ferlixit and Inflammation

Despite the proven benefits of intravenous (i.v.) iron therapy in anemia management, it remains underutilized in the hemodialysis population. Although overall i.v. iron usage continues to increase slowly, monthly usage statistics compiled by the US Renal Data System suggest that clinicians are not implementing continued dosing regimens following repletion of iron stores. Continued therapy with i.v. iron represents a key opportunity to improve patient outcomes and increase the efficiency of anemia treatment. Regular administration of low doses of i.v. iron prevents the recurrence of iron deficiency, enhances response to recombinant human erythropoietin therapy, minimizes fluctuation of hemoglobin levels, hematocrit levels, and iron stores, and may reduce overall costs of care. This article reviews the importance of i.v. iron dosing on a regular basis in the hemodialysis patient with iron-deficiency anemia and explores reasons why some clinicians may still be reluctant to employ these protocols in the hemodialysis setting.

Topics: Anemia, Iron-Deficiency; Dose-Response Relationship, Drug; Drug Resistance; Erythropoiesis; Erythropoietin; Ferric Compounds; Ferritins; Hematocrit; Hemoglobins; Humans; Inflammation; Injections, Intravenous; Iron; Practice Guidelines as Topic; Recombinant Proteins; Renal Dialysis; Risk Assessment; Treatment Outcome

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

This is a post-hoc analysis evaluating erythropoiesis stimulating agents' (ESA) related costs while using an additional ultrafilter (Estorclean PLUS) to produce ultrapure dialysis water located within the fluid pathway after the treatment with reverse osmosis and before the dialysis machine. Twenty-nine patients (19 treated with epoetin alfa and 10 with darboepoetin alfa) were included in the analysis. We showed to gain savings of 210 € per patient (35 € per patient each month) with epoetin alfa during the experimental period of 6 months, compared to the control period and of 545 € per patient (90 € per patient each month) with darboepoetin alfa. Estorclean PLUS had a cost of 600 € (25 € per month per each patient) and was used for 6 months. Intravenous iron therapy with sodium ferrigluconate had a cost of 0,545 €/62,5 mg. In conclusion, during the experimental period with the use of Estorclean, we obtained global savings of 11 € per patient per month with epoetin alfa and 30 € per patient per month with darboepoetin alfa to treat anemia in dialysis patients.

Topics: Aged; Aged, 80 and over; Anemia; Cost Savings; Costs and Cost Analysis; Cross-Over Studies; Darbepoetin alfa; Distillation; Epoetin Alfa; Female; Ferric Compounds; Filtration; Hematinics; Hemodialysis Solutions; Hemoglobins; Humans; Inflammation; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Water

Iron deficiency represents an important problem for dialysis patients. Oral iron administration is frequently ineffective, requiring parenteral administration, which may trigger severe side effects due to inflammation and/or peroxidation. The aim of the present study was to clarify the effects of parenteral iron administration on iron, inflammatory and oxidative status in peritoneal dialysis patients and compare two different modalities of injecting ferric gluconate intravenously.. Twenty peritoneal dialysis patients (10M/10F, mean age 60 +/- 16 years) were given i.v. iron gluconate (62.5 mg) both concentrated (1-2 min, PULSE) and diluted in 100 ml of glucose solution (30 min, SLOW). The interval between the first and second administration was 15-60 days. Blood cell count, serum iron, total iron binding capacity (TIBC), ferritin, C-reactive protein (CRP), reactive oxygen species (ROS) concentrations and total antioxidant capacity (TAC) were measured before iron infusion (T0), after 30 min (T1) and after 24 h (T2).. No patient had clinical symptoms during or within an hour of iron administration. Serum transferrin was oversaturated in 25% of cases, no matter how iron was injected. Oxidative and inflammatory status parameters were not affected by iron administration: no difference in CRP, ROS concentrations or TAC was found at any time between PULSE and SLOW group.. Our findings showed that neither inflammation nor peroxidation in peritoneal dialysis patients was clinically triggered by 62.5 mg i.v. iron infusion. Both modalities were equally safe. Therefore, in the absence of clinical side effects, PULSE intravenous administration, being cheaper and not so problematic for outpatients, is preferable to SLOW.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cross-Over Studies; Female; Ferric Compounds; Humans; Inflammation; Inflammation Mediators; Infusions, Intravenous; Injections, Intravenous; Iron; Male; Middle Aged; Oxidative Stress; Peritoneal Dialysis; Random Allocation

Cardiovascular disease is the principal cause of morbidity and mortality in haemodialysis patients. The classic risk factors do not account for all cases of elevated cardiovascular disease in this patient population and it is becoming increasingly clear that other cardiovascular risk factors are implicated. The objective of this study was to analyse whether or not C-reactive protein (CRP) and plasma copper oxidized anti-lipoprotein (oxLDL) antibody titre are risk factors for cardiovascular mortality during 4 years of follow-up.. A prospective follow-up study was carried out in 94 stable, chronic haemodialysis patients for 48 months (July 1999-July 2003) (gender: 50 males and 44 females; mean age: 67+/-14 years). Eighty-four per cent of these patients were receiving intravenous erythropoietin and 63% were receiving intravenous ferrotherapy (iron gluconate). Basal markers of inflammation and oxidative stress were determined at the beginning of the study. CRP levels were determined by chemiluminescent enzyme-labelled immunometric assay. The oxLDL antibody titre was measured by enzyme-linked immunosorbent assay using native LDL and oxLDL as antigens.. Fifty deaths occurred during the study, 66% (n = 33) of which were due to cardiovascular disease. Patients presented with basal CRP and oxLDL levels indicative of chronic inflammation and elevated oxidative stress [CRP median: 5.16 mg/l (25-75% percentile: 0.35-88.7 mg/l); oxLDL antibodies median: 153 (optical density at 495 nm x 1000) (25-75% percentile: 112-214)]. A positive correlation was found between CRP and age (r = 0.33, P = 0.003). Study of the risk factors demonstrated that age (P = 0.007), oxLDL antibody titre (P = 0.04) and albumin (P = 0.02) were the only predictors of cardiovascular mortality at 4 years of follow-up in this patient population. The Cox proportional hazards model for cardiovascular mortality showed that of the markers studied, oxLDL antibody titre was an independent risk factor for cardiovascular mortality.. Oxidative stress (oxLDL antibody titre) is one of the principal risk factors for cardiovascular mortality in this population of haemodialysis patients. Intravenous ferrotherapy, due to its pro-oxidant properties, probably favours oxidative stress. Serum concentration of CRP was not a good predictive factor of cardiovascular mortality during 4 years of follow-up, possibly because of the slight positive correlation that exists between CRP and age.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Chronic Disease; Female; Ferric Compounds; Follow-Up Studies; Hematinics; Humans; Inflammation; Infusions, Intravenous; Kidney Diseases; Lipoproteins, LDL; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Prospective Studies; Renal Dialysis; Risk Factors; Survival Rate; Time Factors; Treatment Outcome

Elements of malnutrition-inflammation complex syndrome (MICS) may blunt the responsiveness of anemia of end-stage renal disease (ESRD) to recombinant human erythropoietin (EPO).. The authors examined cross-sectional associations between the required dose of EPO within a 13-week interval as prescribed by practicing nephrologists who were blind to the study and several laboratory values known to be related to nutrition and/or inflammation, as well as the malnutrition-inflammation score (MIS), which is a fully quantitative assessment tool based on the subjective global assessment of nutrition.. A total of 339 maintenance hemodialysis (MHD) outpatients, including 181 men, who were aged 54.7 +/- 14.5 years (mean +/- SD), who had undergone dialysis for 36.3 +/- 33.2 months, were selected randomly from 7 DaVita dialysis units in Los Angeles South/East Bay area. The average weekly dose of administered recombinant human EPO within a 13-week interval was 217 +/- 187 U/kg. Patients were receiving intravenous iron supplementation (iron gluconate or dextran) averaging 39.5 +/- 47.5 mg/wk. The MIS and serum concentrations of high-sensitivity C-reactive protein, interleukin 6 (IL-6), tumor necrosis factor-alpha, and lactate dehydrogenase had positive correlation with required EPO dose and EPO responsiveness index (EPO divided by hemoglobin), whereas serum total iron binding capacity (TIBC), prealbumin and total cholesterol, as well as blood lymphocyte count had statistically significant but negative correlations with indices of refractory anemia. Most correlations remained significant even after multivariate adjustment for case-mix and anemia factors and other relevant covariates. Similar associations were noticed across EPO per body weight tertiles via analysis of variance and after estimating odds ratio for higher versus lower tertile via logistic regression after same case-mix adjustment.. The existence of elements of MICS as indicated by a high MIS and increased levels of proinflammatory cytokines such as IL-6 as well as decreased nutritional values such as low serum concentrations of total cholesterol, prealbumin, and TIBC correlates with EPO hyporesponsiveness in MHD patients.

Topics: Aged; Anemia; Biomarkers; C-Reactive Protein; Epidemiologic Methods; Erythropoietin; Female; Ferric Compounds; Humans; Inflammation; Interleukin-6; Iron; Iron-Dextran Complex; Kidney Failure, Chronic; L-Lactate Dehydrogenase; Male; Malnutrition; Middle Aged; Recombinant Proteins; Renal Dialysis; Reproducibility of Results; Sex Factors; Syndrome; Tumor Necrosis Factor-alpha