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(Circulation. 2002;106:2212.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Iron Therapy, Advanced Oxidation Protein Products, and Carotid Artery Intima-Media Thickness in End-Stage Renal Disease

Tilman Drüeke, MD; Véronique Witko-Sarsat, PhD; Ziad Massy, MD; Béatrice Descamps-Latscha, MD, PhD; Alain P. Guerin, MD; Sylvain J. Marchais, MD; Valérie Gausson, MS; Gérard M. London, MD

From INSERM U507 and Service de Néphrologie, Hôpital Necker, Paris (T.D., V.W.-S., Z.M., B.D.-L., V.G.), and Service d’Hémodialyse, Hôpital F.H. Manhès, Fleury-Mérogis (A.P.G., S.J.M., G.L.), France.

Correspondence to Dr Gérard M. London, Hôpital F.H. Manhès, 8 Grande Rue, Fleury-Mérogis, 91712 Cedex, France. E-mail glondon{at}club-internet.fr

	Abstract

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Background— Increased common carotid artery intima-media thickness (CCA-IMT) is a marker of early atherosclerosis. Low-grade inflammation is associated with the pathogenesis of atherosclerosis. Low-grade inflammation and increased CCA-IMT are observed in end-stage renal disease (ESRD). Oxidative stress is involved in uremia-related inflammation. Advanced oxidation protein products (AOPP) are markers of oxidant-mediated protein damage in ESRD. Intravenous iron given to patients on hemodialysis (HD) might induce oxidative stress. We investigated the relationships between AOPP, iron therapy, and CCA-IMT in stable HD patients.

Methods and Results— Plasma AOPP and blood chemistry, including iron status, were analyzed in a cohort of 79 ESRD patients on HD. Measurements of CCA-IMT and CCA diameter, as assessed by B-mode ultrasonography, were obtained in 60 patients. AOPP levels were elevated in ESRD patients, and in univariate (r=0.42, P<0.0001) and multivariate analyses (r=0.38, P<0.001), they correlated with serum ferritin and with the intravenous iron dose received during the 12 months preceding the study (ferritin, P<0001; AOPP, P<0.01). Univariate and multivariate analyses identified the AOPP concentration as being significantly associated with CCA-IMT (P=0.0197) and CCA wall-to-lumen ratio (r=0.560, P<0.0001). Independently of AOPP concentration, cumulative iron dose was positively related to CCA-IMT (P=0.015) in patients <60 years.

Conclusion— In ESRD patients, CCA-IMT and CCA wall-to-lumen ratio were associated with plasma AOPP, serum ferritin, and the annual intravenous iron dose administered. These findings support the concept of a role of oxidative stress in the early atherosclerosis of ESRD patients, which may be increased by the usually recommended doses of intravenous iron.

Key Words: renal dialysis • oxidative stress • atherosclerosis • iron

	Introduction

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Increased common carotid artery (CCA) intima-media thickness (IMT) is considered an early phase of atherosclerosis^1,2 and has been associated with cardiovascular risk and risk of coronary artery disease events.^3,4 Although B-mode ultrasonography cannot distinguish between medial and intimal hypertrophy, IMT assessment is considered a reliable surrogate measurement of intimal thickening.⁵ In addition to atherosclerosis, intima-media thickening also occurs in hypertension,⁶ aging,⁷ diabetes,⁸ hyperlipidemia,⁹ or with changes of shear stress.¹⁰ Damage of large arteries, characterized by increased IMT and arteriosclerosis, is a contributing factor to mortality in patients with end-stage renal disease (ESRD).^11,12 ESRD is associated with an inflammatory syndrome, ¹³ and low-grade inflammation plays a role in the pathogenesis of arterial alterations.¹⁴ Among the mechanisms involved, long-standing oxidative stress enhances the inflammatory state and is atherogenic.^15,16 We previously described the presence of advanced oxidation protein products (AOPP) in patients with ESRD as a reliable marker of the oxidant-mediated protein damage in uremic patients. AOPP also behaved as mediators of inflammation.^15,16 The aims of the present study, which was conducted on stable patients on hemodialysis (HD), were (1) to identify a possible relationship between the plasma AOPP and CCA geometry and (2) to investigate the effect of intravenous iron given repeatedly to HD patients on plasma AOPP and CCA geometry.

	Methods

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Patients
Seventy-nine patients aged 56±16 years who had been on HD for at least 12 months (76.5±75.5 months; range, 12–318 months) were included; 57% were male, 13% had insulin-dependent diabetes mellitus, and 46% were treated with antihypertensive drugs. Patients with acute or chronic infectious or systemic disease, active liver disease, acute myocardial infarction, cerebrovascular disease, congestive heart failure (NYHA stage III-IV), and/or peripheral artery disease (Leriche stage III-IV) were excluded. Patients were dialyzed with synthetic high-flux membranes (AN69 or polysulfone) matched for subject’s body surface area (1.40 to 2.10 m²), bicarbonate dialysate, and controlled ultrafiltration rate. The duration of HD sessions was 4 to 6 hours thrice weekly to achieve a dialysis dose (Kt/V) >1.2 (mean, 1.41±0.19). Patients were receiving recombinant erythropoietin to maintain predialysis hemoglobin at 10 to 11 g/dL. Intravenous iron hydroxide sucrose was prescribed when the transferrin saturation was <20%. The dose was 50 to 100 mg weekly to achieve a serum transferrin saturation between 30% to 40%. The iron therapy was temporarily interrupted when the ferritin levels were >700 pg/mL. The iron dose received by each patient during the 12-month period preceding the investigation was collected from computer records. Each subject gave informed, written consent to participate in the study, which was approved by our institutional review board.

Laboratory Analyses
Predialysis blood chemistries included serum creatinine, urea, calcium, phosphorus, bicarbonate, hemoglobin, albumin, lipids, fibrinogen, high-sensitive C-reactive protein, parathyroid hormone, iron, and ferritin. Plasma AOPP were measured using the semiautomated method devised in our laboratory.^15,16 Briefly, AOPP were measured spectrophotometrically with a microplate reader (MR 5000, Dynatech) and then calibrated with chloramine-T (Sigma Chemical Co) solutions that, in the presence of potassium iodide, absorb at 340 nm. In 96-well microtiter plates (Becton Dickinson) test wells loaded with 200 µL of plasma diluted 1:5, phosphate-buffered saline and 20 µL of acetic acid were added. Internal standard wells contained 10 µL of 1.16 mol/L potassium iodide, to which were added 200 µL of chloramine-T solution (0 to 100 µmol/L) followed by 20 µL of acetic acid. Because chloramine-T absorbance at 340 nm is linear within the range of 0 to 100 µmol/L, AOPP concentrations are expressed in µmol/L of chloramine-T equivalents.

CCA Geometry and Pressure
The CCA pressure waveform was recorded noninvasively with a high-fidelity Millar strain gauge transducer (SPT-301, Millar Instruments) and calibrated assuming that brachial and CCA diastolic and mean blood pressures were equal. A detailed description of this system has been published previously.¹¹ Brachial blood pressure was measured after 15 minutes of recumbency with a mercury sphygmomanometer with a cuff adapted to arm circumference. Investigations were performed in the morning before the midweek HD session.

CCA characteristics were measured by high-resolution B-mode ultrasonography (Scanner 350, PIE Medical) with a 7.5-MHz transducer by an experienced echographist who was unaware of the patient’s status and exposure. Measurements of CCA diameter and CCA-IMT were always performed opposite to the side of atrioventricular shunts 2 cm beneath the bifurcation. Measurements of CCA-IMT were done on the far wall at the same level as the diameter measurements. A localized echostructure encroaching into the vessel lumen was considered plaque if the CCA-IMT was >50% thicker than neighboring sites. CCA diameter and CCA-IMT were always measured in plaque-free arterial segments. The CCA wall-to-lumen ratio was calculated as 2IMT/CCA diameter. The measurements of CCA parameters are observer-independent; we used computer-assisted acquisition, processing, and storage with specific software for edge detection (wall-track for CCA diameter¹¹ and Eurequa for CCA-IMT).^2,11 A detailed description of these systems has been published previously.^2,11 The left ventricular outflow velocity integral (LVOVI), which was shown to be associated with changes of CCA diameter,¹¹ was measured using a Hewlett-Packard Sonos 100 equipped with a 2.25-MHz probe.

Statistics
Data are expressed as mean±SD. Univariate and multivariate regression analyses were conducted using the least-squares method. Sex (0, male; 1, female), diabetes (0, no; 1, yes), use of antihypertensive drugs (0, no; 1, yes) were used as the dummy variables. Statistical analyses were performed using NCSS 6.0. software (J.L. Hintze).

	Results

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Demographic, clinical, and CCA characteristics and blood chemistry data are reported in Table 1. Table 2 summarizes the univariate associations found for AOPP with blood chemistries and intravenous iron dose. Multivariate regression analyses (Table 3) found AOPP was significantly associated with serum ferritin (partial r²=0.147, P=0.0009; Figure 1A), HDL cholesterol (r²=0.07, P=0.0247), and LDL cholesterol (P=0.045). Serum ferritin was significantly correlated with the dose of elemental iron received during the preceding 12-month period (r=0.600, P<0.0001; Figure 1B), but it was not correlated with C-reactive protein (P=0.213). Multivariate analysis of risk factors associated with CCA geometry are reported in Table 3. CCA diameter was positively associated with age, body height, mean blood pressure, and LVOVI, whereas an inverse relationship was observed with AOPP. CCA-IMT increased significantly with age, CCA pulse pressure, CCA diameter, AOPP levels, ferritin, and LDL cholesterol and tended to be lower in women. These parameters accounted for 76% of the CCA-IMT variance, with age alone representing 33.8% of the variance. The opposite associations of AOPP with CCA diameter and IMT resulted in a significant correlation between AOPP and the CCA wall-to-lumen ratio (r=0.560, P<0.0001; Figure 1C).

View this table: [in this window] [in a new window]   TABLE 1. Demographic and Clinical Characteristics and CCA Geometry and Blood Chemistry Values for 79 Patients on HD

View this table: [in this window] [in a new window]   TABLE 2. Univariate Analysis of Risk Factors Associated With AOPP

View this table: [in this window] [in a new window]   TABLE 3. Multivariate Analysis of Factors Associated With AOPP, CCA-IMT, or CCA Diameter in the Overall Population

View larger version (17K): [in this window] [in a new window]   Figure 1. Correlations between AOPP and serum ferritin (A), serum ferritin and annual intravenous iron dose (B), and CCA wall-to-lumen ratio and AOPP (C) in patients with ESRD.

Because age was the major factor associated with CCA-IMT, a multivariate analysis was done in 41 patients aged <60 years (mean, 41.9±11.1 years; range, 13 to 59 years). In this group, the CCA-IMT was positively associated with AOPP, iron dose, male sex, CCA diameter, and triglycerides (Table 4). These parameters accounted for 76.6% of the variance, with AOPP levels accounting for 24.4% of the variance. Moreover, in this younger group, the CCA-IMT was directly associated with yearly iron dose (Table 4 and Figure 2).

View this table: [in this window] [in a new window]   TABLE 4. Multivariate Analysis of Factors Associated With CCA-IMT in Patients <60 Years

View larger version (15K): [in this window] [in a new window]   Figure 2. Correlation between iron dose and CCA-IMT in patients younger than 60 years.

	Discussion

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CCA-IMT has gained acceptance as a marker of the atherosclerotic process. The finding that increased IMT and carotid wall-to-lumen ratio were significantly associated with circulating AOPP is consistent with the hypothesis linking oxidative stress to the atherosclerotic disease in ESRD patients. The relationships observed in the overall population between plasma AOPP and serum ferritin and between ferritin and the annual intravenous iron dose are compatible with the view that parenterally administered iron may contribute to the oxidative stress observed in such patients, and it might play a role in arterial remodeling.

CCA-IMT is considered an early marker of the atherosclerotic process and is currently used to assess the presence and the progression of atherosclerosis.^1,2 Epidemiological studies showed that increased CCA-IMT was correlated with known cardiovascular risk factors and was associated with increased prevalence and incidence of cardiovascular disease.^3,4 Confirming data in the literature, we found that the CCA-IMT increased with age,⁷ male sex,⁷ pulse pressure,¹⁷ CCA diameter,¹¹ LDL cholesterol¹⁸ and serum ferritin.¹⁹ As in our previous study,¹¹ CCA-IMT was positively correlated with the CCA diameter. This was not unexpected, because wall stress is one of the mechanisms regulating the trophic response of arterial IMT and, for any given arterial blood pressure, wall stress increases with diameter.¹⁰ In accordance with previous reports on ESRD patients, the CCA diameter increased with age, distending blood pressure, body height, and LVOVI¹¹ but was inversely correlated with AOPP concentration.

Artery diameters dilate in response to increased blood flow, and the positive relationship between LVOVI and CCA diameter in ESRD results from the chronically increased blood flow due to anemia, arteriovenous shunts, and overhydration. The negative association between AOPP and CCA diameter contrasted with the direct correlation between AOPP and IMT (resulting in the positive correlation between AOPP levels and the CCA wall-to-lumen ratio; Figure 1C). The positive correlation between LVOVI and CCA diameter reflects the chronic flow-dilation mechanism, whose efficiency could be limited in the presence of high AOPP levels. Flow-mediated arterial remodeling is endothelial cell–dependent, and oxidative stress is associated with impaired endothelium-derived NO activity.²⁰ This impairment may be an early mechanism in the development of atherosclerosis. Plasma AOPP are independently associated with alterations in CCA geometry, suggesting that oxidative stress might play a role in the pathogenesis of deleterious arterial alterations in ESRD patients.

CCA-IMT is associated with aging and, in a cross-sectional analysis, the prominent effect of age (Table 3) could minimize the influence of other factors, including oxidative stress. This is supported by the results observed in younger patients (Table 4). In this group, the association between AOPP and the CCA-IMT is stronger, and AOPP accounted for 24.4% of the variance of the CCA-IMT (Table 4). Conditions favoring the generation of oxidative stress are present in patients on HD who may be exposed to the recurrent generation of oxidants and may have defective antioxidant systems. The origin of the oxidative stress is multifactorial. It is, in part, due to the production of reactive oxygen species caused by the HD procedure, as well as by other factors involved in chronic inflammation. The pathophysiological relevance of plasma AOPP has already been documented in the context of chronic uremia^15,16,21 and coronary artery disease in nonuremic subjects.²² Moreover, we demonstrated that the higher AOPP levels resulted from phagocyte activation. Thus, AOPP seem to be a marker of protein oxidation resulting from sustained, inflammatory, cell-associated processes,²³ suggesting that the mechanisms involved in the increase of CCA-IMT might involve phagocyte-induced inflammation.

In the present study, we found a significant relationship between ferritin, AOPP, and the cumulative annual dose of intravenous iron given to treat a patient’s anemia. Moreover, in younger subjects, a direct and independent relationship was observed between intravenous iron and the CCA-IMT (Figure 2). These relationships were independent of C-reactive protein levels and other risk factors. To replace iron losses and to maintain adequate iron stores in patients receiving recombinant erythropoietin therapy, an average of 1.5 to 2 g of supplemental iron per year is required.²⁴ The average amount of iron given to the patients in the present study was within this recommended range, with the weekly dose ranging from 50 to 100 mg when necessary. Nevertheless, even at the recommended dose and infusion duration, this iron supplementation leads to generation of redox-active iron, which is a potent pro-oxidant.²⁵ The generation of reactive oxygen species triggers iron-induced lipid peroxidation (i.e., of lipoproteins and prostanoids). Oxidative modification of LDL is causally involved in atherogenesis, and LDL oxidation has been shown to occur in HD patients, which could favor the development of atherosclerosis.^14,23

Epidemiological studies examining the role of iron in cardiovascular disease have yielded conflicting results.^26–28 A recent study evaluating a possible relationship between blood donation and the risk of coronary heart disease in men did not support the hypothesis that reducing body iron stores lowered the risk for coronary disease mortality,²⁸ and an analysis of prospective studies in nonuremic populations did not provide good evidence of a strong association between iron status and coronary heart disease.²⁹ In contrast, prospective results from the Bruneck study in humans provided strong evidence for a role of iron stores in early carotid atherogenesis,¹⁹ and iron chelation improved endothelial function in human patients with coronary artery disease.²⁰ These conflicting results may, in part, reflect different responses to iron depletion or repletion and the use of different circulating indicators of iron stores and their modulation by various diseases and genetic factors (for example, ferritin levels in the presence of inflammation, infection, or hepatic disease). Most importantly with respect to our present findings, a recent study done in >5000 patients receiving long-term HD concluded that intensive intravenous iron dosing was an independent factor associated with decreased survival and higher rates of hospitalization.³⁰ Moreover, because iron loading markedly alters the antioxidant system³¹ and because uremic patients have numerous defects of antioxidant defense unrelated to iron, iron toxicity could amplify these defects, and ESRD may represent a "specific" condition that enhances the iron toxicity for the vessel walls. In keeping with this, an increased total body iron level in patients receiving long-term HD was shown to exacerbate lycopene deficiency, an antioxidant whose deficiency is present even in the absence of iron excess.³²

Our results show that the annual dose of intravenous iron was significantly correlated with serum ferritin and AOPP concentrations. This association was independent of serum C-reactive protein, which was used as a marker of systemic inflammation. The correlations between the CCA-IMT, serum ferritin, plasma AOPP (Table 3), and iron dose suggest that oxidative stress may play a role in the pathogenesis of arterial remodeling³³ and that the former could, in part, be the consequence of parenteral iron therapy. This possibility is supported by the direct association between the iron dose and the CCA-IMT in younger patients (Table 4 and Figure 2). Pertinently, AOPP were associated with CCA-IMT independently of their association with ferritin and iron. These findings might indicate that the elevation of plasma AOPP levels is only partially explained by the increases of serum ferritin and iron load, in keeping with the view that other oxidative mechanisms are also at work in these patients.

However, the results reported herein must be interpreted with caution. The ability to generalize the results of the present study may be limited because the demographics and clinical characteristics of ESRD patients reported may significantly differ from ESRD populations in North America and northern Europe and because subjects with active cardiovascular complications were not included. The study concerned ESRD patients with stable cardiovascular function, and the proportion of diabetics, although steadily increasing in France, was lower than that in northern Europe or North America and was only 13% in the present population. To minimize the potential oxidative role of the HD procedure, patients were dialyzed exclusively on synthetic biocompatible membranes. The second limitation is the cross-sectional and observational nature of our study. This type of study cannot identify a cause-and-effect relationship.

In conclusion, the present data show that circulating markers of phagocyte-derived oxidative stress and proinflammatory mediators, such as AOPP, are correlated with CCA remodeling in uremic patients, including increased CCA-IMT and wall-to-lumen ratio. Furthermore, the observed correlations between ferritin concentrations, AOPP, and the annual iron dose suggest that iron therapy with the presently recommended doses and mode of administration could contribute to arterial wall damage.

	Acknowledgments

 
This work was supported by the GEPIR (Groupe d’Etude de pathophysiologie de l’Insuffisance Renale) and INSERM U507.

Received June 13, 2002; revision received August 9, 2002; accepted August 9, 2002.

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				S. X. Liu, F. F. Hou, Z. J. Guo, R. Nagai, W. R. Zhang, Z. Q. Liu, Z. M. Zhou, M. Zhou, D. Xie, G. B. Wang, et al. Advanced Oxidation Protein Products Accelerate Atherosclerosis Through Promoting Oxidative Stress and Inflammation Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1156 - 1162. [Abstract] [Full Text] [PDF]

				S. Ashfaq, J. L. Abramson, D. P. Jones, S. D. Rhodes, W. S. Weintraub, W. C. Hooper, V. Vaccarino, D. G. Harrison, and A. A. Quyyumi The Relationship Between Plasma Levels of Oxidized and Reduced Thiols and Early Atherosclerosis in Healthy Adults J. Am. Coll. Cardiol., March 7, 2006; 47(5): 1005 - 1011. [Abstract] [Full Text] [PDF]

				K. Kalantar-Zadeh, D. L. Regidor, C. J. McAllister, B. Michael, and D. G. Warnock Time-Dependent Associations between Iron and Mortality in Hemodialysis Patients J. Am. Soc. Nephrol., October 1, 2005; 16(10): 3070 - 3080. [Abstract] [Full Text] [PDF]

				T. B. Drueke and Z. A. Massy Intravenous Iron: How Much Is Too Much? J. Am. Soc. Nephrol., October 1, 2005; 16(10): 2833 - 2835. [Full Text] [PDF]

				T. Stompor, A. Krasniak, W. Sulowicz, A. Dembinska-Kiec, K. Janda, K. Wojcik, B. Tabor, M. E. Kowalczyk-Michalek, A. Zdzienicka, and E. Janusz-Grzybowska Changes in common carotid artery intima-media thickness over 1 year in patients on peritoneal dialysis Nephrol. Dial. Transplant., February 1, 2005; 20(2): 404 - 412. [Abstract] [Full Text] [PDF]

				Z. A. Massy, O. Ivanovski, T. Nguyen-Khoa, J. Angulo, D. Szumilak, N. Mothu, O. Phan, M. Daudon, B. Lacour, T. B. Drueke, et al. Uremia Accelerates both Atherosclerosis and Arterial Calcification in Apolipoprotein E Knockout Mice J. Am. Soc. Nephrol., January 1, 2005; 16(1): 109 - 116. [Abstract] [Full Text] [PDF]

				M. M. Nascimento, M. E. Suliman, A. Bruchfeld, S. Y. Hayashi, R. C. Manfro, A. R. Qureshi, R. Pecoits-Filho, M. A. Pachaly, L. Renner, P. Stenvinkel, et al. The influence of hepatitis C and iron replacement therapy on plasma pentosidine levels in haemodialysis patients Nephrol. Dial. Transplant., December 1, 2004; 19(12): 3112 - 3116. [Abstract] [Full Text] [PDF]

				G. R. Aronoff Safety of Intravenous Iron in Clinical Practice: Implications for Anemia Management Protocols J. Am. Soc. Nephrol., December 1, 2004; 15(suppl_2): S99 - S106. [Full Text] [PDF]

				D. B. Van Wyck Labile Iron: Manifestations and Clinical Implications J. Am. Soc. Nephrol., December 1, 2004; 15(suppl_2): S107 - S111. [Full Text] [PDF]

				D. W. Coyne Labile iron in parenteral iron formulations: a quantitative and comparative study Nephrol. Dial. Transplant., October 1, 2004; 19(10): 2674 - 2675. [Full Text] [PDF]

				F. Santangelo, V. Witko-Sarsat, T. Drueke, and B. Descamps-Latscha Restoring glutathione as a therapeutic strategy in chronic kidney disease Nephrol. Dial. Transplant., August 1, 2004; 19(8): 1951 - 1955. [Full Text] [PDF]

				C. Canavese, D. Bergamo, G. Ciccone, M. Burdese, E. Maddalena, S. Barbieri, A. Thea, and F. Fop Low-dose continuous iron therapy leads to a positive iron balance and decreased serum transferrin levels in chronic haemodialysis patients Nephrol. Dial. Transplant., June 1, 2004; 19(6): 1564 - 1570. [Abstract] [Full Text] [PDF]

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P. Stenvinkel, U. Diczfalusy, B. Lindholm, and O. Heimburger Phospholipid plasmalogen, a surrogate marker of oxidative stress, is associated with increased cardi