Factors affecting pre-end-stage kidney disease haemoglobin control and outcomes following dialysis initiation: a nationwide study.

BACKGROUND: Attaining the narrow haemoglobin (Hb) range recommended by European Renal Best Practice Guidelines renal anaemia guidelines may be difficult, and whether this leads to better outcomes following dialysis initiation is not known. METHODS: This was an observational study from the Swedish Renal Registry 2012-16, including all patients with non-dialysis-dependent chronic kidney disease (CKD) initiating renal anaemia treatment. We evaluated factors associated with off-target Hb attainment (<10 and >12 g/dL). For those who initiated dialysis, we explored associations between the pre-end-stage kidney disease (pre-ESKD) time in which Hb was within or above range, and pre-ESKD Erythropoietin Resistance Index (ERI) with the 1-year risk of death or major adverse cardiovascular events + (MACE+). RESULTS: About 5000 patients initiated anaemia treatment, contributing to 25 431 consecutive visits over time. Patients with polycystic kidney disease, diabetic nephropathy and nephrosclerosis, with recent bleeding/transfusion, with higher C-reactive protein or abnormal phosphate had higher odds of maintaining Hb below range. Conversely, patients with older age, CKD Stages 3b-4, pyelonephritis, kidney transplant, iron medication, higher ESA doses or abnormal serum calcium and albumin had higher odds of maintaining Hb above range. A total of 1361 patients initiated dialysis, among whom 220 deaths and 453 MACE+ occurred. A greater time spent with a pre-ESKD Hb >12 g/dL was associated with a lower risk of MACE+ (hazard ratio = 0.76; 95% confidence interval 0.61-0.94) after dialysis initiation, and a lower pre-ESKD Erythropoietin Resistance Index (ERI) was associated with improved survival (1.39; 1.02-1.90). CONCLUSIONS: Our study identified populations that require additional efforts to control their Hb. Our outcome analysis supports the value of pre-ESKD anaemia care while illustrating the problems of ESA hyporesponsiveness in clinical practice.

JTZ-951 (enarodustat), a hypoxia-inducible factor prolyl hydroxylase inhibitor, improves iron utilization and anemia of inflammation: Comparative study against recombinant erythropoietin in rat.

Anemia with inflammation-induced defective iron utilization is a pathological condition observed in patients suffering from chronic kidney disease (CKD) or chronic inflammatory disease. There is no reasonable treatment for these conditions, because the effects of erythropoiesis stimulating agents (ESAs) or iron supplementation in the treatment of anemia are insufficient. JTZ-951 (enarodustat) has been characterized as a novel, orally bioavailable inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH), and has been developed as a novel therapeutic agent for anemia with CKD. In this study, the effects of JTZ-951 on iron utilization during erythropoiesis and on anemia of inflammation were compared with those of recombinant human erythropoietin (rHuEPO) using normal rat and rat model of anemia of inflammation. In normal rats, under conditions in which JTZ-951 and rHuEPO showed similar erythropoietic effect, repeated doses of JTZ-951 induced erythropoiesis while retaining the hemoglobin content in red blood cells, while administration of rHuEPO resulted in decrease in some erythrocyte-related parameters. As for iron-related parameters during erythropoiesis, JTZ-951 exhibited more efficient iron utilization compared to rHuEPO. A single dose of JTZ-951 resulted in decrease in hepcidin expression observed within 24 h after administration, but a single dose of rHuEPO did not. In a rat model of anemia of inflammation (also known as a model with functional iron-deficiency), JTZ-951 showed erythropoietic effect, in contrast with rHuEPO. These results suggest that, unlike rHuEPO, JTZ-951 stimulates erythropoiesis by increasing iron utilization, and improves anemia of inflammation.

Renal prognoses by different target hemoglobin levels achieved by epoetin beta pegol dosing to chronic kidney disease patients with hyporesponsive anemia to erythropoiesis-stimulating agent: a multicenter open-label randomized controlled study.

BACKGROUND: There is no evidence regarding appropriate target hemoglobin levels in chronic kidney disease (CKD) patients with an erythropoiesis-stimulating agent (ESA)-hyporesponsiveness. Therefore, we conducted a randomized controlled study in non-dialysis dependent CKD (NDD-CKD) patients with ESA-hyporesponsiveness, comparing results of intensive versus conservative treatment to maintain hemoglobin levels. METHODS: This was a multicenter, open-label, randomized, parallel-group study conducted at 89 institutions. Among NDD-CKD patients, those with ESA-hyporesponsive renal anemia were randomly assigned to an intensive treatment group, to which epoetin beta pegol was administered with target hemoglobin level of 11 g/dL or higher, or conservative treatment group, in which the hemoglobin levels at enrollment (within ± 1 g/dL) were maintained. The primary endpoint was the time to the first kidney composite event defined as (1) transition to renal replacement therapy (dialysis or renal transplantation); (2) reduction of estimated glomerular filtration rate (eGFR) to less than 6.0 mL/min/1.73 m2; or (3) reduction of eGFR by 30% or more. Secondary endpoints were kidney function (change rate in eGFR), cardiovascular (CV) events, and safety. RESULTS: Between August 2012 and December 2015, 385 patients were registered, and 362 patients who met the eligibility criteria were enrolled. There was no significant difference in kidney survival or in CV events between the two groups. However, the incidences of the 3 types of kidney composite events tended to differ. CONCLUSIONS: In NDD-CKD patients with ESA-hyporesponsive renal anemia, the aggressive administration of ESA did not clearly extend kidney survival or result in a significant difference in the incidence of CV events.

A faster decline of residual kidney function and erythropoietin stimulating agent hyporesponsiveness in incident hemodialysis patients.

INTRODUCTION: Erythropoietin stimulating agents (ESA) hyporesposiveness has been associated with increased mortality in hemodialysis (HD) patients. However, the impact of decline of residual kidney function (RKF) on ESA hyporesposiveness has not been adequately elucidated among patients receiving HD. METHODS: The associations of RKF decline with erythropoietin resistance index (ERI; average weekly ESA dose [units])/post-dialysis body weight [kg]/hemoglobin [g/dL]) were retrospectively examined across four strata of annual change in RKF (residual renal urea clearance [KRU] < -3.0, -3.0 to <-1.5, -1.5 to <0, ≥0 mL/min/1.73 m2 per year; urinary volume < -600, -600 to<-300, -300 to <0, ≥0 mL/day per year) using logistic regression models adjusted for clinical characteristics and laboratory variables in 5239 incident HD patients in a large US dialysis organization between 1 January 2007 and 31 December 2011. FINDINGS: The median values of the annual change in KRU and urinary volume were -1.2 (interquartile range [IQR]: -2.8 to 0.1) mL/min/1.73 m2 per year and -250 (IQR: -600 to 100) mL/day per year. A faster KRU decline in the first year of HD was associated with higher odds for ESA hyporesponsiveness: KRU decline of <-3.0, -3.0 to <-1.5, and -1.5 to <0/min/1.73 m2 per year were associated with adjusted odds ratios (OR) of 2.07 (95% confidence interval [CI]: 1.66-2.58), 1.54 (95%CI: 1.28-1.85), and 1.26 (95%CI: 1.07-1.49), respectively (reference: ≥0 mL/min/1.73 m2 per year). These associations were consistent across strata of baseline KRU, age, sex, race, diabetes, congestive heart failure, hemoglobin, and serum albumin. Sensitivity analyses using urinary volume as another index of RKF showed consistent associations. DISCUSSION: A faster RKF decline during the first year of dialysis was associated with ESA hyporesponsiveness and low hemoglobin levels among incident HD patients.

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

RATIONALE & OBJECTIVE: Since 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 DESIGN: Retrospective observational cohort study. SETTING & PARTICIPANTS: US Renal Data System Medicare participants receiving dialysis with a minimum 6 months of continuous ESA use from 2012 to 2014. PREDICTORS: Erythropoietin 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. OUTCOMES: Associations between ESA responsiveness and mortality, cardiovascular hospitalization rates, and health care resource use were evaluated and compared across subgroups. ANALYTICAL APPROACH: Baseline 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. RESULTS: Of 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. LIMITATIONS: Only US Medicare patients were included and different hyporesponder definitions may have influenced the results. CONCLUSIONS: This 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.

The Influence of Inflammation on Anemia in CKD Patients.

Anemia is frequently observed in the course of chronic kidney disease (CKD) and it is associated with diminishing the quality of a patient's life. It also enhances morbidity and mortality and hastens the CKD progression rate. Patients with CKD frequently suffer from a chronic inflammatory state which is related to a vast range of underlying factors. The results of studies have demonstrated that persistent inflammation may contribute to the variability in Hb levels and hyporesponsiveness to erythropoietin stimulating agents (ESA), which are frequently observed in CKD patients. The understanding of the impact of inflammatory cytokines on erythropoietin production and hepcidin synthesis will enable one to unravel the net of interactions of multiple factors involved in the pathogenesis of the anemia of chronic disease. It seems that anti-cytokine and anti-oxidative treatment strategies may be the future of pharmacological interventions aiming at the treatment of inflammation-associated hyporesponsiveness to ESA. The discovery of new therapeutic approaches towards the treatment of anemia in CKD patients has become highly awaited. The treatment of anemia with erythropoietin (EPO) was associated with great benefits for some patients but not all.

An Exploratory Study of Daprodustat in Erythropoietin-Hyporesponsive Subjects.

INTRODUCTION: Hyporesponsiveness to recombinant human erythropoietin (rhEPO) is a major problem affecting some patients with chronic kidney disease (CKD), predominantly those on hemodialysis (HD). Daprodustat (GSK1278863) is a hypoxia-inducible factor prolyl hydroxylase inhibitor that is being investigated as a treatment for anemia of CKD. METHODS: This phase 2a, exploratory, multicenter, single-arm study assessed the ability of daprodustat to increase or maintain hemoglobin concentrations within the target range (10.0-11.5 g/dl) over 16 weeks in subjects with anemia who were on HD and who had a high erythropoietin resistance index (ERI). All included subjects met the criteria for chronic rhEPO hyporesponsiveness (i.e., an ERI based on a series of contiguous strata of patients' hemoglobin-by-epoetin alfa for a minimum of 12 weeks). Eligible adults were on a stable HD regimen 3 to 4 times per week. Markers of iron utilization and safety were also assessed. All subjects initially received oral daprodustat 12 mg once daily. RESULTS: Of the 60 participants screened, 15 were enrolled, and 7 (47%) completed 16 weeks of treatment. At week 16, 2 of 7 subjects (29%) had >1 g/dl increases in hemoglobin from baseline. Daprodustat had minimal effects on markers of iron metabolism and utilization. Fourteen subjects (93%) experienced ≥1 adverse event (AE). The most common AEs included nausea, pneumonia, pleural effusion, and urinary tract infection. The majority of on-therapy AEs were mild or moderate in intensity. CONCLUSION: Daprodustat increased hemoglobin concentrations within the target range in 29% of chronic rhEPO-hyporesponsive subjects. No new safety concerns were identified in this short exploratory study.

Association between responsiveness to methoxy polyethylene glycol-epoetin beta and renal survival in patients with non-dialysis-dependent chronic kidney disease: A pooled analysis of individual patient-level data from clinical trials.

AIM: The association between responsiveness to continuous erythropoietin-receptor activator (CERA) and renal survival in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) is uncertain. METHODS: We performed a pooled analysis of individual patient-level data drawn from five clinical trials involving CERA administration. Based on the responsiveness to CERA, patients were classified into poor- or good-response groups. Primary endpoints were defined as the initiation of dialysis or a 30% decrease in the estimated glomerular filtration rate (eGFR) from baseline. We set the landmark time point at 12 weeks after the start of CERA, from which we evaluated the time to the first renal event. The cumulative renal survival rates were calculated for each group using the Kaplan-Meier method. The adjusted hazard ratio was calculated using a stratified Cox regression model. RESULTS: Of 408 patients, 226 were analyzed. Haemoglobin levels and eGFRs were significantly lower in the poor-response group (n = 113) than in the good-response group (n = 113). Renal events occurred in 36.3% of the poor-response group and in 23.0% of the good-response group. The intergroup difference in renal survival rates was significant (log-rank test, P = 0.03) and the adjusted hazard ratio was 1.71 (95% confidence interval, 1.03-2.83), indicating an unfavorable outcome in the poor-response group. CONCLUSION: Hyporesponsiveness to CERA was associated with poor renal survival, consistent with the results of the conventional erythropoiesis-stimulating agent (ESA). It is recommended that a randomized controlled trial on CERA use be performed in patients with NDD-CKD with ESA-hyporesponsive anaemia.

A randomized, placebo-controlled trial of pentoxifylline on erythropoiesis-stimulating agent hyporesponsiveness in anemic patients with CKD: the Handling Erythropoietin Resistance With Oxpentifylline (HERO) trial.

BACKGROUND: Erythropoiesis-stimulating agent (ESA)-hyporesponsive anemia is common in chronic kidney disease (CKD). Pentoxifylline shows promise as a treatment for ESA-hyporesponsive anemia, but has not been rigorously evaluated. STUDY DESIGN: Multicenter, double-blind, randomized, controlled trial. SETTING & PARTICIPANTS: 53 adult patients with CKD stage 4 or 5 (including dialysis) and ESA-hyporesponsive anemia (hemoglobin≤120g/L and ESA resistance index [calculated as weight-adjusted weekly ESA dose in IU/kg/wk divided by hemoglobin concentration in g/L]≥1.0IU/kg/wk/g/L for erythropoietin-treated patients and ≥0.005µg/kg/wk/g/L for darbepoetin-treated patients). INTERVENTIONS: Pentoxifylline (400mg/d; n=26) or matching placebo (control; n=27) for 4 months. PRIMARY OUTCOME: ESA resistance index at 4 months; secondary outcomes: hemoglobin concentration, ESA dose, blood transfusion requirement, serum ferritin level and transferrin saturation, C-reactive protein level, adverse events, quality of life, and health economics. RESULTS: There was no statistically significant difference in ESA resistance index between the pentoxifylline and control groups (adjusted mean difference, -0.39 [95%CI, -0.89 to 0.10] IU/kg/wk/g/L; P=0.1). Pentoxifylline significantly increased hemoglobin concentration relative to the control group (adjusted mean difference, 7.6 [95%CI, 1.7-13.5] g/L; P=0.01). There was no difference in ESA dose between groups (-20.8 [95%CI, -67.2 to 25.7] IU/kg/wk; P=0.4). No differences in blood transfusion requirements, adverse events, or quality of life were observed between groups. Pentoxifylline cost A$88.05 (US $82.94) per person over the trial and produced mean savings in ESA cost of A$1,332 (US $1,255). The overall economic impact over the trial period was a saving of A$1,244 (US $1,172) per person for the pentoxifylline group compared with controls. LIMITATIONS: Sample size smaller than planned due to slow recruitment. CONCLUSIONS: Pentoxifylline did not significantly modify ESA hyporesponsiveness, but increased hemoglobin concentration. Further studies are warranted to determine whether pentoxifylline therapy represents a safe strategy for increasing hemoglobin levels in patients with CKD with ESA-hyporesponsive anemia.