Low-molecular weight iron dextran and iron sucrose have similar comparative safety profiles in chronic kidney disease

Serious adverse events that occur with the administration of iron dextran are due to the high molecular weight preparations. Conclusions that iron sucrose and ferric gluconate are safer than iron dextran may be premature. Published literature comparing safety profiles of available parenteral iron products is reviewed. Administration of iron salts to pre-dialysis patients with chronic kidney disease may not be optimal. We recommend the total dose infusion of low molecular weight iron dextran as an option for iron replacement.     

Comparing the efficacy of intravenous iron and oral iron in nondialysis patients with chronic kidney disease

This Practice Point commentary discusses the findings and limitations of a phase III trial by Spinowitz et al. that compared oral and intravenous iron therapies in nondialysis patients with chronic kidney disease. In total, 304 patients were randomly assigned in a 3:1 ratio to receive either two 510 mg doses of intravenous ferumoxytol within 5+/-3 days or 200mg of elemental oral iron daily for 21 days. At day 35, hemoglobin levels had increased significantly more in patients who had received intravenous ferumoxytol than in those who had received oral iron therapy. Ferumoxytol was well tolerated. The superiority of ferumoxytol over other intravenous iron preparations, however, needs to be investigated, and optimal serum ferritin levels for the nondialysis CKD population need to be defined.     

Oxidative stress and renal injury with intravenous iron in patients with chronic kidney disease

BACKGROUND: Intravenous iron is widely prescribed in patients with chronic kidney disease (CKD) and can cause oxidative stress. The relationship of oxidative stress and renal injury in patients with CKD is unknown. Whether renal injury can occur at a time point when transferrin is incompletely saturated is also unclear. METHODS: We conducted a randomized, open-label, parallel group trial to compare the oxidative stress induced by intravenous administration of 100 mg iron sucrose over 5 minutes and its protection with N-acetylcysteine (NAC) in 20 subjects with stage 3 or 4 CKD. Transferrin saturation was measured with urea polyacrylamide gel electrophoresis, oxidative stress by malondialdehyde (MDA) measurement by high-performance liquid chromatography, and renal injury by enzymuria and proteinuria. Reduced and oxidized glutathione and free radical scavengers as well as urinary monocyte chemoattractant protein-1 were also measured. RESULTS: Parenteral iron increased plasma concentration and urinary excretion rate of MDA, a biomarker of lipid peroxidation, within 15 to 30 minutes of iron sucrose administration. This was accompanied by enzymuria and increase in proteinuria. In contrast, saturation of transferrin was not maximally seen until 3 hours after the end of infusion. Oxidative stress, enzymuria and proteinuria were transient and were completely resolved in 24 hours. NAC reduced acute generation of systemic oxidative stress but failed to abrogate proteinuria or enzymuria. CONCLUSION: Intravenous iron produces oxidative stress that is associated with transient proteinuria and tubular damage. The rapid production of oxidative stress even when transferrin is not completely saturation suggests free iron independent mechanism(s) to be operative in producing oxidative stress and transient renal injury. Long-term implications of these findings need further study.     

The safety and efficacy of an accelerated iron sucrose dosing regimen in patients with chronic kidney disease

BACKGROUND: Provision of adequate iron to support erythropoiesis in patients with chronic kidney disease (CKD) is time consuming and may present adherence problems for patients in the outpatient setting. We studied an accelerated regimen of high-dose intravenous iron sucrose therapy in a cohort of iron-deficient, anemic CKD patients. METHODS: Intravenous iron sucrose 500 mg was infused over three hours on two consecutive days in 107 CKD patients (glomerular filtration rate, 32.3 +/- 19.6 mL/min/1.73m2, baseline hemoglobin 10.2 +/- 1.7 g/dL). Iron indices (transferrin saturation, ferritin) were measured at baseline and at two and seven days after completion of the iron regimen. Blood pressures were monitored immediately prior to, and hourly throughout the iron sucrose infusions. RESULTS: Transferrin saturation and serum ferritin increased from 18.5 +/- 8.5% and 177 +/- 123.8 ng/mL at baseline to 40.2 +/- 22.3% and 811 +/- 294.1 ng/mL in 102 evaluated patients (P < 0.015). In 55 patients with additional measurements at 7 days post-dosing, the transferrin saturation and ferritin had fallen to 26.3 +/- 10.6% and 691 +/- 261.8 ng/mL (P < 0.015 compared to two days' post-dose). Blood pressure rose slightly, but not significantly, throughout the infusions, and altering the infusion rate was not necessary. Two patients had seven adverse events that were considered related to iron sucrose. CONCLUSION: An accelerated regimen of high-dose intravenous iron sucrose therapy in CKD patients is safe and effective in restoring iron stores, and may potentially save time and improve patient adherence.     

A randomized controlled trial of oral versus intravenous iron in chronic kidney disease

BACKGROUND: It is unknown whether intravenous iron or oral iron repletion alone can correct anemia associated with chronic kidney disease (CKD). We conducted a randomized multicenter controlled trial in adult anemic, iron-deficient non-dialysis CKD (ND-CKD) patients (>or=stage 3) not receiving erythropoiesis-stimulating agents (ESAs). METHODS: The participants were randomized to receive either a sodium ferric gluconate complex (intravenous iron) 250 mg i.v. weekly x 4 or ferrous sulfate (oral iron) 325 mg t.i.d. x 42 days. Hemoglobin (Hgb), ferritin and transferrin saturation (TSAT) were measured serially, and the Kidney Disease Quality of Life (KDQoL) questionnaire was administered on days 1 and 43. The primary outcome variable was change from baseline (CFB) to endpoint in Hgb values. RESULTS: Seventy-five patients were analyzed (intravenous iron n = 36, oral iron n = 39). CFB in Hgb was similar in the two groups (intravenous iron 0.4 g/dl vs. oral iron 0.2 g/dl, p = n.s.). However, the increase in Hgb was only significant with intravenous iron (p < 0.01). In comparison to oral iron, intravenous iron achieved greater improvements in ferritin (232.0 +/- 160.8 vs. 55.9 +/- 236.2 ng/ml, p < 0.001) and TSAT (8.3 +/- 7.5 vs. 2.9 +/- 8.8%, p = 0.007). Intravenous iron caused greater improvements in KDQoL scores than oral iron (p < 0.05). The most common side effect reported with intravenous iron was hypotension, while constipation was more common with oral iron. CONCLUSIONS: Oral and intravenous iron similarly increase Hgb in anemic iron-depleted ND-CKD patients not receiving ESAs. Although in comparison to oral iron, intravenous iron may result in a more rapid repletion of iron stores and greater improvement in quality of life, it exposes the patients to a greater risk of adverse effects and increases inconvenience and cost.     

静脉补铁与口服补铁治疗非透析慢性肾功能不全患者贫血效果比较的Meta分析

目的通过系统评价评估静脉补铁与口服补铁两种补铁方法对治疗非透析慢性肾功能不全(ND-CKD)患者贫血的疗效。 方法通过计算机并结合手工检索,检索EMBASE、PUBMED、Cochrane Library,检索时间截止到2017年12月1日,查找所有关于静脉补铁与口服补铁治疗ND-CKD患者贫血疗效的全部外文随机对照试验(RCT)。所得数据采用Rev Man 5.0软件进行Meta分析。 结果共纳入11项外文RCT研究,合计共1 707例患者,其中静脉补铁852例,口服补铁855例。分析结果示,与口服补铁相比,静脉补铁可显著提高血红蛋白(WMD 0.39 g/dl,95%CI,0.26～0.52;P<0.0001)、转铁蛋白饱和度(TSAT)(WMD 3.97%; 95%CI,2.24～5.7;P<0.0001)及铁蛋白水平(WMD,244.51 ng/ml,95%CI,185.51～303.52; P<0.0001);两种补铁方法的不良事件发生率无明显差别(RR,0.79; 95%CI,0.44～1.44;P＝0.45)。 结论通过系统评价得出：与口服补铁相比,静脉补铁对治疗非透析慢性肾功能不全患者的贫血疗效较好。     

慢性肾小球肾炎患者血清新蝶呤的水平及其意义

静脉使用蔗糖铁已被广泛地用于血液透析患者肾性贫血的治疗,但在非透析慢性肾脏病(NDCKD)患者中使用不多,大剂量蔗糖铁在NDCKD患者中使用的研究报道更少.我科对使用大剂量蔗糖铁治疗肾性贫血伴铁缺乏的NDCKD患者的安全性及有效性进行了观察.     

Iron deficiency in patients with chronic kidney disease: potential role for intravenous iron therapy independent of erythropoietin

The prevalence of iron deficiency and its contribution to the anemia of end stage renal disease has been extensively studied, but much less is known about the role of iron deficiency in the pathogenesis of the anemia of chronic kidney disease in predialysis patients. All new hemodialysis patients entering a single hemodialysis unit between July 1999 and April 2002 were included in the study. The admission laboratory tests and the Health Care Financing Administration (HCFA) 2728 form were examined to determine the prevalence of erythropoietin use, anemia (Hb < 11 g/dl), and iron deficiency (ferritin < 100 ng/ml and transferrin saturation % < 20%). In a second part of the study, the effect of intravenous iron gluconate replacement in patients with stage III & IV chronic kidney disease was examined. Anemia was present in 68% of all patients starting hemodialysis. Iron deficiency was a common feature occurring in 29% of patients taking erythropoietin (49% of all patients) and 26% of patients without erythropoietin (51% of all patients). Following the administration of intravenous iron gluconate to four patients, there was a significant rise in hemoglobin levels from 10.6 ± 0.19 to 11.7 ± g/dl (p = 0.02). Conclusion: Iron deficiency is common in predialysis patients. Replenishing iron stores in anemic patients with chronic kidney disease significantly increases hemoglobin levels and should be considered as an integral part of the therapy for treating anemia in the predialysis population.     

The comparative safety of intravenous iron dextran, iron saccharate, and sodium ferric gluconate

Intravenous iron treatment is an important component of anemia therapy for patients on dialysis. Until recently iron dextran was the only parenteral form of iron available in the United States. This drug has been associated with occasional serious adverse reactions, including full-blown anaphylaxis. In 1999 the Food and Drug Administration approved a second form of iron for intravenous administration, sodium ferric gluconate in sucrose. It is expected that by the time of this publication, a third agent, iron saccharate will also be approved. In this review the comparative safety of these three agents is critically evaluated.     

The safety and efficacy of ferumoxytol therapy in anemic chronic kidney disease patients

BACKGROUND: Administration of safe and effective iron therapy in patients with chronic kidney disease is a time consuming process. This phase II clinical trial studied ferumoxytol, a semi-synthetic carbohydrate-coated iron oxide administered by rapid intravenous injection to anemic chronic kidney disease patients (predialysis or undergoing peritoneal dialysis). METHODS: Inclusion criteria included hemoglobin < or =12.5 g/dL and transferrin saturation < or =35%. Twenty-one adult patients were randomized to receive ferumoxytol in a regimen of 4 doses of 255 mg iron in 2 weeks or 2 doses of 510 mg iron in 1 to 2 weeks. Ferumoxytol was administered at a rate of up to 30 mg iron/sec. RESULTS: The maximum hemoglobin response following ferumoxytol administration occurred at 6 weeks, increasing from a baseline of 10.4 +/- 1.3 g/dL to 11.4 +/- 1.2 g/dL (P < 0.05). Ferritin increased from a baseline of 232 +/- 216 ng/mL to a maximum of 931 +/- 361 ng/mL at 2 weeks (P < 0.05), while the baseline transferrin saturation increased from 21 +/- 10% to 37 +/- 22% at 1 week (P < 0.05). Seven adverse events in 5 patients during this trial were deemed possibly related to ferumoxytol, none serious. These events included constipation, chills, tingling, a gastrointestinal viral syndrome, delayed pruritic erythematous rash, and transient pain at the injection site. CONCLUSION: Although larger studies are required, this small study demonstrates that ferumoxytol can be safe and effective in increasing iron stores, is associated with an increased hemoglobin response, and is well tolerated at a rapid infusion rate.     

Oxidants and iron in chronic kidney disease

Oxidants derived either from leukocytes in proliferative glomerular nephritis or from resident glomerular cells in nonproliferative glomerulonephritis have been shown to have several biologic effects relevant to chronic kidney disease. These include: the ability of oxidants to damage glomerular basement membrane (GBM) and to directly induce proteinuria; effects that would lead to a fall in the glomerular filtration rate; and effects that would account for the morphologic changes observed in chronic kidney disease. In experimental models the role of oxidants has been demonstrated in both proliferative glomerulonephritis (e.g., anti-GBM antibody disease) as well as experimental models of minimal change disease and membranous nephropathy. Oxidants have also been shown to be an important mediator of the various pathways that have been implicated in diabetic nephropathy. Antioxidants and iron chelators have also been shown to retard functional and morphologic changes observed in progressive kidney disease. Taken together, these experimental studies suggest an important role of oxidants in chronic kidney disease.     

Rapid, high-dose intravenous iron sucrose therapy in 2 Jehovah's Witness patients with severe anemia, iron deficiency and chronic kidney disease

AIMS: Two patients with chronic kidney disease presented with severe anemia and iron deficiency. Because of their religious beliefs, red blood cell transfusions were not possible, and an aggressive therapeutic regimen of iron replenishment was instituted. MATERIAL AND METHODS: The regimen included epoetin, folic acid and high-dose intravenous iron sucrose infusions over multiple successive days (total dosages of 2 and 3.5 g). RESULTS: The patients' iron stores were replenished and an erythropoietic response ensued subsequent to this aggressive and unique therapeutic regimen. There were no side effects observed which could be attributed to iron sucrose, and both patients stabilized and were discharged after 3 - 4 weeks. CONCLUSION: In patients with chronic kidney disease who are severely anemic and iron-deficient and where transfusions are not possible, an aggressive regimen of multiple high-dose iron sucrose infusions may be both safe and effective.     

Intravenous iron treatment in paediatric chronic kidney disease patients not on erythropoietin

Intravenous (IV) iron treatment reduces erythropoietin (EPO) dose in paediatric haemodialysis patients. The efficacy in paediatric nonhaemodialysis patients is less well established. IV iron is routinely given in our institution to these patients, including some who have not started EPO. The effect of this strategy was examined. Patients with chronic kidney disease (CKD) or peritoneal dialysis (PD) not on EPO were identified. Case notes were reviewed for haemoglobin (Hb), red cell and iron indices for 6 months before and at least 3 months after IV iron. Five patients were identified. Mean age was 13.3 years and mean IV iron (Venofer) dose = 3.1 mg/kg. Median number of doses = 7 (range 3–10). Hb increased significantly after IV iron from 11.4 ± 0.7 to 12.8 ± 1.3 g/dl (p = 0.02). Mean cell volume increased from 87.7±3.4 to 90.1 ± 3.7 fl (p = 0.01), and mean cell Hb remained unchanged: 29.2 ± 1.2 to 29.7 ± 1.0 pg (p = 0.12). Absolute and percentage reticulocyte count remained unchanged. There was no change in iron indices: ferritin 55.1 ± 31.3 to 97.3 ± 46.5 ng/ml (p = 0.3), iron 18.9 ± 6.9 to 18.1 ± 4.2 μmol/l (p = 0.7), transferrin 1.9 ± 1.6 to 2.0 ± 0.1 g/l (p = 1.0), transferrin saturation 35.7 ± 8.1 to 40.3 ± 18.0% (p = 0.5). IV iron slightly improved Hb levels in five paediatric CKD and PD patients not receiving EPO. This strategy may delay the need for EPO treatment and deserves further evaluation.     

Zinc levels after iron supplementation in patients with chronic kidney disease.

OBJECTIVE: The goal of this study was to evaluate the effects of iron supplementation on zinc distribution in nondialyzed chronic kidney disease (CKD) patients. DESIGN: Prospective nonrandomized observational study. SETTING: Outpatients of the Nephrology Division at Federal University of S?o Paulo. PATIENTS: Zinc and iron status of 38 nondialyzed patients (63% male; creatinine clearance, 34.5+/-13.3 mL/min/1.73 m2) was evaluated before and after 3 intramuscular injections of 100 mg iron each. MAIN OUTCOME MEASURES: The following parameters were analyzed: erythrocytes and plasma zinc, zinc protoporphyrin (ZPP), plasma ferritin, transferrin saturation (TFS), and total iron. The patients' diets were analyzed by the Association of Official Analytical Chemists method for macronutrients, and neutron activation analysis was used for iron and zinc concentration determinations. RESULTS: Ferritin and TFS increased from 86.3+/-67.5 ng/mL to 105.4+/-63.7 ng/mL and from 19.5+/-7.4% to 23.2+/-6.7% (P <.05), respectively, after iron supplementation. Absolute iron deficiency (ferritin <100 microg/L and TFS <20%) was present in 41% of the patients and decreased to 15.7% after iron treatment. In comparison with baseline values (76.4+/-16.7 microg/dL), there were no significant changes in plasma zinc levels, but after supplementation the number of patients with low plasma zinc levels decreased from 46.1% to 23.7% (P =.08). At baseline, erythrocyte zinc was 49.0+/-7.6 microg Zn/gHb, and 76.3% of the patients had high erythrocyte zinc concentration. After iron treatment, erythrocyte zinc decreased to 45.5+/-7.3 microg Zn/gHb (P =.001). No significant change was observed in ZPP concentration. The analysis of the diet showed energy and protein intakes of 26.2+/-7.1 kcal/kg/day and 0.89+/-0.2 g/kg/day, respectively, and a low intake of both iron and zinc. CONCLUSIONS: This study suggests that iron deficiency may contribute to the inadequate distribution of zinc in patients with CKD and that iron supplementation may decrease the abnormal elevated erythrocyte zinc levels of these patients.     

Proinflammatory effects of iron sucrose in chronic kidney disease

Inflammation is a central component of progressive chronic kidney disease (CKD). Iron promotes oxidative stress and inflammatory response in animals and promotes progressive CKD. Parenteral iron provokes oxidative stress in patients with CKD; however, its potential to provoke an inflammatory response is unknown. In 20 veterans with CKD, 100 mg iron sucrose was administered intravenously over 5 min and urinary excretion rate and plasma concentration of monocyte chemoattractant protein-1 (MCP-1) were measured at timed intervals over 24 h. Patients were then randomized to placebo or N-acetyl cysteine (NAC) 600 mg b.i.d. and the experiment was repeated at 1 week. Iron sucrose markedly increased plasma concentration and urinary excretion rate of MCP-1 at baseline and at 1 week visits (P < 0.0001 for time effect). Urinary excretion peaked at 30 min and plasma concentration at 15 min. Plasma MCP-1 concentration fell from 164 +/- 17.7 to 135 +/- 17.7 pg/ml with NAC, whereas it remained unchanged from 133 +/- 12.5 to 132 +/- 17.7 pg/ml with placebo (P=0.001 for visit x antioxidant drug interaction). There was a reduction in MCP-1 urinary excretion rate from visit 1 to 2. At the baseline visit, the urinary excretion rate averaged 305 +/- 66 pg/min and at the second visit 245 +/- 67 pg/min (mean difference 60 +/- 28 pg/min, P = 0.030). There was no improvement in urinary MCP-1 excretion with NAC. In conclusion, iron sucrose causes rapid and transient generation and/or release of MCP-1 plasma concentration and increases urinary excretion rate, and systemic MCP-1 level but the urinary excretion rate is not abrogated with the antioxidant NAC. These results may have implications for the progression of CKD with parenteral iron.     

Efficacy and safety of lanthanum carbonate in chronic kidney disease patients with hyperphosphataemia

Hyperphosphataemia is a frequent complication in patients with chronic kidney disease and is associated with increased cardiovascular morbidity. Lanthanum carbonate is a calcium-free phosphate binder indicated in patients with chronic kidney disease. Its digestive absorption is minimal (<0,002%). This minimal quantity is rapidly excreted by the hepatobiliary system, but there is an initial accumulation in liver and bone, which reaches a plateau within a few weeks. Long-term follow-up until six years did not show any bone or liver toxicity. Efficacy and safety of lanthanum carbonate have been assessed in randomized trials. The most common side effects reported were gastrointestinal and occurred with a similar incidence than with placebo and other phosphate binders. Hypercalcemia was less frequent than with calcium carbonate. This review highlights pharmacokinetic, pharmacodynamic and clinical (efficacy and safety) properties of lanthanum carbonate and discusses its place in the management of hyperphosphataemia in patients with chronic kidney disease.     

Preoperative intravenous hydration confers renoprotection in patients with chronic kidney disease undergoing cardiac surgery

Patients with chronic kidney disease (CKD) are at risk to develop acute renal failure (ARF) after open heart surgery. This complication is associated with high morbidity, mortality, and cost. Because the ability to concentrate urine is lost early in the progression of CKD, renal patients kept on fluid restriction prior to surgery may develop severe dehydration, a situation consistently found to be one of the most critical risk factors for postoperative ARF. Our goal was to investigate whether intravenous hydration for 12 h prior to cardiac surgery could prevent acute renal injury in patients with CKD. This is a prospective study in a tertiary cardiac surgery center. Forty-five patients admitted for elective open heart surgery with moderate-to-severe CKD, as evidenced by a quantified glomerular filtration rate less than 45 mL/min, were assigned using a 2/1 randomization process, to either receive an intravenous infusion of half-isotonic saline (1 mL/kg/h) for 12 h before the operation (hydration group, n = 30, 29 men, 64 + 1.7 years old), or to be simply kept on fluid restriction (control group, n = 15, 14 men, 64.2 + 2.8 years old). Groups were not different in clinical and intraoperative variables associated with postoperative renal injury. ARF developed in 8 of 15 (53%) patients in the control group, but in only 9 of the 30 (30%) patients in the hydration group. Four patients in the control group (27%), but no one in the hydration group, required dialysis after the operation (P < 0.01). Peak creatinine and blood urea nitrogen values were two to three times higher in the control group than in the hydration group. Preoperative intravenous hydration may ameliorate renal damage in patients with moderate-to-severe renal insufficiency undergoing cardiac surgery.