ferric-oxide--saccharated and Proteinuria

Intravenous (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).. IRON-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.. Between October 2015 and April 2018, 521 individuals were identified as potential participants; 216\ were contacted, 56 expressed an interest, 49 attended a screening visit, and 40 were confirmed to meet the eligibility criteria and were randomly assigned. The mean age was 58.8 (standard error of the mean 2.2) years, and 23 (58%) were male. All patients were white and English-speaking. The mean SF was 68.8 μg/L, TS was 21.4%, and haemoglobin was 122.6 g/L at randomization for the whole group. The mean estimated glomerular filtration rate was 28.2 mL/min/1.73 m2 the urinary protein/ creatinine ratio was 154.2 mg/mmol, and CRP was 7.5 mg/L.. IRON-CKD will provide important information on the short-term effects of three preparations of IV iron in CKD patients with biochemical functional or absolute iron deficiency on measures of oxidative stress, inflammation, endothelial function, and renal injury.. European Clinical Trials Database (EudraCT) number 2010-020452-64 .

Topics: Acute Kidney Injury; Anemia, Iron-Deficiency; Biomarkers; Disaccharides; England; Female; Ferric Compounds; Ferric Oxide, Saccharated; Hematinics; Hemoglobins; Humans; Inflammation Mediators; Infusions, Intravenous; Iron-Dextran Complex; Kidney; Lipocalin-2; Male; Middle Aged; Oxidative Stress; Prospective Studies; Proteinuria; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome

Among patients with chronic kidney disease (CKD), differences in proteinuria are seen between intravenous iron preparations after a single dose exposure. This study examined differences in proteinuria between two intravenous iron preparations after multiple doses.. Patients with iron-deficiency anemia and CKD, stratified by angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor-blocker (ARB) use, were randomized to iron sucrose or ferric gluconate. Each patient at 12 centers received 100 mg of study drug weekly for 5 weeks. Urine protein/urine creatinine ratio was measured before each dose and frequently thereafter for 3 hours.. Postbaseline data were available from 33 patients receiving iron sucrose and 29 patients receiving ferric gluconate. Although neither preparation of intravenous iron increased the predose level of proteinuria, the proteinuric response to intravenous iron was dependent on the type of iron and ACEI/ARB use. Without ACEIs/ARBs, ferric gluconate tended to cause less proteinuria with repeated iron administration; iron sucrose did not mitigate or aggravate proteinuria. Among patients receiving ACEIs/ARBs, in contrast to ferric gluconate, which produced only mild transient proteinuria, iron sucrose produced a consistent and persistent proteinuric response that was on average 78% greater.. Although multiple doses of either intravenous iron did not increase basal levels of proteinuria, postdose proteinuria was greater with iron sucrose than with ferric gluconate. These data suggest that nephrotoxicity of iron may depend on type of intravenous iron and on ACEI/ARB use. The long-term effects on kidney function need to be further evaluated.

Topics: Adult; Aged; Albuminuria; Anemia, Iron-Deficiency; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Creatinine; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Humans; Kidney Diseases; Male; Middle Aged; Proteinuria

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

Albuminuria is an excellent marker of cardiovascular and renal prognosis. Commercially available tests of immunodetectable albumin in the urine may not identify posttranslationally modified albumin that makes it undetectable to antibodies. Also, it is unclear whether albumin is degraded to smaller fragments, such as through proteolysis, in the course of acute renal injury. In 20 men with chronic kidney disease, we measured excretion rates of urinary protein (pyragallol red), immundetectable urinary albumin (immunoturbidimetry), and urinary total intact albumin (HPLC) after a single dose of 100 mg intravenous iron sucrose administered over 5 min. Fragmentation of urinary albumin and carbonylation of urinary proteins were assessed by immunoblotting. Results showed that iron infusion increased carbonylation of plasma and urinary proteins in a time-dependent manner. A transient increase in urinary excretion rates of total protein, immunodetectable urinary albumin, and total intact albumin was seen. Fragmentation and loss of immunoreactivity of albumin paralleled the changes in total protein excretion. In conclusion, fragmentation, loss of immunoreactivity, and oxidation of albumin in a time-dependent manner may underestimate the extent of injury with the immunoreactive microalbumin assay. Measurement of total intact albumin may better quantify acute renal injury.

Topics: Aged; Albuminuria; Chronic Disease; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Humans; Immunoassay; Infusions, Intravenous; Kidney; Kidney Diseases; Kinetics; Male; Oxidation-Reduction; Oxidative Stress; Proteinuria; Sensitivity and Specificity; Serum Albumin

Intravenous iron preparations are key components in the management of anaemia of various etiologies. These iron-carbohydrate complexes permit safe systemic delivery of iron, whilst protecting from the potential toxic effects of over-saturation. This in turn permits efficient haematopoiesis following erythropoietin administration. Since the rate of release of iron is dependent upon the structure of this iron-carbohydrate complex, it is essential to ensure that an intravenous iron preparation is well characterized and its properties documented. This report describes physicochemical and toxicological studies into a new iron sucrose generic preparation, "Iron Sucrose Azad (ISA)", using the original iron sucrose product as reference. It could be demonstrated that the specifications and physicochemical characteristics of ISA reflect those of the reference product. Furthermore, in a rat model previously shown to identify possible toxicological effects of "unsimilar" iron sucrose preparations, ISA was found to have the same properties as the reference product, with both being well tolerated.

Topics: Algorithms; Animals; Chromatography, Gel; Chromatography, High Pressure Liquid; Creatinine; Drugs, Generic; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hematinics; Iron; Kinetics; Liver Function Tests; Microscopy, Atomic Force; Molecular Weight; Nephelometry and Turbidimetry; Particle Size; Polarography; Proteinuria; Rats; Rats, Sprague-Dawley; Reference Standards; Superoxide Dismutase

Intravenous (i.v.) iron is associated with a risk of oxidative stress. The effects of ferumoxytol, a recently approved i.v. iron preparation, were compared with those of ferric carboxymaltose, low molecular weight iron dextran and iron sucrose in the liver, kidneys and heart of normal rats. In contrast to iron sucrose and ferric carboxymaltose, low molecular weight iron dextran and ferumoxytol caused renal and hepatic damage as demonstrated by proteinuria and increased liver enzyme levels. Higher levels of oxidative stress in these tissues were also indicated, by significantly higher levels of malondialdehyde, significantly increased antioxidant enzyme activities, and a significant reduction in the reduced to oxidized glutathione ratio. Inflammatory markers were also significantly higher with ferumoxytol and low molecular weight iron dextran rats than iron sucrose and ferric carboxymaltose. Polarographic analysis suggested that ferumoxytol contains a component with a more positive reduction potential, which may facilitate iron-catalyzed formation of reactive oxygen species and thus be responsible for the observed effects. Only low molecular weight iron dextran induced oxidative stress and inflammation in the heart.

Topics: Animals; Antioxidants; Blood Pressure; Creatinine; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferrosoferric Oxide; Glucaric Acid; Heart; Hematinics; Immunohistochemistry; Inflammation; Injections, Intravenous; Iron-Dextran Complex; Kidney; Lipid Peroxidation; Liver; Magnetite Nanoparticles; Male; Maltose; Molecular Weight; Oxidative Stress; Proteinuria; Rats; Rats, Sprague-Dawley

Iron sucrose (Venofer; reference) has a good safety record and is prescribed in patients with anaemia and chronic kidney disease worldwide, but various iron sucrose similar (ISS) preparations are now utilized in clinical practice. This study evaluates possible differences between iron sucrose and ISS preparations on haemodynamic and oxidative stress markers in normal rats. 60 male and 60 female Sprague Dawley rats were divided into four groups and assigned to receive commercially available ISS test 1, ISS test 2, reference or isotonic saline solution (control). A single i.v. dose of iron (40 mg/kg) or saline (equivalent volume) was administered after 24 h and every 7 days for 4 weeks. Blood samples were collected for biological assessment of haemoglobin (Hb), serum iron and percentage transferrin saturation (TSAT), and urine samples were collected to investigate creatinine clearance and proteinuria. Animals were sacrificed after receiving an i.v. dose on days 1, 7 and 28, and kidney, liver, and heart homogenates were then collected to determine antioxidant enzyme levels. Tissues were processed using Prussian blue and immmunohistochemistry techniques to identify iron deposits, tissue ferritin and pro-inflammatory markers. Systolic blood pressure was significantly reduced in the ISS groups relative to the reference and control groups after 24 h and on days 7, 14 and 21 (p < 0.05). Creatinine clearance was reduced (p < 0.01) and proteinuria marked (p < 0.01) in the ISS groups at 24 h and on days 7 and 28 relative to the reference and control groups which did not differ throughout the study. Liver enzymes were also increased in the ISS groups at 24 h and on days 7 and 28. Both ISS test 1 and ISS test 2 groups presented a significant increase in catalase, thiobarbituric reactive species, Cu, Zn-superoxide dismutase (CuZnSOD) and glutathione peroxidase activity, and a decrease in glutathione levels (p < 0.01) in the liver, heart and kidney at 24 h and on day 7 relative to the reference and control groups. Serum iron and percentage TSAT were elevated in all groups (except control) (p < 0.01) but no differences in Hb concentration were observed between them. Finally, levels of the proinflammatory markers TNF-alpha and IL6 were significantly elevated in the ISS groups (liver, heart and kidney) compared with the reference and control groups on day 28 (p < 0.01). These findings suggest significant differences between the reference and ISS test 1/ISS test 2 regarding

Topics: Animals; Biomarkers; Blood Pressure; Chemistry, Pharmaceutical; Creatinine; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Glucaric Acid; Heart; Hematinics; Hemodynamics; Immunohistochemistry; Inflammation; Injections, Intravenous; Kidney; Liver; Male; Myocardium; Oxidative Stress; Proteinuria; Rats; Rats, Sprague-Dawley

Topics: Chronic Disease; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hematinics; Humans; Kidney Diseases; Male; Proteinuria; Renal Dialysis

Intravascular precipitates, comprised at least in part of iron, formed regularly in rabbits given one or more injections of a saccharated iron oxide preparation intravenously, and these lodged in numerous capillaries throughout the body, particularly those of the lungs and kidneys. Large numbers of the brownish precipitates remained in the capillaries of the renal glomeruli during the first few days following injection of the iron, but most of them disappeared after 5 to 7 days, with only moderate amounts of brown pigment remaining in the endothelial cells of the renal glomeruli. Signs of acute injury of the glomerular tufts-namely) pyknosis of some of the endothelial cells, margination of leukocytes within the glomerular capillaries, and slight proliferation of the epithelial cells-also developed some 5 to 7 days following injection of the iron, along with marked proteinuria, which proved transitory if no further injections were given. When the iron preparation was given repeatedly over prolonged intervals, however, the proteinuria persisted and became extreme, and hypoproteinemia developed, often with hypercholesterolemia and transitory edema as well. Histological studies of the kidneys of rabbits manifesting the nephrotic syndrome, as just described, disclosed that virtually all the renal glomeruli were greatly altered, mainly owing to proliferation of the epithelial cells, together with some fibrosis and atrophy. Some of the rabbits having marked proteinuria and other functional changes eventually developed azotemia following repeated injections of the iron, and several of them lost weight and died; the renal glomeruli of these animals showed changes like those just described, but the alterations were more extensive. Considered together, the findings provide evidence that the intravascular precipitates first occluded the glomerular capillaries for a period of several days following injection of the iron and then largely disappeared from them just prior to the development of morphologic signs of glomerular injury and proteinuria. Hence the possibility was considered that the intracapillary precipitates might have produced acute injury to the walls of the glomerular capllaries through the agency of anoxia. But it is plain that the findings of the present study do not disclose the essential nature of the anatomical change responsible for the proteinuria, or the means whereby this was produced. The findings as a whole were briefly considered in relation t

Topics: Animals; Capillaries; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Humans; Iron; Kidney; Kidney Diseases; Kidney Glomerulus; Nephrosis; Nephrotic Syndrome; Proteinuria; Rabbits