High Erythropoiesis-stimulating Agents Doses Research Articles

Proton Pump Inhibitors and Hyporesponsiveness to Erythropoiesis-Stimulating Agents in Hemodialysis Patients: Results from the Japan Dialysis Outcomes and Practice Patterns Study.

Hyporesponsiveness to erythropoiesis stimulating agents (ESAs) is important problem in dialysis patients. While proton pump inhibitors (PPIs) may inhibit iron absorption, few studies have examined associations between PPIs and ESA-resistant anemia in hemodialysis patients. This study examined the associations between PPIs and ESA-resistant anemia in hemodialysis patients. The present study was a cross-sectional study using repeated 4-month observations, up to eight observations/patient, from the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS). The primary outcome was erythropoietin resistance index (ERI). ESA dose, hemoglobin, proportion of erythropoietin-resistant anemia, transferrin saturation (TSAT), and ferritin were also examined. Linear or risk-difference regression models were used with generalized estimating equations to account for repeated measurements. Of 1,644 patients, 867 patients had PPI prescriptions (52.7%). Patients prescribed PPI had higher ERI, higher ESA dose, and lower TSAT levels. Multivariable analysis for 12,048 four-month observations showed significantly greater ERI in PPI users (adjusted difference 0.95 IU/week/kg/[g/dL] [95% CI: 0.40-1.50]). Significant differences were also found in ESA dose (336 IU/week [95% CI: 70-602]) and the prevalence of erythropoietin-resistant anemia (3.9% [2.0-5.8%]) even after adjusted for TSAT and ferritin. Among possible mediators between the association of PPIs and anemia, TSAT was significantly different between PPI users and non-users (adjusted difference, -0.82% [95% CI: -1.56 to -0.07]). This study showed the associations between PPI and ERI, ESA dose, and TSAT in hemodialysis patients; physicians should consider anemia's associations with PPIs in hemodialysis patients.

Aluminum overload in the reverse osmosis dialysis era: does it exist?

Background Aluminum accumulation is a well-described complication in dialysis patients. Improvements in hemodialysis technology have possibly eliminated the occurrence of aluminum overload. Limited evidence suggests that aluminum overload may decline in the era of aluminum removal from dialysis fluids, even with the use of aluminum binders. Methods We examined the data from January 2014 to June 1, 2020, identified through our electronic records, to evaluate the desferrioxamine (DFO) test results for aluminum overload. The presentation and treatment of aluminum overload were recorded. Results Ninety-nine dialysis patients were enrolled for the DFO test. Forty-seven patients (47.5%) were identified as DFO test positive for aluminum overload, of which 14 (14/47) patients had symptoms, including one patient with an unexplained fracture, eight patients with unexplained anemia despite high-dose erythropoiesis-stimulating agents, and five patients with hypercalcemia (serum calcium >11 mg dL-1). None of the patients with aluminum overload developed encephalopathy. Only four of the 47 patients had microcytic anemia. Patients requiring longer treatments (>10 months versus <10 months) had similar basal serum aluminum (p = 0.219) but had an increase in serum aluminum after DFO (p = 0.041). Furthermore, the treatments decreased erythropoietin doses in the aluminum overload group, with serum total alkaline phosphatase levels <60 U L-1 (p = 0.028). Conclusion We concluded that aluminum overload existed in the reverse osmosis dialysis era. In light of non-obvious symptoms, such as anemia and bone turnover change, serum aluminum in dialysis patients should be monitored in countries using aluminum-based phosphate binders, despite reverse osmosis dialysis.

MO796: Short-Term Effect of Roxadustat Combined With Erythropoiesis Stimulating Agents (ESAS) Treatment for Anemia in Patients Undergoing Hemodialysis With ESA Resistance

Abstract BACKGROUND AND AIMS Renal anemia is a common complication of chronic kidney disease (CKD) that can decrease the quality of life of patients, especially for patients with maintenance hemodialysis (MHD). The current standard treatment for renal anemia consists of iron plus erythropoiesis-stimulating agents (ESAs). However, high-dose ESA supplementation may cause an increase in blood pressure and induce cardiovascular events and death [1]. Roxadustat (FG-4592) is a new small-molecule oral medication for the treatment of renal anemia that may improve anemia by increasing endogenous erythropoiesis, transferrin receptor expression, and iron absorption [2]. Currently, the use of roxadustat in the treatment of renal anemia is still being explored. Our study aimed to observe the short-term efficacy of roxadustat combined with ESAs on renal anemia in MHD patients with ESA resistance. METHOD This retrospective study included patients with renal anemia using roxadustat for the first time at West China Hospital of Sichuan University from September 2019 to March 2021. Study inclusion criteria: (1) MHD for &amp;gt;3 months (thrice weekly), (2) basal Hb ≤ 100 g/L and (3) ESAs therapy for &amp;gt;2 months, and the first time use of rosadustat for at least 1 month. We excluded those without hemoglobin data and those with a history of blood transfusion within the first month. Patients treated with roxadustat combined with ESAs were as an observation group, and those treated with roxadustat alone were included as a control group. RESULTS A total of 31 MHD patients were included, the baseline data was shown in Table 1. A total of 15 patients were treated with roxadustat combined with ESAs, and 16 patients were treated with roxadustat alone. In the first month, the mean hemoglobin level was significantly increased in the combined group (1.89 ± 1.45 g/dL) but decreased in the alone group (–0.25 ± 1.32 g/dL). According to an analysis of covariance (ANCOVA), after adjusting for basal hemoglobin levels, the combination therapy improved the hemoglobin level better than therapy alone (F = 6.329, P = .018). We defined the Hb response as: hemoglobin change from baseline ≥ 1 g/dL for patients with basal Hb &amp;gt;8.0 g/dL or ≥ 2.0 g/dL for patients with basal Hb ≤8.0 g/dL. Among the 15 patients treated with roxadustat combined with ESAs, 14 patients showed an increase in hemoglobin within the first month and 8 patients get the Hb response, with the Hb response rate of 53.3%. For the 16 patients treated with roxadustat alone, 7 patients showed an increase in hemoglobin, only 2 patients get the Hb response, with the Hb response rate 12.5%. Patients treated with roxadustat combined with ESAs had a higher Hb response rate (P = .023) than those with roxadustat alone within the first month. CONCLUSION Roxadustat combined with ESAs treatment might be more beneficial to improve renal anemia in MHD patients with ESA resistance during the first month of roxadustat therapy replacement.

Anemia: A Connection Between Heart Failure and Kidney Failure

Erythropoiesis-stimulating agents (ESAs) have improved the quality of life and reduced the need for transfusions in patients with chronic kidney disease. However, randomized trials showed no benefit but possible safety issues following high doses of ESAs given to reach normal hemoglobin levels. Iron therapy is used together with ESA; when given proactively, it may reduce the risk of mortality and cardiovascular events in hemodialysis patients. Recent trials also showed benefits of intravenous iron therapy in patients with heart failure. New drugs for correcting anemia may retain the present efficacy of ESAs as antianemic drugs and reduce cardiovascular risks.

Anemia in Chronic Kidney Disease : Role of Hypoxia Inducible Factor Stabilizer

Anemia contributes to increased morbidity and mortality in chronic kidney disease patients. The pathogenesis of anemia in these patients is multifactorial, but the contribution of erythropoietin deficiency becomes greater as glomerular filtration rate declines which related to decreased nephron mass. The current standard of care includes supplemental iron, erythropoiesis-stimulating agents (ESA), and red blood cell transfusions, although each has drawbacks. Lately, concern has arisen following randomized clinical trials showing that higher hemoglobin targets and/or high ESA doses may cause significant harm including increasing cardiovascular and thrombotic events, and even death. Recent experimental and clinical studies show the promising efficacy of hypoxia inducible factor (HIF) stabilizer which stimulates endogenous erythropoietin production and enhance iron availability.

Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin.

Anemia is a frequent comorbidity of chronic kidney disease (CKD) and is associated with a considerable burden because of decreased patient health-related quality of life and increased healthcare resource utilization. Based on observational data, anemia is associated with an increased risk of CKD progression, cardiovascular events, and all-cause mortality. The current standard of care includes oral or intravenous iron supplementation, erythropoiesis-stimulating agents, and red blood cell transfusion. However, each of these therapies has its own set of population-specific patient concerns, including increased risk of cardiovascular disease, thrombosis, and mortality. Patients receiving dialysis or those who have concurrent diabetes or high blood pressure may be at greater risk of developing these complications. In particular, treatment with high doses of erythropoiesis-stimulating agents has been associated with increased rates of hospitalization, cardiovascular events, and mortality. Resistance to erythropoiesis-stimulating agents remains a therapeutic challenge in a subset of patients. Hypoxia-inducible factor transcription factors, which regulate several genes involved in erythropoiesis and iron metabolism, can be stabilized by a new class of drugs that act as inhibitors of hypoxia-inducible factor prolyl-hydroxylase enzymes to promote erythropoiesis and elevate hemoglobin levels. Here, we review the burden of anemia of chronic kidney disease, the shortcomings of current standard of care, and the potential practical advantages of hypoxia-inducible factor prolyl-hydroxylase inhibitors in the treatment of patients with anemia of CKD.

Types of erythropoiesis-stimulating agents and risk of end-stage kidney disease and death in patients with non-dialysis chronic kidney disease.

Despite the widespread use of erythropoiesis-stimulating agents (ESAs) to treat anaemia, the risk of adverse outcomes associated with the use of different types of ESAs in non-dialysis chronic kidney disease (CKD) is poorly investigated. From a pooled cohort of four observational studies, we selected CKD patients receiving short-acting (epoetin α/β; n = 299) or long-acting ESAs (darbepoetin and methoxy polyethylene glycol-epoetin β; n = 403). The primary composite endpoint was end-stage kidney disease (ESKD; dialysis or transplantation) or all-cause death. Multivariable Cox models were used to estimate the relative risk of the primary endpoint between short- and long-acting ESA users. During follow-up [median 3.6 years (interquartile range 2.1-6.3)], the primary endpoint was registered in 401 patients [166 (72%) in the short-acting ESA group and 235 (58%) in the long-acting ESA group]. In the highest tertile of short-acting ESA dose, the adjusted risk of primary endpoint was 2-fold higher {hazard ratio [HR] 2.07 [95% confidence interval (CI) 1.37-3.12]} than in the lowest tertile, whereas it did not change across tertiles of dose for long-acting ESA patients. Furthermore, the comparison of ESA type in each tertile of ESA dose disclosed a significant difference only in the highest tertile, where the risk of the primary endpoint was significantly higher in patients receiving short-acting ESAs [HR 1.56 (95% CI 1.09-2.24); P = 0.016]. Results were confirmed when ESA dose was analysed as continuous variable with a significant difference in the primary endpoint between short- and long-acting ESAs for doses >105 IU/kg/week. Among non-dialysis CKD patients, the use of a short-acting ESA may be associated with an increased risk of ESKD or death versus long-acting ESAs when higher ESA doses are prescribed.

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.

Mixed hemodiafiltration reduces erythropoiesis stimulating agents requirement in dialysis patients: a prospective randomized study.

Improved responsiveness to erythropoiesis stimulating agents (ESAs) in patients on on-line post-dilution hemodiafiltration (Post-HDF) compared with conventional hemodialysis (HD) was reported by some authors but challenged by others. This prospective, cross-over randomized study tested the hypothesis that an alternative infusion modality of HDF, mixed-dilution HDF (Mixed HDF), could further reduce ESAs requirement in dialysis patients compared to the traditional Post-HDF. One-hundred-twenty prevalent patients from 6 Dialysis Centers were randomly assigned to two six-months treatment sequences: A-B and B-A (A, Mixed HDF; B, Post-HDF). Primary outcome was comparative evaluation of ESA (darbepoetin alfa) requirement and ESA resistance. Treatments efficiency, iron and vitamins status, inflammation and nutrition parameters were monitored. In sequence A, darbepoetin requirement decreased during Mixed HDF from 29.5 to 23.7µg/month and increased significantly during Post-HDF (32.3µg/month at 6th month) while, in sequence B, it increased during Post-HDF from 38.2 to 43.7µg/month and decreased during Mixed HDF (23.9µg/month at 6th month). Overall, EPO doses at 6months on Mixed and Post-HDF were 23.8 and 38.4µg/month, respectively, P < 0.01. A multiple linear model confirmed that Mixed HDF vs Post-HDF reduced significantly ESA requirement and ESA resistance (P < 0.0001), by a mean of 29% (CI 23-35%) in the last three months of the observation periods. Mixed HDF decreased darbepoetin-alfa requirement in dialysis patients. This might help preventing the untoward side effects of high ESA doses, besides having a remarkable economic impact. Additional evidence is needed to confirm this potential benefit of Mixed-HDF.

Low hemoglobin at hemodialysis initiation: an international study of anemia management and mortality in the early dialysis period.

BackgroundAnemia at hemodialysis (HD) initiation is common. Correcting low hemoglobin (Hgb) before HD initiation may improve survival by avoiding potential harms of chronic anemia, high doses of erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron in the early HD period, and/or rapid Hgb rise.MethodsWe included 4604 incident HD patients from 21 countries in the Dialysis Outcomes and Practice Patterns Study Phases 4–5 (2009–15). Because low Hgb at HD start may reflect comorbidity or ESA hyporesponse, we restricted our analysis to the 80% of patients who achieved Hgb ≥10 g/dL 91–120 days after HD start (Month 4).ResultsAbout 53% of these patients had Hgb <10 g/dL in Month 1 (<30 days after HD start); they were younger with a similar comorbidity profile (versus Hgb ≥10 g/dL). Month 1 Hgb was associated with first-year HD mortality (adjusted hazard ratio for 1 g/dL higher Hgb was 0.89; 95% confidence interval: 0.81–0.97), despite minimal differences in Month 4 Hgb. Patients with lower Hgb in Month 1 received higher doses of ESA, but not IV iron, over the first 3 months of HD. Results were consistent when excluding catheter users or adjusting for IV iron and ESA dose over the first 3 months.ConclusionsEven among patients with Hgb ≥10 g/dL 3 months later, anemia at HD initiation was common and associated with elevated mortality. A more proactive approach to anemia management in advanced chronic kidney disease (CKD) may thus improve survival on HD, though long-term prospective studies of non-dialysis CKD patients are needed.

Obesity may be erythropoietin dose-saving in hemodialysis patients

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

Importance of Physiological Erythropoiesis in the Treatment of Chronic Kidney Disease-Associated Anemia.

Recent large clinical trials have reported that despite the maintenance of target hemoglobin (Hb) levels, higher doses of erythropoiesis-stimulating agents (ESAs) and/or iron preparations are significantly associated with higher risks of adverse events and death in maintenance hemodialysis (MHD) patients. Higher doses of ESAs have been demonstrated to result in a higher risk for cardiovascular disease due to elevated blood pressure or increased thrombogenicity. In addition, a high dose of iron might enhance inflammatory responses to infection and impair the phagocytic function of neutrophils. Moreover, iron induces the generation of hydroxyl radicals, which accelerate atherosclerosis. Patients with hyporesponsiveness to ESAs or dysutilization of iron for erythropoiesis tend to be treated with ESAs or iron at doses exceeding the physiological level. However, the optimal doses of ESAs and iron for maintaining target Hb levels in these patients are not well established. Thus, from the perspective of long-term survival in chronic kidney disease patients, it is necessary to treat anemia with appropriate doses of ESAs and an iron that can induce physiological erythropoiesis.

Increased mortality in haemodialysis patients administered high doses of erythropoiesis-stimulating agents: a propensity score-matched analysis.

Increased mortality in haemodialysis patients administered high doses of erythropoiesis-stimulating agents: a propensity score-matched analysis.

Increased mortality in haemodialysis patients administered high doses of erythropoiesis-stimulating agents: a propensity score-matched analysis

Erythropoiesis-stimulating agents (ESAs) are widely used to treat anaemia in patients with chronic kidney disease. The issue of ESA safety has been raised in multiple studies, with correlates derived for elevated cancer incidence and mortality. Whether these associations are related to ESA dose or the typology of the patient remains obscure. A multicentre, observational retrospective propensity score-matched study was designed to analyse the effects of weekly ESA dose in 1679 incident haemodialysis (HD) patients. ESA administration was according to standard medical practice. Patients were grouped as quintiles, according to ESA dose, in order to compare mortality and hospitalization data. Using propensity score matching (PSM), we defined two groups of 324 patients receiving weekly threshold ESA doses of either > or ≤8000 IU. Kaplan-Meier survival curves indicated significant increases in the risk of mortality in patients administered with high doses of ESAs (>8127.4 IU/week). Multivariate Cox models identified a high ESA dose as an independent predictor for all-cause and cardiovascular (CV) mortality. Moreover, logistic regression models identified high ESA doses as an independent predictor for all-cause, CV and infectious hospitalization. PSM analyses confirmed that weekly ESA doses of >8000 IU constitute an independent predictor of all-cause mortality and hospitalization, even though the adjusted cohort displayed the same demographic features, inflammatory profile, clinical HD parameters and haemoglobin levels. Our data suggest that ESA doses of >8000 IU/week are associated with an increased risk of all-cause mortality and hospitalization in HD patients.

Methoxy Polyethylene Glycol-Epoetin Beta as a Novel Erythropoiesis Stimulating Agent with Possible Nephroprotective and Cardiovascular Protective Effects in Non-Dialysis Chronic Kidney Disease Patients.

Chronic kidney disease (CKD) is an important health problem, because of unsuccessful outcomes such as CKD progression to end stage renal disease and high risk of cardiovascular disease (CVD). Anemia, associated with CKD, is considered a non-traditional risk factor for CVD which may contribute to faster CKD progression. Anemia treatment with erythropoiesis-stimulating agents (ESAs) seems to exert non-hematopoietic effects on different tissues and organs, including cardiovascular system and kidneys. On the other hand, clinical use of high doses of short-acting ESAs and higher target hemoglobin level were associated with higher risk of CVD. Literature data indicate the usefulness of long-acting ESAs in treatment of anemia in non-dialysis CKD patients. In particular, continuous erythropoietin receptor activator seems to be a good choice in these patients because of its efficiency, safety and monthly administration. Continuous but slower erythropoietin receptor activation, using methoxy polyethylene glycol-epoetin beta (MPG-EPO), administered once a month, slowly corrects anemia without exceeding the recommended hemoglobin level. An overview of the available literature may suggest nephroprotective and cardiovascular protective effects of MPG-EPO. It seems possible that anemia treatment with a novel ESAs, MPG-EPO in early stages of CKD may reduce CVD risk in these patients and delay CKD progression. This review of available literature evaluates the correlation between continuous erythropoietin receptor activation using MPG-EPO and CKD progression and CVD risk in non-dialysis CKD patients.

Predicting clinical outcomes using phase angle as assessed by bioelectrical impedance analysis in maintenance hemodialysis patients

Protein-energy wasting is common in patients on hemodialysis and is an independent risk factor for adverse events. The aim of this study was to retrospectively investigate whether phase angle (PA), known as a nutritional marker, can predict various clinical outcomes in patients with end-stage renal disease (ESRD) who are receiving hemodialysis. Using bioelectrical impedance analysis (BIA), PA was obtained every 6mo, and patients were divided into two groups according to baseline PA: group A included patients with PA ≥4.5°, and group B included patients with PA <4.5°. We followed 142 patients for a median of 29mo (12-42mo). We found that a decrease in PA was associated with an increased risk for death that persisted after adjusting for age, sex, and comorbidities (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.33-0.97). Cardiovascular events were not associated with PA (P=0.685). We found that PA predicted the occurrence of infection, independent of age, sex, and comorbidities (HR, 0.65; 95% CI, 0.45-0.94). Although levels of hemoglobin did not differ between groups during the study period, patients in group B received higher doses of erythropoiesis-stimulating agents and intravenous iron than those in group A (P=0.004 and 0.044, respectively). In longitudinal analyses, we did not find increases in PA over time in patients who had a mean dialysis adequacy ≥1.4, daily protein catabolic rate ≥1.2g/kg, or total carbon dioxide level ≥22mmol/L. PA assessed in a simple manner using BIA provides practical information to predict clinical outcomes in ESRD patients on maintenance hemodialysis.

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.

New Strategies for Anaemia Management in Chronic Kidney Disease.

Erythropoiesis-stimulating agents (ESAs) and iron therapy are the standard of care for normocytic normochromic anaemia, which is a frequent comorbidity of patients with chronic kidney disease. In a large percentage of patients, ESAs and iron increase haemoglobin levels, thus reducing the risk of blood transfusions and improving patient quality of life. However, randomised trials have raised some concerns about higher haemoglobin targets and/or high ESA dose use. These concerns include higher cardiovascular and thrombosis risk, cancer progression, and increased mortality. A more cautious approach was then advised and partial anaemia correction (haemoglobin 10-12 g/dl) is now strongly suggested. The clinical concerns about ESAs and economic constraints have led to larger intravenous iron use. However, severe anaphylactic reactions, although infrequent, can occur and excessive iron use may be dangerous as well, possibly causing iron overload. Several attempts are being made to develop new drugs with theoretically better activity and safety, and/or easier manufacturing processes as compared to available ESAs. These include drugs manipulating the hypoxia-inducible transcription factor (HIF) system, which stimulates the endogenous erythropoietin (EPO) production and avoids unphysiological EPO plasma levels. Several phase I and II studies support the beneficial role of augmenting HIFs to stimulate erythropoiesis. Here we give an update on this new investigational strategy.

Real-life use of erythropoiesis-stimulating agents in myelodysplastic syndromes: a “Gruppo Romano Mielodisplasie (GROM)” multicenter study

The Gruppo Romano Mielodisplasie (GROM) conducted a retrospective study in 543 patients with myelodysplastic syndromes (MDS) to evaluate the safety and efficacy of erythropoiesis-stimulating agents (ESAs) in "real-life" clinical practice. The 40.000-UI/week erythropoietin (EPO)-alpha and 30.000-UI/week EPO-beta starting dose were defined "standard," and 80,000UI/week EPO-alpha and 60.000UI/week EPO-beta were defined "high." Response was defined according to International Working Group (IWG) 2006 criteria. At ESA's start, median age was 74.2years (interquartile range (IR) 67.8-79.5) and median hemoglobin was 8.9g/dl (IR 8.2-9.6). Median time from diagnosis to ESAs start was 3.8months (IR 0.8-13.2). ESA starting dose was "standard" in 361 patients (66.5%) and "high" in 182 patients (33.5%). Erythroid response was observed in 82/185 (44.3%) transfusion dependent (TD) patients as compared with 226/329 (68.6%) transfusion independent (TI) ones (p < 0.001). At multivariate analysis, in TD patients, only endogenous EPO levels <50mU/l were significant (p = 0.046), whereas in TI patients, high-dose ESAs (p < 0.001), abnormal creatinine levels (0.009), and endogenous EPO levels <50mU/l (p = 0.014) were predictors of response. Responders showed a higher 5-year overall survival (OS) (57.8 vs. 32.2%, p < 0.001) and leukemia-free survival (76.0 vs. 49.8%, p < 0.001). At multivariable analysis for OS, response to ESA, low International Prognostic Scoring System (IPSS), no transfusion need, and female sex showed an independent favorable prognostic role. Our results confirm that treatment with ESAs is effective in a real-life MDS setting, particularly at high dose and in TI patients. Prospective studies are needed to define the optimal starting dose.

Regulation of platelet count by erythropoiesis-stimulating agents - iron axis in hemodialysis patients.

Higher doses of erythropoiesis-stimulating agents (ESAs) contribute to atherothrombotic cardiovascular disease in hemodialysis (HD) patients. Thrombocytosis is associated with increased mortality in ESA-treated HD patients. We investigated variables affecting platelet count and its variability (platelet count increment [Δplatelet count]) in HD patients. This retrospective longitudinal and observational study of HD outpatients was carried out over 3 years. The outcome was independent determinants of platelet count and Δplatelet count, which were associated with iron indices, ESA dose, and C-reactive protein. In univariate regression analysis, V-shaped relationship was observed between platelet count and transferrin saturation (TSAT), ferritin, serum iron, and hemoglobin (Hb) with the bottom of 0.21, 330 ng/mL, 49 µg/dL, and 10.3 g/dL, respectively. Mixed-effect multivariate regression analysis revealed that TSAT (inversely), Hb ≤10.3 g/dL (inversely), C-reactive protein, and ESA dose were independently associated with platelet count. Δplatelet count was independently and inversely correlated with ΔTSAT and directly correlated with Δferritin. TSAT was independently and inversely associated with ESA dose. ESA dose was directly correlated with iron dose and inversely correlated with TSAT, ferritin ≤330 ng/mL, and Hb ≤10.3 g/dL. ESA dose and TSAT were correlated in determining platelet count and Δplatelet count. Targets of iron indices that reflect iron supply sufficient to avoid platelet count increment and variability may be >21% of TSAT and 300 ng/mL of serum ferritin for appropriate ESA therapy in HD patients.