ESA Resistance Index Research Articles

Pentoxifylline improves anemia through its novel effect on hypoxia-inducible factor-2 alpha in hemodialysis patients: a randomized, double-blind, placebo-controlled clinical trial

ABSTRACT Objectives This randomized, double-blind, placebo-controlled clinical trial aimed to prospectively examine the effect of pentoxifylline (PTX) on hypoxia-inducible factor-2 alpha (HIF-2α) and its role in controlling anemia in hemodialysis (HD) patients. Methods Eighty patients on HD were randomized to receive 400 mg of PTX or placebo twice daily for 6 months. The hemoglobin (Hb) and other hematologic parameters, the weekly erythropoiesis-stimulating agents (ESAs), and the ESA resistance index (ERI) were assessed monthly during the study. The HIF-2α, transforming growth factor-β1 (TGF-β1), and high-sensitivity C-reactive protein (hs.CRP) were measured before and after the intervention. Results In the pentoxifylline group, an appreciable increase in Hb from 9.7 (9.3, 10.3) g/dl to 10.5 (9.3, 11.4) g/dl and hematocrit (Hct) from 31.3 (29.6, 32.4)% to 33.2 (29.4, 35.9)% was observed after one month of PTX administration, and this effect was maintained over the study time (p < 0.001). This was along with a decrease in the ESA doses required from 8000 (8000, 11500) IU/wk to 4000 (2000, 8000) IU/wk (p < 0.001), and an improvement in the ERI from 11.6 (8.07, 16.97) IU/kg/wk/g/dl to 5.79 (2.01, 10.09) IU/kg/wk/g/dl (p < 0.001). Additionally, the HIF-2α increased significantly at the end of the intervention in patients who received PTX from 3245.35 (2886.8, 4691.56) pg/ml to 7208.75 (5382, 9182.7) pg/ml, while TGF-β1 and hs.CRP decreased significantly from 657.78 (539.78, 1146.62) pg/ml and 88.08 (39.93, 100.4) mg/l to 329.94 (228.67, 793.18) pg/ml and 48.65 (34.44, 84.61) mg/l, respectively. The percent changes in HIF-2α, TGF-β1, and hs.CRP levels in the pentoxifylline group were also statistically significant in comparison with the placebo group. Conclusions PTX could be a promising agent for correcting anemia in HD patients via increasing HIF-2α levels. Clinical trial registration Clinicaltrials.gov, February 2023, registry number: NCT05708248.

Cutoff Value of Erythropoiesis-Stimulating Agent Resistance Index at Which Iron Replacement Therapy Is Expected to Be Effective

Cutoff Value of Erythropoiesis-Stimulating Agent Resistance Index at Which Iron Replacement Therapy Is Expected to Be Effective

Erythropoiesis-stimulating agent hyporesponsiveness was associated with worse survival of hemodialysis patients independent of the serum ferritin level.

Ferritin level and erythropoiesis-stimulating agent (ESA) responsiveness are each associated with hemodialysis patient survival. We assessed interrelationships between these two vs. survival. Patients in the Japan Dialysis Outcomes and Practice Patterns Study Phases 4-6 (2009-2018) were included. All-cause mortality associations were assessed with progressive adjustment to evaluate covariate influence. During follow-up (median 2.6 years), 773 of 5154 patients died. After covariate adjustment, the mortality hazard ratio (HR) was 0.99 (95% CI: 0.81, 1.20) for low serum ferritin and 1.12 (CI: 0.89, 1.41) for high serum ferritin. By contrast, mortality risk with elevated ESA resistance index (ERI) persisted after covariate adjustment (HR 1.44, CI [1.17-1.78]). The serum ferritin and ERI interaction was not significant; p > 0.96 across all models. Japanese hemodialysis patients with high ERI experienced worse survival independent of serum ferritin levels, highlighting the importance of identifying and mitigating ESA hyporesponsiveness among dialysis patients.

Association between magnesium, erythropoietin resistance and mortality: the Japanese Dialysis Outcomes and Practice Patterns Study (J-DOPPS).

Limited data are now available to evaluate the relationship between serum magnesium level, anemia and mortality in the dialysis population. Using data from the Japanese Dialysis Outcomes and Practice Patterns Study (J-DOPPS) phases 5 and 6, we analyzed the association between serum magnesium (s-Mg) levels and the erythropoiesis-stimulating agents resistance index (ERI) as the primary outcome. To estimate the longitudinal relationship, a mixed-effect model was used with ERI at each 4-month period as the dependent variable and quintiles of s-Mg at the previous 4-month period as the independent variable. We also examined incidence of infectious events, and the all-cause and cardiovascular disease (CVD)-related deaths as secondary outcomes by Cox regression with quintiles of s-Mg at baseline. Of the 4776 participants in J-DOPPS, 1650 were included in the analysis. The median of s-Mg at baseline was 2.5 mg/dL. A significant linear association of s-Mg with ERI (P for trend <.001) was revealed. Low and high s-Mg levels were not associated with the clinical outcomes of interest, except for the highest quintile of s-Mg being significantly associated with lower incidence of all-cause mortality and CVD-related deaths compared with the middle (reference) quintile. We observed that lower s-Mg levels subsequently induced higher ERI and that mild higher s-Mg levels were possibly associated with good rather than poor outcomes in Japanese hemodialysis patients. Adjustment of s-Mg levels may be proposed as a new strategy at a low cost and risk to reduce the risk of premature mortality.

Factors affecting responsiveness of vadadustat in patients with anemia associated with chronic kidney disease: a post-hoc subgroup analysis of Japanese phase 3 randomized studies

BackgroundVadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor developed for treating anemia in chronic kidney disease (CKD). The purpose of this post-hoc analysis was to investigate the factors affecting the responsiveness to vadadustat in anemia patients with nondialysis-dependent (NDD) or hemodialysis-dependent (HDD) CKD in two Japanese phase 3 studies.MethodsOf 151 and 162 patients enrolled in NDD-CKD and HDD-CKD studies, 136 and 140 patients, respectively, were included and divided into subgroups for the analysis. To assess vadadustat responsiveness, the resistance index was defined as the mean body weight-adjusted dose of vadadustat (mg/kg) at weeks 20–24 divided by the mean hemoglobin (g/dL) at weeks 20–24. Multivariate analysis was performed to identify the variables affecting the resistance index.ResultsIndependent factors identified as determinants for better response to vadadustat were as follows: high baseline hemoglobin, low baseline eGFR, high week-20–24 ferritin, and CKD not caused by autoimmune disease/glomerulonephritis/vasculitis in NDD-CKD; and male sex, high baseline C-reactive protein, and low baseline erythropoiesis-stimulating agent resistance index (ERI) in HDD-CKD.ConclusionsIn this post-hoc analysis, several factors were identified as affecting the response to vadadustat. These results may provide useful information leading to an appropriate dose modification for vadadustat.Clinical trial registrationNCT03329196 (MT-6548-J01) and NCT03439137 (MT-6548-J03).

Regional Variation of Erythropoiesis-Stimulating Agent Hyporesponsiveness in the Global Daprodustat Dialysis Study (ASCEND-D)

Introduction: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) affects 10–15% of the chronic dialysis population. We explored baseline characteristics and predictors of ESA hyporesponsiveness in a global randomized cardiovascular outcomes study comparing an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), daprodustat, with conventional ESA treatment. Methods: ASCEND-D (NCT02879305) recruited 2,964 chronic dialysis patients receiving ESA treatment (standardized to weekly intravenous [IV] epoetin) who were iron replete at baseline. The primary ESA hyporesponsiveness definition was an ESA Resistance Index (ERI, ESA units/kg/week/hemoglobin g/L) ≥2 or IV standardized ESA dose ≥450 units/kg/week. Predictors of ESA hyporesponsiveness were determined using a multivariable regression model. Alternative hyporesponder definitions were explored. Results: Using the primary definition, 354 (12%) patients were ESA hyporesponsive. Geographic region, notably Latin America, lower baseline body mass index and transferrin saturation, younger age, lower albumin concentration, and a higher baseline IV iron dose were identified as strongly associated (p < 0.001) with ESA hyporesponsiveness. Additional predictors of ESA hyporesponsiveness included female sex (p = 0.010), history of heart failure (p = 0.035), longer dialysis vintage (p = 0.077), smoking status (p = 0.247), aspirin use (p = 0.121), and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use (p = 0.214). Conclusion: This is the first global HIF-PHI study to report prespecified definitions and predictors of ESA hyporesponsiveness. While most of the predictors identified in our study have been previously reported, geographic region stands out as an unexpected finding, meriting further investigation.

Responsiveness to an erythropoiesis-stimulating agent is correlated with body composition in patients undergoing chronic hemodialysis.

Resistance to erythropoiesis-stimulating agents (ESA) is associated with adverse outcomes in patients undergoing chronic hemodialysis. However, the impact of body composition on ESA response remains uncertain. This study retrospectively investigated whether there is an association between the ESA resistance index (ERI) and body composition in patients undergoing chronic hemodialysis. Multifrequency bioelectrical impedance analysis was used to measure body composition every six months. The ERI was calculated by dividing the weekly body weight-adjusted erythropoietin dose by the hemoglobin concentration. The ERI values were recorded every three months. A total of 123 patients were followed up for 24 (interquartile range 5, 75) months. The ERI was negatively correlated with body mass index, arm circumference, arm muscle circumference, body fat percentage, and visceral fat area (P = 0.057, 0.001, 0.017, 0.063, and 0.041, respectively). Patients with a higher mean ERI during the study period had an increased risk of all-cause mortality, cardiovascular events, and infection requiring hospitalization than those with a lower mean ERI (P = 0.027, 0.021, and 0.037, respectively). We also evaluated the association between the slope of body composition parameters and the ERI trend over time and found that the ERI increased over time in patients who had an increased ratio of extracellular water to total body water (P = 0.002) as well as decreased arm circumference, arm muscle circumference, visceral fat area, and phase angle (P = 0.001, P < 0.001, P = 0.036, and 0.002). ESA responsiveness appears to be associated with body composition in patients undergoing chronic hemodialysis. Therefore, measures improving body composition, such as nutrition and exercise, may have a favorable effect on the response to ESA.

Effect of different hemodialysis modalities on hepcidin clearance in patients undergoing maintenance hemodialysis.

Hepcidin is a master regulator of iron utilization and takes part in the pathophysiology of anemia in maintenance hemodialysis (MHD) patients. Hepcidin is a moderate-molecular-weight substance and partially binds to plasma proteins in the circulation, which theoretically might be removed efficiently by hemoperfusion (HP). This study aimed to compare the effect of different dialysis modalities on hepcidin removal and discuss its effect on the iron and anemia status in MHD patients. In a longitudinal interventional study of 26 stable MHD patients, the serum hepcidin, β2-microglobulin (β2-MG), and intact parathyroid hormone (iPTH) were measured before and after one treatment session of hemodialysis (HD), hemodiafiltration (HDF), HD + HP, and HDF + HP, separately. One-way analysis of variance (ANOVA) was used to identify the effect of dialysis modalities on the intra-dialysis clearance ratios. The combined dialysis modalities (HD + HP and HDF + HP) achieved greater clearance ratios of serum hepcidin than HD and HDF alone, HD + HP vs. HD (16 ± 15% vs. 4 ± 13%, p < 0.001), HDF + HP vs. HDF (18 ± 5% vs. 10 ± 13%, p = 0.0036). Similarly, the combined dialysis modalities also performed better than HD and HDF alone in removing β2-MG. There was no significant difference in iPTH clearance among these four modalities, except that HDF + HP achieved a greater clearance ratio than HD. Furthermore, the anemia was improved after the 6-month treatment with regular HD/HDF plus HP, which was indicated by increasing hemoglobin (p = 0.0004) and reduction of erythropoiesis-stimulating agents (ESAs) resistance index (ERI) (p = 0.0431). Our findings suggest that the combined dialysis modalities of HD/HDF plus HP could achieve better clearance ratios of hepcidin than HD/HDF alone, thereby, might improve iron utilization, and benefit anemia management in MHD patients. Further studies with larger sample-size patients and longer follow-up duration are still needed.

Resistance to Erythropoiesis-Stimulating Agents among Patients on Hemodialysis Is Typically Transient

Introduction: This study examines factors associated with erythropoiesis-stimulating agent (ESA) hyporesponsiveness, the duration of ESA hyporesponsiveness, the frequency of new episodes, and variation across countries. Methods: We used international Dialysis Outcomes and Practice Patterns Study data from 2015 to 2018 (N = 26,656) to investigate changes in ESA Resistance Index (ERI), calculated as epoetin dose divided by [hemoglobin × body weight] in patients on hemodialysis. We illustrated the proportion of patients who moved to other ERI quintiles over 12 months, and we studied the incidence and duration of ESA resistance. We examined case-mix factors associated with quintiles of ERI. Results: Most patients migrated out of their original ERI quintile within 4 months. Only 22% of patients in the top quintile of ERI at baseline (4.4% of all patients) remained in the top quintile during all 12 months of follow-up. A total of 42% of patients manifested an upper-quintile ERI during at least 1 month. Median duration of a new episode of ESA resistance was 2 months. Catheter hemoaccess, elevated C-reactive protein, lower transferrin saturation, lower serum albumin concentration, and recent hospitalization occurred more frequently among patients in the highest ERI quintile at baseline. ERI values were highest in the USA, Italy, and Mideastern nations and lowest in Russia and Japan. Discussion/Conclusion: It is a misconception to envision a sizable, fixed segment of the population with permanent resistance to ESA – resistance fluctuates frequently. The implications of these findings for prescription of ESAs and of hypoxia-inducible factor-prolyl hydroxylase inhibitors are discussed.

Factors Affecting Doses of Roxadustat Versus Darbepoetin Alfa for Anemia in Nondialysis Patients

Introduction: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese, open-label, partially randomized, phase 3 study in nondialysis-dependent (NDD) CKD patients treated with traditional erythropoiesis-stimulating agents (ESAs) evaluated dosing trends of roxadustat and darbepoetin alfa (DA) required to maintain target hemoglobin concentrations in patients with risk factors associated with ESA hyporesponsiveness. Methods: Patients enrolled in the 1517-CL-0310 study (NCT02988973) that demonstrated noninferiority of roxadustat to DA for change in average hemoglobin levels of week 18–24 from baseline who had used human recombinant erythropoietin or DA before conversion and who were randomized to either roxadustat or DA were included. The endpoints were the average allocated dose of roxadustat and DA per administration in the last 6 weeks (AAD/6W), assessed by subgroups known to be associated with ESA hyporesponsiveness. The analysis of variance was performed by the treatment group to test the influence of subgroup factors on the AAD/6W of study drug. The ratios between the mean AAD/6W in each subgroup category and the within-arm mean AAD/6W were calculated. Results: Two hundred and sixty-two patients were randomized to either the roxadustat or DA comparative group and received treatment (roxadustat, n = 131; DA, n = 131). Higher mean (standard deviation) doses of both roxadustat (63.15 [24.84] mg) and DA (47.33 [29.79] μg) were required in the highest ESA resistance index (≥6.8) quartile (p = 0.003 and p < 0.001, respectively). Patients with adequate iron repletion had the lowest doses for both roxadustat (45.54 [18.01] mg) and DA (28.13 [20.98] μg). High-sensitivity C-reactive protein ≥28.57 nmol/L and the estimated glomerular filtration rate <15 mL/min/1.73 m² were associated with requiring higher DA but not roxadustat doses. Discussion/Conclusion: The roxadustat dose required to maintain target hemoglobin in NDD patients in Japan with anemia of CKD relative to DA dose may not be impacted by low-grade inflammation. Roxadustat may be beneficial for ESA-hyporesponsive NDD CKD patients.

Association of the erythropoiesis-stimulating agent resistance index and the geriatric nutritional risk index with cardiovascular mortality in maintenance hemodialysis patients.

Hyporesponsiveness to erythropoiesis-stimulating agent (ESA) may be associated with protein-energy wasting. We investigated the relationship of the ESA resistance index (ERI) and the geriatric nutritional risk index (GNRI) for cardiovascular mortality in hemodialysis (HD) patients. A total of 180 maintenance HD patients were enrolled. The patients were stratified by the GNRI of 91.2, a previously reported cut-off value, and the ERI of 13.7 (IU/week/kg/g/dL), a cut-off value for predicting cardiovascular-specific mortality, and they were classified into four groups (group 1[G1]: higher GNRI and lower ERI, G2: higher GNRI and higher ERI, G3: lower GNRI and lower ERI, G4: lower GNRI and higher ERI). The ERI was independently associated with the GNRI (β = -0.271, p = 0.0005). During a median follow-up of 4.6 years, higher ERI and lower GNRI were independently associated with cardiovascular mortality, respectively (adjusted hazard ratio [aHR], 3.10; 95% confidence interval [CI], 1.31-7.34, and aHR, 6.64; 95%CI, 2.60-16.93, respectively). The 7-year survival rates were 96.1%, 70.3%, 77.3%, and 50.1% in G1, G2, G3, and G4, respectively. The aHR values for G4 versus G1 were 12.63 (95%CI, 3.58-44.59). With regards to model discrimination, adding the GNRI alone, the ERI alone, and both to the traditional risk model significantly improved the net reclassification improvement by 0.421, 0.662, and 0.671, respectively. Similar results were obtained for all-cause mortality. The ERI was independently associated with the GNRI, and could predict cardiovascular mortality in HD patients. Moreover, the combination of GNRI and ERI could improve the predictability for cardiovascular mortality.

Association between Dipeptidyl Peptidase-4 Inhibitor Prescription and Erythropoiesis-Stimulating Agent Hyporesponsiveness in Hemodialysis Patients with Diabetes Mellitus

Introduction: Dipeptidyl peptidase-4 (DPP-4) has been hypothesized to improve responsiveness to erythropoiesis-stimulating agent (ESA). We aimed to describe the trend in DPP-4 inhibitor prescription patterns and assess the association between DPP-4 inhibitor prescription and ESA hyporesponsiveness (eHypo) in Japanese hemodialysis (HD) patients with diabetes mellitus (DM). Methods: We analyzed data from the Japan Dialysis Outcomes and Practice Patterns Study phase 4–6 (2009–2017) on patients with DM who underwent HD thrice per week for at least 4 months. The primary exposure of interest was having a DPP-4 inhibitor prescription. The primary analysis outcomes were a binary indicator of eHypo (mean hemoglobin <10 and mean ESA dose >6,000 units/week over 4 months) and the natural log-transformed ESA resistance index (ERI). We used conditional logistic regression to compare within-patient changes in eHypo before and after initial DPP-4 inhibitor prescription. We used linear generalized estimating equation models to compare continuous ERI outcomes while accounting for within-patient repeated measurements with an exchangeable correlation structure. Results: There was a monotonic increase in DPP-4 inhibitor prescription according to study year up to 20% in 2017. Moreover, 12.8% of patients with a DPP-4 inhibitor prescription were ESA hyporesponsive before the initial DPP-4 inhibitor prescription. After DPP-4 inhibitor prescription, the odds of eHypo and mean log-ERI remained unchanged in the whole cohort of our study. The interaction analysis of DPP-4 inhibitor and sideropenia showed that DPP-4 inhibitors attenuated eHypo in the patients without iron deficiency. Conclusion: Our findings indicate a recent increase in DPP-4 inhibitor prescription among Japanese HD patients with DM. DPP-4 inhibitors could improve ERI in patients undergoing HD without iron deficiency.

Ziltivekimab for Treatment of Anemia of Inflammation in Patients on Hemodialysis: Results from a Phase 1/2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Patients with CKD who are on hemodialysis are hyporesponsive to erythropoiesis-stimulating agents (ESAs) because of anemia of inflammation. Interleukin-6 (IL-6) induced hepcidin expression is a key mediator of such inflammation. This phase 1/2, placebo-controlled trial assessed effects of ziltivekimab, a novel anti-IL-6 ligand antibody, in patients on hemodialysis with rs855791, a single nucleotide polymorphism of the TMPRSS6 gene that is hypothesized to heighten susceptibility to IL-6-mediated inflammatory effects. After a screening period documenting stable ESA and iron dosing, we randomized 61 patients with elevated IL-6 (≥4 pg/ml) to receive placebo or ziltivekimab (doses of 2, 6, or 20 mg), administered intravenously every 2 weeks for 12 weeks during hemodialysis. ESA dose adjustments were allowed after 4 weeks. We analyzed safety and effects on inflammation, iron metabolism, serum albumin, and anti-drug antibodies. No patient experienced dose-limiting toxicity. Four patients (two each in the 6- and 20-mg cohorts) died of a treatment-emergent adverse event. Compared with patients receiving placebo, those receiving ziltivekimab experienced significantly greater reductions of high-sensitivity C-reactive protein, serum amyloid A, and fibrinogen from baseline to end of treatment. Median ESA usage decreased by 15,000, 15,000, or 33,000 IU/wk per patient in the 2-, 6-, and 20-mg ziltivekimab cohorts, respectively, compared with no change in the placebo group. We also noted significant dose responses for decreased ESA resistance index and increased serum iron, total iron binding capacity, transferrin saturation, and serum albumin. Ziltivekimab significantly improved markers of inflammation, reduced ESA requirements, and increased serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to ESA therapy. Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001, NCT02868229.

Occult hepatitis C virus infection among Egyptian hemodialysis patients and its potential effect on anemia management

BackgroundHepatitis C virus (HCV) infection is still a main health problem in hemodialysis (HD) patients. The prevalence of occult hepatitis C infection (OCI) in HD patients may be underestimated, and its possible influence on anemia management has not been studied. We aimed to determine the existence of OCI in Egyptian HD patients as well as its possible effect on anemia management.Patients and methodsThis cross-sectional multicenter study included 98 HCV-negative HD patients (negative for both anti-HCV antibody and HCV-RNA), 43 anti-HCV-positive HD patients, and 10 volunteer people matched for age and sex as a healthy control group. Serology test for anti-HCV antibody, reverse-transcription PCR for HCV-RNA (both serum and peripheral mononuclear cell (PMNC)), complete blood count (CBC), liver transaminases, serum iron, serum ferritin, and high-sensitivity C-reactive protein (hsCRP) were done. The average erythropoiesis-stimulating agent (ESA) doses were calculated over 6 months, and ESA resistance index was calculated. The frequency of packed red blood corpuscle (RBC) transfusion for each patient was recorded.ResultsOur HD patients had significant higher levels of serum ferritin (P=0.011), higher serum alanine aminotransferase and aspartate aminotransferase (P=0.002 and 0.006, respectively), higher hsCRP (P<0.0001), and significant lower level of hemoglobin (P<0.0001) compared with the healthy control group. The prevalence of OCI was 8.16% (8 of 98 patients). OCI patients had significant longer dialysis duration, higher transaminases, higher hsCRP, higher serum ferritin, and higher frequency of packed RBCs transfusion (P<0.0001), whereas mean hemoglobin levels and ESA resistance index showed insignificant differences compared with HCV-negative HD patients. Using logistic regression analysis, frequency of packed RBC transfusion and aspartate aminotransferase were the only independent predictors for OCI (P=0.012 and 0.049, respectively), and by multivariate analysis, no significant predictors were found to be associated with anemia in patients with OCI.ConclusionThe prevalence of OCI in our study was 8.16%. OCI had no effect on anemia managements.

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.

Achievement of renal anemia KDIGO targets by two different clinical strategies \u2013 a European hemodialysis multicenter analysis

BackgroundThe optimal treatment algorithm for iron therapy and the use of erythropoiesis-stimulating agents (ESA) in anemic hemodialysis (HD) patients has not been established. Hemoglobin (Hb) target levels can be achieved through more frequent intravenous (IV) iron use with lower ESA dose, or with less iron dosing but higher ESA. ESA therapy to correct anemia may result in severe arterial and venous thrombotic complications and the evidence base evaluating hard clinical outcomes related to the use of IV iron is sparse.MethodsA total of 1247 maintenance HD patients from 12 dialysis centers in Portugal (n = 730) and Poland (n = 517) were considered. We assessed achievement of KDIGO renal anemia targets with focus on treatment strategies, which typically differ between countries. In Poland the use and dose of IV iron was 35–72% higher than that in Portugal (p < 0.001) during three consecutive months; use and dose of ESA was 61% higher in Portugal (5034 vs 3133 IU (adjusted)/week, p < 0.001).ResultsMean Hb concentration was similar (11.0 vs 11.0 g/dL) in patients treated in both countries and the proportion of patients within KDIGO anemia target was 69.5% in Poland vs 65.8% in Portugal (NS). Ferritin and TSAT levels and the proportion of patients with TSAT > 20 and > 50% were both significantly higher in patients in Poland (88.8 and 14.6%) than in Portugal (76.3 and 5.7% respectively, p < 0.001). Significantly more patients in Poland had a ferritin concentration > 800 μg/L (35.6%) compared to Portugal (15.8%, p < 0.001). The ESA resistance index (ERI) was significantly higher in patients treated in Portugal (p < 0.001). Correlation analyses showed confounding by treatment indication in unadjusted models. Multiple and logistic regression analyses showed that with ferritin within KDIGO recommended range of 200–800 μg/L the odds for Hb within guidelines increased significantly. Annual gross mortality was 16% in Poland and 13% in Portugal (NS); there were no differences in cause-specific mortality.ConclusionsAdministration of high doses of IV iron in routine clinical HD practice may not be associated with considerable harm. However, large randomized controlled trials are needed to provide absolute evidence of iron safety.

Forecast post-dialysis blood pressure in hemodialysis patients with intradialytic hypertension

ABSTRACTBackground: Intradialytic hypertension (IDH) is emerging as an important issue in maintenance hemodialysis (MHD) patients. This study aimed to discuss potential factors related to IDH and build forecasting models for post-dialysis blood pressure (BP) in MHD patients with IDH.Methods: A total of 266 MHD patients were enrolled, included 133 (50%) patients with IDH and 133 patients without IDH. The BP and pulse were determined and recorded over six consecutive dialysis treatments. Forecasting models were established by simple and multiple linear regressions. The Pearson correlation coefficient was used to estimate the association between the values of SBP at pre-HD, intra-HD and post-HD.Results: Lower levels of hemoglobin, albumin, folic acid and magnesium, higher levels of high sensitivity C-reactive protein, ferritin, and erythropoiesis-stimulating agents resistance index (ERI) were detected in the IDH patients. The IDH patients also had lower dry weight, ejection fraction of left ventricular (LVEF), higher interdialytic weight gain (IDWG, % post-HD body weight), and ventricular cardiothoracic ratio (CTR) than non-IDH patients. A linear relationship was revealed between intradialytic SBP in IDH patients, indicating that the pre-HD and intra-HD SBP were correlated with post-HD SBP. Furthermore, simple and multiple linear regression models were built to forecast the values of post-HD SBP in IDH patients.Conclusions: The chronic inflammation, poor IDWG control, LV diastolic dysfunction, as well as low serum folic acid and magnesium might be associated with increasing prevalence of IDH in MHD patients. Forecasting models for post-HD SBP could help to control hypertension during HD treatments.

Association between resistance to erythropoiesis-stimulating agents and carnitine profile in patients on maintenance haemodialysis.

Patients on dialysis are in a chronic carnitine-deficient state. This condition may be associated with abnormalities in fatty acid and organic acid metabolism; however, the details are unknown. We investigated the association between carnitine profiles before and after dialysis and the erythropoiesis-stimulating agent (ESA) resistance index (ERI), which is a significant prognostic factor in patients on maintenance haemodialysis. This was a cross-sectional study. We measured the carnitine profile of 79 patients on maintenance haemodialysis before and after dialysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The associations between the ERI and pre-dialysis carnitine profile, removal rate of various carnitines, and previously-reported ERI-related factors were investigated. Significant factors were determined with stepwise multiple regression analysis and validated with the bootstrap method. SPSS version 22.0 was used for analysis, and P < 0.05 was considered statistically significant. The removal rate of long-chain acylcarnitine with dialysis was lower than that of short-chain or medium-chain acylcarnitines. Stepwise multiple regression analysis (n = 79) demonstrated that 3-hydroxy isovalerylcarnitine (C5-OH, P < 0.001, β = -0.469) and stearoylcarnitine (C18, P < 0.001, β = 0.390) were independent significant factors (R2 = 0.239) of ERI. The bootstrap method similarly indicated these two to be significant factors. ERI positively correlated with long-chain C18 acylcarnitine and negatively correlated with short-chain C5-OH acylcarnitine. C5-OH and C18 acylcarnitines at baseline might be contributing factors in distinguishing responders from nonresponders after L-carnitine administration.

Oral Versus Intravenous Iron Supplementation for the Treatment of Iron Deficiency Anemia in Patients on Maintenance Hemodialysis—Effect on Fibroblast Growth Factor-23 Metabolism

Iron administration affects serum levels of intact (I-) fibroblast growth factor-23 (FGF23) and its cleavage product C-terminal (C-) FGF23 in iron-deficient patients on maintenance hemodialysis (MHD). The objective of this study was to compare the effect of oral or intravenous iron administration on serum levels of I-FGF23 and C-FGF23 in iron-deficient patients on MHD. A prospective randomized study. Participants on MHD with severe iron deficiency (n=61). Participants were randomized to receive oral iron (50mg of sodium ferrous citrate daily; oral group, n=29) or intravenous iron (40mg of saccharated ferric oxide weekly; IV group, n=32). Changes in I-FGF23 and C-FGF23 after 10 weeks of treatment. Iron supplementation significantly increased hemoglobin, mean corpuscular volume, ferritin, and transferrin saturation rate, and decreased erythropoiesis-stimulating agent dose and erythropoiesis-stimulating agent resistance index value. Serum phosphate, calcium, and intact parathyroid hormone levels did not change significantly during the study. I-FGF23 levels increased significantly in the IV group and did not change in the oral group, whereas C-FGF23 levels were significantly reduced in both groups. Serum interleukin-6 and tumor necrosis factor-α levels were increased in both groups. Multiple regression analysis indicated the relationship between iron or erythropoiesis and FGF23 metabolism. Iron administration to patients on MHD with severe iron deficiency decreased C-FGF23 levels, whereas intravenous iron increased I-FGF23 levels though oral iron did not. If the target of chronic kidney disease-mineral and bone disorder therapy is reducing I-FGF23 levels, we suggest the use of oral iron.

Butyrylcholinesterase level as an independent factor of erythropoiesis-stimulating agent resistance in patients on maintenance hemodialysis: a single-center cross-sectional study.

Erythropoiesis-stimulating agent (ESA) responsiveness is related to the nutritional status of patients on hemodialysis (HD). Serum butyrylcholinesterase (BChE), an alpha-glycoprotein, may decrease in case of malnutrition. We investigated whether BChE was independently related to ESA resistance in patients on HD. The laboratory data and ESA resistance index (ERI), defined as ESA dosage per week divided by dry weight and hemoglobin, were investigated in 215 patients on HD between July and September 2017. Malnutrition was defined as Geriatric Nutritional Risk Index (GNRI) of < 91.2. The patients were stratified into two groups: ERI-high (ERI ≥ 9.44) and ERI-low (ERI < 9.44) groups. Variables such as patient's background, medication, and laboratory data were compared between the two groups. The optimal cutoff value of BChE for higher ERI was determined using receiver operating characteristic analysis. Factors independently associated with higher ERI were determined using multivariate logistic regression analysis. The median and optimal cutoff values of ERI and BChE were 6.51 and 200IU/L, respectively. The study included 71 (33%) and 144 (67%) patients in the ERI-high and ERI-low groups, respectively. Significant between-group differences were observed concerning age, hemoglobin, ESA dose, lipid profiles, serum albumin, body mass index, GNRI, iron metabolism markers, ferric medicines, and BChE. Multivariate analysis showed that BChE < 200IU/L (odds ratio 3.67; 95% confidence interval 1.73-7.77) continued to be an independent factor associated with higher ERI after adjusting for potential confounders, which was a similar odds ratio as GNRI < 91.2. BChE may be an independent indicator of ESA resistance.