Anemia In Chronic Hemodialysis Patients Research Articles

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.

MO795: Management of Anemia in Hemodialysis Patients With Thalassaemia Minor

Abstract BACKGROUND AND AIMS Thalassemia is a group of hemoglobinopathies characterized by the decrease or lack of β or α globin chain production (Hb) [1]. Minor thalassemia has little to no symptoms since the other gene is capable of compensating for the anomaly; however, it represents a rare cause of resistance to erythropoietin (EPO) in chronic hemodialysis patients (CHP) in multiple regions, particularly the Mediterranean region [2]. As a matter of fact, CHP suffering from minor thalassemia often take higher EPO doses to correct the anemia [3], even if all causes of EPO resistance are resolved; a recent Italian investigation indicated that EPO need in this population is almost double in comparison with other groups [4]. EPO résistance can be secondary to the quantitative anomalies of the hemoglobin chain, notably Hb A2 and Hb F, Biagio Di Lorio et al. reported a positive correlation between the percentage of Hb A2 and EPO doses [5], actually patients that had an Hb A2 &amp;gt;6% needed higher EPO doses and vice versa. The aims of this study were to evaluate the efficiency of different therapeutic means [Erythropoiesis-stimulating agents (ESA), blood transfusion (TS)] aiming to correct the anemia in CHP with minor thalassemia. To detect the correlation between quantitative anomalies in hemoglobin chains and EPO resistance. METHOD It's a descriptive multi-centric study, involves eight CHP suffering from minor thalassemia. The statistical analysis of the data was done through Excel using the correlation coefficient and SPSS using the P-value. A value &amp;lt;.05 was considered as significant. RESULTS The average value of hemoglobin was 7.35 g/dL, Ferritin (M: 964 ± 971 ng/L) and PTH levels (M: 433 ± 126 pg/mL). These results are detailed in Table 1. Electrophoresis was done for all our patients with an average of HbA à 96.2 ± 1.7%; HbA2 à 3.43 ± 1.41%; HbF à 0.35 ± 0.45%. We have noticed that a decreased percentage up to nul of Hb F fraction is correlated with the lowest Hb levels (Fig. 1). The main therapeutic mean in anemia patients is epoietin beta, the average dose given to patients is 300 UI/kg/week, 326UI/kg/s at 2 months, 233 UI/kg/s at 6 months and 326 UI/kg/s at 12 months. Figure 2 illustrates the response to the EPO during the maintenance phase. The Darbepoetin alpha (μg/Kg/s) is administered (depending on availability) to two patients out of the eight. One of the two was receiving a dose of 0.57 μg/kg/s for 8 weeks, the other one was receiving a dose 0.7 μg/kg/s for 8 weeks as well, with a different response in the two patients. CONCLUSION: The presence of minor thalassemia in chronic hemodialysis patients entails erythropoietin resistance and a serious case of anemia. In our study, the maximum EPO dose used was 500 UI/kg/s reaching a value of 9.7 g/dL of Hb.

Correlation between parathormone level and anemia in chronic hemodialysis patients

Correlation between parathormone level and anemia in chronic hemodialysis patients

Cost-minimization analysis between intravenous iron sucrose and iron sucrose similar in hemodialysis patients

ABSTRACT Objectives Intravenous iron and erythropoiesis-stimulating agents are used to manage anemia in chronic hemodialysis patients. The interchangeability between intravenous iron sucrose preparations is still debated. We evaluated how cost and effectiveness were impacted when chronic hemodialysis patients were switched from an original iron sucrose product to an iron sucrose similar preparation. Methods A single center sequential observational retrospective study was conducted at a French hospital. The same patients were followed during two 24-week periods (iron sucrose in period P1; and iron sucrose similar in period P2). Anemia-related treatment costs were assessed in P1 and P2 from a hospital perspective. Sensitivity analyses were performed to assess the robustness of the results. Results Our study included 109 patients (105 analyzed patients and 4 patients with missing data). The mean hemoglobin level was not different between P1 and P2 (p = 0.92). The mean differential cost per patient was + €13.90 (P2 – P1). The factors with the biggest impact on this result were the prices of epoetin alfa and iron sucrose. Conclusion This cost minimization analysis suggests that for chronic hemodialysis patients, iron sucrose and iron sucrose similar have the same efficacy and that using iron sucrose similar was more expensive in 66.7% of iterations.

2015 Japanese Society for Dialysis Therapy: Guidelines for Renal Anemia in Chronic Kidney Disease

Renal anemia is a complication of chronic kidney disease. Guidelines for safe and effective treatment in patients with renal anemia are needed. The Japanese Society for Dialysis Therapy (JSDT) published guidelines for the treatment of renal anemia in chronic hemodialysis patients in 2004 and in hemodialysis, peritoneal dialysis, predialysis, and pediatric patients in 2008. These two publications provide excellent guidance with respect to clinical practice issues, including the definition and diagnosis of renal anemia, the criteria for the initiation of treatment, target hemoglobin levels, iron supplementation therapy, blood transfusion, and side effects. The guidelines significantly improved the treatment of renal anemia in Japan. However, since 2008, many studies have assessed the treatment of renal anemia, and erythropoiesis-stimulating agents (ESAs) are now available. Therefore, the Executive Board of the JSDT decided that it was time to revise the guidelines to make them more appropriate to the situation of chronic kidney disease patients in Japan. This is the third edition of the guidelines for renal anemia published by the JSDT. The purpose is to improve the prognosis of chronic kidney disease patients, including after renal transplantation, through the treatment of renal anemia. The intended users of the guidelines are all healthcare professionals engaged in the treatment of chronic kidney disease. Regarding the treatment of adult dialysis and predialysis patients, statements and commentary are provided in the context of answers to clinical questions in Chapter 2 (Target Hb level and criteria for starting renal anemia treatment) and Chapter 4 (Evaluation of iron status and iron therapy). Furthermore, the essential information is provided alongside the critical issues in Chapter 1 (Diagnosis of renal anemia), Chapter 3 (Administration of ESAs—administration route and dose), Chapter 5 (ESA hyporesponsiveness), Chapter 6 (Side effects and concomitant symptoms of ESAs), and Chapter 7 (Red blood cell transfusion). In addition, the treatment of pediatric patients and post-renal transplant patients is discussed in Chapter 8 and Chapter 9, respectively.

Effects of Secondary Hyperparathyroidism Treatment on Improvement in Anemia: Results from the MBD-5D Study.

ObjectivesAnemia is an important prognostic factor in hemodialysis patients. It has been reported that parathyroidectomy ameliorates anemia and reduces the requirement of postoperative erythropoiesis-stimulating agents. The objective of this study was to assess the effect of cinacalcet, which is considered as a pharmacological parathyroidectomy, on anemia in hemodialysis patients.MethodsWe used data from a prospective cohort of Japanese hemodialysis patients with secondary hyperparathyroidism; the criteria were: intact parathyroid hormone concentrations ≥ 180 pg/mL or use of an intravenous or oral vitamin D receptor activator. All patients were cinacalcet-naïve at study enrollment. The main outcome measure was achievement of the target hemoglobin level (≥10.0 g/dL), which was measured repeatedly every 6 months. Cinacalcet exposure was defined as cumulative time since initiation. Both conventional longitudinal models and marginal structural models were adjusted for confounding factors.ResultsAmong 3,201 cinacalcet-naïve individuals at baseline, cinacalcet was initiated in 1,337 individuals during the follow up. Cinacalcet users were slightly younger; included more patients with chronic glomerulonephritis and fewer with diabetes; were more likely to have a history of parathyroidectomy; and were more often on activated vitamin D agents, phosphate binders, and iron supplements. After adjusting for both time-invariant and time-varying potential confounders, including demographics, comorbidities, comedications, and laboratory values, each additional 6-month duration on cinacalcet was associated with a 1.1-fold increase in the odds of achieving the target hemoglobin level.ConclusionsCinacalcet may improve anemia in chronic hemodialysis patients with secondary hyperparathyroidism, possibly through pathways both within and outside the parathyroid hormone pathways. Further investigations are warranted to delineate the roles of cinacalcet not only in the management of chronic kidney disease–mineral and bone disorder but also in anemia control.

Correlation between serum L-carnitine concentration and neutrophil engraftment in patients treated with cord blood transplantation

In cord blood transplantation (CBT), the amount of time elapsing until hematological engraftment has effects on the transplantation results. Carnitine deficiency has been reported to cause erythropoietin refractory anemia in chronic hemodialysis patients and thrombocytopenia or leukopenia of cirrhosis, and carnitine supplementation can improve hematopoiesis in patients with hepatic or renal failure. Patients who receive CBT may suffer from carnitine deficiency, but no studies have investigated the carnitine status of such patients. Herein, we determined the concentration of free carnitine (FC) and investigated the correlation between FC and engraftment in patients who received CBT. Twenty-three patients who received CBT at our hospital during the period from April 2013 to January 2015 were enrolled in this study. One patient was excluded because of graft failure, such that 22 patients were ultimately evaluable. FC concentrations of the patients were sequentially monitored at 4 time points (before conditioning therapy, day 0, day 7, and day 14), basic laboratory data were collected, and their correlations with engraftment were analyzed. FC concentrations of the patients were generally low (before conditioning therapy: 33.1, day 0: 43.2, day 7: 38.3, and day 14: 37.8 μmol/l). Significant inverse correlations were observed between FC concentrations and the number of days required for neutrophil engraftment on day 0 and day 14 (before conditioning therapy: P=0.15, r=-0.33, day 0: P=0.04, r=-0.43, day 7: P=0.30, r=-0.23, and day 14: P=0.01, r=-0.55). These results suggest carnitine to be an important nutrient that promotes hematopoietic recovery after CBT.

Impact of hepcidin, interleukin 6, and other inflammatory markers with respect to erythropoietin on anemia in chronic hemodialysis patients

Hepcidin is a peptide hormone produced by the liver and appears to be the master regulator of iron homeostasis. This peptide is upregulated in inflammatory conditions, including uremia. Hepcidin functions to regulate (inhibit) iron transport across the gut mucosa, thereby preventing excess iron absorption and maintaining normal iron levels within the body. In this study, we aimed to investigate hepcidin levels and their relationship with the parameters of iron status, inflammation, anemia therapy, and parameters of dialysis efficiency in hemodialysis patients. Plasma hepcidin-25, inflammatory markers (high-sensitivity C-reactive protein and interleukin 6), and peripheral iron indices (serum iron, total iron-binding capacity, transferrin saturation and serum ferritin) were measured before hemodialysis in 40 end-stage renal disease (ESRD) patients treated with regular hemodialysis in a single dialysis unit as well as in 20 healthy individuals matched for age and sex serving as the control group. Plasma levels of hepcidin-25 were significantly higher in hemodialysis patients compared with controls. In a simple correlation analysis, plasma hepcidin levels were positively correlated with ferritin, transferrin saturation, CRP, and interleukin 6; however, it was negatively correlated with hemoglobin, dose of epoitin-α, and dose of iron. Serum hepcidin levels were associated with iron status and inflammation in maintenance hemodialysis patients, and the high hepcidin serum levels, found in hemodialysis (HD) patients, are dependent on the magnitude of the inflammatory process and on recombinant human erythropoietin doses. Hepcidin and its regulatory pathways are potential therapeutic targets, which could lead to effective treatment of anemia in chronic hemodialysis.

Hepcidin levels in chronic hemodialysis patients: a critical evaluation

Altered systemic iron metabolism is a key element of uremia, and functional iron deficiency mainly related to subclinical inflammation makes it difficult to maintain proper control of anemia in chronic hemodialysis patients (CHD). In the last decade, the hepatic hormone hepcidin has been progressively recognized as the master regulator of circulating iron levels through the modulation of cellular iron fluxes in response to iron stores, as well as to erythroid and inflammatory stimuli. Hepcidin is cleared by the kidney and progression of renal disease has been associated to increased serum hepcidin levels. This, in turn, reduces iron availability for erythropoiesis, suggesting anti-hepcidin strategies for improving anemia control. Moreover, hepcidin has been recently implicated in the pathogenesis of long-term complications of dialysis, like accelerated atherosclerosis. Initial studies almost invariably reported a sustained increase of serum hepcidin in chronic hemodialysis patients. Noteworthy, such studies included relatively few patients and controls that were poorly matched for major determinants of serum hepcidin at population level, i.e., age and gender. More recent data based on accurately matched larger series challenge the view that hepcidin is intrinsically increased in hemodialysis patients, showing a marked inter- and intra-individual variability of hormone levels. Here we take a critical look to the data published so far on hepcidin levels in CHD, analyze the reasons underlying the discrepancies in available studies and the hepcidin variability in CHD, and point out the need for further studies in large series of well-characterized CHD patients and controls.

Total and HMW Adiponectin is Independently Associated with B-type Natriuretic Peptide and Anemia in Chronic Hemodialysis Patients

A number of vasculo-protective roles have been reported for adiponectin. In contrast, higher, rather than lower, plasma adiponectin levels are associated with an increased risk of cardiovascular disease and mortality in patients undergoing hemodialysis (HD). The mechanisms by which high adiponectin levels are associated with adverse outcome are unclear. This study measured the level of total and high molecular weight (HMW) adiponectins in 70 patients with HD patients (age: 65.2±8.6 years, man/woman: 30/40), and examined the association between adiponectins, metabolic and echocardiographic parameters. Women had a significantly higher total, HMW levels and HMW to total ratio than men. The levels of total and HMW adiponectin were positively correlated with those of HDL-cholesterol and B-type natriuretic peptide (BNP) levels, and negatively associated with body mass index (BMI), triglyceride, high sensitive-C reactive protein (CRP) and hemoglobin levels. A multiple linear regression analysis showed that HMW adiponectin had an independent association with BMI (β=-0.270, p=0.003), HDL-cholesterol (β=0.356, p<0.001), hemoglobin (β=-0.180, p=0.034) and BNP (β=0.200, p=0.014) as total did adiponectin. Anemia and BNP levels had independent influence on the total and HMW adiponectin levels in chronic HD patients.

2008 Japanese Society for Dialysis Therapy: Guidelines for Renal Anemia in Chronic Kidney Disease

2008 Japanese Society for Dialysis Therapy: Guidelines for Renal Anemia in Chronic Kidney Disease

Biocompatibility and Permeability of Dialyzer Membranes Do Not Affect Anemia, Erythropoietin Dosage or Mortality in Japanese Patients on Chronic Non-Reuse Hemodialysis: A Prospective Cohort Study from the J-DOPPS II Study

Background: Considerable controversy existsover the impact of the biocompatibility and flux characteristics ofdialyzer membranes on anemia in chronic hemodialysis patients. Methods: A subset of 1,207 subjects from the Japanese arm of DOPPS phase II was analyzed. Results: Patient characteristics included mean age 59 years, male sex 60%, BMI 20.6, time on dialysis therapy 7.8 years, and diabetes rate 27%. Dialysis parameters were Kt/V 1.33, and normalized protein catabolic rate 1.05 g/kg/day. Initial hemoglobin level was 10.1 g/dl. 79% were treated by intravenous erythropoietin with mean weekly doses of 4,500 IU. Hemoglobin levels and erythropoietin doses during 2-year study period were not affected by dialysis membrane biocompatibility (unmodified cellulose or biocompatible) or flux (standard or high performance). The 2-year survival rate was 90.9% and was influenced by older age, presence of cardiovascular diseases and amyloidosis, lower levels of BMI and serum albumin, but not by other variables, including dialysis membranes. Use of biocompatible membranes was associated with a lower all-cause mortality (8.3 vs. 13.0% for bioincompatible, p = 0.037), but this difference was not significant in multivariate analyses (hazard ratio 0.70, p = 0.17 by Cox multivariate analysis). Conclusion: The biocompatibility and permeability of dialyzer membranes had no effect on anemia, erythropoietin dosage or all-cause mortality in Japanese chronic hemodialysis patients treated by non-reuse dialysis.

Intravenous Iron, Inflammation, and Oxidative Stress: Is Iron a Friend or an Enemy of Uremic Patients?

Intravenous iron supplementation is a recognized therapy for anemia in chronic hemodialysis patients, especially in those treated with erythropoietin. The vast majority of patients with chronic kidney disease (CKD) seem to be iron-deficient, as evaluated by the usual parameters and by iron staining on bone marrow biopsy, because of multiple forms of interference with all phases of iron metabolism. The need for iron supplementation in CKD patients becomes obvious. Intravenous iron was demonstrated to be superior to oral iron in hemodialysis patients. There is also evidence for the superiority of intravenous iron in peritoneal dialysis and in nondialysis-dependent CKD patients. On the other hand, intravenous iron could promote cytotoxicity and tissue injury, and exacerbate oxidative stress and thus endothelial dysfunction, as well as inflammation and the progression of both CKD and cardiovascular disease. Nevertheless, correction of anemia is effective in reducing oxidative stress and, consequently, cardiovascular risk. The overall risk-benefit ratio favors the use of intravenous iron alone or with an erythropoietic stimulating agent in the management of renal anemia. Clinical judgment is necessary in each individual case to diagnose iron deficiency and effectively use intravenous iron.

Prevalence and Correlates of Anemia and Uncontrolled Anemia in Chronic Hemodialysis Patients – The Campania Dialysis Registry

This study investigated prevalence and correlates of anemia and uncontrolled anemia in chronic hemodialysis patients. A cross-sectional analysis was performed on registry data for 2,746 chronic (>6 months) hemodialysis patients aged 25-84. Data collection included years of dialysis, hours of dialysis/wk, disease causing hemodialysis, body mass index (BMI), erythropoietin (EPO) treatment, hemoglobin, markers of viral hepatitis, serum albumin, calcium, and phosphorus. Prevalence was 88.7% for anemia (hemoglobin <11 g/100 mL and EPO treatment at any Hb level), 39.4% for uncontrolled anemia (hemoglobin<11 g/100 mL). Gender, years of dialysis, hereditary cystic kidney disease (HCKD), and low BMI (<24 kg/m2) were independent correlates of anemia (P<0.001). Gender, HCKD, low BMI, serum albumin and calcium were independent correlates of uncontrolled anemia (P<0.05). An interaction was found between age (not correlated with anemia and uncontrolled anemia) and the association of gender with uncontrolled anemia (P<0.05). EPO doses were higher in patients with high prevalence of uncontrolled anemia than in patients with low prevalence (i.e., women vs men, other diseases vs HCKD, low vs not-low BMI, P<0.01). Gender, years of dialysis, HCKD, BMI, serum albumin, and calcium were independent correlates of the hemoglobin/EPO dose ratio in patients on EPO treatment (P<0.05). Anemia and uncontrolled anemia are more frequent in hemodialysis patients with shortterm dialysis, diseases other than HCKD, low BMI, and female gender. Gender effect was lower in elderly patients. Uncontrolled anemia was also associated with low serum albumin and calcium, suggesting that these parameters are indices of EPO resistance.

Polyamines as an Inhibitor on Erythropoiesis of Hemodialysis Patients by In Vitro Bioassay Using the Fetal Mouse Liver Assay

The pathogenesis of anemia in patients with chronic renal failure has been greatly attributed to erythropoietin (EPO) deficiency. Recently, however, there has been some thought that uremic inhibitors might suppress the activity of EPO and reduce the maturation of erythropoiesis. Polyamines are well known to be involved in the regulation of cellular proliferation and differentiation. Furthermore, the polyamine levels in the serum or erythrocytes are elevated in chronic hemodialysis patients, and can be lowered immediately by hemodialysis. In the present study, we first measured the polyamines levels (putrescine, spermidine, spermine) by high performance liquid chromatography (HPLC) in 20 chronic hemodialysis patients, and investigated the effects of polyamines on erythropoiesis by in vitro bioassay using fetal mouse liver cells. The direct effects of polyamines in erythroid colony formation in the medium with and without EPO were evaluated. Each polyamine level in chronic hemodialysis patients was higher than in the healthy subjects, and a significant negative correlation was found between polyamines and erythropoiesis. Polyamines inhibited the activity of EPO, but they did not have any direct effect on colony formation of the fetal mouse liver cells. These results suggest that polyamines have inhibitory effects on the proliferation or maturation of erythroid precursor cells and are intimately involved in the pathogenesis of renal anemia in chronic hemodialysis patients.

2004 Japanese Society for Dialysis Therapy Guidelines for Renal Anemia in Chronic Hemodialysis Patients*

The guideline committee of Japanese Society for Dialysis Therapy (JSDT), chaired by Professor F. Gejyo of Niigata University, now publishes an original Japanese guideline entitled 'Guidelines for Renal Anemia in Chronic Hemodialysis Patients'. It includes the re-evaluation of the usage of recombinant human erythropoietin (rHuEPO) with the medical and economical arguments regarding the prognosis and the quality of life of Japanese hemodialysis patients. This guideline consists of 7 sections. The first section comprises the general definition and the differential diagnosis of anemia. The hemoglobin (Hb) level of the Japanese population seemed to be low when compared with that of the European and American populations. The second section describes the target Hb level in hemodialysis patients. Multivariate analysis of the data that were collected from dialysis institutions throughout the country showed that an Hb level of 10-11 g/dL (Ht level 30-33%) at the first dialysis session in a week is the ideal range for chronic hemodialysis patients in terms of the 3-5 year survival rate. The supine position at blood sampling and the sampling timing at the first dialysis session in a week might affect the lower setting of target Hb hematocrit (Ht), compared to that of European and American guidelines. However, we particularly recommended that an Hb level of 11-12 g/dL (Ht level from 33 to 36%) at the first dialysis session in a week is desirable in relatively young patients. In the third section, the markers of iron deficiency are discussed. The Transferin saturation test (TSAT) and serum ferritin were emphasized as the standard markers. The routes of administration of rHuEPO and its dosages are written in the fourth section. The subcutaneous route was associated with the occurrence of secondary red cell aplasia due to anti-rHuEPO antibodies; however, secondary red cell aplasia was seldom observed in the venous injection. From this fact we recommend venous injection for chronic hemodialysis patients. We advocate an initial dosage of 1500 U three times per week. The fifth section deals with the factors refractory to treatment with rHuEPO. If the patient shows an inadequate response to the usage of 9000 U per week, this condition defines the inadequate response to rHuEPO in Japan. Blood transfusion must be avoided where possible. The reasons for this and the adverse effects are interpreted in section six. In the final section, the adverse effects of rHuEPO are listed. Among them, hypertension, thrombotic events and secondary red cell aplasia were emphasized as the major complications.

The Critical Role of Src Homology Domain 2–Containing Tyrosine Phosphatase-1 in Recombinant Human Erythropoietin Hyporesponsive Anemia in Chronic Hemodialysis Patients

The molecular mechanism of anemia that is hyporesponsive to recombinant human erythropoietin (rHuEPO) in hemodialysis patients without underlying causative factors has not been investigated fully in hematopoietic stem cell system. Circulating CD34+ cells (1 x 10(4)) were isolated from rHuEPO hyporesponsive hemodialysis patients (EPO-H; n = 9), patients who were responsive to rHuEPO (EPO-R; n = 9), and healthy control subjects (n = 9). The patients with known causes of EPO hyporesponsiveness were eliminated from the current study. The cells were cultured in STEM PRO 34 liquid medium, supplemented with rHuEPO, IL-3, stem cell factor, and granulocyte-macrophage colony stimulating factor for 7 d and then transferred to a semisolid methylcellulose culture medium for performing burst forming unit-erythroid (BFU-E) colony assay. Expression of src homology domain 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1), phosphorylated Janus kinase 2 (p-JAK2), and phosphorylated signal transducer and activator of transcription 5 (p-STAT5) was assessed with Western blot analysis. In EPO-H patients, SHP-1 antisense or scrambled S-oligos were included in the culture medium, and its effects were evaluated. The number of circulating CD34+ cells was not statistically different among the three groups, and their proliferation rates were similar for 7 d in culture. However, BFU-E colonies were significantly decreased in EPO-H patients compared with EPO-R and control groups. The mRNA and protein expression of SHP-1 and p-SHP-1 was significantly increased, whereas that of p-STAT5 was reduced in EPO-H patients. The inclusion of SHP-1 antisense S-oligo in culture suppressed SHP-1 protein expression associated with p-STAT5 upregulation, increase in p-STAT5-regulated genes, and partial recovery of BFU-E colonies. In EPO-H hemodialysis patients, the EPO signaling pathway is attenuated as a result of dephosphorylation of STAT5 via upregulation of SHP-1 phosphatase activity, and SHP-1 may be a novel target molecule to sensitize EPO action in these patients.

Melatonin prevents oxidative stress resulting from iron and erythropoietin administration

Intravenous iron (Fe) and recombinant human erythropoietin (rHuEPO) are routine treatments in the management of anemia in patients with chronic renal failure. We investigated the oxidative stress acutely induced by these therapies and whether pretreatment with oral melatonin (MEL) would have a beneficial effect. Nine patients (four women) were studied within 1 month of entering a chronic hemodialysis program in the interdialytic period. Plasma malondialdehyde (MDA), red blood cell glutathione (GSH), and catalase (CAT) activity were measured in blood samples obtained before (baseline) and 1, 3, and 24 hours after the administration of Fe (100 mg of Fe saccharate intravenously over 1 hour) or rHuEPO (4,000 U intravenously). One hour before these treatments, patients were administered a single oral dose of MEL (0.3 mg/kg) or placebo. Each patient was studied on four occasions, corresponding to studies performed using either placebo or MEL in association with intravenous Fe and rHuEPO administration. Baseline data showed increased oxidative stress in patients with end-stage renal failure. Increments in oxidative stress induced by Fe were more pronounced at the end of the administration: MDA, baseline, 0.74 ± 0.09 nmol/mL; 1 hour, 1.50 ± 0.28 nmol/mL (P < 0.001); GSH, baseline, 2.51 ± 0.34 nmol/mg of hemoglobin (Hb); 1 hour, 1.66 ± 0.01 nmol/mg Hb (P < 0.001); and CAT activity, baseline, 27.0 ± 5.7 Κ/mg Hb; 1 hour, 23.3 ± 4.2 Κ/mg Hb (P < 0.001). rHuEPO-induced increments in oxidative stress were more pronounced (P < 0.001) at 3 hours (MDA, 1.24 ± 0.34 nmol/mL; GSH, 1.52 ± 0.23 nmol/mg Hb; CAT activity, 18.0 ± 3.1 Κ/mg Hb). MEL administration prevented the changes induced by Fe and rHuEPO and had no adverse side effects. These studies show that intravenous Fe and rHuEPO in doses commonly used to treat anemia in chronic hemodialysis patients acutely generate significant oxidative stress. Oral MEL prevents such oxidative stress and may be of clinical use.

Adverse Events in Chronic Hemodialysis Patients Receiving Intravenous Iron Dextran – A Comparison of Two Products

Background: Parenteral iron therapy is required in a majority of chronic dialysis patients who are receiving recombinant human erythropoietin (r-HuEPO) in order to provide adequate iron for erythropoiesis. At this time, there are only two formulations of parenteral iron dextran available for clinical use in the USA. These two preparations of iron dextran have different physical and chemical characteristics that might affect the adverse events experienced by dialysis patients receiving iron dextran. Methods: We performed a retrospective analysis of all 665 courses of parenteral iron dextran which were administered in our hemodialysis unit from June 1992 through July 1997. An adverse event (AE) was defined as any event which led to interruption of the prescribed course of iron therapy or precluded subsequent administration of parenteral iron in the presence of documented iron deficiency. Database elements included patient age, gender, cause of renal failure, and prior history of drug allergy. The average hemoglobin value and serum iron parameters (iron, total iron binding capacity (TIBC), percent saturation of TIBC, and ferritin) were recorded both pre- and post-iron administration, when available. A course of parenteral iron dextran consisted of a 25-mg test dose, followed by four or five doses of 300 mg each. Iron dextran was infused into the venous limb of the hemodialysis blood circuit over the last 30–60 min of a dialysis treatment. The two forms of iron dextran were designated as Iron A (molecular weight = 165,000) and Iron B (molecular weight = 267,000). Results: Fifty-seven percent of our patients were male, 92% were of white race, and diabetes was the most common cause of renal failure (34%). Sixty-four percent of the patients were 60 years of age or older, and 39% had a history of allergy to one or more drugs. We observed 33 AEs during the administration of parenteral iron dextran, and these AEs occurred in 21 courses of parenteral iron dextran administration. Eighteen of the AEs were gastrointestinal in nature; 7 AEs were cutaneous in nature, 6 AEs had systemic manifestations, while only 2 AEs caused respiratory problems. Two of the AEs were felt to be anaphylactoid in nature. Female gender (p = 0.06) and iron dextran product (p = 0.02) were identified as potential risk factors for the development of an AE. There were 468 courses of Iron A administered, 10 of these courses were complicated by 15 AEs (one or more AE per course). One hundred and ninety-seven courses of Iron B were administered and 11 (5.6%) courses were complicated by the development of 18 AEs (9.1 AEs per 100 courses). Serum iron rose by 22 µg/dl and TIBC saturation increased by 14% after the administration of parenteral iron. The average serum ferritin level rose by 430 µg/l and hemoglobin values rose by an average of 0.8 g/dl. There were no significant differences in the changes of iron parameters or hemoglobin levels between the two iron dextran preparations. Conclusions: The administration of parenteral iron dextran to chronic hemodialysis patients has a relatively high degree of safety. Both iron products were equally efficacious in increasing serum iron parameters and hemoglobin levels. Even when corrected for other factors, there was a significant difference in the observed AEs between the two formulations of parenteral iron dextran. Our observations, if true, may have important implications for the management of anemia in chronic hemodialysis patients. If a significant number of AEs prohibit the administration of a specific iron dextran product to a large number of chronic hemodialysis patients, then anemia management may become suboptimal. In the future, newer iron products may provide even safer alternatives for the administration of parenteral iron to chronic hemodialysis patients.

A 6-month study of low-dose recombinant human erythropoietin alone and in combination with androgens for the treatment of anemia in chronic hemodialysis patients

Two previous short-term studies (12 weeks and up to 16 weeks) that used androgens to supplement recombinant human erythropoietin (rHuEPO) for the treatment of the anemia associated with end-stage renal disease showed divergent results. Both studies were limited by their brief duration, since the hematopoietic effect of androgens does not peak until 5 months. Therefore, we conducted a 6-month, prospective, randomized trial comparing low-dose rHuEPO alone and in combination with androgens for the treatment of the anemia of end-stage renal failure. Nineteen anemic chronic hemodialysis patients were randomized into two groups. Group A (n = 10) received 1,500 U rHuEPO intravenously three times a week for 26 weeks. Group B (n = 9) received the same dose of rHuEPO plus nandrolone decanoate 100 mg intramuscularly weekly. Baseline transferrin saturation, serum ferritin, intact serum parathyroid hormone, plasma aluminum, and hematocrit levels were not significantly different between the groups. At study completion, both groups showed a significant increase in mean hematocrit compared with baseline [group A: 24.8% ± 1.4% to 28.3% ± 2.8%, P = 0.003; group B: 25.1% ± 1.5% to 33.2% ± 4.5%, P = 0.001). The increase in hematocrit in the rHuEPO plus androgen-treated group was statistically greater than in the rHuEPO-alone group (8.2% ± 4.4% v 3.5% ± 2.8%; P = 0.012). With the exception of mild discomfort at the injection site, there were no significant side effects from nandrolone. We conclude that the combination of low-dose rHuEPO and nandrolone decanoate is effective treatment for the anemia of end-stage renal failure.