Erythropoietin Resistance Index Research Articles

Residual renal function in chronic dialysis is not associated with reduced erythropoietin-stimulating agent dose requirements: a cross-sectional study

BackgroundAnaemia is a very common problem in patients with end-stage kidney disease (ESKD) and the use of erythropoietin-stimulating agents (ESA) has revolutionised its treatment. Residual renal function (RRF) is associated with a reduction in ESA resistance and mortality in chronic dialysis. The primary aim was to establish whether RRF has an association with ESA dose requirements in ESKD patients receiving chronic dialysis.MethodsA single center, cross-sectional study involving 100 chronic dialysis patients was conducted from December 2015 to May 2016. Participants were divided into two groups depending on presence of RRF, which was defined as a 24-h urine sample volume of ≥ 100 ml. Erythropoietin resistance index [ERI = total weekly ESA dose (IU)/weight (kg)/haemoglobin concentration (g/dL] was used as a measure of ESA dose requirements.ResultsThere was no difference in ERI between those with RRF as compared to those without (9.5 versus 11.0, respectively; P = 0.45). Also, ERI did not differ between those receiving haemodialysis as compared with peritoneal dialysis (10.8 versus 10.2, respectively; P = 0.84) or in those using renin-angiotensin system (RAS) blockers as compared with no RAS blocker use (11.6 versus 9.2, respectively; P = 0.10). Lower ERI was evident for those with cystic kidney disease as compared to those with other causes of ESKD (6.9 versus 16.5, respectively; P = 0.32) although this did not reach statistical significance. Higher ERI was found in those with evidence of systemic inflammation as compared to those without (16.5 versus 9.5, respectively; P = 0.003).ConclusionsThere was no association between RRF and ESA dose requirements, irrespective of dialysis modality, RAS blocker use, primary renal disease or hyperparathyroidism.

Asymmetric Dimethylarginine Contributes to the Impaired Response to Erythropoietin in CKD-Anemia.

Erythropoietin-resistant anemia is associated with adverse cardiovascular events in patients with ESRD, but the underlying mechanism remains unclear. Here, we evaluated the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). In 54 patients with advanced CKD, erythrocyte but not plasma ADMA levels independently associated with low hemoglobin values, although levels of both types of ADMA were elevated compared with those in healthy volunteers. Furthermore, erythrocyte ADMA level associated with the erythropoietin resistance index in patients receiving a weekly injected dose of erythropoiesis-stimulating agents standardized for hemoglobin levels and body weight, whereas it correlated with the erythropoietin demand index (plasma erythropoietin units divided by the hemoglobin value) in patients not receiving erythropoiesis-stimulating agents. Compared with sham-operated controls, wild-type mice with 5/6 subtotal nephrectomy (Nx), a remnant kidney model with advanced CKD, had decreased hemoglobin, hematocrit, and mean corpuscular volume values but increased erythrocyte and plasma ADMA and plasma erythropoietin levels. In comparison, dimethylarginine dimethlaminohydrolase-1 transgenic (DDAH-1 Tg) mice, which efficiently metabolized ADMA, had significant improvements in all of the values except those for erythropoietin after 5/6 Nx. Additionally, wild-type Nx mice, but not DDAH-1 Tg Nx mice, had reduced splenic gene expression of erythropoietin receptor and erythroferrone, which regulates iron metabolism in response to erythropoietin. This study suggests that erythrocyte ADMA accumulation contributes to impaired response to erythropoietin in predialysis patients and advanced CKD mice via suppression of erythropoietin receptor expression.

Ferritin Elevation and Improved Responsiveness to Erythropoiesis-Stimulating Agents in Patients on Ferric Citrate Hydrate

IntroductionIn hemodialysis patients on ferric citrate hydrate, the increase in ferritin level is mainly due to the administration of the compound. We investigated possible other factors associated with ferritin level and how erythropoietin resistance index and erythropoiesis in those patients were affected. We looked at ferritin-elevating factors using data from a Japanese phase III long-term clinical trial of ferric citrate hydrate.MethodsThe factors with a strong association with ferritin levels at week 28 were selected by the process of variable selection. In addition, selected factors were analyzed by Mixed Model for Repeated Measurement. Subjects were divided into 3 groups by quantiles (<Q1, Q1–Q3, Q3<) of the most strongly correlated factors. Then the least-squares means of change of ferritin at each time point for each group were calculated. Finally, the differences of the least-squares means were examined. Changes of both erythropoiesis-stimulating agent dose and erythropoietin resistance index for each group were investigated. The differences in mean erythropoietin resistance index between groups at baseline, week 28, and week 52 were analyzed using t tests.ResultsDose of ferric citrate hydrate showed the strongest correlation with change of ferritin and the second strongest was the reduction of erythropoiesis-stimulating agents. The mean erythropoietin resistance index was lowered in group <Q1. Group <Q1 showed significantly lower levels of ferritin at baseline.DiscussionIt is suggested that not only iron load but also the erythropoiesis-stimulating agent dose reduction may be involved in ferritin elevation during ferric citrate hydrate treatment, resulting in a decrease of erythropoietin resistance index.

Impact of gender and dialysis adequacy on anaemia in peritoneal dialysis

PurposeIn the general population, haemoglobin (Hb) concentration is higher in men than in women. However, target Hb levels in dialysis patients are set constant regardless of the patient’s sex. The aim of this study was to evaluate Hb concentration and the use of erythropoiesis-stimulating agents (ESA) in peritoneal dialysis (PD) patients taking gender and dialysis adequacy into account.MethodsThe study comprised two parts. The first was a cross-sectional analysis of Hb and ESA in 2180 prevalent PD patients. The second included 88 incident PD patients, followed for 36 months. During this time, the major parameters recorded at 12-month intervals included: Hb concentration, weekly ESA, total, renal, and peritoneal Kt/V. Erythropoietin resistance index (ERI) was calculated as the ratio between ESA dose and achieved Hb.ResultsIn prevalent PD patients, Hb concentration was significantly lower in women, (11.2 ± 1.4 vs. 11.5 ± 1.6 g/dl; p < 0.001), despite higher doses of ESA (2691 ± 1821 vs. 2344 ± 1422; p = 0.001). Hb concentrations were related to dialysis adequacy in both cohorts. However, despite significantly higher Kt/V, women were characterized by a lower Hb level. In incident patients, this association was present throughout the observation period, while the ESA dose in women was significantly higher at every time point. In multiple regression analysis, gender was an independent determinant of ERI (b = 0.34; p < 0.05).ConclusionsDespite higher dialysis adequacy, Hb concentration in women treated with PD is significantly lower, and the ability to correct it impaired, as compared to men.

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.

Effects of Vitamin E-Coated versus Conventional Membranes in Chronic Hemodialysis Patients: A Systematic Review and Meta-Analysis

Introduction: Accruing evidence suggests that vitamin E-coated membranes (ViE-m) might improve the clinical management of chronic hemodialysis (HD) patients. Methods: We conducted a systematic review and meta-analysis of RCTs comparing ViE-m to conventional HD. Endpoints of interest were a series of biomarkers pertaining to anemia status, inflammation, oxidative stress and dialysis efficacy/status. Results: Sixty studies were included. ViE-m significantly improved the Erythropoietin Resistance Index but had no impact on other anemia parameters. As for oxidative stress and inflammation, ViE-m produced a significant decrease in interleukin-6 levels, thiobarbituric acid reactive substances, plasma and red blood cell (RBC) malonylaldehyde and a significant increase in blood and RBC vitamin E. Conversely, ViE-m use had no impact on lipid profile, dialysis adequacy, blood pressure, albumin and uric acid. Conclusions: ViE-m might ameliorate anemia management by reducing oxidative stress and inflammation. Benefits of these bio-membranes on harder clinical outcomes are uncertain and need to be investigated by future, targeted trials.

Association of Erythropoietin Resistance with Fatigue in Hemodialysis Patients: A Cross-Sectional Study

Background/Aims: Fatigue is a common symptom in patients receiving hemodialysis (HD) and is generally associated with anemia. However, it can be difficult to resolve, even when anemia has been treated using erythropoiesis-stimulating agents and iron replacement therapy. In the present study, we examined the associations of anemia, the erythropoietin resistance index (ERI) and iron deficiency with fatigue during HD. Methods: In this cross-sectional study, fatigue score was calculated on the basis of questionnaire responses in HD patients. Participants were divided into 3 groups according to their hemoglobin (Hb) levels (low, normal and high). Iron deficiency was assessed as a transferrin saturation (TSAT) of <20%. Results: We included 571 HD patients (men/women 368/203; mean age 62.2 ± 10.8 years). Among the 3 groups, fatigue scores increased significantly with decreasing Hb levels. HD patients with low Hb levels (<90 g/l) had significantly higher fatigue scores than those with higher Hb levels (≥120 g/l). In the multiple regression analysis, we showed that a high ERI (β = 0.208) and a low TSAT (β = -0.155), but not the Hb level, were significantly associated with increased fatigue score. Moreover, this was independent of age, gender and modifiable confounders linked to anemia. Even after restricting patients to those without iron deficiency (TSAT ≥20%), the ERI (β = 0.258) retained a significant and independent association with the fatigue score. Conclusion: Iron deficiency and a high ERI despite iron sufficiency may cause fatigue in HD patients.

Eight-Year Experience with Nocturnal, Every-Other-Day, Online Haemodiafiltration

Background: New haemodialysis therapeutic regimens are required to improve patient survival. Longer and more frequent dialysis sessions have produced excellent survival and clinical advantages, while online haemodiafiltration (OL-HDF) provides the most efficient form of dialysis treatment. Methods: In this single-centre observational study, 57 patients on 4-5-hour thrice-weekly OL-HDF were switched to nocturnal every-other-day OL-HDF. Inclusion criteria consisted of stable patients with good prospects for improved occupational, psychological and social rehabilitation. The aim of this study was to report our 8-year experience with this schedule and to evaluate analytical and clinical outcomes. Results: Nocturnal, every-other-day OL-HDF was well tolerated and 56% of patients were working. The convective volume increased from 26.7 ± 2 litres at baseline to 46.6 ± 6.5 litres at 24 months (p < 0.01). Increasing the dialysis dose significantly decreased bicarbonate, blood-urea-nitrogen and creatinine values. Predialysis phosphate levels fell markedly with complete suspension of phosphate binders from the second year of follow-up. Although haemoglobin was unchanged, there was a 50.4% reduction in darbepoetin dose at 24 months and a significant decrease in the erythropoietin resistance index. Blood pressure significantly decreased in a few months. Antihypertensive medication requirements were decreased by 60% after 3 months and by 73% after 1 year and this difference was maintained thereafter. Conclusions: Nocturnal, every-other-day OL-HDF could be an excellent therapeutic alternative since it is well tolerated and leads to clinical and social-occupational rehabilitation with satisfactory morbidity and mortality. These encouraging results strengthen us to continue and invite other clinicians to join this initiative.

The impact of malnutritional status on survival in elderly hemodialysis patients

BackgroundThe number of geriatric patients with end-stage renal disease undergoing maintenance hemodialysis has increased in Taiwan. However, protein-energy wasting is prevalent and associated with poor outcome in this patient population. It is generally well-known that geriatric nutritional risk index (GNRI) is a good survival predictor in general elderly patients. However, the association of GNRI with mortality in geriatric end-stage renal disease patients remains unclear. The present study aimed to assess the predictive ability of GNRI for overall mortality in elderly hemodialysis patients. MethodsGNRI was measured in a cohort of 104 hemodialysis patients aged ≥65 years. Thereafter, these patients were followed for a median period of 38.5 months. For all cases, all-cause mortality was the primary endpoint. ResultsPatients with baseline GNRI <92 had significantly lower body weight, body mass index, serum albumin, and hemoglobin level, but were administered a higher erythropoietin dose as compared to those with GNRI ≥92. Basal GNRI independently correlated with erythropoietin resistance index (β = −1.97, p < 0.001) and serum high-sensitivity C-reactive protein (β = −0.71, p = 0.021). By the conclusion of the study, 45 patients had died. High GNRI was associated with the lower risk of mortality after adjustment for other potential confounders [hazard ratio = 0.41; 95% confidence interval (CI) = 0.22–0.90; p = 0.005]. ConclusionGNRI is a significant predictor for mortality in elderly hemodialysis patients, and may be adopted to improve assessment of the malnutrition–inflammation status.

Daily Home Hemodialysis Is an Available Option for Renal Replacement Therapy in Spain.

The objective of the present study was to analyze the characteristics and survival of patients from our hospital who started home hemodialysis. We analyzed all patients receiving home hemodialysis from 1969 to 2015 (51 patients; age 45 ± 23 years; men 77%). We collected characteristics, hospital admission, and mortality. After a median follow-up of 43 (22-76) months, we found 0-1 hospital admissions per year. Sixty-nine percent received a kidney transplant, and the global mortality was 10%. Survival at 5 years was 96%. Mean equivalent renal urea clearance was 15.6 ± 4.2 mL/min, the β-2 microglobulin reduction rate was 67 ± 18%, the number of antihypertension drugs was 0.7 ± 0.3, and the erythropoietin resistance index was 3.7 ± 2.1 IU/kg/week/g/dL. Daily home hemodialysis is a viable option for renal replacement therapy and should be offered alongside other therapies.

The greatly misunderstood erythropoietin resistance index and the case for a new responsiveness measure.

Introduction The optimal use of erythropoiesis stimulating agents (ESAs) to treat anemia in end stage renal disease remains controversial due to reported associations with adverse events. In analyzing these associations, studies often utilize ESA resistance indices (ERIs), to characterize a patient's response to ESA. In this study, we examine whether ERI is an adequate measure of ESA resistance. Methods We used retrospective data from a nonconcurrent cohort study of incident hemodialysis patients in the United States (n = 9386). ERI is defined as average weekly erythropoietin (EPO) dose per kg body weight (wt) per average hemoglobin (Hgb), over a 3-month period (ERI = (EPO/wt)/Hgb). Linear regression was used to demonstrate the relationship between ERI and weight-adjusted EPO. The coefficient of variation was used to compare the variability of Hgb with that of weight-adjusted EPO to explain this relationship. This analysis was done for each quarter during the first year of dialysis. Findings ERI is strongly linearly related with weight-adjusted EPO dose in each of the four quarters by the equation ERI = 0.0899*(EPO/wt) (range of R(2) = 0.97-0.98) and weakly linearly related to 1/Hgb (range of R(2) = 0.06-0.16). These correlations hold independent of age, sex, hgb level, ERI level, and epo-naïve stratifications. Discussion ERI is strongly linearly related to weight-adjusted (and nonweight-adjusted) EPO dose by a "universal," not patient-specific formula, and thus is a surrogate of EPO dose. Therefore, associations between ERI and clinical outcomes are associations between a confounded EPO dose and those outcomes.

Impact of anaemia treatment for left ventricular remodelling prior to initiation of dialysis in chronic kidney disease patients: Efficacy and stability of long acting erythropoietin stimulating agents

Anaemia is a common complication in patients with chronic kidney disease (CKD), which may initiate or accelerate left ventricular (LV) hypertrophy (LVH). The present study is a retrospective analysis to assess whether anaemia treatment is independently associated with LV remodelling prior to initiation of dialysis in CKD patients. Biochemical and physical values were collected over a period of more than 120 days prior to the initiation of dialysis in 27 patients with CKD. The left ventricular mass index (LVMI) was evaluated by echocardiography twice (at the baseline and the follow-up at the initiation of the dialysis period). Patients using long-acting erythropoietin stimulating agents (L-ESA) had the tendency of maintaining higher levels of haemoglobin (Hb) than those using short-acting ESA (S-ESA). Patients using L-ESA showed a more significant improvement in the erythropoietin resistance index (ERI) than those of using S-ESA. In a multivariate regression analysis, the average Hb level for the observational period, the level of Hb at the initiation of dialysis and the use of L-ESA were independently associated factors for the LVMI at the initiation of dialysis. A lower LVMI at the initiation of dialysis and an improvement of the LVMI during the observational period were detected in the highest tertile of average Hb (10.4 g/dL). Long-acting ESA was effective and stable when treating anaemia until the start of dialysis. It is important to treat anaemia for the prevention of LV remodelling in CKD patients. These findings have some therapeutic implications for treatment strategies for pre-dialysis patients.

Factors Contributing to Erythropoietin Hyporesponsiveness in Patients on Long-Term Continuous Ambulatory Peritoneal Dialysis: A Cross-Sectional Study

Background: Factors contributing to erythropoietin (EPO) hyporesponsiveness in patients on long-term continuous ambulatory peritoneal dialysis are not well understood. Therefore, we investigated the factors contributing to EPO hyporesponsiveness using the EPO resistance index (ERI). Methods: A total of 14 patients (7 males and 7 females, age 65.0 ± 11.9 years) were selected for this study. We defined ERI as the weekly dose of EPO per body weight divided by hemoglobin (U/kg/g/dl/week). Bioelectrical impedance analysis was used to assess the patients' body composition and fluid status. We examined associations between ERI and clinical parameters, such as physiological, chemical and nutrition status, by correlation and multiple linear regression analyses. Results: Peritoneal dialysis duration was 95 ± 23 months, and all patients underwent peritoneal dialysis for >5 years. Hemoglobin, blood pressure and ultrafiltration volume of peritoneal dialysis were 11.5 ± 1.2 g/dl, 123 ± 14/72 ± 8 mm Hg and 834 ± 317 ml/day, respectively. Renal Kt/V and peritoneal Kt/V, which are indices of dialysis adequacy, were 0.32 ± 0.31 and 1.70 ± 0.31, respectively. Age and extracellular water/total body water (ECW/TBW) ratio had significant positive correlations with ERI (both p < 0.05). Levels of C-reactive protein, serum albumin, parathyroid hormone and normalized protein catabolic rate were not significantly correlated with ERI. In a multiple regression analysis, ECW/TBW was independently associated with ERI (p < 0.05). Conclusions: This study demonstrates that ECW/TBW was a factor contributing to ERI and that appropriate maintenance of body fluid volume could contribute to low EPO dosing.

Analysis of the correlation between serum resistin and the variability of erythropoietin responsiveness in patients with chronic kidney disease.

Chronic kidney disease (CKD) is commonly accompanied by inflammation and anemia; however, the pathogenesis of CKD is unclear. Expression of resistin, a cysteine-rich secretory plasma protein, is correlated with the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and lipoprotein-associated phospholipase A2, indicating that resistin may be involved in inflammatory events. In addition, inflammation inhibits the activity of erythropoietin (EPO) and, thus, erythropoiesis. The aim of the present study was to analyze the correlation between serum resistin and the variability of EPO responsiveness in CKD patients. The levels of serum creatinine (SCr), C-reactive protein (CRP), total cholesterol, triglycerides, IL-6 and serum resistin were measured in the samples obtained from 138 CKD patients and healthy control subjects. The levels of serum resistin in the CKD groups with and without hemodialysis were significantly higher than those observed in the normal control group (P<0.01) and the levels of serum resistin in the hemodialysis CKD group were higher than those observed in the CKD group without dialysis (P<0.01). The levels of serum resistin in patients in the randomly selected CKD group (with hemodialysis) were positively correlated with the duration of dialysis and the levels of SCr and CRP (P<0.05), however, were negatively correlated with the estimated glomerular filtration rate. The EPO resistance index (ERI) was identified to be associated with body mass index and the levels of CRP and resistin; furthermore, EPO reactivity was correlated with the level of resistin and ERI. The levels of serum resistin were correlated with the variability in EPO responsiveness that was observed in the CKD patients. Therefore, the measurement of serum resistin may aid with understanding the mechanisms, clinical diagnosis and treatment of CKD.

Efficiency of Original versus Generic Intravenous Iron Formulations in Patients on Haemodialysis.

AimsThe appropriate use of intravenous (IV) iron is essential to minimise the requirements for erythropoiesis-stimulating agents (ESAs). The clinical efficacy of generic IV iron compared to the original formulation is controversial. We evaluated the changes that were induced after switching from a generic IV iron to an original formulation in a stable, prevalent haemodialysis (HD) population.MethodsA total of 342 patients were included, and the follow-up period was 56 weeks for each formulation. Anaemia parameters and doses of ESA and IV iron were prospectively recorded before and after the switch from generic to original IV iron.ResultsTo maintain the same haemoglobin (Hb) levels after switching from the generic to the original formulation, the requirements for IV iron doses were reduced by 34.3% (from 52.8±33.9 to 34.7±31.8mg/week, p<0.001), and the ESA doses were also decreased by 12.5% (from 30.6±23.6 to 27±21μg/week, p<0.001). The erythropoietin resistance index declined from 8.4±7.7 to 7.4±6.7 IU/kg/week/g/dl after the switch from the generic to the original drug (p = 0.001). After the switch, the transferrin saturation ratio (TSAT) and serum ferritin levels rose by 6.8%(p<0.001) and 12.4%(p = 0.001), respectively. The mortality rate was similar for both periods.ConclusionsThe iron and ESA requirements are lower with the original IV iron compared to the generic drug. In addition, the uses of the original formulation results in higher ferritin and TSAT levels despite the lower dose of IV iron. Further studies are necessary to analyse the adverse effects of higher IV iron dosages.

Effects of vitamin E-coated dialysis membranes on anemia, nutrition and dyslipidemia status in hemodialysis patients: a meta-analysis

Background: This was controversial whether vitamin E-coated dialyzer therapy was beneficial for the complications associated with hemodialysis. Therefore, we performed this systematic review to evaluate the effects of vitamin E-coated dialyzer. Methods: Related trials were searched from multiple electronic databases. We conducted meta-analysis to assess changes in the predefined outcomes using RevMan 5.3 software. Results: Meta-analysis showed vitamin E-coated dialyzer therapy could decrease erythropoietin (EPO) resistance index (SMD, −0.24; 95% CI, −0.47 to −0.01; p = 0.04). However, pooled-analysis showed vitamin E-coated dialyzer therapy could not decrease weekly EPO dose (SMD, −0.11; 95% CI, −0.32 to 0.09; p = 0.28) and intima–media thickness (IMT) of the carotid artery (MD, −0.09; 95% CI, −0.2 to 0.01; p = 0.09), and vitamin E-coated dialyzer therapy did not improve the serum hemoglobin (MD, −0.03; 95% CI, −0.18 to 0.13; p = 0.74), albumin levels (SMD, −0.64; 95% CI, −1.62 to 0.34; p = 0.2), in addition, there was no significant difference in serum cholesterol (SMD, −0.07; 95% CI, −0.45 to 0.31; p = 0.71), triglycerides (MD, −2.77; 95% CI, −32.42 to 26.87; p = 0.85), high density lipoprotein (HDL) (SMD, 0.24; 95% CI, −0.14 to 0.62; p = 0.22) and low density lipoprotein (LDL) (SMD, 0.00; 95% CI, −0.38 to 0.37; p = 0.98) levels. Conclusions: Vitamin E-coated dialyzer may reduce the EPO resistance, but there is no conclusive evidence that vitamin E-coated dialyzer can improve the renal anemia, malnutrition, dyslipidemia and atherosclerosis status in hemodialysis (HD) patients. However, high-quality trials with hard clinical endpoints are required to fully elucidate the clinical value of vitamin E-coated dialyzer therapy.

A randomized crossover study of single biweekly administration of epoetin-α compared with darbepoetin-α in chronic kidney disease patients not receiving dialysis

BackgroundRecent evidence demonstrates that high doses of epoetin-alpha (EPO-α) can be administrated at extended intervals, despite its relatively short serum half-life. However, no prospective randomized trials on the effects of extended dosing intervals of EPO-α compared with darbepoetin-alpha (DA-α) have been performed. This study was designed to investigate whether a single biweekly (Q2W) administration of a high dose of EPO-α is as effective as DA-α for anemia in chronic kidney disease (CKD) patients not receiving dialysis. MethodsSixty non-dialysis CKD patients were equally randomized to either Q2W subcutaneous EPO-α (10,000 unit) or DA-α (50μg) therapy groups for the first 6 weeks. After a 6-week washout period, the participants of the EPO-α and DA-α treatment groups switched to the alternate regimen for 6 weeks. The mean hemoglobin (Hb) levels after erythropoiesis stimulating agent (ESA) therapy and percentage change in Hb levels from baseline to the end of the study were analyzed. ResultsThe mean Hb levels of postESA therapy increased significantly compared with those of preESA therapy in both ESA regimens. The percentage increase in Hb levels and erythropoietin resistance index did not show a significant difference between the different ESA regimens. No difference was observed between the regimens regarding mean Hb levels after ESA therapy. Additionally, there were no serious adverse effects leading to withdrawal from treatment. ConclusionBiweekly high doses of EPO-α therapy may be equally as effective as Q2W DA-α therapy in maintaining target Hb levels in non-dialysis CKD patients.

Longitudinal Assessments of Erythropoietin-Stimulating Agent Responsiveness and the Association with Specific Clinical Outcomes in Dialysis Patients

Background: Dose requirements of erythropoietin-stimulating agents (ESAs) can vary considerably over time and may be associated with cardiovascular outcomes. We aimed to longitudinally assess ESA responsiveness over time and to investigate its association with specific clinical end points in a time-dependent approach. Methods: The German Diabetes and Dialysis study (4D study) included 1,255 diabetic dialysis patients, of whom 1,161 were receiving ESA treatment. In those patients, the erythropoietin resistance index (ERI) was assessed every 6 months during a median follow-up of 4 years. The association between the ERI and cardiovascular end points was analyzed by time-dependent Cox regression analyses with repeated ERI measures. Results: Patients had a mean age of 66 ± 8.2 years; 53% were male. During follow-up, a total of 495 patients died, of whom 136 died of sudden death and 102 of infectious death. The adjusted and time-dependent risk for sudden death was increased by 19% per 5-unit increase in the ERI (hazard ratio, HR = 1.19, 95% confidence interval, CI = 1.07-1.33). Similarly, mortality increased by 25% (HR = 1.25, 95% CI = 1.18-1.32) and infectious death increased by 27% (HR = 1.27, 95% CI = 1.13-1.42). Further analysis revealed that lower 25-hydroxyvitamin D levels were associated with lower ESA responsiveness (p = 0.046). Conclusions: In diabetic dialysis patients, we observed that time-varying erythropoietin resistance is associated with sudden death, infectious complications and all-cause mortality. Low 25-hydroxyvitamin D levels may contribute to a lower ESA responsiveness.

Cumulative iron dose and resistance to erythropoietin.

Optimizing anemia treatment in hemodialysis (HD) patients remains a priority worldwide as it has significant health and financial implications. Our aim was to evaluate in a large cohort of chronic HD patients in Fresenius Medical Care centers in Spain the value of cumulative iron (Fe) dose monitoring for the management of iron therapy in erythropoiesis-stimulating agent (ESA)-treated patients, and the relationship between cumulative iron dose and risk of hospitalization. Demographic, clinical and laboratory parameters from EuCliD(®) (European Clinical Dialysis Database) on 3,591 patients were recorded including ESA dose (UI/kg/week), erythropoietin resistance index (ERI) [U.I weekly/kg/gr hemoglobin (Hb)] and hospitalizations. Moreover the cumulative Fe dose (mg/kg of bodyweight) administered over the last 2 years was calculated. Univariate and multivariate analyses were performed to identify the main predictors of ESA resistance and risk of hospitalization. Patients belonging to the 4th quartile of ERI were defined as hypo-responders. The 2-year iron cumulative dose was significantly higher in the 4th quartile of ERI. In hypo-responders, 2-year cumulative iron dose was the only iron marker associated with ESA resistance. At case-mix adjusted multivariate analysis, 2-year iron cumulative dose was an independent predictor of hospitalization risk. In ESA-treated patients cumulative Fe dose could be a useful tool to monitor the appropriateness of Fe therapy and to prevent iron overload. To establish whether the associations between cumulative iron dose, ERI and hospitalization risk are causal or attributable to selection bias by indication, clinical trials are necessary.

Hyporesponsiveness to erythropoiesis-stimulating agent as a prognostic factor in Japanese hemodialysis patients: the Q-Cohort study.

Previous epidemiological evidence has suggested that responsiveness to erythropoiesis-stimulating agents (ESAs) is related to prognosis in hemodialysis (HD) patients. We investigated the effects of hyporesponsiveness to ESA on mortality and cardiovascular events in Japanese HD patients, taking modifying factors into account. A total of 2,905 Japanese HD patients aged ≥18 years who received ESA treatment were prospectively followed up for 4 years. Responsiveness to ESA was estimated using an erythropoietin resistance index (ERI), defined as erythropoietin dosage per week divided by post-HD weight and hemoglobin value (U/kg/week/g/dl). Patients were divided into three groups by tertiles of ERI levels: low ERI, ≤5.10; intermediate ERI, 5.11-9.43; high ERI, ≥9.44. Risk estimates were calculated by a Cox proportional hazards model, adjusting for potential confounders. During follow-up, 482 patients died from any causes. The 4-year survival rate decreased linearly with higher ERI levels, being 87.5, 82.9, and 72.0% for low, intermediate, and high ERI group (p for trend <0.001). Compared with the low ERI group, the multivariate-adjusted hazard ratio (mHR) was significantly higher in the high ERI group [mHR, 1.64 (95% confidence interval, 1.27-2.11)]. In the high ERI group, patients with Kt/V ≥ 1.57 had a significantly lower risk of death from any causes compared with those with Kt/V ≤ 1.56 [mHR, 0.73 (0.54-0.98)]. Our findings suggest that ESA responsiveness can be considered a significant prognostic factor in Japanese HD patients.