Iron Supplementation In Hemodialysis Patients Research Articles

Study of the effect and safety of oral lactoferrin therapy for functional iron deficiency anemia in prevalent hemodialysis patients

Background The commonly available therapeutic approaches for treating anemia of chronic kidney disease include oral and IV iron supplementation and erythropoiesis-stimulating agents. Lactoferrin, an iron-binding glycoprotein, has been studied for its effect on iron homeostasis. Aim of the work To study the effect and safety of oral lactoferrin therapy for functional iron deficiency anemia in prevalent hemodialysis patients. Patients and methods This is an interventional case–control study, conducted at Ain Shams University Hospital hemodialysis unit on 70 prevalent hemodialysis patients, who were divided into two groups: (Group A): 35 patients with functional iron-deficiency anemia, who received lactoferrin together with the recommended dose of ESA therapy for 3 months, (Group B): 35 patients with functional iron-deficiency anemia, who received only their recommended dose of ESA therapy for 3 months. Results Both groups were age and sex-matched. Both groups showed a significant improvement in their hemoglobin, ferritin, and iron levels after 3 months’ follow-up, with no difference between both groups. No significant difference was noticed in either WBCs or platelets during the study period. Conclusion Oral lactoferrin failed to show a superior effect on ESAs alone and could not be used as a substitute to totally replace IV iron supplementation in hemodialysis patients with FID.

Évaluation du fer sérique comme facteur prédictif d’une réponse de l’hémoglobine au traitement par fer injectable chez les patients hémodialysés chroniques

BackgroundThe detection and correction of iron deficiency are essential for the treatment of anemia in chronic hemodialysis patients. The aim of our study was to assess the ability of serum iron to predict hemoglobin response to intravenous iron supplementation in hemodialysis patients. MethodsIt is a retrospective study in 91 hemodialysis patients during 2016 at Clermont-Ferrand University Hospital for whom intravenous iron supplementation had been started. A responder patient was defined as an increase in hemoglobin greater than or equal to 1 g/dL/month and/or a decrease in the dose of erythropoiesis stimulating agent after two months of iron supplementation. ResultsIn responding patients, serum iron was significantly lower (6.7 ± 2.7 μmol/L) compared to non-responding patients (8.9±2.9 μmol/L; P<0.001). The positive response to iron supplementation was significantly associated with low serum iron (odds ratio = 0.58 [0.42–0.81]; P=0.002) in a logistic regression model taking into account ferritin, transferrin saturation coefficient, dose variation monthly iron and erythropoiesis stimulating agent and the duration of dialysis. The area under the receiver operating characteristic curve of serum iron, ferritin and transferrin saturation coefficient to predict the response to iron supplementation were 0.72, 0.51 and 0.64, respectively (serum iron versus ferritin [P=0.006] and serum iron versus transferrin saturation coefficient [P=0.04]). The sensitivity for serum iron below 7.5 μmol/L was better than that for ferritin below 86 ng/mL (P<0.001) and the specificity for serum iron below 7.5 μmol/L was better than that for TSC less than 19% (P=0.02). ConclusionSerum iron below 7.5 μmol/L can predict the success of the response to iron supplementation in chronic hemodialysis patients.

Protein-energy wasting and inflammation intervenes in control de anemia in hemodialysis patients treated with darbepoetin alpha as an erythropoiesis-stimulating agent

Rationale: Anemia is a multifactorial disorder that can be partially modified by eritropoyesis stimulating agents (ESA) and iron supplementation in hemodialysis patients (HD).The study aimed to analyse the relationship between protein-energy wasting (PEW), inflammation and anaemia and to assess whether the response to darbepoetin alpha (DA) was influenced by either of these two factors.

Holding Iron Measurement to a Gold Standard: Comparing Reticulocyte Hemoglobin Content to Traditional Biomarkers in Predicting Response to Intravenous Iron Supplementation in Hemodialysis Patients

Background: Patients suffering from end stage renal disease (ESRD) commonly develop functional and absolute iron deficiency due to various etiologies, requiring regular intravenous iron supplementation. Current methods of quantifying iron stores, such as serum iron and transferrin saturation (TSAT), may be inaccurate measures for detecting functional iron deficiency. This increases the likelihood of incomplete correction of iron deficiency or the risk of developing iron overload, both resulting in higher healthcare and administrative costs. Recent studies focusing on reticulocyte hemoglobin content (CHr) have shown it to be a specific and sensitive indicator of absolute and functional iron deficiency.Aims: To determine whether CHr is a more sensitive and accurate surrogate measure of response to iron infusion than traditional measurements such as serum iron and TSAT.Methods: We performed a retrospective chart review of patients aged ≥18 years with ESRD receiving dialysis and regular intravenous iron infusions at University of Iowa Hospitals and Clinics between October 2016 and March 2017 who also had applicable serial laboratory monitoring. Parameters analyzed included hemoglobin, hematocrit, CHr, serum iron, TSAT, total iron binding capacity, and ferritin. 3 months later, along with the total dose of iron infused over that specific timeframe, we obtained subsequent sets of these values.Results: Fifty-three eligible patients were identified, of which 63% were male and 37% female with a median age of 59 years. The median time interval between initial and subsequent laboratory testing was 91 days; the median cumulative iron infusion was 300 mg with doses ranging from 0 to 2100 mg. Correlation between variables of interest and iron dosing were calculated for serum iron (p = 0.49), TSAT (p = 0.16), and CHr (p = 0.99). With removal of subjects who had received the median 300 mg dose, correlation coefficients were recalculated for serum iron (p = 0.49), TSAT (p = 0.21), and CHr (p = 0.93).Conclusions: Contrary to published data, our study did not show any statistically significant support for CHr as a superior predictor of response to iron infusion when compared to traditional biomarkers. Our negative finding could be tempered by small sample size; this data was also not adjusted for other factors including hemoglobin level or erythropoiesis-stimulating agent administration. Given their reported resilience in response to acute fluctuations in patient inflammatory states and potentially decreased cost of testing versus the traditional iron panel, interest in reticulocyte parameters remains high. We plan to control for or identify any confounding factors by performing a prospective cohort study on a larger population to further elucidate the validity of this finding. DisclosuresNo relevant conflicts of interest to declare.

Potential effective treatment of shortening continuous erythropoietin receptor activator treatment interval combined with iron supplementation in hemodialysis patients

Our previous randomized controlled trial comparing the total dose of weekly versus biweekly continuous erythropoietin receptor activator (CERA) therapy to maintain optimal hemoglobin (Hb) levels showed no significant differences between the two therapies. This post-hoc analysis assessed whether the total dose of weekly versus biweekly CERA therapy to maintain Hb levels among HD patients differed among groups with or without iron supplementation. Of 107 patients, 40 received intravenous iron supplementation due to iron deficiency (iron group) and 67 did not (non-iron group). In the iron group, the weekly therapy tended to require a lower total CERA dose compared with the biweekly therapy (274 ± 274 vs 381 ± 223 μg/12 weeks, P = 0.051). Changes in circulating hepcidin levels, a negative regulator of intestinal iron uptake, after 2 weeks of CERA treatment were significantly lower in the weekly therapy compared with the biweekly therapy (−4.2 ± 6.3 vs 11.1 ± 7.3 ng/mL, P = 0.015). In the non-iron group, there were no significant differences in total CERA dose or changes in hepcidin levels between the two therapies. Shortening the CERA treatment interval combined with iron supplementation may lead to the more efficient treatment of HD patients with iron deficiency.

High fibroblast growth factor 23 levels are associated with decreased ferritin levels and increased intravenous iron doses in hemodialysis patients.

A recent study demonstrated the association between inflammation, iron metabolism and fibroblast growth factor (FGF) 23. The present clinical study aimed to assess associations between anemia, iron metabolism and FGF23 in hemodialysis (HD) patients. This prospective observational study examined a cohort of prevalent HD patients (n = 282). Blood samples were obtained before dialysis sessions to measure baseline levels of hemoglobin (Hb), transferrin saturation (TSAT), ferritin, albumin-adjusted calcium (Ca), phosphate (P), intact (i)-PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, intact (i)-FGF23, high sensitive (hs)-CRP, and interleukin-6. After the baseline measurement, study patients were followed-up for 6 months. Biochemical measurements were subsequently performed at 1 (Hb), 2 (TSAT and ferritin) or 3 (Ca, P and hs-CRP) month intervals. Doses of ESAs and intravenous iron supplementation during the study period were recorded. i-FGF23 was positively correlated with Ca, P, i-PTH and inversely correlated with TSAT and ferritin. However, levels of Hb and hs-CRP and doses of ESAs during the study period did not differ among the i-FGF23 tertiles, with levels of ferritin and TSAT in the higher i-FGF23 tertile being consistently lower than in the middle to lower i-FGF23 tertiles. Multivariate repeated measures analysis indicated that the higher i-FGF23 tertile was independently associated with repeated measurements of ferritin, but not of TSAT. Doses of intravenous iron supplementation were significantly increased in the higher i-FGF23 tertile in multivariate models. In conclusion, high i-FGF23 levels may be associated with prolongation of low levels of ferritin, resulting in increased usages of iron supplementation in HD patients.

Safety of intravenous iron in hemodialysis patients.

Among end-stage renal disease patients maintained by hemodialysis, anemia has been managed primarily through erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron. Following concerns about the cardiovascular (CV) safety of ESAs and changes in the reimbursement policies in Medicare's ESRD program, the use of IV iron has increased. IV iron supplementation promotes hemoglobin production and reduces ESA requirements, yet there exists relatively little evidence on the long-term safety of iron supplementation in hemodialysis patients. Labile iron can induce oxidative stress and is also essential in bacterial growth, leading to concerns about IV iron use and risk of CV events and infections in hemodialysis patients. Existing randomized controlled trials provide little evidence about safety due to insufficient power and short follow-up; recent observational studies have been inconsistent, but some have associated iron exposure with increased risk of infections and CV events. Given the widespread use and potential safety concerns related to IV iron, well-designed large prospective studies are needed to assess to identify optimal strategies for iron administration that maximize its benefits while avoiding potential risks.

Beneficial Effects of Oral Iron in Japanese Patients on Hemodialysis.

Objective Iron deficiency anemia (IDA) has become important with regard to mortality in hemodialysis (HD) patients. Therefore, it is necessary to optimize the treatment of these patients. Methods IDA in end-stage renal disease patients on HD was observed in 42 (33.6%) of 125 patients. We examined the influence of daily orally iron [sodium ferrous citrate (SFC) iron/tablet 50 mg, 1-2 tablets] on the renal function markers, anemia and iron data for about 6 months. Results The hematocrit and hemoglobin levels were significantly increased in the patients treated with SFC [hematocrit: before 28.5%±2.1% (mean ± standard deviation), 1st month 30.0%±2.3%, p<0.05; 3rd month 32.4%±2.9%, p<0.05; 6th month 31.3%±3.4%, p<0.05; and hemoglobin: before 9.25±0.70, 1st month 9.72±0.71, p<0.05; 3rd month 10.54±0.96, p<0.05; 6th month 10.25±1.21 g/dL, p<0.05]. The transferrin saturation (TSAT) and serum ferritin levels were significantly increased in the patients treated with SFC (TSAT: before 21.5%±10.0%, 1st-3rd month, 34.1%±15.1%, p<0.05; 6-8th month 34.7%±11.9%, p<0.05; and ferritin: before 38.2±37.1, 6-8th month 67.5±44.0 ng/mL, p<0.05). The present findings clearly indicate that oral iron is an effective route of iron supplementation in HD patients, and no adverse effects associated with SFC occurred during the treatment and follow-up period. Conclusion Our results clearly indicate that oral iron delivered via SFC is a well-tolerated and effective form of iron supplementation in long-term HD and IDA patients in Japan.

Hepcidin-25, mean corpuscular volume, and ferritin as predictors of response to oral iron supplementation in hemodialysis patients.

The benefit of oral iron therapy (OIT) and factors predictive of OIT response are not established in hemodialysis (HD) patients with iron deficiency anemia (IDA). We examined the values of hepcidin-25, mean corpuscular volume (MCV), and ferritin as predictors of OIT response. Oral ferrous fumarate (50 mg/day, 8 weeks) was given to 51 HD patients with IDA (hemoglobin (Hb) < 12 g/dL, ferritin < 100 ng/mL) treated with an erythropoietin activator. Sixteen patients were responders (improvement of Hb (ΔHb) ≥ 2 g/dL) and 35 were non-responders (ΔHb < 2g/dL). Baseline Hb, MCV, serum hepcidin-25, ferritin, iron parameters, and C-reactive protein (CRP) before and ΔHb after OIT were compared between groups. Hepcidin-25, MCV, ferritin, and transferrin saturation were lower in the responders than in the non-responders. Hepcidin-25 positively correlated with ferritin. Hepcidin-25, MCV, and ferritin positively correlated with baseline Hb and negatively correlated with ΔHb. Despite normal CRP levels in all patients, CRP correlated positively with hepcidin-25 and ferritin. Stepwise multiple linear regression analysis and receiver operating characteristics curve analysis revealed that hepcidin-25, MCV, and ferritin could predict OIT response. We conclude that hepcidin-25, MCV, and ferritin could be useful markers of iron storage status and may help predict OIT response in HD patients.

Investigation of Lipid Peroxidation Products and Antioxidant Enzyme Activities in End-Stage Renal Disease Patients

Background: Intravenous application of iron preparations which is a routine treatment of anemia in hemodialysis patients with end-stage renal disease can lead to iron overload in the body. Redox-active iron can catalyze the formation of hydroxyl radicals and initiation of lipid peroxidation, increase oxidative stress and speed up the development of complications in these patients. Objective: In this study, we determined the markers of lipid peroxidation, protein oxidation and antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase, glutathione S-transferase) in serum of patients with end-stage renal disease on hemodialysis, who had received repeated treatment of iron supplementation. Patients and Methods: The study included 29 patients undergoing regular hemodialysis treatment. These patients were divided into three groups according to the serum ferritin levels: group I (serum ferritin between 100 and 300 mg/L); group II (serum ferritin between 301 and 600 mg/L), and group III (serum ferritin above 601 mg/L). Results: The serum of patients with the highest concentration of serum ferritin and iron contained significantly higher level of lipid peroxidation products, total hydroperoxides and malondialdehyde and advanced oxidation protein products and the lowest concentration of sulfhydryl groups, reduced glutathione and total antioxidant capacity. Conclusion: Based on the obtained results, it can be concluded that iron supplementation in hemodialysis patients and consequently body iron overload of exacerbated oxidative stress have already been present in these patients.

Infection Risk with Bolus versus Maintenance Iron Supplementation in Hemodialysis Patients

Intravenous iron may promote bacterial growth and impair host defense, but the risk of infection associated with iron supplementation is not well defined. We conducted a retrospective cohort study of hemodialysis patients to compare the safety of bolus dosing, which provides a large amount of iron over a short period of time on an as-needed basis, with maintenance dosing, which provides smaller amounts of iron on a regular schedule to maintain iron repletion. Using clinical data from 117,050 patients of a large US dialysis provider merged with data from Medicare's ESRD program, we estimated the effects of iron dosing patterns during repeated 1-month exposure periods on risks of mortality and infection-related hospitalizations during the subsequent 3 months. Of 776,203 exposure/follow-up pairs, 13% involved bolus dosing, 49% involved maintenance dosing, and 38% did not include exposure to iron. Multivariable additive risk models found that patients receiving bolus versus maintenance iron were at increased risk of infection-related hospitalization (risk difference [RD], 25 additional events/1000 patient-years; 95% confidence interval [CI], 16 to 33) during follow-up. Risks were largest among patients with a catheter (RD, 73 events/1000 patient-years; 95% CI, 48 to 99) and a recent infection (RD, 57 events/1000 patient-years; 95% CI, 19 to 99). We also observed an association between bolus dosing and infection-related mortality. Compared with no iron, maintenance dosing did not associate with increased risks for adverse outcomes. These results suggest that maintenance iron supplementation may result in fewer infections than bolus dosing, particularly among patients with a catheter.

Labile Plasma Iron Generation After Intravenous Iron is Time‐dependent and Transitory in Patients Undergoing Chronic Hemodialysis

Iron supplementation in hemodialysis patients is fundamental to erythropoiesis, but may cause harmful effects. We measured oxidative stress using labile plasma iron (LPI) after parenteral iron replacement in chronic hemodialysis patients. Intravenous iron saccharate (100 mg) was administered in patients undergoing chronic hemodialysis (N = 20). LPI was measured by an oxidant-sensitive fluorescent probe at the beginning of dialysis session (T0), at 10 min (T1), 20 min (T2), and 30 min (T3) after the infusion of iron and at the subsequent session; P < 0.05 was significant. The LPI values were significantly raised according to the time of administration and were transitory: -0.02 +/- 0.20 micromol/L at the beginning of the first session, 0.01 +/- 0.26 micromol/L at T0, 0.03 +/- 0.23 micromol/L at T1, 0.09 +/- 0.28 micromol/L at T2, 0.18 +/- 0.52 micromol/L at T3, and -0.02 +/- 0.16 micromol/L (P = 0.001 to 0.041) at the beginning of the second session. The LPI level in patients without iron supplementation was -0.06 +/- 0.16 micromol/L. Correlations of LPI according to time were T1, T2, and T3 vs. serum iron (P = 0.01, P = 0.007, and P = 0.0025, respectively), and T2 and T3 vs. transferrin saturation (P = 0.001 and P = 0.0003, respectively). LPI generation after intravenous saccharate administration is time-dependent and transitorily detected during hemodialysis. The LPI increment had a positive correlation to iron and transferrin saturation.

TOTAL DOSE INFUSION IRON DEXTRAN THERAPY IN PREDIALYSIS CHRONIC RENAL FAILURE PATIENTS

Background: Intravenous iron therapy is now the standard modality of iron supplementation in hemodialysis patients, but its role in predialysis chronic renal failure patients is less well established. The efficacy and safety of intravenous iron dextran as a total dose infusion in predialysis chronic renal failure patients, not receiving erythropoietin was assessed in this study. Methods: Fifty-six predialysis chronic renal failure patients with anemia, not receiving erythropoietin were included in the study, after obtaining informed consent. Hemoglobin, serum creatinine, creatinine clearance rate and serum ferritin were assessed in all the patients at baseline. Iron dextran in a dose of 1 g dissolved in 500 mL normal saline was administered to all patients as a total dose infusion over 6 h after a prior test dose. Patients were kept in hospital under observation for at least 24 h. All the parameters were repeated in all the patients at 12 weeks and in 21 patients at 1 year. Results: The mean hemoglobin (g/dL) in the patients at baseline and at 12 weeks was 8.28 ± 0.57 and 9.22 ± 0.44 respectively (p<0.001). The mean serum ferritin (ng/mL) increased from 29.73 ± 9.38 at baseline to 218.43 ± 15.66 at 12 weeks (p< 0.00001). The mean ferritin value in the 21 patients at 1 year was 136.5 ± 23.4 (p<0.01). There were no major adverse events and only minor side effects were observed in 4.9% patients. Conclusion: Iron dextran as a total dose infusion corrects anemia in predialysis patients and is an effective method to replenish iron stores. The effect on serum ferritin are evident even at 1 year after the total dose infusion.

Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation

We have compared the efficacy of oral to intravenous iron for the chronic maintenance of iron stores in hemodialysis patients. Fifty-two hemodialysis patients with initial serum ferritin greater than 100 ng/mL and transferrin saturation greater than 15% were randomly assigned to one of two groups: those receiving oral iron therapy (n = 32) and those receiving intravenous iron dextran (100 mg twice weekly) (n = 20). At study completion (4 months), the mean hematocrit was significantly higher in the intravenous group than in the oral iron group (34.4% ± 0.7% v 31.8% ± 0.4%, respectively; P < 0.05), the final mean recombinant human erythropoietin dose was 46% lower in the intravenous iron group than in the oral group (4,050 ± 634 U/treatment v 7,563 ± 378 U/ treatment; P < 0.05), and the mean serum ferritin was significantly higher in the intravenous group than in the oral iron group (753.9 ± 30.2 ng/mL v 157.3 ± 15.4 ng/mL, respectively; P < 0.05). We have found that administering iron intravenously instead of orally for chronic maintenance iron supplementation in hemodialysis patients resulted in improved erythropoiesis. We hypothesize that most hemodialysis patients have inadequate iron stores for optimal erythropoiesis when currently recommended levels of ferritin and transferrin saturation are used to guide therapy, and that the chronic use of intravenous iron could reduce recombinant human erythropoietin requirements by maximizing iron stores. The improvement in erythropoiesis was accompanied, however, by an increase in iron indices to levels that could be indicative of tissue iron overload. Future studies must be performed to determine whether lower doses of intravenous iron dextran would improve erythropoiesis without causing potential organ iron overload.