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Effects of carnitine on oxidative stress response to intravenous iron administration to patients with CKD: impact of haptoglobin phenotype.

ABSTRACT: Anemia is a common disorder in CKD patients. It is largely attributed to decreased erythropoietin (EPO) production and iron deficiency. Therefore, besides EPO, therapy includes iron replenishment. However, the latter induces oxidative stress. Haptoglobin (Hp) protein is the main line of defense against the oxidative effects of Hemoglobin/Iron. There are 3 genotypes: 1-1, 2-1 and 2-2. Hp 2-2 protein is inferior to Hp 1-1 as antioxidant. So far, there is no evidence whether haptoglobin phenotype affects iron-induced oxidative stress in CKD patients. Therefore, the present study examines the influence of carnitine treatment on the intravenous iron administration (IVIR)-induced oxidative stress in CKD patients, and whether Hp phenotype affects this response.Current Controlled Trials ISRCTN5700858. This study included 26 anemic (Hb = 10.23 ± 0.28) CKD patients (stages 3-4) that were given a weekly IVIR (Sodium ferric gluconate, [125 mg/100 ml] for 8 weeks, and during weeks 5-8 also received Carnitine (20 mg/kg, IV) prior to IVIR. Weekly blood samples were drawn before and after each IVIR for Hp phenotype, C-reactive protein (CRP), advanced oxidative protein products (AOPP), neutrophil gelatinase-associated lipocalin (NGAL), besides complete blood count and biochemical analyses.Eight percent of CKD patients were Hp1-1, 19 % Hp2-1, and 73 % Hp2-2. IVIR for 4 weeks did not increase hemoglobin levels, yet worsened the oxidative burden as was evident by elevated plasma levels of AOPP. The highest increase in AOPP was observed in Hp2-2 patients. Simultaneous administration of Carnitine with IVIR abolished the IVIR-induced oxidative stress as evident by preventing the elevations in AOPP and NGAL, preferentially in patients with Hp2-2 phenotype.This study demonstrates that Hp2-2 is a significant risk factor for IVIR-induced oxidative stress in CKD patients. Our finding, that co-administration of Carnitine with IVIR preferentially attenuates the adverse consequences of IVIR, suggests a role for Carnitine therapy in these patients.

SUBMITTER: Armaly Z

PROVIDER: S-EPMC4535251 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Effects of carnitine on oxidative stress response to intravenous iron administration to patients with CKD: impact of haptoglobin phenotype.

Armaly Zaher Z Abd El Qader Amir A Jabbour Adel A Hassan Kamal K Ramadan Rawi R Bowirrat Abdalla A Bisharat Bishara B

BMC nephrology 20150813

<h4>Background</h4>Anemia is a common disorder in CKD patients. It is largely attributed to decreased erythropoietin (EPO) production and iron deficiency. Therefore, besides EPO, therapy includes iron replenishment. However, the latter induces oxidative stress. Haptoglobin (Hp) protein is the main line of defense against the oxidative effects of Hemoglobin/Iron. There are 3 genotypes: 1-1, 2-1 and 2-2. Hp 2-2 protein is inferior to Hp 1-1 as antioxidant. So far, there is no evidence whether hapt ...[more]

PMID: 26268514

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Project description:BACKGROUND AND OBJECTIVES:Intravenous iron therapy for chronic anemia management is largely driven by dosing protocols that differ in intensity with respect to dosing approach (i.e., dose, frequency, and duration). Little is known about the safety of these protocols. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Using clinical data from a large United States dialysis provider linked to health care utilization data from Medicare, we constructed a cohort of patients with ESKD aged ?65 years who initiated and continued center-based hemodialysis for ?90 days between 2009 and 2012, and initiated at least one of the five common intravenous iron administration strategies; ranked by intensity (the amount of iron given at moderate-to-high iron indices), the order of strategies was 3 (least intensive), 2 (less intensive), 1 (reference), 4 (more intensive), and 5 (most intensive). We estimated the effect of continuous exposure to these strategies on cumulative risks of mortality and infection-related events with dynamic Cox marginal structural models. RESULTS:Of 13,249 eligible patients, 1320 (10%) died and 1627 (12%) had one or more infection-related events during the 4-month follow-up. The most and least commonly initiated strategy was strategy 2 and 5, respectively. Compared with the reference strategy 1, more intensive strategies (4 and 5) demonstrated a higher risk of all-cause mortality (e.g., most intensive strategy 5: 60-day risk difference: 1.3%; 95% confidence interval [95% CI], 0.8% to 2.1%; 120-day risk difference: 3.1%; 95% CI, 1.0% to 5.6%). Similarly, higher risks were observed for infection-related morbidity and mortality among more intensive strategies (e.g., strategy 5: 60-day risk difference: 1.8%; 95% CI, 1.2% to 2.6%; 120-day risk difference: 4.3%; 95% CI, 2.2% to 6.8%). Less intensive strategies (2 and 3) demonstrated lower risks of all-cause mortality and infection-related events. CONCLUSIONS:Among dialysis patients surviving 90 days, subsequent intravenous iron administration strategies promoting more intensive iron treatment at moderate-to-high iron indices levels are associated with higher risks of mortality and infection-related events.

Project description:BackgroundIntravenous (IV) iron is frequently used to treat iron deficiency/anemia in patients who are unable to tolerate oral iron or the oral iron is not sufficient toreplete iron requirements. However, safety concerns regarding the potential increase in oxidative stress and other adverse effects persist and it remains unclear whether all iron preparations are equivalent. Indeed, the comparative risk of adverse events with IV iron preparations has not been extensively assessed. We hypothesize that IV iron leads to changes in oxidative stress, endothelial function, and potential renal damage depending on the iron formulation (related to the generation of "free" or catalytic labile iron) and this may result in more tubular and glomerular injury manifested as increased proteinuria and raised neutrophil gelatinase-associated lipocalin (NGAL) levels in patients with chronic kidney disease (CKD).MethodsIRON-CKD is a prospective, open-label, explorative, randomized, single-center study designed to compare the safety and efficacy of three parenteral iron preparations: low-molecular-weight iron dextran-Cosmofer, iron sucrose-Venofer, and iron isomaltoside-Monofer. The study includes 40 adults who have established CKD stages 3-5 and serum ferritin (SF) of less than 200 μg/L or transferrin saturation (TS) of less than 20% (or both); they were randomly assigned in a 1:1:1:1 ratio to 200 mg iron dextran, 200 mg iron sucrose, 200 mg iron isomaltoside, or 1000 mg iron isomaltoside. After randomization, participants undergo baseline assessments and then an iron infusion. Each participant is followed up at 2 h, day 1, week 1, and months 1 and 3. At each follow-up visit, patients undergo clinical review, measurement of pulse wave velocity (PWV), blood tests for renal function, and collection of serum/plasma samples for oxidative stress and inflammatory markers. The primary outcomes are measures of oxidative stress, inflammatory markers, and markers of acute renal injury in comparison with baseline measures of each iron preparation and between each of the iron preparations. Secondary objectives include effects on hematinic profiles and hemoglobin concentrations, changes in arterial stiffness, incidence of significant side effects, and change in patients' quality of life.ResultsBetween October 2015 and April 2018, 521 individuals were identified as potential participants; 216

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Effects of carnitine on oxidative stress response to intravenous iron administration to patients with CKD: impact of haptoglobin phenotype.

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Effects of carnitine on oxidative stress response to intravenous iron administration to patients with CKD: impact of haptoglobin phenotype.

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