Erythropoiesis-stimulating Agents Hyporesponsiveness Research Articles

Association of erythropoietin resistance and fibroblast growth factor 23 in dialysis patients: Results from the Japanese Dialysis Outcomes and Practice Patterns Study.

BackgroundFibroblast growth factor 23 (FGF23) plays an important role in chronic kidney disease (CKD)‐related mineral and bone disorders. High FGF23 levels are associated with increased risk of anaemia in non‐haemodialysis CKD patients. FGF23 also negatively regulates erythropoiesis in mice. We hypothesized that higher FGF23 levels are associated with increased erythropoietin hyporesponsiveness among haemodialysis patients.MethodsThe study included 1044 patients from the Japanese Dialysis Outcomes and Practice Patterns Study (J‐DOPPS) phase 5 (2012‐2015). The outcome was erythropoiesis‐stimulating agent hyporesponsiveness (ESA‐hypo), defined as mean Hgb <10 g/dL and standardized mean ESA dose >6000 u/week over 4 months following FGF23 measurement. The association between ESA‐hypo and FGF23 was estimated using multivariable‐adjusted logistic generalized estimating equation regression models.ResultsPatients with higher levels of FGF23 were younger and had higher levels of serum albumin, creatinine, albumin‐corrected calcium, phosphorus, PTH, 25(OH)‐vitamin D, and had higher percentages of intravenous (IV) iron, IV vitamin D and cinacalcet use. ESA‐hypo was present in 144 patients (13.8%). Compared with the third quintile of FGF23 levels, the odds ratio (95% CI) of ESA‐hypo was 2.14 (0.99, 4.62) and 1.74 (0.74, 4.11) for the first and fifth quintiles, respectively.ConclusionThe lowest and highest levels of FGF23 were associated with higher odds of ESA‐hypo in patients on maintenance haemodialysis, although the associations were not statistically significant. The relationship between FGF23 and anaemia, and particularly the increased risks of ESA‐hypo at low FGF23 levels which might be the result of energy saving, must be confirmed in larger clinical studies.

Clinical and Economic Outcomes of Erythropoiesis-Stimulating Agent Hyporesponsiveness in the Post-Bundling Era

Rationale & ObjectiveSince the change in erythropoiesis-stimulating agent (ESA) labeling and bundling of dialysis services in the United States, few studies have addressed the clinical importance of ESA hyporesponsiveness and none have considered health care resource use in this population. We aimed to further explore ESA hyporesponsiveness and its consequences.Study DesignRetrospective observational cohort study.Setting & ParticipantsUS Renal Data System Medicare participants receiving dialysis with a minimum 6 months of continuous ESA use from 2012 to 2014.PredictorsErythropoietin resistance index (≥2.0 U/kg/wk/g/L) and ESA dose were used to identify ESA hyporesponders and hyporesponsive subgroups: isolated, intermittent, and chronic.OutcomesAssociations between ESA responsiveness and mortality, cardiovascular hospitalization rates, and health care resource use were evaluated and compared across subgroups.Analytical ApproachBaseline characteristics were compared using Wilcoxon rank sum tests for continuous variables and χ2 tests for categorical variables. Incidence rates of health care resource use were modeled using an unadjusted and adjusted generalized linear model.ResultsOf 834,115 dialysis patients in the CROWNWeb database, 38,891 ESA hyporesponders and 59,412 normoresponders met all inclusion criteria. Compared with normoresponders, hyporesponders were younger women, weighed less, and had longer durations of dialysis (all P < 0.001). Hyporesponders received 3.8-fold higher ESA doses (mean, 94,831 U/mo) and erythropoietin resistance index was almost 5 times higher than in normoresponders. Hyporesponders had lower hemoglobin levels and parathyroid hormone levels > 800 pg/mL, and iron deficiency was present in 26.5% versus 10.9% in normoresponders. One-year mortality was higher among hypo- compared with normoresponders (25.3% vs 22.6%). Hyporesponders also had significantly higher rates of hospitalization for cardiovascular events, emergency department visits, inpatient stays, home health agency visits, skilled nursing facility, and hospice days.LimitationsOnly US Medicare patients were included and different hyporesponder definitions may have influenced the results.ConclusionsThis study explored ESA hyporesponsiveness using new definitions and incorporated clinical and economic outcomes. It established that ESA-hyporesponsive dialysis patients had higher mortality, cardiovascular hospitalization rates, and health care costs as compared with ESA-normoresponsive patients.

P0855ASSOCIATIONS BETWEEN A COMPREHENSIVE PANEL OF BIOMARKERS WITH ESA HYPORESPONSIVENESS: ROLE OF IMMUNE DYSFUNCTION IN THE PATHOPHYSIOLOGY OF CKD ANEMIA

Abstract Background and Aims An inadequate response to the treatment of anemia with erythropoiesis-stimulating agents (ESAs) in patients with chronic kidney disease is a challenging and common clinical condition previously associated with signs of inflammation and episodic clinical events. The associations between different immune response pathways and ESA hyporesponsiveness remain poorly understood. Here we describe the associations between a comprehensive panel of inflammatory biomarkers and ESA resistance in a group of stable HD patients. Method This is post-hoc analysis of the baseline evaluation of patients enrolled in the HDFIT, a randomized controlled trial. A panel comprising a more general (CRP), innate (IL-1β and IL-6), adaptive (IFNγ, IFNα2) biomarkers of immune response, and also a specific vascular inflammation (MCP-1) biomarkers were simultaneously measured with the same serum sample through turbidimetry and Milliplex Human Cytokine Magnetic Bead Panel - EMD Milipore Corporation, USA. Multivariable analysis was used to assess the association of their concentrations with the erythropoietin resistance index (ERI), defined as the weekly ESA dose divided by hemoglobin level. Results A total of 155 patients were included in this analysis (mean age 52 ± 6; 70% male; 32% with diabetes; mean hemoglobin 11.7 ± 1.5; median ESA dose/week 8000 IU IQR: 4000-12.000). Patients in the highest ERI tercile were mostly female, younger, more diabetic and with slightly higher proportion of iron prescription compared to those in the lowest tercile of ERI. The multivariable models adjusted for age, sex, diabetes and vascular access demonstrated that higher serum levels of IL-1β and IFN-γ were associated with higher ESA resistance, while there were no detectable associations of serum levels of IL-6 or CRP and ERI. Conclusion Among the biomarkers included in this comprehensive panel of biomarkers representing the multilevel nature of immune dysfunction in CKD, we observed associations between higher concentrations of innate (IL-1β) and adaptive (IFN) immune response and ESA hyporesponsiveness. Our results support the role of immune dysfunction in the pathophysiology of CKD anemia.

Inflammation and Erythropoiesis-Stimulating Agent Response in Hemodialysis Patients: A Self-matched Longitudinal Study of Anemia Management in the Dialysis Outcomes and Practice Patterns Study (DOPPS)

Rationale & ObjectivePrevious studies of inflammation and anemia management in hemodialysis (HD) patients may be biased due to patient differences. We used a self-matched longitudinal design to test whether new inflammation, defined as an acute increase in C-reactive protein (CRP) level, reduces hemoglobin response to erythropoiesis-stimulating agent (ESA) treatment.Study DesignSelf-matched longitudinal design.Setting & Participants3,568 new inflammation events, defined as CRP level > 10 mg/L following a 3-month period with CRP level ≤ 5 mg/L, were identified from 12,389 HD patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 4 to 6 (2009-2018) in 10 countries in which CRP is routinely measured.Predictor“After” (vs “before”) observing a high CRP level.OutcomesWithin-patient changes in hemoglobin level, ESA dose, and ESA hyporesponsiveness (hemoglobin < 10 g/dL and ESA dose > 6,000 [Japan] or >8,000 [Europe] U/wk).Analytical ApproachLinear mixed models and modified Poisson regression.ResultsComparing before with after periods, mean hemoglobin level decreased from 11.2 to 10.9 g/dL (adjusted mean change, −0.26 g/dL), while mean ESA dose increased from 6,320 to 6,960 U/wk (adjusted relative change, 8.4%). The prevalence of ESA hyporesponsiveness increased from 7.6% to 12.3%. Both the unadjusted and adjusted prevalence ratios of ESA hyporesponsiveness were 1.68 (95% CI, 1.48-1.91). These associations were consistent in sensitivity analyses varying CRP thresholds and were stronger when the CRP level increase was sustained over the 3-month after period.LimitationsResidual confounding by unmeasured time-varying risk factors for ESA hyporesponsiveness.ConclusionsIn the 3 months after HD patients experienced an increase in CRP levels, hemoglobin levels declined quickly, ESA doses increased, and the prevalence of ESA hyporesponsiveness increased appreciably. Routine CRP measurement could identify inflammation as a cause of worsened anemia. In turn, these findings speak to a potentially important role for anemia therapies that are less susceptible to the effects of inflammation.

Factors associated with erythropoiesis-stimulating agent hyporesponsiveness anemia in chronic kidney disease patients.

Anemia is one of the most common problems in chronic kidney disease (CKD). Despite comprehensive investigations in several cases, definite causes of anemia frequently remain unknown. Our study aimed to analyze the factors that possibly affect anemia in CKD patients who were referred for hematology consultation. A total of 87 patients were retrospectively included in the cohort. Forty-four cases were excluded, including 30 cases with unavailable intact parathyroid hormone (iPTH) data, 11 cases with bone marrow diseases (8 Pure red cell aplasia, 3 Myelodysplastic syndrome) and 3 cases with thalassemia. In total, 43 patients were analyzed. Patients with high iPTH had a significantly lower Hemoglobin (Hb) level and required a higher dose of erythropoiesis stimulating agents (ESAs) compared with the normal iPTH group (Hb 8.29 vs 9.24 mg/dL, P=0.032 and ESAs dose of 16,352.94 vs. 12,444.44 U/week, P=0.024). Univariate, followed by stepwise multivariate analysis was performed and determined that serum phosphate (PO4) was significantly associated with lower Hb level (P=0.01 and P=0.013, respectively). In addition, Hb level was inversely correlated with iPTH and serum phosphate (PO4) level (r=-0.54, P<0.001 and r=-0.47, P=0.005; respectively). Mineral disequilibrium is an important factor associated with anemia in ESA hyporesponsive CKD. Also, hyperphosphatemia and secondary hyperparathyroidism are significantly correlated with low Hb. As a result, we strongly suggest correction of mineral disequilibrium factors prior to performing bone marrow study.

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.

Relationship between anti-erythropoietin receptor autoantibodies and responsiveness to erythropoiesis-stimulating agents in patients on hemodialysis: a multi-center cross-sectional study.

A decreased response to erythropoiesis-stimulating agents (ESAs) leads to refractory anemia and worse prognosis in patients with chronic kidney disease. We examined the association between autoantibodies to the erythropoietin receptor (EPOR) and responsiveness to ESAs in patients on maintenance hemodialysis. A total of 108 Japanese patients on maintenance hemodialysis at three institutions were enrolled. Sera from these patients were screened for anti-EPOR antibodies using an enzyme-linked immunosorbent assay. An ESA resistance index (ERI) was calculated, and patients in the highest ERI quartile were defined as ESA hyporesponsive. Anti-EPOR antibodies were detected in 11 patients (10%). Body mass index and hemoglobin, platelet, magnesium, and ferritin levels decreased with higher ERI levels. On the other hand, C-reactive protein (CRP) levels and the prevalence of anti-EPOR antibodies increased with higher ERI levels. In multivariate analysis, the presence of anti-EPOR antibodies together with CRP was a significant risk factor for ESA hyporesponsiveness. Anti-EPOR antibodies were detected in patients on maintenance hemodialysis, and these autoantibodies were independent factors for hyporesponsiveness to ESAs in these patients.

Statin therapy and erythropoiesis-stimulating agent hyporesponsiveness in patients with nondialysis chronic kidney disease: A retrospective study in Beijing, China.

Erythropoiesis-stimulating agents (ESAs) are frequently used among patients with renal anemia, while a significant proportion of patients exhibit ESA hyporesponsiveness despite adequate dosing. Previous studies have suggested an inverse association between ESA hyporesponsiveness and statin use among patients receiving dialysis therapy. However, studies based on predialysis patients are extremely limited.Based on electronic medical records of a tertiary hospital in Beijing, China between April 2010 and April 2015, we investigated the association between statin use and ESA hyporesponsiveness among patients with predialysis-chronic kidney disease (CKD).Altogether 232 patients with CKD initiating ESA therapy and with hemoglobin levels monitored for at least 6 months were included in our analyses. Among them, 77 (38.5%) were long-term statin users (regular statin treatment for more than 3 months) before ESA initiation. Overall, 6.5% of the statin users and 17.1% of nonusers were considered to have ESA hyporesponsiveness. Long-term statin therapy was significantly associated with a lower proportion of ESA hyporesponsiveness in fully adjusted model (odds ratio 0.15, 95% confidence interval: 0.03–0.64).We found that long-term statin therapy was inversely associated with ESA hyporesponsiveness among predialysis patients with CKD. Further studies are needed to validate our observations, and to explore the potential mechanisms between ESA resistance and statin therapy.

Renal anemia syndromes in iraqi hemodialysis patients according to iron status.

Anemia is common in patients on hemodialysis (HD). Adequate iron stores are essential for achieving the best hemoglobin level through maximum benefit from erythropoiesis-stimulating agents (ESA). Decreased iron stores or decreased availability of iron are the most common reasons for resistance to the effect of these agents. Our objective was to categorize a group of Iraqi HD patients according to absolute or functional iron deficiency anemia (IDA); this study was conducted in the HD unit of the Baghdad Teaching Hospital from October 2012 to January 2013. Seventy prevalent adult HD Iraqi patients were enrolled. All patients were tested for full blood counts and iron parameters. They were categorized as nonanemic and those with absolute or functional iron deficiency. The patients were also tested for serum albumin, C-reactive protein (CRP), parathyroid hormone, and serum hepcidin levels. Data were expressed as mean ± standard deviation, and frequencies (number) and proportions (%). The mean age of the study group was 49.8 ± 12.3 years. Diabetes was the primary cause of end-stage renal disease, seen in 30 patients (42.8%). Majority of the HD patients were anemic, [51 (82.9%)] and among them, 39 (76.4%), had functional IDA. The mean serum iron, serum ferritin, and transferrin saturation were significantly higher in patients with functional IDA than those with absolute IDA (P <0.05). The mean highly sensitive CRP, parathormone and hepcidin values were also significantly higher in functional IDA patients than in those with absolute IDA and the nonanemic group (P <0.05). More than half of the study patients had functional IDA, and this can explain ESA hyporesponsiveness. This is besides the interplay of other factors including inflammation, inadequate dialysis, and secondary hyperparathyroidism. It is essential to diagnose functional IDA early, before the initiation of unnecessary iron therapy.

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.

Effectiveness of Switch to Erythropoiesis-Stimulating Agent (ESA) Biosimilars versus Maintenance of ESA Originators in the Real-Life Setting: Matched-Control Study in Hemodialysis Patients.

In hemodialysis (HD), switching from erythropoiesis-stimulating agent (ESA) originators to biosimilars is associated with the need for doses approximately 10% higher, according to industry-driven studies. The aim of this study was to evaluate the efficacy on anemia control of switching from ESA originators to biosimilars in daily clinical practice. We retrospectively selected consecutive HD patients receiving stable intravenous ESA doses, and who had not been transfused in the previous 6months, from 12 non-profit Italian centers. Patients switched from originators to biosimilars (n=163) were matched with those maintained on ESA originators (n=163) using a propensity score approach. The study duration was 24weeks, and the primary endpoint was the mean dose difference (MDD), defined as the difference between the switch and control groups of ESA dose changes during the study (time-weighted average ESA dose minus baseline ESA dose). Age (70±13years), male sex (63%), diabetes (29%), history of cardiovascular disease (40%), body weight (68±14kg), vascular access (86% arteriovenous fistula), hemoglobin [Hb] (11.2±0.9g/dL) and ESA dose (8504±6370IU/week) were similar in the two groups. Hb remained unchanged during the study in both groups. Conversely, ESA dose remained unchanged in the control group and progressively increased in the switch group from week8 to 24. The time-weighted average of the ESA dose was higher in the switch group than in the control group (10,503±7389 vs. 7981±5858IU/week; p=0.001), leading to a significant MDD of 2423IU/week (95% confidence interval [CI] 1615-3321), corresponding to a 39.6% (95% CI 24.7-54.6) higher dose of biosimilars compared with originators. The time-weighted average of Hb was 0.2g/dL lower in the switch group, with a more frequent ESA hyporesponsiveness (14.7 vs. 2.5%). Iron parameters and other resistance factors remained unchanged. In stable dialysis patients, switching from ESA originators to biosimilars requires 40% higher doses to maintain anemia control.

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.

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.

Erythropoietin Hyporesponsiveness in Dialysis Patients: Possible Role of Statins

Background: Hypothesizing that statins may be useful as adjuvant treatment for renal anemia, we examined the association between statin prescription (Rx) and erythropoiesis-stimulating agent (ESA) hyporesponsiveness in Japanese hemodialysis (HD) patients prescribed ESAs. Methods: We examined 3,602 patients in 60 HD facilities dialyzed 3 times/week for ≥4 months from the Japan Dialysis Outcomes and Practice Patterns Study phases 3-5 (2005-2015). Statin Rx was reported at the end of a 4-month interval (baseline) for each patient. ESA hyporesponsiveness in the subsequent 4 months was then defined as a binary indicator (mean hemoglobin [Hgb] level <10 g/dL and mean ESA dose >6,000 units/week) and separately as the ESA resistance index (ERI; mean ESA dose/[dry weight × mean Hgb]). We used adjusted logistic and linear regressions to evaluate the associations between statin Rx and ESA hyporesponsiveness. Results: At baseline, 16.2% of patients reported statin Rx; 12.8% were classified as having ESA hyporesponsiveness during 4 months of follow-up. Compared to patients without statin Rx, patients with statin Rx had lower odds of ESA hyporesponsiveness (OR 0.87; 95% CI 0.66-1.15). Similarly, the ERI was lower for those with statin Rx than without (ratio of means, 0.94; 95% CI 0.89-0.99) after adjustment for possible confounders. Conclusions: Our results suggest that statins may slightly reduce ESA hyporesponsiveness in HD patients. However, any causal inference is limited by the observational study design and unmeasured compliance with statin Rx.

Spectrum and Burden of Erythropoiesis-Stimulating AgentHyporesponsiveness Among Contemporary HemodialysisPatients.

Hemodialysis patients with erythropoiesis-stimulating agent (ESA) hyporesponsiveness have been a topic of active research. However, there have been no studies of ESA hyporesponsiveness among US patients following the dramatic change in anemia management that resulted from the 2011 changes in ESA product labeling and bundling of dialysis remuneration. Retrospective observational study. We studied prevalent hemodialysis patients treated at a large dialysis organization in calendar years 2012 to 2013 (N=98,972). ESA hyporesponsiveness, defined as 2 consecutive hemoglobin measurements< 10g/dL (every other week) with contemporaneous ESA dose > 7,700U/treatment. Patients with ESA hyporesponsiveness were identified during the first quarter of 2012 and followed up through 2013 using intention-to-treat principles. Associations between the study exposure (ESA hyporesponsiveness) and mortality, missed hemodialysis treatments, ESA and iron use, and hemoglobin levels were determined using generalized estimating equations adjusting for imbalanced baseline covariates. At baseline, 12,361 (12.5%) patients were identified as having ESA hyporesponsiveness. The mean hemoglobin level among patients with ESA hyporesponsiveness was ∼1g/dL lower than in patients without ESA hyporesponsiveness at baseline, narrowing over follow-up to 0.4g/dL. Initially, mean ESA use was approximately 3-fold greater for patients with ESA hyporesponsiveness than for those without ESA hyporesponsiveness, decreasing to 2-fold greater at study end; iron use and missed hemodialysis treatment rates were also greater among patients with ESA hyporesponsiveness throughout. ESA hyporesponsiveness was associated with enhanced mortality risk versus non-ESA hyporesponsiveness: adjusted incidence rate ratios were estimated at 2.24 (95% CI, 1.93-2.60) in the second quarter, gradually decreasing to 1.48 (95% CI, 1.18-1.84) by study end. It is possible that an alternative ESA hyporesponsiveness definition may be optimal. As such, the associations we observed may be conservative estimates of true relationships. When using a contemporary definition at one point in time, ESA hyporesponsiveness was potently and persistently associated with greater mortality, greater iron and ESA use, and lower hemoglobin levels compared to non-ESA hyporesponsiveness.

A Prospective Multicenter Randomized Controlled Study on Interleukin-6 Removal and Induction by a new Hemodialyzer With Improved Biocompatibility in Hemodialysis Patients: A Pilot Study.

We compared interleukin-6 (IL-6) removal and induction between conventional polysulfone (Con) and TORAYLIGHT NV (NV) dialyzers in hemodialysis patients. Twenty patients on Con with high IL-6 concentrations (2.7-8.5 pg/mL) were randomized to Con or NV group. Dialyzer performance was determined in NV group while patients were on Con and after being switched onto NV. Erythropoiesis-stimulating agent (ESA) response index (ERI) was assessed every 4 months for one year. IL-6 clearance was comparable between Con and NV. IL-6 removal rates were comparable for the first 1 h, but were higher with NV for the entire session (P = 0.03). Before-to-during-dialysis IL-6 concentration ratios were lower with NV on the venous side after the session (P = 0.03). During the one-year study, hemoglobin was lower in Con group than in NV group at month 8 (P = 0.046). ERI decreased in NV and increased in Con group, with a significant difference between the groups (P = 0.002). NV and Con are comparable in removing IL-6 and both induce IL-6. However, the data suggest that NV induces less IL-6, which may reduce the risk of ESA hyporesponsiveness.

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.

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.

The effect of pentoxifylline on oxidative stress in chronic kidney disease patients with erythropoiesis-stimulating agent hyporesponsiveness: Sub-study of the HERO trial

Objective: Pentoxifylline has previously been shown to increase haemoglobin levels in patients with chronic kidney disease (CKD) and erythropoietin-stimulating agent (ESA)-hyporesponsive anaemia in the HERO multi-centre double-blind, randomized controlled trial. The present study evaluated the effects of pentoxifylline on oxidative stress in ESA-hyporesponsive CKD patients.Methods: This sub-study of the HERO trial compared 15 patients in the pentoxifylline arm (400 mg daily) and 17 in the matched placebo arm on oxidative stress markers: plasma total F2-isoprostanes, protein carbonyls, glutathione peroxidase (GPX), and superoxide dismutase (SOD) activities.Results: Pentoxifylline did not significantly alter total F2-isoprostanes (adjusted mean difference (MD) 35.01 pg/ml, P = 0.11), SOD activity (MD 0.82 U/ml, P = 0.07), GPX activity (MD −6.06 U/l, P = 0.09), or protein carbonyls (MD −0.04 nmol/mg, P = 0.52). Replicating results from the main study, pentoxifylline significantly increased haemoglobin concentration compared with controls (MD 7.2 g/l, P = 0.04).Conclusions: Pentoxifylline did not alter oxidative stress biomarkers, suggesting that alternative mechanisms may be responsible for the agent's ability to augment haemoglobin levels in CKD patients with ESA-hyporesponsive anaemia.

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.