Oxidative Stress and Inflammation in Chronic Kidney Disease: Role of Intravenous Iron and Vitamin D

Journal of Pharmacy Practice Volume 21 Number 3 June 2008 214-224 © 2008 Sage Publications 10.1177/0897190008316288 http://ajhpm.sagepub.com hosted at http://online.sagepub.com

Amy Barton Pai, PharmD, BCPS, FASN and Todd A. Conner, PharmD

Cardiovascular disease (CVD) is the leading cause of death among chronic kidney disease patients (CKD). The etiology of CVD in CKD is multifactorial and increasing evidence points to the important contribution of “nontraditional” risk factors including oxidative stress and inflammation. CKD is associated with a chronic imbalance of prooxidant and antioxidant factors that results in a state of chronic inflammation. Intravenous iron supplementation has been shown to induce oxidative stress and has been associated with lipid peroxidation and DNA damage. Conversely, treatment with vitamin D analogs

has been associated with improved mortality in hemodialysis patients in 2 recent large cohort studies. These data suggest that vitamin D analogs may exert effects beyond their pharmacologic role in parathyroid hormone suppression. This article addresses the current data regarding the relative contributions of intravenous iron supplementation and vitamin D analog therapy on oxidative stress and inflammation in CKD patients.

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with advanced CKD have an imbalance of prooxidant (eg, reactive oxygen species, proinflammatory cytokines) and antioxidant (eg, serum albumin, transferrin, water soluble vitamins) mediators that ultimately favor a large oxidative stress burden.5 Data demonstrating the strong predictive value of Creactive protein (CRP) for development of cardiovascular disease supports the importance of the inflammatory process in the pathogenesis of atherosclerosis in the general population as well as those with ESRD.6-8 Progression of CKD is associated with incremental increases in CRP (Figure 1).9-12

ardiovascular disease is the leading cause of death among patients with ESRD receiving hemodialysis.1 Despite vast improvements in pharmacotherapeutic interventions (eg, erythropoeisis stimulating agents [ESAs]) and dialysis modalities, cardiovascular mortality is 10 to 20 times higher among ESRD patients on hemodialysis compared to the general population.2 Emerging data indicate the importance of nontraditional versus traditional risk factors on the development of cardiovascular disease in patients with chronic kidney disease (CKD), including inflammation and oxidative stress (Table 1).3,4 It is well established that patients

From the University of New Mexico Health Sciences Center, College of Pharmacy and School of Medicine, Albuquerque, New Mexico. Address correspondence to: Amy Barton Pai, PharmD, BCPS, FASN, University of New Mexico Health Sciences Center, College of Pharmacy and School of Medicine, MSC09 5360, Albuquerque, NM 87131; phone (505) 272-8831; e-mail: abpai @salud.unm.edu.

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Keywords: chronic kidney disease; oxidative stress; inflammation; intravenous iron; vitamin D

Nontraditional Risk Factors for Cardiovascular Disease in End-stage Renal Disease (ESRD) Atherosclerosis is an inflammatory disease that is accelerated in the presence of reactive oxygen species (ROS) that oxidize LDL (OxLDL). OxLDL promotes the development of atherosclerosis by enhancing

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Table 1. Traditional and Nontraditional Risk Factors for Cardiovascular Disease (CVD) in Chronic Kidney Disease (CKD) Traditional Risk Factors in the General Population Age Men ≥45 yr Women ≥55 yr Sex (male) Current smoker Diabetes mellitus Blood pressure >140/90 mm Hg Current antihypertensive therapy Serum cholesterol levels Total cholesterol ≥ 160 mg/dL HDL ≤ 40 mg/dL

Nontraditional Risk Factors Identified in CKD Patients Malnutrition ↓Serum albumin Renal failure ↑Serum creatinine Inflammatory cytokines ↑IL-6 ↑CRP Oxidative stress ↑Oxidized LDL Vascular calcification ↑Calcium ↑Phosphorus ↑Calcium/phosphorus product ↑Homocysteine levels ↑Lipoprotein ↑Fibrinogen

foam cell formation, fatty streak development, and endothelial lesion progression.13 OxLDL may also promote atherosclerosis by inhibiting nitric oxide mediated vasodilation, stimulating renin release, and inducing apoptosis. Several studies have demonstrated that enhanced lipid peroxidation occurs in patients with ESRD, particularly in hemodialysis patients.14,15 In a recent large cohort study, it was reported that levels of antibodies to oxidized LDL were predictive of cardiovascular mortality in patients with ESRD.13 Oxidative DNA damage has also been found in atherosclerotic lesions.16,17 Cytokine activation is the key inducer of the inflammatory response. Proinflammatory cytokines such as IL-1, IL-6, and TNF-α and the antiinflammatory cytokine IL-10 are elevated in hemodialysis patients.18 These cytokines may exert direct atherogenic effects by stimulating leukocyte migration across the endothelial surface, altering lipid metabolism, promoting vascular calcification, and causing endothelial dysfunction.18 IL-6 plays a key role in the induction of acute phase responses and has been found to be a predictor of cardiovascular mortality in hemodialysis patients.19-21 The increasing evidence of the importance of nontraditional risk factors on cardiovascular disease in CKD patients justifies efforts to identify causes and develop treatments that could potentially ameliorate the inflammatory process. Pharmacists caring for CKD patients should be aware of this data.

Figure 1. Highly sensitive C-reactive protein increases as CKD progresses.

Sources of Oxidative Stress in CKD Factors that have been implicated in generation of oxidative stress in CKD patients include: uremia, diabetes mellitus, loss of antioxidants through the hemodialysis process, hypoalbuminemia (which prevents free radical scavenging), and interaction with the dialysis membrane.22-25 In a study comparing lipid peroxidation products in 29 hemodialysis patients and 27 age- and gender-matched controls, Dasgupta et al found that hemodialysis patients had significantly higher levels of prooxidant compounds including lipid hydroperoxide and malonaldehyde (MDA) compared to controls.26 Additionally, within the hemodialysis group, levels of lipid hydroperoxide and MDA were significantly higher in the patients dialyzed with conventional (cuprophane) filters compared to those dialyzed with high flux (polysulfone) filters. Spittle et al found that markers of lipid peroxidation (F2-isoprostanes and ethane) were significantly higher in ESRD patients compared to normal controls. Elevated levels of F2-isoprostanes correlated with high plasma levels of CRP.23 Hemodialysis patients are subjected to many factors that enhance their oxidative stress burden compared to patients without CKD; therefore, the ability to mount an adequate antioxidant response to additional oxidative stress is compromised.

Drugs and Imbalance of Prooxidant and Antioxidant Factors Intravenous iron products are administered to hemodialysis patients and CKD stage 3 through

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5 patients to support red blood cell production enhanced by the ESAs (eg, epoetin alfa and darbepoetin alfa). However, administering iron intravenously circumvents the tightly regulated gastrointestinal absorption mechanisms and increases the risk of catalytically active iron participating in potentially deleterious reduction-oxidation reactions. Conversely, recent large, observational cohort studies have found that survival is improved among hemodialysis patients receiving vitamin D analogs versus those who did not receive these agents.27,28 Reduced mortality was observed in patients receiving vitamin D in these studies even after model adjustment for bone and mineral metabolism parameters and multiple comorbidities. This suggests that vitamin D analogs may exert “nonclassical” pharmacologic effects that may be responsible for the survival benefit observed in hemodialysis patients.29

Relationships Between Iron and Oxidative Stress The iron (Fe) atom can readily change its oxidation state from the more stable ferrous (Fe2+, reduced state) to the highly reactive ferric (Fe3+, oxidized state) state and as such participates in a variety of physiologic oxidation-reduction reactions. Free iron can catalyze Fenton/Haber-Weiss reactions generating highly reactive hydroxyl radicals. Under normal physiologic conditions, iron is not available to participate in deleterious redox reactions since it binds to transferrin and ferritin. Administration of intravenous iron, however, can result in “oversaturation” of transferrin and exposure to free, catalytically active Fe molecules that are available to catalyze unwanted systemic redox reactions before they are incorporated into ferritin. Additionally, hemodialysis patients often have lower serum transferrin concentrations than normal patients, reducing the amount of iron that can bind to this carrier protein after administration of intravenous iron.30 A recent analysis from a large sample of US hemodialysis patients identified an increased risk of mortality associated with cumulative iron dextran doses greater than 1000 mg over 6 months. However, these findings did not persist when more sophisticated statistical techniques were applied to the data.31 There are several limitations that affect the interpretation of these data including the fact that the study period was from 1996-1998 and intravenous iron

administration has risen dramatically since then. Additionally, iron dextran was the only intravenous iron product available during that time period and thus data cannot be extrapolated to the newer, more widely used products. In a prospective analysis, Yoshimura et al found that higher serum ferritin values (>600 ng/mL) and total iron doses administered over 6 months were independently associated with higher levels of 8-hydroxy-2’deoxyguanosine (8-OHdG), a marker of oxidative DNA injury.32

Intravenous Iron Products Used in CKD The Kidney Disease Outcome Quality Initiative guidelines for anemia of chronic kidney disease recommend intravenous iron for supplementing patients on chronic hemodialysis receiving ESA therapy.33 The guidelines also suggest that either intravenous or oral iron can be used in CKD stages 3 and 4. There are currently 3 commercially available intravenous iron products in the United States, iron dextran (InFeD, DexFerrum; FDA approved, 1974 and 1996, respectively), sodium ferric gluconate (Ferrlecit; FDA approved, 1999), and iron sucrose (Venofer; FDA approved, 2000). There is an additional iron preparation (ferumoxytol; AMAG Pharmaceuticals, Cambridge, MA) that has recently completed phase III clinical testing, and a new drug application has been filed with the FDA.34 Differences exist between the iron compounds with regard to size of the carbohydrate group, stability of the iron-carbohydrate complex, and the rapidity with which iron is released form the iron-carbohydrate complex (Table 2). An investigation to evaluate the appearance of free iron in vitro among the 4 intravenous iron products (iron sucrose, sodium ferric gluconate, iron dextran, and ferumoxytol) demonstrated that the most stable preparations (iron dextran and ferumoxytol) produced the least amount of catalytically active free iron.35 Current data has demonstrated that all of the available intravenous iron products are effective in repleting iron and enhancing erythropoiesis with ESA therapy.36,37 Analysis of the incidence of allergic reactions for the 3 intravenous iron products suggests that sodium ferric gluconate and iron sucrose may offer superior safety profiles in this regard than iron dextran.38,39 However, more data are needed on potential short- and long-term effects of oxidative stress generated by the individual agents.

Oxidative Stress and Inflammation in CKD / Pai, Conner

Table 2. Intravenous Iron Formulation Iron dextran InFeD DexFerrum Ferumoxytol AMAG Pharmaceuticals Iron sucrose Venofer, American Regent Sodium ferric gluconate Ferrlecit, Watson Labs

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Comparison of Intravenous Iron Formulations

Molecular Weight

Description of Compound/ Structural Formula

Relative Rate of Iron Release35,36,51 Slow

96 kd ± 7.5% 265 kd ± 1.5% 750 kd

Complex of ferric oxohydride with dextrans of 5000-7000 daltons Semi-synthetic, carbohydrate coated ultrasmall, superparamagnetic iron oxide

Slow

43.3 kd

38 kd

[Na2Fe5O8(OH)*3(H2O)]n*m(C12H22O11)]

Moderate

[NaFe2O3(C6H11O7)(C12H22O11)5]≈200

Fast

Review of Studies to Assess Oxidative Stress Associated with Iron Dextran, Sodium Ferric Gluconate, and Iron Sucrose There is a paucity of data examining oxidative stress with the currently available intravenous iron formulations. The available studies have evaluated different plasma biomarkers of oxidative stress over relatively short time periods. In a single intravenous dose study of iron saccharate (marketed as iron sucrose in the United States), catalytically active free iron measured by the bleomycin detectable iron (BDI) assay was detected within 5 minutes after administration.40 Six of the 12 patients in the study were still positive for BDI at 3.5 hours, the last time point assessed. BDI was also positive in 76% of the serum samples having transferrin saturation >80%. Lim et al examined the oxidative status of maintenance hemodialysis patients receiving a single 100 mg dose of ferric (iron) saccharate.41 Increased oxidative stress, measured by increasing erythrocyte and plasma levels of antioxidant enzymes and lipid peroxides, was present 15 minutes after administration of intravenous iron. The patients in the highest serum ferritin strata (>600 ng/mL) demonstrated the highest levels of plasma lipid peroxides, indicating potentially greater risk for toxicity for patients with underlying inflammation. Roob et al found that administration of 100 mg of iron sucrose significantly elevated plasma levels of MDA and resulted in the appearance of BDI at 30 minutes, an effect that persisted until the last time point assessed (180 min).42 Administration of 1200 IU of vitamin E, as an antioxidant, prior to a subsequent intravenous infusion of iron sucrose, resulted in reduced MDA levels as compared to administration of the iron sucrose alone.42

In a study examining lipid peroxidation after an intravenous infusion of 700 mg of iron dextran, Salahudeen et al. found that at 30 minutes post infusion, all patients had transferrin saturation values greater than 100% and F2-isoprostanes esterified in plasma lipoproteins were significantly elevated compared to baseline.36 A recent study also found that multiple doses of intravenous iron (sodium ferric gluconate) were also associated with increases in lipid peroxidation markers.43 Repeated intravenous doses of ferric saccharate (40 mg per hemodialysis session) were associated with increased 8-OHdG levels damage in hemodialysis patients who were iron deficient (serum ferritin sodium ferric gluconate > iron dextran. 50 Data from a recent crossover study of the 3 available intravenous iron products indicated that although all of the available intravenous iron products are associated with the appearance of free, nontransferrin bound iron (NTBI) at 30, 60, 90 and 120 minutes post administration, only the most labile compound (sodium ferric gluconate) was associated with significant oxidative stress as measured by MDA (Table 3).51 However, more than half the samples obtained after iron sucrose administration also had

elevated MDA concentrations compared to baseline. Peak NTBI values occurred at 30 minutes post intravenous iron administration. Exposure to NTBI measured by area-under-the-curve0-360 (AUC0-360) was similar when patients received sodium ferric gluconate or iron sucrose. The NTBI AUC0-360 for iron dextran was significantly lower than both sodium ferric gluconate and iron sucrose. It is unclear whether peak NTBI concentrations or overall exposure to NTBI is more important for induction of oxidative stress and lipid peroxidation. There are no definitive criteria for identifying patients who may be at risk for intravenous ironinduced oxidative stress. Based on the limited data available, it may be reasonable to consider patients with high baseline ferritin values >500-600 ng/mL and low serum albumin concentrations at higher risk.41,52 Low serum transferrin values (