Lipid Peroxidation Products Formation with Various Intravenous Iron Preparations in Chronic Kidney Disease

Ganguli, Anirban; Kohli, Harbir Singh; Khullar, Madhu; Gupta, Krishan Lal; Jha, Vivekanand; Sakhuja, Vinay

doi:10.1080/08860220802599106

Cited by 27 publications

(23 citation statements)

References 15 publications

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“…Administration of IV iron preparations, particularly when used indiscriminately, increases the plasma level of catalytically active, non-transferrin bound labile iron which is capable of causing oxidative stress [12]. In fact, several studies have documented the ability of IV iron preparations to cause oxidative stress in dialysis patients and in experimental animals [13,14,15,16,17]. Oxidative stress, in turn, results in endothelial damage and dysfunction and triggers inflammation via activation of NF-ĸB, a redox-sensitive transcription factor, which is a master regulator of numerous proinflammatory cytokines and chemokines.…”

Section: Discussionmentioning

confidence: 99%

Iron Sucrose Promotes Endothelial Injury and Dysfunction and Monocyte Adhesion/Infiltration

Kamanna

Ganji²,

Shelkovnikov³

et al. 2011

Am J Nephrol

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Background/Aims: Intravenous (IV) iron preparations are widely used in the management of anemia in ESRD populations. Recent changes in reimbursement policy have dramatically increased the use of IV iron to lower the use of costly erythropoiesis-stimulating agents. These preparations are frequently administered with insufficient attention to the total body iron stores or presence of inflammation which is aggravated by excess iron. Endothelial injury and dysfunction are critical steps in atherosclerosis, thrombosis and cardiovascular disease. IV iron preparations raise plasma non-transferrin-bound iron which can promote oxidative stress, endothelial damage and dysfunction. We explored the effect of an IV iron preparation on endothelial cells, monocytes and isolated arteries. Methods: Primary cultures of human aortic endothelial cells (HAEC) were treated with pharmacologically relevant concentrations of iron sucrose (10–100 µg/ml) for 4–24 h. Endothelial cell morphology, viability, and monocyte adhesion were tested. Endothelial function was assessed by measuring the vasorelaxation response to acetylcholine in normal rat thoracic aorta rings preincubated with iron sucrose (200 µg/ml). Results: In contrast to the control HAEC which showed normal cobblestone appearance, cells treated with iron sucrose (50–100 µg/ml) for 4 h showed loss of normal morphological characteristics, cellular fragmentation, shrinkage, detachment, monolayer disruption and nuclear condensation/fragmentation features signifying apoptosis. HAEC exposure to iron sucrose (10–100 µg/ml) increased monocyte adhesion 5- to 25-fold. Incubation in media containing 200 µg/ml iron sucrose for 3 h caused marked reduction in the acetylcholine-mediated relaxation in phenylephrine-precontracted rat aorta. Conclusion: Pharmacologically relevant concentration of iron sucrose results in endothelial injury and dysfunction and marked increase in monocyte adhesion.

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Section: Discussionmentioning

confidence: 99%

Iron Sucrose Promotes Endothelial Injury and Dysfunction and Monocyte Adhesion/Infiltration

Kamanna

Ganji²,

Shelkovnikov³

et al. 2011

Am J Nephrol

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“…These have been reviewed extensively and were the focus of a Kidney Disease: Improving Global Outcomes Controversies Conference on Iron Management [1]. These concerns include the potential for increased oxidative stress due to hydroxyl radical generation observed in some studies, which could exacerbate cardiovascular toxicity [1,[17][18][19]. Similarly, there is laboratory evidence that IV iron can enhance bacterial proliferation and reduce neutrophil killing of bacteria, generating concerns about an increased risk of infection [1,18,20].…”

Section: Introductionmentioning

confidence: 99%

Randomized Trial Comparing Proactive, High-Dose versus Reactive, Low-Dose Intravenous Iron Supplementation in Hemodialysis (PIVOTAL): Study Design and Baseline Data

et al. 2018

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Background: Intravenous (IV) iron supplementation is a standard maintenance treatment for hemodialysis (HD) patients, but the optimum dosing regimen is unknown. Methods: PIVOTAL (Proactive IV irOn Therapy in hemodiALysis patients) is a multicenter, open-label, blinded endpoint, randomized controlled (PROBE) trial. Incident HD adults with a serum ferritin < 400 µg/L and transferrin saturation (TSAT) levels < 30% receiving erythropoiesis-stimulating agents (ESA) were eligible. Enrolled patients were randomized to a proactive, high-dose IV iron arm (iron sucrose 400 mg/month unless ferritin > 700 µg/L and/or TSAT ≥40%) or a reactive, low-dose IV iron arm (iron sucrose administered if ferritin <200 µg/L or TSAT < 20%). We hypothesized that proactive, high-dose IV iron would be noninferior to reactive, low-dose IV iron for the primary outcome of first occurrence of nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure or death from any cause. If noninferiority is confirmed with a noninferiority limit of 1.25 for the hazard ratio of the proactive strategy relative to the reactive strategy, a test for superiority will be carried out. Secondary outcomes include infection-related endpoints, ESA dose requirements, and quality-of-life measures. As an event-driven trial, the study will continue until at least 631 primary outcome events have accrued, but the expected duration of follow-up is 2–4 years. Results: Of the 2,589 patients screened across 50 UK sites, 2,141 (83%) were randomized. At baseline, 65.3% were male, the median age was 65 years, and 79% were white. According to eligibility criteria, all patients were on ESA at screening. Prior stroke and MI were present in 8 and 9% of the cohort, respectively, and 44% of patients had diabetes at baseline. Baseline data for the randomized cohort were generally concordant with recent data from the UK Renal Registry. Conclusions: PIVOTAL will provide important information about the optimum dosing of IV iron in HD patients representative of usual clinical practice. Trial Registration: EudraCT number: 2013-002267-25.

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“…Iron ions are strong catalysts for the peroxidation of membrane lipids, and give rise to membrane damage (12)(13)(14). It has become increasingly evident that this type of peroxidative damage to low-density lipoprotein plays a pivotal role in the etiology of atherosclerosis (15,16).…”

Section: Introductionmentioning

confidence: 99%

Reaction of ferritin with hydrogen peroxide induces lipid peroxidation

Yoon¹,

Lee²,

Kang³

2010

BMB Reports

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Lipid peroxidation is known to be an important factor in the pathologies of many diseases associated with oxidative stress. We assessed the lipid peroxidation induced by the reaction of ferritin with H2O2. When linoleic acid micelles or phosphatidyl choline liposomes were incubated with ferritin and H2O2, lipid peroxidation increased in the presence of ferritin and H2O2 in a concentration-dependent manner. The hydroxyl radical scavengers, azide and thiourea, prevented lipid peroxidation induced by the ferritin/H2O2 system. The iron specific chelator desferoxamine also prevented ferritin/H2O2 systemmediated lipid peroxidation. These results demonstrate the possible role of iron in ferritin/H2O2 system-mediated lipid peroxidation. Carnosine is involved in many cellular defense processes, including free radical detoxification. In this study, carnosine, homocarnosine, and anserine were shown to significantly prevent ferritin/H2O2 system-mediated lipid peroxidation and also inhibited the free radical-generation activity of ferritin. These results indicated that carnosine and related compounds may prevent ferritin/H2O2 system-mediated lipid peroxidation via free radical scavenging. [BMB reports 2010; 43(3): 219-224]

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Lipid Peroxidation Products Formation with Various Intravenous Iron Preparations in Chronic Kidney Disease

Cited by 27 publications

References 15 publications

Iron Sucrose Promotes Endothelial Injury and Dysfunction and Monocyte Adhesion/Infiltration

Iron Sucrose Promotes Endothelial Injury and Dysfunction and Monocyte Adhesion/Infiltration

Randomized Trial Comparing Proactive, High-Dose versus Reactive, Low-Dose Intravenous Iron Supplementation in Hemodialysis (PIVOTAL): Study Design and Baseline Data

Reaction of ferritin with hydrogen peroxide induces lipid peroxidation

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