal anemia it-
self and, possibly, of iron therapy as pro-oxidative
factors.
21
IV Iron: Pro-oxidative Effects?
More unambiguous results regarding the rela-
tionship between IV iron and oxidative stress
have been reported ( Table 1 ). Experimental in
vitro and in vivo studies suggested that parenteral
iron administration has highly potent pro-oxidative, cytotoxic, and proinflammatory effects.Increased malondialdehyde was found in renalcortical homogenates exposed to iron, in a dose-dependent manner.
28Accordingly, clinical trials
to test this hypothesis were conducted.
Indeed, in a randomized, open, parallel group
trial on 20 iron-deficient patients with stage 3 to4 CKD, a rapid increase in lipid peroxidation(plasma concentration and urinary excretion rateof malondialdehyde) was found within 15 to 30minutes after a single dose of iron sucrose. TheOXIDATIVE STRESS, RENAL ANEMIA, AND ITS THERAPIES S73

Table 1. Summary of Clinical Trials Investigating the Contribution of Renal Anemia or its Therapy to the Oxidative Stress
Study, Year (Reference) Study Design ResultsCause of
Oxidative
Stress?
Anemia itself could enhance oxidative stress
Sommerburg et al., 199811Observational, cross-sectional Yes
8 HD, Hb ,10 g/dL; 8 HD, Hb .10 g/dL;
27 HD1rHuEpo, Hb .10 g/dL; 20 C[LPO products in Hb ,10 g/dL group versus Hb .10 g/dL groups
LPO products were inversely correlated with Hb
Siems et al., 200510Observational, cross-sectional/prospective Yes
107 HD;
76 HD1rHuEpo, 12-24mo.LPO products were inverse correlated with HbYLPO products after correction of anemia with rHuEpo
Wiswedel et al., 2008
9Observational, cross-sectional Yes
14 HD, Hb ,11 g/dL HNE was inversely correlated with Hb
Erythropoietin therapy could enhance oxidative stress
Herrera et al., 200116Cross-over, prospective Yes
9H D [MDA, YGSH and CAT after a single dose of rHuEpo
Mircescu et al., 200521Observational, cross-sectional No
14 HD1rHuEpo; 15 HD; 13 C MDA and antioxidant parameters were similar in both HD groups
Marsillach et al., 200719Observational, prospective No
49 CKD, Hb ,11 g/dL 1rHuEpo, 6mo. [Hb,Yox-LDL and [PON activity after treatment
Parissis et al., 200920Randomized 1:1, controlled No
30 CKD, CHF 1Darb or placebo, 3mo. YMDA, [GSH only in Darb-treated patients
Intravenous iron could enhance oxidative stress
Herrera et al., 200116Cross-over, prospective Yes
9H D [MDA, YGSH and CAT after a single dose of IV iron saccharate
Tovbin et al., 200222Observational Yes
19 HD [AOPP after a single dose of IV iron saccharate
Michelis et al., 200323Observational, prospective Yes
17 HD Intradialytic [in carbonylated fibrinogen after 125 mg IV iron
gluconate
Agarwal et al., 20045Randomized, open Yes
20 CKD 1IV iron1NAC or placebo Transient [in MDA at 15-30 minutes after IV iron dose
Scheiber-Mojdehkar et al., 200424Observational No
27 HD1100 mg IV iron; 8 HD Intradialytic [in plasma peroxides irrespective of IV iron
C/C21apus x/C21a et al., 200925Observational, prospective Yes
20 HD1100 mg IV iron Intradialytic [in plasma MDA and ox-LDL after IV iron dose
Guz et al., 200626Cross-over, prospective No
10 HD130-100 mg IV iron and placebo No changes in ROS generation (chemiluminescence)
C/C21apus x/C21a et al., 200627Observational, prospective Yes
20 HD1100 mg IV iron Yerythrocyte GSH and TEAC after IV iron dose
HD, hemodialysis; Hb, serum hemoglobin; rHuEpo, recombinant human erythropoietin; C, controls; LPO, lipid peroxidation products; HNE, 4-hydroxy nonenal; mo, months;
MDA, malondialdehyde; GSH, reduced glutathione; CAT, erythrocyte catalase activity; IV, intravenous; CKD, chronic kidney disease; ox-LDL, oxidi zed LDL; PON, serum para-
oxonase; CHF, chronic heart failure; Darb, darbepoietin alpha; AOPP, advanced oxidation protein products; NAC, N-acetylcysteine; ROS, reactive o xygen species; TEAC, total
antioxidant capacity of erythrocytes; [, increased; Y, decreased.C/C21APUS x/C21A AND MIRCESCU S74

oxidative stress completely resolved in 24 hours
and was blunted by N-acetylcysteine. Enzymuria
and proteinuria, markers of tubular damage, si-multaneously increased, but were not influencedby antioxidant co-administration. These data sug-gest the induction of oxidative stress and transientrenal injury in response to IV iron, possibly free
iron-independent, since they occurred before
transferrin was completely saturated.
5
In another study comparing IV iron administra-
tion during HD with placebo in iron-depleted pa-tients, 37% higher levels of advanced oxidationprotein products were reported shortly after ironinfusion. The oxidative response was dependenton inflammation, as was positively correlated to
predialysis C-reactive protein and tumor necrosis
factor- alevels.
22In HD patients, a dose-
dependent increase of carbonylated fibrinogenwas also acutely induced by IV iron, furthermoresustaining the acute enhancement of proteinoxidation.
23
The intradialytic changes in some oxidative and
carbonyl stress markers were assessed in an obser-
vational, prospective study performed by our
team on 20 nondiabetic, nonsmoker, HD patientstreated with stable doses of erythropoietin but noiron in the last month. We found that a commondose of IV iron sucrose seems to further enhancethe oxidative stress as sustained by the increase inplasma lipid peroxidation markers shortly afteriron infusion, but without significant influence
on the carbonyl stress during HD session.
25More-
over, IV iron acutely aggravated the impaired non-
enzymatic erythrocyte antioxidant defense, assustained by the consumption of reduced glutathi-one and the increase in total thiols (includes oxi-dized glutathione) and a greater decrease of totalantioxidant capacity of erythrocytes.
27Erythro-
cytes enzymes antioxidant defense27and plasma
antioxidant systems, assessed by intradialytic varia-tions of total plasma free thiols and total antioxi-dant capacity, did not change after iron infusion.
29
Because no clear causal link between IV iron
and clinical outcome was demonstrated to date,the clinical significance of these biochemical dis-orders is not yet clear, although there is some sup-port for the involvement of iron in the
pathogenesis of cardiovascular disease.
In fact, opposite results were described. An ob-
servational study on 27 HD patients treated with
100 mg IV iron sucrose administered during HDsession and 8 HD untreated controls reportedhigher total peroxide concentration in bothgroups, regardless of whether they received iron.The authors concluded that the observed increasein peroxide generation is more likely to result fromother HD-related sources of oxidative stress.
24In
another study with a crossover design, the genera-tion of reactive oxygen species assessed by chemi-
luminescence did not significantly change after IV
administration of 30 and 100 mg iron sucrose dur-ing HD as compared with placebo, suggestinga neutral effect of parenteral iron toward leuko-cytes activation and oxidative stress.
26
Despite such controversies, the great bulk of ex-
perimental and clinical data support the iron con-tribution to the generation of oxidized LDL,
endothelial cell dysfunction, arterial smooth mus-
cle proliferation, and ischemia-reperfusion in-jury.
30However, until hard evidence to sustain
causal relationship between IV iron and worseningof clinical outcome will arise, the benefits of cau-tious, correctly administered iron therapy seem toprevail in the renal anemia management.
Conclusion
Renal anemia itself acts as a contributor factor
to CKD-associated oxidative stress, whereas
adjuvant therapies, especially IV iron, appear to
enhance it. However, the actual clinical signifi-cance should be proven by future randomized pro-spective studies designed to establish causalitybefore recommending any changes in the currenttherapeutic guidelines.
References
1. Locatelli F , Pisoni RL, Combe C, et al: Anaemia in haemo-
dialysis patients of five European countries: association with
morbidity and mortality in the Dialysis Outcomes and PracticePatterns Study (DOPPS). Nephrol Dial Transplant 19:121-132,2004
2. Locatelli F , Aljama P , Barany P , et al: European Best Practice
Guidelines Working Group: revised European best practice guide-lines for the management of anaemia in patients with chronic renalfailure. Nephrol Dial Transplant 19(Suppl 2):ii1-ii47, 2004
3. K/DOQI clinical practice guidelines and clinical practice
recommendations for anemia in chronic kidney disease in adults.Am J Kidney Dis 47(Suppl 3):S11-S145, 2006
4. Usberti M, Gerardi G, Bufano G, et al: Effects of erythropoi-
etin and vitamin E-modified membrane on plasma oxidative stressmarkers and anemia of hemodialyzed patients. Am J Kidney Dis40:590-599, 2002
5. Agarwal R, V asavada N, Sachs NG, et al: Oxidative stress and
renal injury with intravenous iron in patients with chronic kidneydisease. Kidney Int 65:2279-2289, 2004OXIDATIVE STRESS, RENAL ANEMIA, AND ITS THERAPIES S75

6. Ward RA, McLeish KR: Oxidant stress in hemodialysis
patients: what are the determining factors? Artif Organs 27:
230-236, 2003
7. Mircescu G: Oxidative stress—an accomplice to uremic
toxicity? J Ren Nutr 16:194-198, 2006
8. Vaziri ND, Zhou XJ: Potential mechanisms of adverse out-
comes in trials of anemia correction with erythropoietin inchronic kidney disease. Nephrol Dial Transplant 24:1082-1088,2009
9. Wiswedel I, Peter D, Gardemann A, et al: Serum concentra-
tions of F2-isoprostanes and 4-hydroxynonenal in hemodialysispatients in relation to inflammation and renal anemia. BiomarkInsights 3:419-428, 2008
10. Siems W , Carluccio F , Radenkovic S, et al: Oxidative stress
in renal anemia of hemodialysis patients is mitigated by epoetintreatment. Kidney Blood Press Res 28:295-301, 2005
11. Sommerburg O, Grune T, Hampl H, et al: Does long-term
treatment of renal anemia with recombinant erythropoietin influ-ence oxidative stress in hemodialyzed patients? Nephrol DialTransplant 13:2583-2587, 1998
12. Nagababu E, Gulyani S, Earley CJ, et al: Iron-deficiency
anemia enhances red blood cell oxidative stress. Free Radic Res42:824-829, 2008
13. Stenvinkel P , Barany P: Anemia, rHu EPO resistance, and
cardiovascular disease in end-stage renal failure: links to inflamma-
tion and oxidative stress. Nephrol Dial Transplant 17(Suppl 5):
32-37, 2002
14. Grune T, Sommerburg O, Siems WG: Oxidative stress in
anemia. Clin Nephrol 53(Suppl 1):S18-S22, 2000
15. Scalera F , Kielstein JT , Martens-Lobenhoffer J, et al: Eryth-
ropoietin increases asymmetric dimethylarginine in endothelialcells: role of dimethylarginine dimethylaminohydrolase. J Am
Soc Nephrol 16:892-898, 2005
16. Herrera J, Nava M, Biol L, et al: Melatonin prevents oxida-
tive stress resulting from iron and erythropoietin administration.
Am J Kidney Dis 37:750-757, 2001
17. Katavetin P , Tungsanga K, Eiam-Ong S, et al: Antioxidative
effects of erythropoietin. Kidney Int 72(Suppl 107):S10-S15,2007
18. Jie KE, V erhaar MC, Cramer MJ, et al: Erythropoietin and
the cardiorenal syndrome: cellular mechanisms on the cardiorenalconnectors. Am J Physiol Renal Physiol 291:932-944, 2006
19. Marsillach J, Martinez-Vea A, Marcas L, et al: Administra-
tion of exogenous erythropoietin baffects lipid peroxidation andserum paraoxonase-1 activity and concentration in predialysis
patients with chronic renal disease and anaemia. Clin Exp Phar-
macol Physiol 34:347-349, 2007
20. Parissis JT , Kourea K, Andreadou I, et al: Effects of darbe-
poetin alfa on plasma mediators of oxidative and nitrosative stress
in anemic patients with chronic heart failure secondary to ische-
mic or idiopathic dilated cardiomyopathy. Am J Cardiol 103:1134-1138, 2009
21. Mircescu G, C /C21apusx/C21a C, Stoian I, et al: The influence of
epoietinum therapy on the oxidative stress in haemodialysispatients. Nephron Clin Pract 100:126-132, 2005
22. T ovbin D, Mazor D, Vorobiov M, et al: Induction of pro-
tein oxidation by intravenous iron in hemodialysis patients: role
of inflammation. Am J Kidney Dis 40:1005-1012, 2002
23. Michelis R, Gery R, Sela S, et al: Carbonyl stress induced
by intravenous iron during haemodialysis. Nephrol Dial Trans-
plant 18:924-930, 2003
24. Scheiber-Mojdehkar B, Lutzky B, Schaufler R, et al: Non–
transferrin-bound iron in the serum of hemodialysis patients whoreceive ferric saccharate: No correlation to peroxide generation.J Am Soc Nephrol 15:1648-1655, 2004
25. C /C21apusx/C21a C, Stoian I, Martinescu R, et al: Does intravenous
iron acutely enhance the oxidative and carbonyl stress in hemodi-alysis patients? Sa-662, 2009 (abstr). doi: 10.3252/pso.eu.WCN
2009
26. Guz G, Glorieux GL, De Smet R, et al: Impact of iron su-
crose therapy on leucocyte surface molecules and reactive oxygenspecies in haemodialysis patients. Nephrol Dial Transplant 21:
2834-2840, 2006
27. C /C21apusx/C21a C, Stoian I, Barbulescu C, et al: Does intravenous
iron administration acutely influence the erythrocyte antioxidant
status in hemodialysis patients? Nephrol Dial Transplant 21(Suppl
4):iv202 (abstr), 2006
28. Zager RA: Parenteral iron compounds: potent oxidants but
mainstays of anemia management in chronic renal disease. Clin J
Am Soc Nephrol 1(Suppl 1):S24-S31, 2006
29. Mircescu G, C /C21apusx/C21a C, Stoian I, et al: The acute effects of
intravenous iron on extracellular oxidative stress parameters in
hemodialysis patients. Nephrol Dial Transplant 22(Suppl 6):
vi349 (abstr), 2007
30. Shah SV , Alam MG: Role of iron in atherosclerosis. Kidney
Int 41(Suppl 1):S80-S83, 2003C/C21APUS x/C21A AND MIRCESCU S76