Erythropoiesis-stimulating Agents Responsiveness Research Articles

A Brief Review for Clinicians of Iron Metabolism and the Safety, Efficacy, and Rationale for Use of Intravenous Iron Products

Iron is an abundant element that is essential for multiple biologic processes. Iron metabolism is not entirely understood, but since the discovery of hepcidin, much progress has been made especially in the last five years. This article is intended to enhance clinician understanding of iron metabolism which may inform decisions about parenteral iron use in iron-restricted erythropoiesis (IResE). This article briefly discusses intravenous (IV) iron utilization in iron deficiency, anemia of chronic inflammation (ACI), functional iron deficiency (FID), and anemia associated with chronic kidney disease, heart failure, pregnancy, inflammatory bowel disease and cancer. Oral iron therapy is valuable in mild to moderate pure iron deficiency. Intravenous iron is required when a prompt response is needed in severe pure iron deficiency. ACI is a hypoferremic state resulting from altered iron metabolism. In ACI, IV iron is needed to overcome the blocking effects of hepcidin on intestinal absorption. ESAs stimulate erythropoiesis increasing iron utilization. This surge in iron requirement can result in FID, especially when ESAs are used in patients with ACI. Intravenous iron is required to treat or avoid iron deficiency in FID when inflammation is present. Parenteral iron maximizes ESA response and can make using erythropoiesis-stimulating agents (ESAs) safer by being ESA sparing. The complex and seemingly ubiquitous nature of iron in humans and the inadequate methods of assessment of iron status in inflammatory states means clinical and laboratory monitoring and individualization of care remain essential. The decision to administer intravenous iron is complex as it often lacks robust consensus guidelines; despite this we can expect utilization of these products to increase as they are safe, effective and necessary.

Evaluating Mean Corpuscular Volume As Predictor for Erythropoiesis Stimulating Agent Response in Elderly Patients Diagnosed with Myelodysplasia

Background: Low-Risk Myelodysplastic Syndrome (LR-MDS) is genetically heterogeneous. Transfusion dependency (TD) adversely impacts overall survival (OS). Erythropoiesis-stimulating agents (ESAs) are first line for anemia and delay onset of TD, improving quality of life. In older LR-MDS patients harboring a larger number of mutations, ESA response is dramatically reduced. Predictors of ESA response include hemoglobin between 8-10 g/dL, del (5q) anomaly, erythropoietin (EPO) level <100 IU/L, low blast count, and transfusion independence (TI). Macrocytosis is not only observed at MDS diagnosis, but it is also associated with inflammasome activation upon mutation acquisition. Prior studies in mice, for example, have shown that TET2 haploinsufficiency leads to larger erythroid size and pyroptosis. Mean Corpuscular Volume (MCV) is the most practical way to detect red cell size modification in MDS patients. There are no prior studies that have investigated the correlation between diagnostic red cell size (MCV) and prediction of response to MDS directed therapy (i.e. ESA, hypomethylating agents). Given the known association between myeloid mutations and red cell size modifications, we investigated the correlation between MCV and ESA response in LR-MDS patients older than 65 years. Methods: After IRB approval, 81 LR-MDS patients diagnosed at Michael E. DeBakey Houston VA were screened. 68/81 (83.9%) patients had data to evaluate ESA response. ESA response was classified by International Working Group (IWG) MDS 2016 criteria. Statistical analysis was performed with SAS software. Relevant variables with ability to predict ESA response including age, hemoglobin, lactate dehydrogenase (LDH), blast percentage, ferritin, EPO level, and TD history were investigated. Logistic regression analysis was used to examine the independent MCV modification effect on ESA response when adjusting for potential confounders selected from our univariate analysis. Results: 26/68 (38.2%) and 42/68 (61.7%) patients were ESA responders and non-responders, respectively. Median MCV among LR-MDS patients exhibiting ESA response was 98.6 fL (79.4-116.3) vs 93.9 fL (74.6-112.8) in non-responders, p=0.04. Median (range) for age, hemoglobin, LDH, blast percentage, ferritin, and EPO among responders and non-responders were 75.7 years (66-91) vs 76 years (66-88), p=0.80; 9.4 g/dL (8-11.1) vs 8.9 g/dL (5.3-13), p=0.24; 159.2 U/L (68-278) vs 203.1 U/L (119-372), p=0.04; 0.89% (0-5) vs 0.92% (0-10), p=0.96; 249 ng/mL (8.2-649) vs 395 ng/mL (9.3-945), p=0.02; and 195 mIU/mL (7.7-925) vs 174 mIU/mL (19-1626), p=0.80. TD history was observed in 50% and 66% of responders and non-responders, respectively, p=0.34. After accounting for potential confounders, MCV remained the only predictor for ESA response among LR-MDS patients, p=0.04, HR=1.12 (95% CI 1.01-1.25). Conclusions: Superior ESA response was observed among LR-MDS patients older than 65 years who exhibited higher MCV at diagnosis. Our data suggests that ESA response is associated with modifications in erythroid cell morphology (i.e. larger red cell size). In LR-MDS patients exhibiting higher MCV, probability of ESA response increases by 12% per 1-unit MCV increase at diagnosis. Although investigation into a "mutation type and/or mutation combination" leading to MCV modification is needed, MCV could discriminate subgroup of elderly LR-MDS patients who exhibit differential ESA response. Disclosures Yellapragada: Novartis: Employment, Other: Spouse Employment ; Celgene: Research Funding; BMS: Research Funding; Takeda: Research Funding.

Response to Erythropoiesis Stimulating Agents in Patients with WHO-Defined Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T)

Background: Myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) was formally included as a unique WHO-defined entity in the 2016, iteration of the classification of hematological neoplasms (under MDS/MPN overlap syndromes). Patients with MDS/MPN-RS-T have features of MDS-RS-single lineage dysplasia (SLD), persistent thrombocytosis (platelet count ≥450x109/L), with proliferation of large atypical megakaryocytes. Anemia, including red blood cell transfusion dependency (RBC-TD) is a major problem. While extensive studies have documented erythroid response rates (ERR) to erythropoiesis stimulating agents (ESA) in MDS and MDS-RS-SLD, the data in MDS/MPN-RS-T is less clear. We carried out this study to asses ERR in ESA treated patients with MDS/MPN-RS-T. Methods: After approval by the IRB, patients with 2016, WHO-defined MDS/MPN-RS-T were included in the study. The bone marrow (BM) morphology, cytogenetics and BM RS% were retrospectively reviewed. All study patients underwent next generation sequencing for 29 myeloid-relevant genes, obtained on BM mononuclear cells, at diagnosis, or at first referral, by previously described methods (Patnaik et al., BCJ 2016). Treatment details, including the type of ESA used, dose administered, side effects and reason for discontinuation were retrospectively abstracted. Erythroid responses were assessed using the 2006, international working group (IWG) MDS and the 2015, IWG MDS/MPN response criteria. Results: Forty seven patients with MDS/MPN-RS-T were identified, of which 37 (79%) patients received ESA treatment at any time point during their disease course; median age 73 years (range, 52-93), 46% male.The hemoglobin at diagnosis (HB) and baseline erythropoietin (EPO) levels were 9.1 gm/dL (range, 6.6-12.1) and 39 IU/L (range, 8-500), respectively. Ten (29%) patients were RBC-TD at baseline. None of the 37, ESA-treated patients were on concomitant cyto-reductive therapy for thrombocytosis. Twenty (54%) patients were treated with erythropoietin-a, 13 (35%) with darbepoetin, and 4 (11%) with both sequentially. Median doses were 40,000 IU weekly (range, 20,000-80,000) for erythropoietin-a and 200 mcg every 2 weeks (range, 100-500), for darbepoetin. Median treatment duration was 14 months (range, 1-173) and causes for discontinuation included; ESA failure/loss of response in 20 (54%), sustained HB rise in 1 (3%) and other causes, including adverse events in 4 (11%) patients. With regards to safety, the following events were considered potentially ESA related; treatment emergent hypertension in 2 (5%), venous thromboembolism, ischemic stroke and splenic infarction in 1 (3%) patient each, respectively. All patients with thrombotic/ischemic events had been on low dose aspirin prophylaxis. Erythroid responses by the IWG MDS and MDS/MPN response criteria were assessable in 35 (95%) patients: with 16 (46%) meeting criteria for an erythroid response, by both assessment systems. The median duration of ER was 20 months (range, 2-172). In comparison to ESA non-responders, those that responded were more likely to have baseline EPO levels ≤44 IU/L (ROC analysis; median, 28 vs 112 IU/L; p=0.0080), while there was a trend for inferior responses associated with RBC-TD (p=0.0857). Age, gender, baseline white blood cell and platelet counts, type of ESA used, BM RS %, JAK2V617F, SF3B1, DNMT3A, TET2 and ASXL1 mutational status did not impact ESA response (Table 1). On a univariate survival analysis (OS), survival was not significantly different between ESA responders vs non-responder (median OS, 76 vs 45 months; p=0.2929). After ESA failure, 7 (19%) patients received hypomethylating agents (HMA), while 5 (14%) received lenalidomide. There were no erythroid responses to HMA, while 1 of 3 (33%) assessable lenalidomide treated patients achieved a morphological complete response. Conclusion: Erythropoiesis stimulating agents are effective first line therapies for the management of anemia in patients with MDS/MPN-RS-T, with 46% achieving an erythroid response (median duration of response of 20 months). Low baseline endogenous EPO level (<44 IU/L) was the best predictor of response, with a trend towards an inferior response in the presence of RBC-TD. In the context of clonal thrombocytosis, potentially related thrombotic/ischemic events were documented in 8% of patients. Disclosures Al-Kali: Astex Pharmaceuticals, Inc.: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

In search of potential predictors of erythropoiesis-stimulating agents (ESAs) hyporesponsiveness: a population-based study

BackgroundEvidences show that around 20% of biosimilar or originator erythropoiesis-stimulating agents (ESAs) users are hyporesponsive. Controversial post-marketing data exist on the predictors of ESA hyporesponsiveness. The aim of this study was to identify predictors of ESA hyporesponsiveness in patients with chronic kidney disease (CKD) or cancer in clinical practice.MethodsDuring the years 2009–2015, a multi-center, population-based, cohort study was conducted using claims databases of Treviso and Caserta Local Health Units (LHUs). All incident ESA users were characterized at baseline and the differences between the baseline hemoglobin (Hb) value, that is the Hb registered within 30 days prior to the first ESA dispensing (index date, ID) and each outcome Hb value (registered between 30 and 180 days after ID) were calculated and defined as delta Hb (ΔHb). Incident ESA users were defined as hyporesponsive if, during follow-up, they registered at least one ΔHb < 0 g/dL. Including all potential predictors of ESA hyporesponsiveness and stratifying by indication for use, univariate and multivariate binary logistic regression models and Receiver Operating Characteristic (ROC) curves were carried out.Results`In general, 1080 incident ESA users (CKD: 57.0%; cancer: 43.0%) were identified. In CKD, predictors of ESA hyporesponsiveness were C-reactive protein (OR = 1.2, 95% CI: 1.0–1.5; P-value = 0.060) and high levels of baseline Hb (OR = 1.7, 95% CI: 1.2–2.2; P-value< 0,001), the latter being also predictor of ESA hyporesponsiveness in cancer (OR = 1.7, 95% CI: 1.1–2.4; P-value = 0.007). Both in CKD and in cancer, the type of ESA, biosimilar or originator, was not a predictor of ESA hyporesponsiveness. In CKD, concomitant use of iron preparations (OR = 0.3, 95% CI: 0.2–0.7; P-value = 0.002) and of high dosage of angiotensin-converting enzyme inhibitors/angiotensin II-receptor blockers (OR = 0.5, 95% CI: 0.3–0.9; P-value = 0.022) were protective factors against ESA hyporesponsiveness.ConclusionsThe study confirmed traditional potential predictors of hyporesponsiveness to ESA. The use of biosimilar or originator ESA was not a predictor of hyporesponsiveness in an outpatient setting from two large Italian areas. A better knowledge of the predictors of ESA response would allow a better anemia management to improve patients’ quality of life.

SAT-036 ERYTHROPOIESIS STIMULATING AGENT HYPORESPONSIVENESS AND ITS ASSOCIATION WITH MORTALITY AND HOSPITALISATION

In patients with CKD, higher erythropoiesis stimulating agents (ESA) dose might cause higher mortality and increased cardiovascular complications. Hyporesponsiveness to ESA treatment is a known predictor of poor clinical outcomes in haemodialysis (HD) patients. Poor outcomes could be the result of high ESA dosage required in these groups or patient related cause of hypo-responsiveness or a combination of both. We sought to examine whether high erythropoietin resistance index (ERI) was associated with increased all-cause mortality and hospitalisation among incident HD patients. Incident HD patients between January 2010 and December 2016, who completed six months of HD were included in this retrospective observational cohort study. Patients were followed up for one year from the index date (last day of 6 months exposure period) until first of the following – death, withdrawal or end of study (Dec 31, 2017). The main predictor variable was ESA responsiveness measured by ERI (IU/kg/week/g/dl) which was defined as average weekly weight-adjusted EPO dose per average haemoglobin concentration. Patients were divided into 2 groups based on ERI quartiles - ESA hyporesponsive (4th quartile, ERI >15.25+) and ESA responsive group (1st, 2nd and 3rd quartile combined, ERI < 15.25). ESA responsiveness was also assessed by a combination of ESA dosage (high: ≥ median value of ESA dose or low: < median value of ESA dose) and haemoglobin levels (high: ≥ 10 g/dl or low: <10 g/dl). Patients were then divided into 4 groups with low-dose ESA therapy and high haemoglobin (Hb) level as reference category.Primary outcomes were all-cause mortality and hospitalisation during the one year follow-up. Cox regression and Negative binomial regression models were used to determine associations with mortality and hospitalisation among the ERI groups. Binary logistic regression model was used to define the predictors of high ERI. A total of 2302 incident HD patients (mean age 60.1 ± 11.4 years, 56.2% male, 59% Chinese and 69.9% with diabetes as cause of ESRD) were included in the study. During the mean follow-up time of 0.95 ± 0.16 years, 113 (4.9%) patients died. The median EPO dose and mean ERI were 113.9 (IQR, 77.8 to 154.8) IU/kg/week and 12.1± 6.4 IU/kg/week/g/dl respectively. The ESA hyporesponsive group (ERI >15.25+) were more likely to be females, have low albumin, low BMI, low SGA scores and low transferrin saturation % levels but higher KT/V and ferritin levels compared to the ESA responsive group (p<0.001). ESA hyporesponsive group (ERI>15.25+) had 83% higher risk of all-cause mortality (aHR 1.83, 95% CI 1.20 – 2.79, p=0.005) after adjusting for potential confounders. HD patients with high-dose EPO and low Hb levels (ESA hyporesponsive) had significantly higher risk of mortality (aHR 2.42, 95% CI 1.41 – 4.19, p=0.001). The high ERI group also had 36% higher incidence of hospitalisation (IRR 1.36, 95% CI 1.20 – 1.54, p<0.001) compared to low ERI group. The independent predictors of high ERI were female gender, low albumin, high ferritin, low transferrin saturation %, low BMI, high KT/V, high acuity status and increased hospital admissions in the exposure period.View Large Image Figure ViewerDownload Hi-res image Download (PPT) High ERI levels are associated with increased risk of all-cause mortality and hospitalisation in incident HD patients. Lack of data on inflammatory markers is a study limitation.

The fraction of CD117/c-KIT-expressing erythroid precursors predicts ESA response in low-risk myelodysplastic syndromes.

Compelling evidence has emerged for the relevance of flow cytometry (FC) in the diagnostic work-up of myelodysplastic syndromes (MDS) but due to technical issues, the erythroid lineage has been under investigated, specifically in the therapeutic context. Using the "no red cell lysis" method developed to set up the RED-score, we specifically quantified the fraction of CD117/c-KIT-expressing erythroid precursors in a cohort of 144 MDS patients and studied the correlation with response to erythropoiesis-stimulating agents (ESA) in a sub cohort of 63 low-risk MDS patients. We confirmed the previously reported increase in CD117/c-KIT-expressing erythroid precursors in a subset of MDS patients and demonstrated a strong association between a cut off of CD117/c-KIT-expressing erythroid precursors ≥3% and ESA response (P = 0.001), independent of red blood cell requirement. From our observations, we hypothesized that a decrease in CD117/c-KIT-expressing erythroid precursors could be a mechanism of ESA failure. Moreover, the fraction of CD117/c-KIT-expressing erythroid precursors was correlated with progression-free survival in low-risk MDS patients (P = 0.018). In vitro, we demonstrated in an EPO dependent cell line that CD117/c-KIT expression is necessary for cell survival under EPO stimulation. The quantification of the CD117/c-KIT-expressing erythroid precursors could be proposed as a new theranostic and prognostic marker in MDS treated by ESA. Future studies will be required to determine whether modulating CD117/c-KIT expression and signaling could be used to improve anemia in MDS. © 2019 International Clinical Cytometry Society.

Definition and Validation of a Novel Metric of Erythropoiesis-Stimulating Agent Response in Hemodialysis Patients.

Erythropoiesis-stimulating agents (eg, epoetin alfa) are the primary treatment for anemia in patients with end-stage renal disease. Hemoglobin variability in and out of a narrow target range is common and associated with higher morbidity and mortality risk. More robust erythropoiesis-stimulating agent response metrics are needed to define optimal dosing and their association with clinical outcomes. In this cross-sectional, single-center, retrospective study, 49 patients with end-stage renal disease on hemodialysis were followed over 12 months. To quantify hemoglobin deviations outside the target range (10-12 g/dL), the area under the curve of hemoglobin versus time over a 12-month period (AUC-HGB) was calculated using the trapezoidal rule. Patients were categorized into 4 responder groups based on AUC-HGB quartiles. Comparative analyses of demographic and clinical characteristics between responder groups were performed. Correlations between AUC-HGB, erythropoietin resistance index, and time within therapeutic range were calculated. There were no significant differences in laboratory and dialysis parameters between responder groups except hemoglobin concentration and epoetin alfa dose. There was a negative correlation between AUC-HGB and time within therapeutic range (r = -.92; P < .001) and hemoglobin concentration (r = -.85; P < .01), indicating internal validity of the metric. There was a positive correlation between AUC-HGB and erythropoietin resistance index (r = .70; P < .001) indicating external validity. The poor response group received a higher median epoetin alfa dose (160 U/kg/week) compared to the excellent response group (68.8 U/kg/week; P < .001) with a similar number of dose changes between the groups. AUC-HGB is a valid marker of epoetin alfa response and should be considered in future analyses of larger populations.

Obesity may be erythropoietin dose-saving in hemodialysis patients

BackgroundIn dialysis patients, the obesity-survival paradox still requires an explanation. Anemia and high doses of erythropoiesis-stimulating agents (ESAs) are associated with worse outcomes in the hemodialysis (HD) population. In the present study, we explored the relation between obesity and anemia control in a sample of maintenance HD patients in Egypt.MethodsThis multicenter observational study included 733 patients on maintenance HD from 9 hemodialysis centers in Egypt. Clinical and laboratory data as well as average doses of ESAs and parenteral iron were recorded. The erythropoietin resistance index (ERI) was calculated.ResultsObesity, defined as a body mass index (BMI) ≥ 30 kg/m2, was present in 22.6% of the studied population. The target hemoglobin level (10.0–11.5 g/dL) was achieved in 27.3% of non-obese and 25.3% of obese patients, with no significant difference. The median serum ferritin and the values of transferrin saturation index did not differ significantly between these two groups. The weekly ESA dose was significantly lower in obese than in non-obese patients (P = 0.0001). A trend toward higher ESA doses and ERI values was observed in patients with lower BMIs (P < 0.0001). Multiple linear regression revealed that the BMI and urea reduction ratio were the strongest predictors of the ERI.ConclusionOur study adds more evidence to obesity-associated advantages in HD patients. BMI may determine ESA response, with better responses observed in patients with higher BMIs.

Intravenous iron and erythropoiesis‐stimulating agents in haemodialysis: A systematic review and meta‐analysis

ABSTRACTAimHigher dosages of erythropoiesis‐stimulating agents (ESAs) have been associated with adverse effects. Intravenous iron is used to optimize ESA response and reduces ESA doses in haemodialysis patients; this meta‐analysis evaluates the magnitude of this effect.MethodsA literature search was performed using MEDLINE, Embase and the Cochrane Collaboration Central Register of Clinical Trials from inception until December 2014, to identify randomized controlled trials of intravenous iron and ESA, in patients undergoing haemodialysis for end‐stage kidney disease. Dosing of IV iron in concordance with the Kidney Disease Improving Global Outcomes guidelines was considered optimal iron therapy.ResultsOf the 28 randomized controlled trials identified, seven met the criteria for inclusion in the meta‐analysis. Results of random‐effects meta‐analysis show a statistically significant weighted mean (95% CI) difference of −1733 [−3073, −392] units/week in ESA dose for optimal iron versus suboptimal iron. The weighted average change in ESA dose was a reduction of 23% (range −7% to −55%) attributable to appropriate dosing of intravenous iron. A comparison of intravenous iron versus oral iron/no iron (five trials) showed a greater reduction in ESA dose, although this did not reach statistical significance (weighted mean difference, 95% CI: −2,433 [−5183, 318] units/week). The weighted average change in ESA dose across the five trials was a reduction of 31% (range −8% to −55%).ConclusionSignificant reductions in ESA dosing may be achieved with optimal intravenous iron usage in the haemodialysis population, and suboptimal iron use may require higher ESA dosing to manage anaemia.

Erratum to: Rationale and design of oBservational clinical Research In chronic kidney disease patients with renal anemia: renal proGnosis in patients with Hyporesponsive anemia To Erythropoiesis-stimulating agents, darbepoetiN alfa (BRIGHTEN Trial).

Renal anemia is an important complication in non-dialysis chronic kidney disease (CKD) patients as well as in dialysis patients. Although recombinant human erythropoietin has dramatically improved prognosis and quality of life in these patients, there have been issues among non-dialysis CKD patients who exhibit hyporesponsiveness to erythropoiesis-stimulating agent (ESA). The causes and definition of ESA hyporesponsiveness, as well as the incidence of renal and cardiovascular disease (CVD) events in such patients, are yet to be clarified. This ongoing trial is a multicenter, prospective, observational study of non-dialysis CKD patients with renal anemia. The primary objective is to survey the current realities of the therapy with ESA in Japan and evaluate the correlation between hyporesponsiveness to darbepoetin alfa and CKD progression. The secondary objective is to investigate relationship between ESA hyporesponsiveness and CVD events based on the clinical situation in Japan, and to explore an ESA response index. The subjects consist of CKD patients with estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2 who present renal anemia. The target number of registered cases is 2000 patients, based on estimates of incidences of renal and CVD events from past studies. Renal function and CVD events will be observed for 96 weeks after the initiation of darbepoetin alfa administration. Definitions of ESA hyporesponsiveness will also be investigated. By clarifying markers and factors involved in ESA hyporesponsiveness and their relationships with renal and CVD events, this ongoing study aims to improve evidence-based therapies for renal anemia in non-dialysis CKD patients.

Rationale and design of oBservational clinical Research In chronic kidney disease patients with renal anemia: renal proGnosis in patients with Hyporesponsive anemia To Erythropoiesis-stimulating agents, darbepoetiN alfa (BRIGHTEN Trial)

BackgroundRenal anemia is an important complication in non-dialysis chronic kidney disease (CKD) patients as well as in dialysis patients. Although recombinant human erythropoietin has dramatically improved prognosis and quality of life in these patients, there have been issues among non-dialysis CKD patients who exhibit hyporesponsiveness to erythropoiesis-stimulating agent (ESA). The causes and definition of ESA hyporesponsiveness, as well as the incidence of renal and cardiovascular disease (CVD) events in such patients, are yet to be clarified.MethodsThis ongoing trial is a multicenter, prospective, observational study of non-dialysis CKD patients with renal anemia. The primary objective is to survey the current realities of the therapy with ESA in Japan and evaluate the correlation between hyporesponsiveness to darbepoetin alfa and CKD progression. The secondary objective is to investigate relationship between ESA hyporesponsiveness and CVD events based on the clinical situation in Japan, and to explore an ESA response index.ResultsThe subjects consist of CKD patients with estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2 who present renal anemia. The target number of registered cases is 2000 patients, based on estimates of incidences of renal and CVD events from past studies. Renal function and CVD events will be observed for 96 weeks after the initiation of darbepoetin alfa administration. Definitions of ESA hyporesponsiveness will also be investigated.ConclusionBy clarifying markers and factors involved in ESA hyporesponsiveness and their relationships with renal and CVD events, this ongoing study aims to improve evidence-based therapies for renal anemia in non-dialysis CKD patients.

Evaluation of the Impact of a New Synthetic Vitamin E-Bonded Membrane on the Hypo-Responsiveness to the Erythropoietin Therapy in Hemodialysis Patients: A Multicenter Study

Background: Oxidative stress has been related to hypo-response to erythropoiesis-stimulating agents (ESAs) in hemodialysis (HD) patients. The aim of this study was to verify whether vitamin E (ViE) on a synthetic polysulfone dialyzer can improve ESA responsiveness. Methods: This controlled, multicenter study involved 93 HD patients on stable ESA therapy, who were randomized to either ViE-coated polysulfone dialyzer or to a low-flux synthetic dialyzer. The primary outcome measure was the change in ESA resistance index (ERI) from baseline. Results: Mean ERI decreased in the ViE group by 1.45 IU/kg*g/dl and increased in the control group by 0.53 IU/kg*g/dl, with a mean difference of 1.98 IU/kg*g/dl (p = 0.001 after adjusting for baseline ERI, as foreseen by the study protocol). Baseline ERI was inversely related to its changes during follow-up only in the control group (R² = 0.29). Conclusions: The ViE dialyzer can improve ESA response in HD patients. Changes in ERI during follow-up are independent from baseline ERI only in the ViE group. Video Journal Club ‘Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=453442.

Hepcidin serum levels and resistance to recombinant human erythropoietin therapy in hemodialysis patients

ObjectiveThe aim of this study was to analyze the factors that are associated with the response to erythropoiesis-stimulating agents (ESAs) and its association with hospitalization and mortality rates; to evaluate the serum hepcidin level and its associations with iron profile, inflammatory markers, ESA responsiveness, and mortality; and to determine independent factors affecting ERI and hepcidin. Materials and methodsTo evaluate a dose-response effect of ESAs we used the erythropoietin resistance index (ERI). Patients were stratified in two groups: nonresponders and responders (ERI>15, n=20, and ERI ≤15U/kg/week/g per 100mL, n=153, respectively). Hematological data, hepcidin levels, iron parameters, inflammatory markers, hospitalization and mortality rates were compared between the groups. Multiple regression analysis was used to determine independent factors affecting ERI and hepcidin. ResultsC-reactive protein (CRP) (β=0.078, P=0.007), albumin (β=−0.436, P=0.004), body mass index (β=−0.374, P<0.001), and hospitalization rate per year (β=3.017, P<0.001) were found to be significant determinants of ERI in maintenance hemodialysis (MHD) patients. Inadequate dialysis was associated with higher ERI. Patients with concomitant oncological diseases had higher ERI (31.2±12.4 vs 9.7±8.1U/kg/week/g per 100mL, P=0.002). The hepcidin level was 158.51±162.57 and 120.65±67.28ng/mL in nonresponders and responders, respectively (P=0.33). Hepcidin correlated directly with ERI, dose of ESAs, ferritin and inversely with Hb, transferrin saturation, and albumin. ERI (β=4.869, P=0.002) and ferritin (β=0.242, P=0.003) were found to be significant determinants of hepcidin in MHD patients. The hospitalization rate per year was 2.35±1.8 and 1.04±1.04 in nonresponders and responders, respectively (P=0.011). The mean length of one hospitalization was 25.12±21.26 and 10.82±17.25 days, respectively (P=0.012). Death occurred in 30% of the patients from the responders’ group and in 50% from the nonresponders’ group (P=0.289). The mean hepcidin concentration of patients who died was 141.9±129.62ng/mL and who survived, 132.98±109.27ng/mL (P=0.797). ConclusionsCRP, albumin, BMI, and hospitalization rate per year were found to be significant determinants of ERI in MHD patients. Inadequate dialysis was associated with higher epoetin requirements. There were no difference in patient mortality by ERI, but a significant difference in hospitalization rates and mean length of one hospitalization was revealed. A significant positive relation between hepcidin and ERI was revealed. ERI and ferritin were found to be significant determinants of hepcidin in MHD patients. Hepcidin was not related to mortality.

Relationship between variations in time-dependent response to erythropoiesis-stimulating agents and mortality in hemodialysis patients: a single-center study

Hemodialysis (HD) patients who are resistant to erythropoiesis-stimulating agents (ESAs) have a higher mortality rate. The aim of this study was to assess the relationship between the time-dependent variability of ESA response in HD patients and mortality. A total of 375 HD patients were enrolled in this study. The ESA resistance index (ERI) was calculated by dividing the weekly weight-adjusted ESA dose by hemoglobin concentration, and the average ERI was calculated from the ERI values every 2 months during a 36-month follow-up period. We divided the patients into six groups based on the patterns of their ERI level fluctuations: low-low (Low group), intermediate-intermediate (Intermediate group), high-high (High group), Low-intermediate group, Intermediate-high group, and Low-high group. There were 94 (25.1 %) deaths, and they included 51 (13.6 %) deaths from cardiovascular disease (CVD). A multivariate analysis with adjustment for age, serum albumin and C-reactive protein levels, and history of CVD showed that the High group was independently and significantly related to all-cause mortality (odds ratio = 5.53, 95 % CI 2.29–13.99, p = 0.0001) and CVD-related mortality (odds ratio = 3.49, 95 % CI 1.40–8.47, p = 0.0081). High ERI levels are an independent risk factor for all-cause and CVD mortality in HD patients.

ESA Hyporesponsiveness Is Associated with Adverse Events in Maintenance Hemodialysis (MHD) Patients, But Not with Iron Storage.

ObjectiveIt has been reported that hyporesponsiveness to erythropoiesis-stimulating agent (ESA) is associated with adverse events in patients on maintenance hemodialysis (MHD). However, it has not been determined whether higher iron storage is associated with an improved response, including better survival, to ESA.Design and MethodWe measured serum ferritin, hemoglobin (Hb), and transferrin saturation (TSAT) levels every three months for two years in 1,095 MHD patients. The weekly dose of ESA to Hb ratio was also calculated as an index of ESA responsiveness (ERI).ResultsA significant correlation (p<0.001, R = 0.89) between ferritin and Hb was only observed in the patients with ferritin levels <50 ng/mL. High-dose (≥50 mg/week) intravenous iron administration, female sex, low serum albumin, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were significant predictors of a high ERI value (>280); however, serum ferritin and TSAT levels did not predict a higher ERI. In the time-dependent Cox hazard model, the risk for a composite event in the patients with a high ERI (≥280) and a high ferritin level (≥100 ng/mL) was significantly greater (hazard ratio [HR], 2.09, P = 0.033) than that for patients with a high ERI and a low ferritin (<100 ng/mL) level.ConclusionHb was dependent upon ferritin levels in patients with ferritin levels <50 ng/mL but not in patients with ferritin levels ≥50 ng/mL. Patients with hyporesponsiveness to ESA had a greater risk of composite events, but ERI was unrelated to iron storage.

Association of Erythropoietin-Stimulating Agent Responsiveness with Mortality in Hemodialysis and Peritoneal Dialysis Patients.

Erythropoiesis-stimulating agent (ESA) responsiveness has been reported to be associated with increased mortality in hemodialysis (HD) patients. ESA requirement to obtain the same hemoglobin (Hb) level is different between HD and peritoneal dialysis (PD) patients. In this study, we investigated the impact of ESA responsiveness on mortality between both HD and PD patients. Prevalent HD and PD patients were selected from the Clinical Research Center registry for end-stage renal disease, a prospective cohort study in Korea. ESA responsiveness was estimated using an erythropoietin resistant index (ERI) (U/kg/week/g/dL). Patients were divided into three groups by tertiles of ERI. ESA responsiveness was also assessed based on a combination of ESA dosage and hemoglobin (Hb) levels. The primary outcome was all-cause mortality. A total of 1,594 HD and 876 PD patients were included. The median ESA dose and ERI were lower in PD patients compared with HD patients (ESA dose: 4000 U/week vs 6000 U/week, respectively. P<0.001, ERI: 7.0 vs 10.4 U/kg/week/g/dl, respectively. P<0.001). The median follow-up period was 40 months. In HD patients, the highest ERI tertile was significantly associated with higher risk for all-cause mortality (HR 1.96, 95% CI, 1.07 to 3.59, P = 0.029). HD patients with high-dose ESA and low Hb levels (ESA hypo-responsiveness) had a significantly higher risk of all-cause mortality (HR 2.24, 95% CI, 1.16 to 4.31, P = 0.016). In PD patients, there was no significant difference in all-cause mortality among the ERI groups (P = 0.247, log-rank test). ESA hypo-responsiveness was not associated with all-cause mortality (HR = 1.75, 95% CI, 0.58 to 5.28, P = 0.319). Our data showed that ESA hypo-responsiveness was associated with an increased risk of all-cause mortality in HD patients. However, in PD patients, ESA hypo-responsiveness was not related to all-cause mortality. These finding suggest the different prognostic value of ESA responsiveness between HD and PD patients.

Effect of a More Permeable Dialysis Membrane on ESA Resistance in Hemodialysis Patients - A Pilot Investigation

Background/Aims: Hemodialysis (HD) patients often show impaired response to erythropoiesis-stimulating agents (ESAs). Extended HD membrane permeability may potentially improve ESA response. Methods: Twenty-four prevalent HD patients were randomly assigned to 12 weeks use of high cut-off (HCO) membrane (in every second dialysis treatment) or continued treatment with high-flux membrane. We monitored changes in hemoglobin (Hb), ESA dose, and key biochemical markers. Results: The Hb level increased in the study group (from 11.6 ± 1.0 to 12.5 ± 1.5 g/dl; p = 0.038) but was stable in the control group. Variation over time in ESA dose and ESA resistance index did not differ between groups. HCO membrane usage for 12 weeks led to decreased hepcidin level, from 303 ± 189 to 157 ± 83 ng/ml (p = 0.024); serum albumin level decreased and stabilized 15 ± 6% below baseline. Conclusions: These results indicate that use of a more permeable dialysis membrane may improve ESA responsiveness in iron-replete HD patients. Extensive albumin removal may preclude long-term use of the HCO membrane.

Can iron overload in patients with lower-risk myelodysplastic syndromes be reduced using erythropoiesis-stimulating agents?

Iron overload (IOL) portends inferior outcome in myelodysplastic syndromes (MDS). Erythropoiesis-stimulating agents (ESA) may reduce red blood cell transfusion requirements. MDS patients receiving ESA were reviewed for characteristics, response to ESA by International Working Group 2006 criteria and ferritin levels. Forty-nine patients received an ESA, had ferritin levels available, and were not receiving iron chelation therapy. Baseline characteristics were not significantly different between ESA responders (ER) and non-responders (ENR; P = NS). The median ESA treatment duration was 6.7 (1.5-85.9) months. Twenty-one (43%) patients had an ESA response. Median ferritin level in ER was pre-ESA, 473 (range 91-2727) and post-ESA, 801 (130-11,164) ng/mL (P = 0.01), and in ENR pre-ESA, 672 (76-3285) and post-ESA, 1423 (431-6593) ng/mL (P < 0.0001). There was a significant association between ESA response, post-ESA hemoglobin ≥100g/L, and post-ESA ferritin <1000ng/mL (P = 0.0003 and 0.03, respectively). At a median follow-up of 28months, the 2-year overall survival for ER and ENR, respectively, were 80% and 86% (P = NS). In lower-risk MDS patients responding to ESA, although an expected decrease in ferritin levels over treatment was not seen, ferritin levels increased less than in non-responders. Whether IOL may be reduced by ESA over a longer treatment duration may require analysis of larger numbers of patients.

Characterization of chronic and acute ESA hyporesponse: a retrospective cohort study of hemodialysis patients.

BackgroundSome patients with chronic kidney disease do not respond adequately to erythropoiesis-stimulating agent (ESA) treatment; these patients are referred to as ESA hyporesponders. There is no widely accepted contemporary definition for chronic ESA hyporesponse. The study objective was to propose and validate an operational definition for chronic ESA hyporesponse.MethodsThis was a retrospective cohort study using electronic health care records. Participants were anemic hemodialysis patients treated during February 2012 and were followed for 15 months. Patients’ ESA response (responders) or lack of response (chronic and acute hyporesponders) based on longitudinal patterns of ESA dose and hemoglobin level was assessed. Persistence of hyporesponse, longitudinal iron measures, transfusion rates, and mortality rates were analyzed. Frequency of blood transfusions (monthly) and death rates (quarterly) were calculated. Log normalized serum ferritin concentration was analyzed.ResultsOf 97,677 eligible patients, 6632 had acute hyporesponsiveness (ESA responsiveness restituted in ≤ 4 months) and 3086 had chronic hyporesponsiveness (lack of ESA response for > 4 months). Over months 1–4 among chronic hyporesponders, mean serum ferritin (722–785 ng/mL) and transferrin saturation (TSAT; 26.76 %-27.08 %) were constant, while acute hyporesponsive patients experienced increased ferritin (654-760 ng/mL) and TSAT (25.71–30.88 %) levels. Compared to ESA responders (0.19–0.30 %), chronic hyporesponders were transfused 7-times (1.20–2.17 %) more frequently over follow-up. Quarterly mortality was greatest in chronic ESA hyporesponders (2.98–5.48 %), followed by acute ESA hyporesponders (2.17–3.30 %) and ESA responders (1.43–2.49 %). With consistence over the study, chronic hyporesponders died more frequently than patients in the other study cohorts.ConclusionsFindings indicate that 4 months of continuous ESA hyporesponsiveness can be used to differentiate acute from chronic hyporesponsiveness. This definition of chronic hyporesponsiveness is supported by outcome data showing higher mortality and transfusion rates in chronic hyporesponders compared to acute hyporesponders.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-015-0138-x) contains supplementary material, which is available to authorized users.

Association of plasma F2-isoprostanes and isofurans concentrations with erythropoiesis-stimulating agent resistance in maintenance hemodialysis patients.

BackgroundIn patients undergoing maintenance hemodialysis (HD), hyporesponsiveness to erythropoiesis stimulating agents (ESAs) is associated with adverse clinical outcomes. Systemic inflammation is highly prevalent in HD patients and is associated with ESA hyporesponsiveness. Oxidative stress is also highly prevalent in HD patients, but no previous study has determined its association with ESA response. This study assessed the association of plasma markers of oxidative stress and inflammation with ESA resistance in patients undergoing maintenance HD.MethodsWe analyzed data from 165 patients enrolled in the Provision of Antioxidant Therapy in Hemodialysis study, a randomized controlled trial evaluating antioxidant therapy in prevalent HD patients. Linear and mixed-effects regression were used to assess the association of baseline and time-averaged high sensitivity F2-isoprostanes, isofurans, C-reactive protein (hsCRP), and interleukin-6 (IL-6) with ESA resistance index (ERI), defined as the weekly weight-adjusted ESA dose divided by blood hemoglobin level. Unadjusted models as well as models adjusted for potential confounders were examined. Predicted changes in ERI per month over study follow-up among baseline biomarker quartiles were also assessed.ResultsPatients with time-averaged isofurans in the highest quartile had higher adjusted mean ERI compared with patients in the lowest quartile (β = 14.9 ng/ml; 95 % CI 7.70, 22.2; reference group <0.26 ng/ml). The highest quartiles of hsCRP and IL-6 were also associated with higher adjusted mean ERI (β = 10.8 mg/l; 95 % CI 3.52, 18.1 for hsCRP; β = 10.2 pg/ml; 95 % CI 2.98, 17.5 for IL-6). No significant association of F2-isoprostanes concentrations with ERI was observed. Analyses restricted to baseline exposures and ERI showed similar results. Baseline hsCRP, IL-6, and isofurans concentrations in the highest quartiles were associated with greater predicted change in ERI over study follow-up compared to the lowest quartiles (P = 0.008, P = 0.004, and P = 0.04, respectively). There was no association between baseline F2-isoprostanes quartile and change in ERI.ConclusionsIn conclusion, higher concentrations of isofurans, hsCRP and IL-6, but not F2-isoprostanes, were associated with greater resistance to ESAs in prevalent HD patients. Further research is needed to test whether interventions that successfully decrease oxidative stress and inflammation in patients undergoing maintenance HD improve ESA responsiveness.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-015-0074-9) contains supplementary material, which is available to authorized users.