Acceleration of Iron Utilization After Intravenous Iron Administration During Activated Erythropoiesis in Hemodialysis Patients: A Randomized Study

This study aimed to evaluate the effect of different timings of iron administration during erythropoiesis activated by continuous erythropoietin receptor activator (CERA) on reticulocyte iron uptake in hemodialysis patients. In total, 110 patients were randomized to receive 40 mg intravenous elemental iron doses at all three hemodialysis sessions in the first week (IW1 group: n = 57) or in the third week (IW3 group: n = 53) after CERA administration. Following CERA administration at day 0, reticulocyte count increased, peaking at day 7. At days 7 and 14, the observed changes in Ret‐He were higher in the IW1 group than in the IW3 group. Increases in total reticulocyte hemoglobin at day 7 were higher in the IW1 group than in the IW3 group. In contrast, there was only tendency toward greater total reticulocyte hemoglobin after iron administration in the third week in the IW3 group. Intravenous iron supplementation in the first week of CERA administration increases reticulocyte iron uptake; however, iron supplementation in the third week does not. The findings indicate that iron should be intravenously administered to increase the efficacy of CERA within 1 week of CERA administration during highly active erythropoiesis.     

Impact of Switching From Darbepoetin Alfa to Epoetin Beta Pegol on Iron Utilization and Blood Pressure in Peritoneal Dialysis Patients

New erythropoiesis‐stimulating agents with a longer half‐life have been developed for the treatment of anemia in patients with end‐stage renal disease. This study evaluated the efficacy of darbepoetin alfa (DA) and long‐acting epoetin beta pegol (continuous erythropoietin receptor activator, CERA) in patients on peritoneal dialysis (PD). Twenty‐nine patients who had undergone PD for at least 6 months and were iron replacement‐naïve and negative for inflammatory parameters were enrolled. Hemoglobin (Hgb) levels and blood pressure were evaluated before and after switching from DA to CERA. Percent transferrin saturation (TSAT), serum ferritin levels and blood pressure were also assessed. Twenty‐eight patients were subject to the analysis, excluding one patient with a decrease in Hgb by ≥10%. Switching from DA to CERA did not alter Hgb levels. The doses of DA and CERA after 12 month treatment of each agent were 118.48 ± 79.63 and 89.88 ± 47.50 μg/4 weeks, respectively (conversion ratio, 1:0.76). The CERA dose administered during the final 6 months was abated, compared with that given during the initial 6 months (P = 0.035). The frequency of CERA injection over a 12‐month period was less than that of DA (10.0 ± 3.0 vs. 16.4 ± 5.0, P < 0.01). The conversion from DA to CERA did not alter TSAT, but decreased serum ferritin levels (from 202.69 ± 132.57 to 150.15 ± 110.07 ng/mL, P = 0.012) and systolic blood pressure (from 133.8 ± 17.3 to 129.5 ± 11.3 mm Hg, P = 0.024). In PD patients, lower doses and less frequent injection of CERA are sufficient to maintain Hgb at levels similar to those achieved by DA therapy, with improved iron utilization and reduced blood pressure.     

Erythropoiesis‐driven regulation of hepcidin in human red cell disorders is better reflected through concentrations of soluble transferrin receptor rather than growth differentiation factor 15

Growth differentiation factor 15 (GDF‐15) is a bone marrow‐derived cytokine whose ability to suppress iron regulator hepcidin in vitro and increased concentrations found in patients with ineffective erythropoiesis (IE) suggest that hepcidin deficiency mediated by GDF‐15 may be the pathophysiological explanation for nontransfusional iron overload. We aimed to compare GDF‐15 production in anemic states with different types of erythropoietic dysfunction. Complete blood counts, biochemical markers of iron status, plasma hepcidin, GDF‐15, and known hepcidin regulators [interleukin‐6 and erythropoietin (EPO)] were measured in 87 patients with red cell disorders comprising IE and hemolytic states: thalassemia, sickle cell anemia, and cobalamin deficiency. Healthy volunteers were also evaluated for comparison. Neither overall increased EPO, nor variable GDF‐15 concentrations correlated with circulating hepcidin concentrations (P = 0.265 and P = 0.872). Relative hepcidin deficiency was found in disorders presenting with concurrent elevation of GDF‐15 and soluble transferrin receptor (sTfR), a biomarker of erythropoiesis, and sTfR had the strongest correlation with hepcidin (r_S = ?0.584, P < 0.0001). Our data show that high concentrations of GDF‐15 in vivo are not necessarily associated with pathological hepcidin reduction, and hepcidin deficiency was only found when associated with sTfR overproduction. sTfR elevation may be a necessary common denominator of erythropoiesis‐driven mechanisms to favor iron absorption in anemic states and appears a suitable target for investigative approaches to iron disorders. Am. J. Hematol. 89:385–390, 2014. © 2013 Wiley Periodicals, Inc.     

Effects of Long‐Term Erythropoiesis‐Stimulating Agents on Iron Metabolism in Patients on Hemodialysis

Continuous erythropoietin receptor activator (CERA) and darbepoetin‐α (DA) might differently affect iron metabolism and erythropoiesis in patients on hemodialysis (HD). This prospective study examined a cohort of patients on HD who had received either intravenous CERA every 2 or 4 weeks (N = 25) or DA once each week (N = 47). Blood was sampled before HD sessions on days 0, 2, 4, 7 and 14, and on days 0, 3, 5, 7 and 14 from patients who were injected with ESA at the beginning and end of the dialysis week, respectively. Changes in factors indicating erythropoiesis and biomarkers of iron metabolism were examined. Hemoglobin levels were maintained in the target range between 10.0 and 11.0 g/dL and ferritin levels at baseline and during the study period were similar between the DA and CERA groups. Levels of hepcidin 25 decreased from days 2–3 to day 5 and returned to the baseline at day 7 in the DA group, whereas those and transferrin saturation were serially suppressed from days 2–3 to day 14 in the CERA group. Levels of soluble transferrin receptor and reticulocyte counts were significantly elevated from days 4–5 to day 14 by CERA. Both DA and CERA stabilized erythropoiesis, but CERA might mobilize iron from body stores more effectively than DA in patients on HD.     

Comparison of 2‐Week Versus 4‐Week Dosing Intervals of Epoetin Beta Pegol on Erythropoiesis and Iron Metabolism in Hemodialysis Patients

Epoetin beta pegol (a continuous erythropoietin receptor activator; CERA) is usually administered once in 4 weeks or once monthly. However, the optimal dosing interval remains unknown. We, therefore, compared the effect of CERA administration between dosing intervals of 2 weeks (TWICE group) and 4 weeks (ONCE group) on erythropoiesis and iron metabolism in 20 hemodialysis patients. CERA was administered intravenously at weeks 0 and 2 for the TWICE group, and at week 0 for the ONCE group. Levels of hemoglobin (Hb), reticulocyte count, ferritin, transferrin saturation, content of Hb in reticulocytes and hepcidin‐25 were monitored weekly for 4 weeks. Hemoglobin levels were significantly increased at weeks 3 and 4 in the TWICE group, while a gradual decrease after a significant increase at week 1 was observed in the ONCE group. Ferritin levels remained significantly low from week 1 to week 4 in the TWICE group. On the other hand, ferritin levels increased beyond baseline levels at week 4 in the ONCE group. Although hepcidin‐25 did not significantly increase in the TWICE group, significant increases beyond baseline levels at weeks 3 and 4 were found in the ONCE group. These results indicate that continuous erythropoiesis was achieved with biweekly administration of CERA. Moreover, CERA at a 2‐week interval led to a sustained suppression of ferritin and hepcidin‐25 levels, suggesting a favorable influence on iron metabolism.     

Impaired regulation of serum hepcidin during phlebotomy in patients with chronic hepatitis C

Aim: This study was conducted to determine the clinical relevance of hepcidin, a recently identified key iron regulatory hormone, in patients with chronic hepatitis C virus (C‐HCV). Methods: Serum hepcidin levels were measured in 9 C‐HCV patients by surface‐enhanced laser desorption/ionization time of flight mass spectrometry (SELDI‐TOF‐MS), and compared to those of healthy controls. Sequential changes of hepcidin were also investigated during phlebotomy. Results: Serum hepcidin and ferritin were significantly higher in C‐HCV than in controls (P = 0.0002), these two variables were strongly related to each other (r = 0.658; P < 0.01), and phlebotomy significantly decreased serum hepcidin in C‐HCV (P = 0.0007); all these results recollect the hepcidin response to iron signal. Hepcidin/ferritin ratio, an index of the appropriateness of hepcidin expression relative to iron overload, was significantly lower in C‐HCV than in controls (0.33 ± 0.41 vs. 0.73 ± 0.36, P = 0.0068). This relative impairment of hepcidin expression was not reversible after phlebotomy (P = NS). Conclusions: Although the hepcidin expression responds to iron conditions in C‐HCV, this response is relatively limited. This relative impairment of hepcidin expression may be relevant to disease progression, and thus correction of its regulation may be beneficial for these iron‐overloaded C‐HCV patients.     

Labile plasma iron,more practical and more sensitive to iron overload in myelodysplastic syndromes

Objectives: In order to gain an insight into labile plasma iron (LPI) in iron metabolism microenvironment in MDS.

Methods: We performed ELISA, quantitative real-time polymerase chain reaction, flow cytometry, MRI T2* assays to test LPI, iron biochemical parameters, and liver iron concentration (LIC) among 22 MDS patients.

Results: LPI has a statistical difference (P?P?=?0.086 by ANOVA). After DFO treatment, serum hepcidin expression increased from 301.26?±?59.78 to 340.33?±?49.78?µg/l (P?=?0.032), while hepcidin/ASF was upregulated gradually from 0.16?±?0.08 to 0.22?±?0.03 (P?=?0.045). APAF-1 expression (P?=?0.047) and erythroid apoptosis rate (P?=?0.009) decreased significantly, respectively. No statistical difference was found in EPO (P?=?0.247) and GDF15 expression (P?=?0.172). LIC dropped from 9.83?±?4.84 to 6.28?±?4.01?mg/g dry weight (P?P?=?0.594). LPI has a closer connection to LIC than ASF (r?=?0.739, P?r?=?0.321, P?=?0.034).

Discussion: LPI seems to be a real-time indicator which reflects body iron loading status instantaneously. Despite the limited knowledge available on LPI speciation in different types and degrees of IO, LPI measurements can be and are in fact used for identifying systemic IO and for initiating/adjusting chelation regimens.     

Ret‐Y a measure of reticulocyte size: a sensitive indicator of iron deficiency anemia

In this study the size of reticulocytes was measured, reticulocyte‐Y (Ret‐Y), to distinguish iron deficiency anemia from the anemia of chronic disease using a Sysmex XE2100 cell counter. We evaluated this parameter prospectively in 100 patients seen for the evaluation of anemia. A clinical diagnosis of iron deficiency anemia or anemia of chronic disease was made on the basis of a complete blood count, examination of the peripheral smear, and serum ferritin along with a history and physical examination. We analyzed the sensitivity and specificity of the Ret‐Y in relationship to the clinical diagnosis. We also measured serum transferrin receptor levels to use as the gold standard laboratory test for iron deficiency against which we compared the Ret‐Y. In 40 normal individuals with normal serum ferritin and transferrin receptor levels the mean Ret‐Y was 1874 ± 178 (1 SD). The mean Ret‐Y in the anemia of chronic disease group (n = 62) was 1722 ± 162, not significantly different from normal. The mean Ret‐Y value among iron‐deficient patients (n = 38), was 1407 ± 136 (P < 0.01 vs. the anemia of chronic disease group's Ret‐Y value). Receiver operator curves showed that Ret‐Y correlated closely to the serum transferrin receptor and was superior to the mean corpuscular volume, and ferritin level, in differentiating the type of anemia. The Ret‐Y parameter has the highest overall sensitivity and specificity of the panel of tests routinely used in differentiating iron deficiency anemia from anemia of chronic disease.     

Association between baseline serum hepcidin levels and infection in kidney transplant recipients: Potential role for iron overload

Background

The liver‐synthesized peptide hepcidin is a key regulator of iron metabolism and correlates with total iron stores. We analyzed the association between pre‐transplant hepcidin‐25 levels and infection after kidney transplantation (KT).

Methods

Serum hepcidin‐25 levels were measured at baseline by high‐sensitivity ELISA in 91 patients undergoing KT at our institution between December 2011 and March 2013. The impact of this biomarker on the incidence of post‐transplant infection (excluding lower urinary tract infection) during the first year was assessed by Cox regression.

Results

Mean hepcidin‐25 level was 82.3 ± 67.4 ng/mL and strongly correlated with serum ferritin (Spearman's rho = 0.703; P < .001). There were no significant differences in hepcidin‐25 levels between patients with or without overall infection (96.4 ± 67.5 vs 72.6 ± 66.7 ng/mL; P = .101). Such difference was evident for opportunistic (128.9 ± 75.0 vs 73.0 ± 62.3 ng/mL; P = .003) and, to a lesser extent, surgical‐site infection (107.5 ± 73.3 vs 76.5 ± 65.2 ng/mL; P = .087). Patients with hepcidin‐25 levels ≥72.5 ng/mL had higher 12‐month cumulative incidence of overall infection (51.2% vs 29.2%; P = .032). After multivariate adjustment, hepcidin‐25 ≥72.5 ng/mL acted as an independent risk factor for overall (adjusted hazard ratio [aHR] 3.86; 95% confidence interval [CI] 1.49‐9.96; P = .005) and opportunistic infection (aHR 4.32; 95% CI 1.18‐15.75; P = .027).

Conclusion

Elevated baseline serum hepcidin‐25 levels were associated with increased risk of infection after KT, suggesting a role for iron overload in the individual susceptibility to post‐transplant infection.     

Shortened Red Blood Cell Lifespan Is Related to the Dose of Erythropoiesis‐Stimulating Agents Requirement in Patients on Hemodialysis

Renal anemia is an important complication of chronic kidney disease (CKD). One of the most important complications of renal anemia is reduced red blood cell (RBC) lifespan, but there has been little research conducted into the causes of and treatments for this anemia. We measured alveolar carbon monoxide (CO) and then estimated RBC lifespan in patients on hemodialysis (HD). We also examined their requirement for erythropoiesis‐stimulating agents (ESA), HD dose, nutrition factors, iron metabolism factor, reticulocyte counts and % reticulocytes. We enrolled 140 patients undergoing intermittent HD; among this group, 31 were not administered ESA and the others were on ESA therapy. Twelve healthy volunteers served as controls. The RBC lifespans in the healthy volunteers and in the HD patients were 128 ± 28 and 89 ± 28 days (mean ± SD), respectively. The RBC lifespan significantly and negatively correlated with ESA requirement (r = ?0.489, P < 0.0001) in the HD patients. Other factors suspected to influence the RBC lifespan did not significantly correlate with the RBC lifespan in HD patients, in contrast to the correlation observed for S‐Cr, BUN, S‐ALB and total cholesterol vs. RBC lifespan. A shortened RBC lifespan seems to rather significantly affect the ESA requirement. Better nutritional status or active HD patients also seem to have longer RBC lifespans and lower ESA requirement.     

Comparative effects of liraglutide 3 mg vs structured lifestyle modification on body weight,liver fat and liver function in obese patients with non‐alcoholic fatty liver disease: A pilot randomized trial

We compared the effects of weight loss induced by the glucagon‐like peptide 1‐agonist liraglutide with a structured lifestyle intervention in obese adults with non‐alcoholic fatty liver disease (NAFLD). Obese (body mass index ≥30 kg/m², mean weight 96.0 ± 16.3 kg) non‐diabetic Asian adults, with NAFLD diagnosed by liver fat fraction (LFF) ≥ 5.5% on magnetic resonance imaging without other causes of hepatic steatosis, were randomized to a supervised program of dieting (restriction by 400 kilocalories/d) plus moderate‐intensity aerobic exercise (~200 min/wk; DE group, n = 12), or liraglutide at the 3 mg daily dose approved for weight loss (LI group, n = 12), for 26 weeks. Both DE and LI groups had significant (P < .01) and similar reductions in weight (?3.5 ± 3.3 vs ?3.5 ± 2.1 kg, respectively, P = .72), LFF (?8.9 ± 13.4 vs ?7.2% ± 7.1%, P = .70), serum alanine aminotransferase (?42 ± 46 vs ?34 ± 27 U/L, P = .52) and aspartate aminotransferase (?23 ± 24 vs ?18 ± 15 U/L, P = .53). In this first randomized study comparing the 2 weight‐loss modalities for improving NAFLD, liraglutide was as effective as structured lifestyle modification.     

RAP‐011, an activin receptor ligand trap,increases hemoglobin concentration in hepcidin transgenic mice

Over expression of hepcidin antimicrobial peptide is a common feature of iron‐restricted anemia in humans. We investigated the erythroid response to either erythropoietin or RAP‐011, a “murinized” ortholog of sotatercept, in C57BL/6 mice and in hepcidin antimicrobial peptide 1 over expressing mice. Sotatercept, a soluble, activin receptor type IIA ligand trap, is currently being evaluated for the treatment of anemias associated with chronic renal disease, myelodysplastic syndrome, β‐thalassemia, and Diamond Blackfan anemia and acts by inhibiting signaling downstream of activin and other Transforming Growth Factor‐β superfamily members. We found that erythropoietin and RAP‐011 increased hemoglobin concentration in C57BL/6 mice and in hepcidin antimicrobial peptide 1 over expressing mice. While erythropoietin treatment depleted splenic iron stores in C57BL/6 mice, RAP‐011 treatment did not deplete splenic iron stores in mice of either genotype. Bone marrow erythroid progenitors from erythropoietin‐treated mice exhibited iron‐restricted erythropoiesis, as indicated by increased median fluorescence intensity of transferrin receptor immunostaining by flow cytometry. In contrast, RAP‐011‐treated mice did not exhibit the same degree of iron‐restricted erythropoiesis. In conclusion, we have demonstrated that RAP‐011 can improve hemoglobin concentration in hepcidin antimicrobial peptide 1 transgenic mice. Our data support the hypothesis that RAP‐011 has unique biologic effects which prevent or circumvent depletion of mouse splenic iron stores. RAP‐011 may, therefore, be an appropriate therapeutic for trials in human anemias characterized by increased expression of hepcidin antimicrobial peptide and iron‐restricted erythropoiesis. Am. J. Hematol. 90:8–14, 2015. © 2014 Wiley Periodicals, Inc.     

Initiating insulin therapy in elderly patients with Type 2 diabetes: efficacy and safety of lispro mix 25 vs. basal insulin combined with oral glucose‐lowering agents

Aims To compare starter insulins in the elderly subgroup of the DURABLE trial 24‐week initiation phase. Methods In a post‐hoc analysis of the ≥ 65 years subgroup enrolled in the DURABLE trial, we compared the safety and efficacy of lispro mix 25 (LM25: lispro 25%/insulin lispro protamine suspension 75%), n = 258, vs. glargine, n = 222, added to oral glucose‐lowering agents. Results Baseline glycated hemoglobin (HbA_1c) was similar (LM25 8.7 ± 1.2, glargine 8.8 ± 1.1%, P = 0.612). At 24‐weeks, LM25 patients had lower HbA_1c (7.0 ± 0.9 vs. 7.3 ± 0.9%, P < 0.001), greater HbA_1c reduction (?1.7 ± 1.2 vs. ?1.5 ± 1.1%, P < 0.001), and more patients reaching HbA_1c < 7.0% (55.6 vs. 41.0%, P = 0.005). LM25 patients were on more insulin (0.40 ± 0.19 vs. 0.33 ± 0.19 u/kg/day, P < 0.001) and experienced more weight gain (3.6 ± 3.6 vs. 1.8 ± 3.2 kg, P < 0.001). Additionally, LM25‐treated patients reported a higher mean overall hypoglycaemia rate than glargine patients (40.8 ± 47.6 vs. 31.1 ± 48.5 episodes/patient/year, P = 0.037), while nocturnal hypoglycaemia rates were similar. Over 24 weeks, incidence of severe hypoglycaemia was higher for LM25 (4.3% vs. 0.9%, P = 0.018); however, by 24‐week endpoint incidence was similar (0.8% vs. 0.0%P = 0.125). Conclusions In this elderly subgroup post‐hoc analysis, LM25 demonstrated a lower endpoint HbA_1c and a higher % of patients reaching HbA_1c target of < 7.0%, but with more weight gain and higher rates of hypoglycaemia compared to glargine.     

Comparison of Longitudinal Myocardial Deformation and Dyssynchrony in Children with Left and Right Ventricular Morphology after the Fontan Operation Using Two‐dimensional Speckle Tracking

Objective. Two‐dimensional speckle tracking can assess ventricular deformation independent of ventricular geometry. Using this technique, the aim of our study was therefore to compare global and regional longitudinal deformation and intraventricular dyssynchrony between children with left and right ventricular morphology after Fontan operation. Design and Patients. In this retrospective study, we examined 29 children with systemic right (group 1: age 7.7 ± 2.7 years, time after Fontan 5.3 ± 3.0 years) and 22 children with systemic left (group 2: age 7.8 ± 4.8 years, time after Fontan 4.6 ± 4.2 years) ventricles after Fontan surgery using two‐dimensional speckle tracking. We compared global and regional longitudinal strain and strain rate (SR) as well as time to peak strain in basal lateral and septal segments. Results. Global strain (?18.5 ± 3.5 vs. ?17.9 ± 3.2%, P= NS) and global SR (?1.0 ± 0.2 vs. ?1.0 ± 0.2/s, P= NS) did not differ between groups. Regional strain (?8.7 ± 8.6 vs. ?14.7 ± 6.7%, P= .008) and SR (?0.7 ± 0.4 vs. ?1.0 ± 0.3%, P= .002) in the basal septal segment were lower in group 1, while regional strain was higher in group 1 in the apical septal segment (?23.5 ± 8.0 vs. ?18.4 ± 5.9%, P= .02). Time to peak strain was higher in the basal septal segment in group 1 (410 ± 78 vs. 338 ± 90 ms, P= .004) but not different in the basal lateral segment. Conclusions. Despite minor regional differences in longitudinal deformation and dyssynchrony, overall ventricular longitudinal deformation was not different between morphologic right and left ventricles. These findings may reflect similar adaptation of longitudinal function of both ventricular morphologies to the single‐ventricle circulation in our cohort, albeit relatively early after Fontan surgery.     

The Predictive Value of Platelet/Lymphocyte Ratio in Hemodialysis Patients With Erythropoietin Resistance

The most important cause of anemia in CKD is relative deficiency of erythropoietin (EPO) secretion from the diseased kidney and EPO therapy has become the standard treatment for anemia of CKD. However, some patients do not respond well to erythropoiesis stimulating agent (ESA), so‐called ESA resistance. One of the most important causes of ESA resistance is chronic inflammation in hemodialysis (HD) patients. ESA hyporesponsiveness index (EHRI), calculated as the weekly dose of EPO divided by kilograms of body weight divided by the hemoglobin level, and has been considered useful to assess the EPO resistance. Neutrophil/lymphocyte (NLR) ratio and platelet/lymphocyte ratio (PLR) were also found to be associated with inflammation in HD patients. However, the relationship between NLR, PLR and EHRI has not been investigated before. HD patients underwent medical history taking, physical examination, calculation of dialysis adequacy and biochemical analysis and calculation of EHRI. Logarithmically converted EHRI (logEHRI) was correlated only with hemoglobin (r –0.381, P < 0.0001) and PLR (r = 0.227, P = 0.021) but not with NLR. Comparison of PLR among 25th, 50th and 75th percentile of EHRI showed that PLR levels increased going from the 25th to 75^th percentile (P = 0.032). Posthoc analysis revealed that 25–75th percentile (P = 0.014) and 50–75th percentile (P = 0.033) were different with respect to PLR. In linear regression analysis, PLR (standardized β = 0.296, confidence interval: 0.000–0.001, P = 0.003) was independently associated with logEHRI. We found that PLR was independently associated with EHRI in HD patients. PLR, which is quite a simple and cheap method, may guide clinicians for detecting EPO resistance.     

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 µmol/L at the beginning of the first session, 0.01 ± 0.26 µmol/L at T0, 0.03 ± 0.23 µmol/L at T1, 0.09 ± 0.28 µmol/L at T2, 0.18 ± 0.52 µmol/L at T3, and −0.02 ± 0.16 µmol/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 µmol/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.     

Twice‐Monthly Administration of a Lower Dose of Epoetin Beta Pegol Can Maintain Adequate Hemoglobin Levels in Hemodialysis Patients

Epoetin beta pegol is a continuous erythropoietin receptor activator (CERA) with a long half‐life. Although CERA has been shown to maintain adequate hemoglobin (Hb) levels at prolonged dosing intervals, the optimal dosing schedule remains unclear. We therefore compared the efficacy of maintaining hemoglobin levels with administration of twice‐monthly CERA (TWICE) versus once‐monthly CERA (ONCE). Twenty hemodialysis patients receiving epoetin beta (EPO) were enrolled in this crossover study. Patients were assigned to either the TWICE or the ONCE group based on matching Hb levels and EPO doses. After 6 months of treatment, the CERA dosage was interchanged between the groups and the study was continued for an additional 6 months. The effect of the different regimens on iron metabolism was also assessed during the first 6 months of the study. Hb levels significantly increased in the TWICE group, allowing for a reduction in CERA dosage, while the dose of CERA required to maintain Hb levels in the ONCE group remained unchanged. After the interchange, a decrease in Hb levels with incremental increase in CERA dosage was observed in the TWICE→ONCE group, with the opposite effect observed in the ONCE→TWICE group. Although increases in ferritin and hepcidin‐25 levels in the ONCE group were noted at one month, they disappeared at 6 months. Although Hb levels were maintained in both the ONCE and TWICE groups, a twice‐monthly administration was advantageous, as it required a lower dose of CERA.     

Low dose erythropoietin‐beta improves anemia and maintains ribavirin dose in chronic hepatitis C patients receiving combination therapy with ribavirin plus pegylated interferon Alfa‐2b

Aim: Anemia during combination therapy with pegylated interferon alfa‐2b plus ribavirin (RBV) for chronic hepatitis C virus (HCV) patients usually leads to RBV dose reduction or discontinuation. This study evaluated the effect of erythropoietin‐beta (EPO‐β) to maintain RBV dose and hemoglobin (Hb) level in chronic HCV patients treated with antiviral combination therapy. Methods: Eighty‐eight chronic HCV patients who developed anemia during therapy were enrolled into this retrospective study: 55 in the EPO‐β group and 33 in the untreated group. The study endpoints were to assess the RBV maintenance and the changes in Hb. Results: A higher percentage of patients with RBV maintenance was observed in the EPO‐β group compared with the untreated group (nadir Hb level <10.5 g/dL; 70% vs. 38%, P = 0.020; nadir Hb < 10 g/dL; 62% vs. 27%, P = 0.046). The mean Hb change from week 12 to week 20 was higher in the EPO‐β group when compared with the untreated group, especially for patients receiving a total EPO‐β dose of more than 16 000 U (+0.70 g/dL vs. ?0.32 g/dL, P = 0.023) and of 10 000 U‐14 000 U (+0.60 g/dL vs. ?0.32 g/dL, P = 0.023). Conclusions: Low‐dose EPO‐β can maintain RBV dose and increase Hb levels in anemic chronic HCV patients receiving combination therapy.     

Erythropoietin stimulation decreases hepcidin expression through hematopoietic activity on bone marrow cells in mice

Erythropoiesis-stimulating agents (ESA) are now central to the treatment of renal anemia and are associated with improved clinical outcomes. It is well known that erythropoietin (EPO) is a key regulator of erythropoiesis through its promotion of red blood cell production. In order to investigate the role of ESA on iron metabolism, we analyzed the regulation of the iron regulatory hormone hepcidin by ESA treatment in a bone marrow transplant model in mouse. After treating C57BL/6 mice with continuous erythropoietin receptor activator (C.E.R.A.), recombinant human epoetin-β (rhEPO), or recombinant human carbamylated epoetin-β (rhCEPO), we investigated serum hepcidin concentrations and parameters of erythropoiesis. Serum hepcidin concentrations after rhEPO treatment were analyzed in mice subjected to total body irradiation followed by bone marrow transplantation. C.E.R.A. administration caused long-term downregulation of serum hepcidin levels. Serum hepcidin levels in rhEPO-treated mice decreased significantly, whereas there was no change in rhCEPO-treated mice. The reduction in circulating hepcidin levels after rhEPO administration was not observed in irradiated mice. Finally, bone marrow transplantation recovered the response to rhEPO administration that downregulates hepcidin concentration in irradiated mice. These results indicate that ESA treatment downregulates serum hepcidin concentrations, mainly by indirect mechanisms affecting hematopoietic activity in bone marrow cells.