ferlixit and Renal-Insufficiency--Chronic

Intravenous iron is widely used to maintain adequate iron stores and prevent iron deficiency anemia in patients with chronic kidney disease, yet concerns remain about its long-term safety with respect to oxidative stress, kidney injury, and accelerated atherosclerosis, which are the subjects of this review. Three parenteral iron formulations are available for use in the United States: Iron dextran, iron gluconate, and iron sucrose. Iron dextran, especially the high molecular form, has been linked with anaphylactoid and anaphylactic reactions, and its use has been declining. A portion of intravenous iron preparations is redox-active, labile iron available for direct donation to transferrin. In vitro tests show that commonly available intravenous iron formulations have differing capacities to saturate transferrin directly: Iron gluconate > iron sucrose > iron dextran. Intravenous iron treatment produces oxidative stress, as demonstrated by increases in plasma levels of lipid peroxidation products (malondialdehyde), at a point that is much earlier than the time to peak concentration of catalytically active iron, suggesting a direct effect of iron sucrose on oxidative stress. Furthermore, iron sucrose infusion produces endothelial dysfunction that seems to peak earlier than the serum level of free iron. Intravenous iron sucrose infusion also has been shown to produce acute renal injury and inflammation as demonstrated by increased urinary albumin, enzyme (N-acetyl-beta-glucosaminidase), and cytokine (chemokine monocyte chemoattractant protein-1) excretions. Although the long-term dangers of intravenous iron are unproved, these data call for examination of effects of intravenous iron on the potential for long-term harm in patients with chronic kidney disease.

Topics: Acute Kidney Injury; Anemia, Iron-Deficiency; Animals; Atherosclerosis; Endothelium, Vascular; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hematinics; Humans; Inflammation; Infusions, Intravenous; Iron-Dextran Complex; Oxidative Stress; Renal Dialysis; Renal Insufficiency, Chronic; Time Factors; Transferrin

Ferric iron (Fe)-carbohydrate complexes are widely used for treating Fe deficiency in patients who are unable to meet their Fe requirements with oral supplements. Intravenous Fe generally is well tolerated and effective in correcting Fe-deficient states. However, the complexing of Fe to carbohydrate polymers does not block its potent pro-oxidant effects; systemic free radical generation and, possibly, tissue damage may result. The purpose of this review is to (1) underscore the capacity of currently used parenteral Fe formulations to induce oxidative stress, (2) compare the severity of these oxidant reactions with those that result from unshielded Fe salts and with each other, and (3) speculate as to the potential of these agents to induce acute renal cell injury and augment systemic inflammatory responses. The experimental data that are reviewed should not be extrapolated to the clinical setting or be used for clinical decision making. Rather, it is hoped that the information provided herein may have utility for clinical hypothesis generation and, hence, future clinical studies. By so doing, a better understanding of Fe's potential protean effects on patients with renal disease may result.

Topics: Acute Kidney Injury; Adenosine Triphosphate; Anemia, Iron-Deficiency; Animals; Endothelial Cells; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hematinics; Humans; Inflammation; Infusions, Intravenous; Iron Compounds; Iron-Dextran Complex; Kidney Cortex; Kidney Tubules, Proximal; Lipid Peroxidation; Mitochondria; Oxidative Stress; Renal Dialysis; Renal Insufficiency, Chronic; Tumor Necrosis Factor-alpha

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.

Topics: Acute-Phase Proteins; Advanced Oxidation Protein Products; Aged; Anemia, Iron-Deficiency; C-Reactive Protein; Carnitine; Cross-Over Studies; Female; Ferric Compounds; Genotype; Haptoglobins; Humans; Lipocalin-2; Lipocalins; Male; Middle Aged; Oxidative Stress; Phenotype; Prospective Studies; Proto-Oncogene Proteins; Renal Insufficiency, Chronic

Non-dextran intravenous (i.v.) iron preparations seem to differentially affect proteinuria in patients with chronic kidney disease. To study effects of ferric gluconate and iron sucrose on proteinuria, we conducted a crossover trial in 12 patients with stage 3-4 chronic kidney disease. These patients were randomized to receive the same dose of either drug 1 week apart. Urine samples were obtained immediately before and at frequent intervals after the drug. The urine total protein/creatinine ratio was significantly greater after iron sucrose than ferric gluconate treatment with the effect noted within 15 min post-infusion. Furthermore, when iron sucrose was given first, a significantly greater protein/creatinine ratio was seen subsequently with ferric gluconate than with the reverse order of treatment. The urine albumin/creatinine ratio was also significantly greater with iron sucrose than with ferric gluconate. There was no significant difference, however, between the two i.v. irons in the measured urine N-acetyl-beta-D-glucosaminidase/creatinine ratio. Although our study showed that acutely, iron sucrose increased proteinuria, the long-term effects of repeated i.v. non-dextran iron on kidney function requires further study.

Topics: Aged; Cross-Over Studies; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Humans; Male; Middle Aged; Proteinuria; Renal Insufficiency, Chronic; Treatment Outcome

Oral iron is recommended as first line treatment of anemia in non-dialysis chronic kidney disease (ND-CKD) patients. Sucrosomial® iron, a new generation oral iron with high absorption and bioavailability and a low incidence of side effects, has shown to be not inferior to intravenous (IV) iron in the replacement of iron deficiency anemia in patients with ND-CKD. Besides the clinical benefit, it is also important to determine the comparative total costs of oral versus IV iron administrations. The aim of this study was to perform a cost-minimization analysis of oral Sucrosomial iron, compared with IV iron gluconate from an Italian societal perspective.. Cost analysis was performed on the 99 patients with ND-CKD and iron-deficiency anemia of the randomized trial by Pisani et al. Human and material resources utilization was recorded during each iron administration. According to study perspective, direct and indirect costs were considered. Costs for each resource unit were taken from official Italian sources. Probabilistic sensitivity analyses were carried out to test the robustness of the results.. The base case analysis showed an average cost/cycle per patient of € 111 for oral iron and € 1302 for IV iron. Thus, the potential saving was equal to € 1191 per patient/cycle. The sensitivity analysis showed that the most sensitive driver is the time loss by patient and caregivers for the therapy and related-care, followed by the minutes of nursing care and the number of kilometres travelled to reach the referral centre.. This study showed that oral Sucrosomial® iron could offer specific advantages in terms of potential savings, and allowed identifying some implications for future research. Such advantages still persist with the new single dose IV iron formulation available in the market, although to a lesser extent.

Topics: Administration, Oral; Anemia, Iron-Deficiency; Cost Savings; Costs and Cost Analysis; Drug Costs; Ferric Compounds; Health Care Costs; Hematinics; Humans; Infusions, Intravenous; Iron; Renal Insufficiency, Chronic

Ferumoxytol was first approved for clinical use in 2009 solely based on data from trial comparisons with oral iron on biochemical anemia efficacy end points. To compare the rates of important patient outcomes (infection, cardiovascular events and death) between facilities predominantly using ferumoxytol versus iron sucrose (IS) or ferric gluconate (FG) in patients with end-stage renal disease (ESRD)-initiating hemodialysis (HD).. Using the United States Renal Data System, we identified all HD facilities that switched (almost) all patients from IS/FG to ferumoxytol (July 2009-December 2011). Each switching facility was matched with three facilities that continued IS/FG use. All incident ESRD patients subsequently initiating HD in these centers were studied and assigned their facility exposure. They were followed for all-cause mortality, cardiovascular hospitalization/death or infectious hospitalization/death. Follow-up ended at kidney transplantation, switch to peritoneal dialysis, transfer to another facility, facility switch to another iron formulation and end of database (31 December 2011). Cox proportional hazards regression was then used to estimate adjusted hazard ratios [HR (95% confidence intervals)].. In July 2009-December 2011, 278 HD centers switched to ferumoxytol; 265 units (95.3%) were matched with 3 units each that continued to use IS/FG. Subsequently, 14 206 patients initiated HD, 3752 (26.4%) in ferumoxytol and 10 454 (73.6%) in IS/FG centers; their characteristics were very similar. During 6433 person-years, 1929 all-cause, 726 cardiovascular and 191 infectious deaths occurred. Patients in ferumoxytol (versus IS/FG) facilities experienced similar all-cause [0.95 (0.85-1.07)], cardiovascular [0.99 (0.83-1.19)] and infectious mortality [0.88 (0.61-1.25)]. Among 5513 Medicare (Parts A + B) beneficiaries, cardiovascular events [myocardial infarction, stroke and cardiovascular death; 1.05 (0.79-1.39)] and infectious events [hospitalization/death; 0.96 (0.85-1.08)] did not differ between the iron exposure groups.. In incident HD patients, ferumoxytol showed similar short- to mid-term safety profiles with regard to cardiovascular, infectious and mortality outcomes compared with the more commonly used intravenous iron formulations IS and FG.

Topics: Administration, Intravenous; Aged; Anemia; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferrosoferric Oxide; Glucaric Acid; Hematinics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Prognosis; Proportional Hazards Models; Renal Dialysis; Renal Insufficiency, Chronic; Stroke; United States

Intravenous (IV) iron is used in the treatment of anemia in patients with chronic kidney disease (CKD). Several lines of evidence have brought up potential concerns regarding the effect of IV iron on the kidney, specifically the possibility of IV iron leading to renal injury and hastening the progression of CKD.. We performed a retrospective analysis of 77 patients to assess the rate of change in kidney function prior to and after IV iron infusion.. Patients were followed for an average of 21.3 months (range 2-35) prior and 32.8 months (range 2-58) after the single iron infusion. Sixty-one percent of patients had CKD stage 3 and 30% were at CKD stage IV at the time of iron infusion. Of the 77 patients, 74.1% received iron dextran and 25.9% received ferric gluconate (1 g total). The average slope before and after iron infusion for 1/serum creatinine versus time (months) were -0.0066 and -0.0053, respectively (p = 0.12). The average slope before and after iron infusion for glomerular filtration rate versus time (months) were -0.5439 and -0.2998, respectively (p = 0.14). There was no difference in subgroup analysis in the rate of change in renal function in those with more advanced renal function as opposed to those with more preserved renal function.. In this limited retrospective study, IV iron dextran or ferric gluconate was not associated with a change in the rate of progression of CKD.

Topics: Adult; Aged; Aged, 80 and over; Cohort Studies; Disease Progression; Female; Ferric Compounds; Humans; Infusions, Intravenous; Iron; Iron-Dextran Complex; Kidney Function Tests; Male; Middle Aged; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors; Young Adult