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.

BACKGROUND: Vadadustat 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. METHODS: Of 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. RESULTS: Independent 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. CONCLUSIONS: In 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 REGISTRATION: NCT03329196 (MT-6548-J01) and NCT03439137 (MT-6548-J03).

Theranova versus FX80: The impact on anemia management in hemodialysis.

BACKGROUND: Middle uremic toxins (MUTs) can cause anemia and erythropoietin hyporesponsiveness. Theranova dialyzers may improve anemia management by removing MUTs. Hence, the impact of Theranova dialyzers on erythropoietin responsiveness was studied. METHODS: This exploratory single-center prospective observational study, encompassing 50 patients undergoing dialysis with either the Theranova-400 or FX80 membrane for 6 months, involved monthly tracking of hemoglobin levels, weight-adjusted erythropoiesis-stimulating agent (w-ESA) dosing, and erythropoietin resistance index (ERI), with ESA treatment decisions guided by a proprietary algorithm. RESULTS: The groups were similar in terms of demographics and baseline laboratory test results. The median hemoglobin levels, w-ESA and ERI, were found to be similar between FX80 and Theranova-400 groups at both baseline (11.06 vs 10.57, p = 0.808; 92.3 vs 105.2, p = 0.838; 8.1 vs 10.48, p = 0.876) and the end of the study (11.43 vs 11.03, p = 0.076; 48.7 vs 71.5; 4.48 vs 6.41, p = 0.310), respectively. There was a trend toward lower w-ESA and ERI at the end of the study compared to baseline in both groups, but the difference was non-significant. CONCLUSIONS: Based on this study of 50 patients undergoing high-flux dialysis with near-target hemoglobin levels, switching to Theranova 400 dialyzers compared to FX80 dialyzers did not show statistically significant differences in maintaining hemoglobin levels, reducing ESA dose, or lowering ERI. The non-randomized design and small sample size limit the study's power to detect true differences. Larger, randomized trials are needed to confirm findings and definitively assess Theranova 400's benefits.

Impact of anemia requiring transfusion or erythropoiesis-stimulating agents on new-onset cardiovascular events and mortality after continuous renal replacement therapy.

Anemia is common in critically ill patients undergoing continuous renal replacement therapy (CRRT). We investigated the impact of anemia requiring red blood cell (RBC) transfusion or erythropoiesis-stimulating agents (ESAs) on patient outcomes after hospital discharge in critically ill patients with acute kidney injury (AKI) requiring CRRT. In this retrospective cohort study using the Health Insurance Review and Assessment database of South Korea, 10,923 adult patients who received CRRT for 3 days or more between 2010 and 2019 and discharged alive were included. Anemia was defined as the need for RBC transfusion or ESAs. Outcomes included cardiovascular events (CVEs) and all-cause mortality after discharge. The anemia group showed a tendency to be older with more females and had more comorbidities compared to the control group. Anemia was not associated with an increased risk of CVEs (adjusted hazard ratio [aHR]: 1.05; 95% confidence interval [CI]: 0.85-1.29), but was associated with an increased risk of all-cause mortality (aHR: 1.41; 95% CI 1.30-1.53). For critically ill patients with AKI requiring CRRT, anemia, defined as requirement for RBC transfusion or ESAs, may increase the long-term risk of all-cause mortality.

The Use of Anemia Control Model Is Associated with Improved Hemoglobin Target Achievement, Lower Rates of Inappropriate Erythropoietin Stimulating Agents, and Severe Anemia among Dialysis Patients.

INTRODUCTION: The Anemia Control Model (ACM) is a certified medical device suggesting the optimal ESA and iron dosage for patients on hemodialysis. We sought to assess the effectiveness and safety of ACM in a large cohort of hemodialysis patients. METHODS: This is a retrospective study of dialysis patients treated in NephroCare centers between June 1, 2013 and December 31, 2019. We compared patients treated according to ACM suggestions and patients treated in clinics where ACM was not activated. We stratified patients belonging to the reference group by historical target achievement rates in their referral centers (tier 1: <70%; tier 2: 70-80%; tier 3: >80%). Groups were matched by propensity score. RESULTS: After matching, we obtained four groups with 85,512 patient-months each. ACM had 18% higher target achievement rate, 63% smaller inappropriate ESA administration rate, and 59% smaller severe anemia risk compared to Tier 1 centers (all p < 0.01). The corresponding risk ratios for ACM compared to Tier 2 centers were 1.08 (95% CI: 1.08-1.09), 0.49 (95% CI: 0.47-0.51), and 0.64 (95% CI: 0.61-0.68); for ACM compared to Tier 3 centers, 1.01 (95% CI: 1.01-1.02), 0.66 (95% CI: 0.63-0.69), and 0.94 (95% CI: 0.88-1.00), respectively. ACM was associated with statistically significant reductions in ESA dose administration. CONCLUSION: ACM was associated with increased hemoglobin target achievement rate, decreased inappropriate ESA usage and a decreased incidence of severe anemia among patients treated according to ACM suggestion.

Impact of C-reactive protein on the effect of Roxadustat for the treatment of anemia in chronic kidney disease: a systematic review of randomized controlled trials.

BACKGROUND: Chronic inflammation, reflected by an increased blood C-reactive protein (CRP) level, is common in patients with chronic kidney disease (CKD) and is involved in the development of renal anemia. This systematic review aims to investigate the impacts of CRP on the efficacy of hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) in the treatment of renal anemia in patients with CKD. METHODS: We conducted a comprehensive search of electronic databases including Pubmed, Web of Science, Embase, Cochrane Library, CNKI, Wanfang, and the International Clinical Trials Registry Platform (ICTRP), from their inception to May 19, 2022. We systematically reviewed evidence from randomized controlled trials using HIF-PHIs for renal anemia treatment. The mean difference (MD) in changes in hemoglobin concentration (∆Hb) before and after treatment served as the meta-analysis outcome, utilizing a random-effects model. We compared groups with CRP levels greater than or equal to the upper limit of normal (ULN) and less than the ULN. Additionally, further analysis was conducted in the CRP ≥ ULN group comparing HIF-PHIs and erythropoiesis-stimulating agents (ESA). RESULTS: A total of 7 studies from 6 publications were included in the analysis. In the comparison between the CRP ≥ ULN group and the CRP < ULN group, 524 patients from 4 studies were incorporated into the analysis. All patients received roxadustat as the primary intervention. The pooled results revealed no significant difference in ΔHb between patients with CRP ≥ ULN and CRP < ULN at baseline (Mean Difference: 0.00, 95% Confidence Interval: -0.32 to 0.33, P = 0.99). Moreover, within the CRP ≥ ULN group, three studies involving 1399 patients compared the efficacy of roxadustat and erythropoiesis-stimulating agents (ESAs). The results indicated no significant difference in ΔHb between patients treated with ESAs and HIF-PHIs (Mean Difference: 0.24, 95% Confidence Interval: -0.08 to 0.56, P = 0.14). In terms of medication dosage, an increase in ESA dose over time was observed across various studies, particularly evident in the CRP ≥ ULN group, while the dose of roxadustat remains constant over time and is not influenced by the baseline levels of CRP. CONCLUSIONS: Our systematic review demonstrates that roxadustat exhibits similar efficacy across different CRP levels. Moreover, within the CRP ≥ ULN group, roxadustat can maintain efficacy comparable to ESA without the necessity for dose escalation. TRIAL REGISTRATION: CRD42023396704.

Zinc Supplementation Enhances the Hematopoietic Activity of Erythropoiesis-Stimulating Agents but Not Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors.

Since zinc is involved in many aspects of the hematopoietic process, zinc supplementation can reduce erythropoiesis-stimulating agents (ESAs) in patients undergoing hemodialysis. However, it remains unclear whether hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have similar reduction effects. HIF-PHI stabilizes HIF, which promotes hematopoiesis, although HIF-1α levels are downregulated by zinc. This study aimed to investigate the effect of zinc supplementation on the hematopoietic effect of HIF-PHI in patients undergoing hemodialysis. Thirty patients undergoing maintenance hemodialysis who underwent periods of treatment with roxadustat or darbepoetin alfa during the past 3 years were retrospectively observed. Participants who underwent periods with and without zinc supplementation were selected, with nine treated with darbepoetin alfa and nine treated with roxadustat. Similarly to the ESA responsiveness index (ERI), the hematopoietic effect of zinc supplementation was determined by the HIF-PHI responsiveness index (HRI), which was calculated by dividing the HIF-PHI dose (mg/week) by the patient's dry weight (kg) and hemoglobin level (g/L). Zinc supplementation significantly increased ERI (p < 0.05), but no significant change was observed (p = 0.931) in HRI. Although zinc supplementation did not significantly affect HRI, adequate zinc supplementation is required to alleviate concerns such as vascular calcification and increased serum copper during the use of HIF-PHI.

Anemia diagnosis and therapy in malignant diseases: implementation of guidelines-a representative study.

PURPOSE: Anemia in cancer should be diagnosed and treated according to guideline recommendations. The implementation of ESMO and German guidelines and their effect on anemia correction was analyzed. METHODS: This retrospective epidemiological study, representative for Germany, analyzed data on anemia management of cancer patients with anemia ≥ grade 2. The Guideline Adherence Score (GLAD) for diagnosis (GLAD-D) and therapy (GLAD-T) was defined as follows: 2 points for complete, 1 point for partial, 0 point for no adherence. RESULTS: Data were analyzed for 1046 patients. Hb levels at diagnosis of anemia were 8-10 g/dL in 899 (85.9%) patients, 7-8 g/dL in 92 (8.7%), and < 7 g/dL (5.0%) in 52. Transferrin saturation was determined in 19% of patients. Four hundred fifty-six patients received RBC (43.6%), 198 (18.9%) iron replacement, 106 (10.1%) ESA, and 60 (5.7%) vitamin B12 replacement. 60.6% of patients receiving iron replacement were treated intravenously and 39.4% were treated orally. Two hundred eighty-eight (36.6%) of 785 patients receiving transfusions had no guideline-directed indication. GLAD-D was 2 in 310 patients (29.6%), 1 in 168 (16.1%), and 0 in 568 (54.3%). GLAD-T was 2 in 270 patients (25.8%), 1 in 320 patients (30.6%), and 0 in 456 patients (43.6%). Higher GLAD-D significantly correlated with higher GLAD-T (τB = 0.176, p < 0.001). GLAD-T 2 was significantly associated with greater Hb increase than GLAD-T 0/1 (p < 0.001) at 28 days (10.2 vs. 9.7 g/dL) and at 2 months (10.4 vs. 9.9 g/dL). CONCLUSIONS: Anemia assessment is inadequate, transfusion rates too high, and iron and ESA therapy too infrequent. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05190263, date: 2022-01-13.

Management of Preoperative Anemia.

Anemia is the most common modifiable risk factor for postoperative morbidity and mortality. Early identification and optimal management are key to restore iron stores and ensure its resolution before surgery. Several therapies have been proposed to treat anemia in the perioperative period, such as iron supplementation and erythropoiesis-stimulating agents, though it remains unclear which is the most optimal to improve clinical outcomes. This article summarizes the most updated evidence on perioperative management of anemia and denotes differences among the international guidelines to reflect the conflicting evidence in this field and the need for further research in specific areas.

The influencing factors of the erythropoietin resistance index and its association with all-cause mortality in maintenance hemodialysis patients.

Anemia is a common complication of chronic kidney disease with major option treatment of erythropoiesis-stimulating agents (ESAs). This study aimed to investigate the influencing factors of erythropoietin resistance index (ERI) and its association with mortality in maintenance hemodialysis (MHD) patients. Patients enrolled from China Dialysis Outcomes and Practice Patterns Study (DOPPS) 5 were included. ERI was calculated as follows: ESA (IU/week)/weight (kg, post-dialysis)/hemoglobin level (g/dL). The Cox regression model was used to analyze the influencing factors on survival outcomes. Stepwise multivariate logistic regression was used to identify the related risk factors, and subgroup analyses were performed. A total of 1270 MHD subjects (687 males and 583 females) were included, with an average age of 60 (49.0, 71.0) years. All subjects were divided into two groups by the median ERI of 14.03. Multivariate logistic regression showed that dialysis vintage (OR 0.957, 95% CI: 0.929-0.986), white blood cells (OR 0.900, 95% CI: 0.844-0.960), high flux dialyzer use (OR 0.866, 95% CI: 0.755-0.993), body mass index (OR 0.860, 95% CI: 0.828-0.892), males (OR 0.708, 95% CI: 0.625-0.801), and albumin (OR 0.512, 95% CI: 0.389-0.673) had a negative association with high ERI baseline (all p < 0.05). There were 176 (13.9%) deaths in total including 89 cardiac/vascular deaths during follow-up. Cox regression analysis showed that ERI was positively associated with all-cause mortality, especially in some subgroups. ERI was associated with increased all-cause mortality in MHD patients, indicating the possibility of death prediction by ERI. Patients with high ERI warrant more attention.

The Influence of Precursor Depletion and dose Regimens on Resistance to Erythropoiesis-Stimulating Agents: Insights from Simulations with Instantaneous Dose-Adaptation Algorithm.

Erythropoiesis-stimulating agents (ESAs) have been a common treatment for anemia associated with chronic kidney disease (CKD), while 10-20 % of patients continue to suffer from persistent anemia despite receiving ESA treatments. Our previous findings suggested that intensive ESA usage can cause resistance by depleting the erythroid precursor cells. Here, we used a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model of ESAs and conducted simulations to evaluate the influence of dose regimens and other factors (such as administration route, individual PK/PD parameters, types of ESAs, and disease status) on ESA resistance with instantaneous dose adaptations in healthy populations and anemic patients. The simulated results show that instantaneous dose-adaptation can reduce ESA resistance, but up to 30 % of subjects still ended up developing ESA resistance in healthy populations. The Smax is markedly higher in hypo-responders than in normal-responders, while hypo-responders possess fewer precursors and experience a faster decline compared to normal-responders. There is a ceiling effect of increasing ESA dosage to improve HGB responses and reduce ESA resistance, and the limit is lower in anemic patients compared to healthy populations. Subcutaneous administrations and ESAs with longer half-lives lead to stronger HGB responses and less resistance at equivalent doses. Taken together, this study indicates that precursor depletion contributes to ESA resistance and dose regimens can greatly influence the occurrence of ESA resistance. Furthermore, ESA treatment for patients showing ESA resistance should avoid continuously increasing doses and instead consider stimulating the renewal of precursors.

Evaluation of bone marrow findings in hemodialysis patients with erythropoietin-resistant anemia.

INTRODUCTION: Treatment with erythropoietin-stimulating agents (ESAs) is widely used in anemia of chronic kidney disease (CKD). Acquired ESA resistance is an important problem. The aim of this study is to examine the bone marrow findings in hemodialysis patients with ESA-resistant anemia. METHODS: The data of 210 patients with acquired ESA resistance were reviewed retrospectively. The patients were divided into groups according to having diagnosis of dysplasia and hematological disease, and survival analysis was performed. RESULTS: A total of 26 patients were included in the study. While dysplasia was present in 10 (38.5%) patients, five of them were diagnosed hematologically. When survival analysis was performed between those with and without a hematological diagnosis, a difference in survival was observed against the group with the diagnosis (24.4 vs. 72 months, p = 0.045). CONCLUSION: Unresponsiveness to ESA treatment in CKD patients or a decrease in one of the other cell lines along with hemoglobin, it would be appropriate to perform early bone marrow examination.

A phase 3b, multicenter, open-label, single-arm study of roxadustat within a US dialysis organization: The DENALI study.

INTRODUCTION: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in several regions for the treatment of anemia of chronic kidney disease (CKD). DENALI, a phase 3b study, evaluated the efficacy, safety, and feasibility of roxadustat in patients with anemia of CKD receiving in-center or home dialysis. METHODS: Eligible patients received open-label roxadustat, dosed three times weekly for 24 weeks, with an optional extension of ≤1 year. Initial dosing depended on erythropoiesis-stimulating agent (ESA) dose at screening for patients receiving ESAs (≥6 weeks) and weight-based for those not (total <6 weeks). Primary efficacy endpoints were proportion of patients with mean hemoglobin (Hb) ≥10.0 g/dL averaged over Weeks 16-24, and mean Hb change from baseline to the average during Weeks 16-24. Treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) were assessed. FINDINGS: Of 281 patients screened, 203 were treated and 201 included in the full analysis set. Overall, 166 patients completed the 24-week treatment period and 126 continued into the extension period. Mean baseline Hb was 10.4 g/dL and 82.6% received in-center hemodialysis. Overall, 84.6% of patients achieved a mean Hb ≥ 10.0 g/dL averaged Weeks 16-24. Mean (standard deviation) Hb change from baseline averaged Weeks 16-24 was 0.5 (1.0) g/dL. Prespecified subgroup analyses were consistent with primary analyses. Dosing adherence was 94%. Overall, 3.0% of patients received a red blood cell transfusion at up to Week 24. TEAEs and TESAEs were reported by 71.4% and 25.6% of patients, respectively. The most frequently reported TESAEs were COVID-19 (n = 5; 2.5%), and acute myocardial infarction, pneumonia, and sepsis (each n = 4; 2.0%). DISCUSSION: Roxadustat effectively achieved and/or maintained mean Hb levels ≥10.0 g/dL in patients receiving dialysis. The feasibility of incorporating oral roxadustat into dialysis organizations was successfully demonstrated with high dosing adherence. No new safety signals were identified.

Continuous Erythropoietin Receptor Activator for the Treatment of Chronic Dialysis Patients with Renal Anemia in Daily Clinical Practice in Poland: A Non-Interventional, Multi-Center, Pragmatic NAVIGO Trial.

BACKGROUND: Renal anemia is one of the most common complications of chronic kidney disease (CKD). This real-life study assessed the effectiveness of methoxy polyethylene glycol-epoetin beta, a continuous erythropoietin receptor activator (C.E.R.A.), for the treatment of CKD-associated anemia in patients receiving dialysis in daily clinical practice. METHODS: 247 patients receiving chronic intermitted dialysis in 26 centers in Poland with CKD-associated symptomatic anemia, ESA-naïve, and with balanced iron stores in the investigators' opinion were enrolled this real-life study. Over 12 months, the following data were collected: hemoglobin (Hb) concentration and dosage, route of administration and dosing scheme of C.E.R.A., dialysis adequacy, adverse events, iron therapy, and blood transfusions. RESULTS: During the treatment, a Hb concentration of ≥10 g/dL was noted in 90.9% of hemodialysis patients (n = 224) and 96.0% of peritoneal dialysis patients (n = 23). At baseline, 7.8% of patients had a Hb concentration of 10-12 g/dL, which increased to 63.3% after 12 months. The median time when Hb concentration was maintained within 10-12 g/dL was 115.2 (interquartile range 49.1-188.7) days. A Hb concentration ≥12 g/dL was observed after 7 months of treatment in a maximum of 24.1% of hemodialysis patients, and 31.8% of peritoneal dialysis patients. The median time elapsed between the start of treatment and the first Hb concentration >10 g/dL was 42.0 (21.0-78.2) days. C.E.R.A. was well tolerated. CONCLUSIONS: C.E.R.A. corrects CKD-associated anemia in dialysis patients, and maintains Hb levels within the recommended target range. The study also confirmed the acceptable safety profile of the drug.

The fatigue after infusion or transfusion pilot trial and feasibility study: A three-armed randomized pilot trial of intravenous iron and blood transfusion for the treatment of postpartum anemia.

BACKGROUND: Evidence for the management of moderate-to-severe postpartum anemia is limited. A randomized trial is needed; recruitment may be challenging. STUDY DESIGN AND METHODS: Randomized pilot trial with feasibility surveys. INCLUSION: hemoglobin 65-79 g/L, ≤7 days of birth, hemodynamically stable. EXCLUSION: ongoing heavy bleeding; already received, or contraindication to intravenous (IV)-iron or red blood cell transfusion (RBC-T). Intervention/control: IV-iron; RBC-T; or IV-iron and RBC-T. PRIMARY OUTCOME: number of recruits; proportion of those approached; proportion considered potentially eligible. SECONDARY OUTCOMES: fatigue, depression, baby-feeding, and hemoglobin at 1, 6 and 12 weeks; ferritin at 6 and 12 weeks. Surveys explored attitudes to trial participation. RESULTS: Over 16 weeks and three sites, 26/34 (76%) women approached consented to trial participation, including eight (31%) Maori women. Of those potentially eligible, 26/167 (15.6%) consented to participate. Key participation enablers were altruism and study relevance. For clinicians and stakeholders the availability of research assistance was the key barrier/enabler. Between-group rates of fatigue and depression were similar. Although underpowered to address secondary outcomes, IV-iron and RBC-T compared with RBC-T were associated with higher hemoglobin concentrations at 6 (mean difference [MD] 11.7 g/L, 95% confidence interval [CI] 2.7-20.7) and 12 (MD 12.8 g/L, 95% CI 1.5-24.2) weeks, and higher ferritin concentrations at 6 weeks (MD 136.8 mcg/L, 95% CI 76.6-196.9). DISCUSSION: Willingness to participate supports feasibility for a future trial assessing the effectiveness of IV-iron and RBC-T for postpartum anemia. Dedicated research assistance will be critical to the success of an appropriately powered trial including women-centered outcomes.

Fatigue visual analogue scale score correlates with quality of life in cancer patients receiving epoetin alfa (Sandoz) for chemotherapy-induced anaemia: The CIROCO study.

PURPOSE: Available tools to measure fatigue and health-related quality of life (HRQoL) in cancer patients are often difficult to use in clinical practice. The fatigue visual analogue scale (VAS) provides a simple method to assess fatigue. This study evaluated the correlation between HRQoL and fatigue perceived by cancer patients undergoing chemotherapy. METHODS: This was a non-interventional prospective study of adult cancer patients in France presenting with chemotherapy-induced anaemia (CIA) treated with epoetin alfa (Sandoz). Data were collected using an electronic case report form at study inclusion (T0), after 2-3 chemotherapy cycles (T1) and after 4-6 cycles (T2). RESULTS: The study included 982 patients from September 2015 to October 2017. Overall, there was a negative correlation between fatigue VAS and HRQoL. The overall haemoglobin (Hb) change between T0 and T2 was +17.8 % (± 18.1 %). Fatigue assessed by both patients and physicians showed a clinically significant improvement during the study. Global HRQoL also increased. CONCLUSION: Treatment of CIA with epoetin alfa (Sandoz) improved Hb levels, fatigue, and HRQoL, with a correlation observed between fatigue VAS score and HRQoL. Fatigue VAS could act as a simple alternative to more complex methods to measure HRQoL; however, further analyses are required to confirm this association.

Next-generation therapy for lower-risk MDS.

Myelodysplastic syndromes (MDS) are malignant myeloid neoplasms characterized by ineffective clonal hematopoiesis leading to peripheral blood cytopenia and a variable risk of transformation to acute myeloid leukemia. In lower-risk (LR) MDS, as defined by prognostic scoring systems recently updated with the addition of a mutation profile, therapeutic options aim to reduce cytopenia, mainly anemia. Although options for reducing the transfusion burden have recently been improved, erythropoiesis-stimulating agents (ESAs), lenalidomide, hypomethylating agents, and, more recently, luspatercept have shown efficacy in rarely more than 50% of patients with a duration of response often far inferior to the patient's life expectancy. Nevertheless, several new therapies are currently under investigation aiming at improving cytopenia in patients with LR-MDS, mostly by targeting different biological pathways. Targeting ligands of the transforming growth factor ß pathway has led to the approval of luspatercept in LR-MDS with ring sideroblasts or SF3B1 mutation, potentially replacing first-line ESAs in this population. Here, we also discuss the evolving standard of care for the treatment of LR-MDS and explore some of the most promising next-generation agents under investigation.

Epidemiology and treatment of renal anaemia in Spain: RIKAS retrospective study.

BACKGROUND AND OBJECTIVE: Studies on the prevalence of anaemia in chronic kidney disease in adults not on dialysis (CKD-ND) and in dialysis programmes (CKD-D) in Spain are not recent or focus on certain subgroups. The aim of this study was to know the epidemiology and current treatment patterns of anaemia associated with CKD in Spain. MATERIALS AND METHODS: Multicentre, non-interventional, retrospective study with CKD-ND stage 3a-5 and CKD-D patients treated in Spain between 2015 and 2017 (RIKAS study). RESULTS: The prevalence of anaemia in CKD-ND and CKD-D in 2015 was 33.8% and 91.5%, respectively, with similar results during 2016-2017. The prevalence of systemic inflammation in anaemic patients (18.1% and 51.8% for CKD-ND and CKD-D, respectively) was higher, especially in those treated with erythropoiesis-stimulating agents (ESA), compared to the general population with CKD-ND. After 12 months of follow-up, mean ferritin and transferrin saturation index (TSI) values in anaemic patients with CKD-ND were 187.1 ng/mL and 22.2%, respectively, while in CKD-D were 254.6 ng/mL and 20.2%. In ESA-treated patients, mean values were 190.6 ng/mL and 22.0% in ND-CKD, and 255.0 ng/mL and 20.2% in D-CKD. CONCLUSIONS: The prevalence of anaemia and inflammation increased with the disease severity, being higher in D-CKD. Iron parameters in anaemic patients treated or not with ESA are insufficient according to the guidelines, so there is room for improvement in the treatment of anaemia associated with CKD.

Investigating the relationship between erythropoiesis-stimulating agents and mortality in hemodialysis patients: A systematic review and meta-analysis.

BACKGROUND: In recent years, various studies have been conducted to investigate the relationship between erythropoiesis-stimulating agents (ESAs) and mortality in hemodialysis patients, who showed contradictory results. Therefore, this study aimed to investigate the relationship between ESAs and mortality in hemodialysis patients. METHODS: The current study is a systematic review and meta-analysis based on observational and interventional studies published in the Web of Science, Cochrane Library, Science Direct, PubMed, Scopus, and Google Scholar databases between 1980 and the end of 2022. Jadad scale checklist and Newcastle Ottawa scale were used to evaluate the quality of articles. The study data were analyzed using Stata 15 software. RESULTS: In the initial search, 3933 articles were extracted, and by screening and considering the research criteria, 68 studies were finally included in the meta-analysis. According to the meta-analysis results, the risk ratio (RR) of overall mortality in hemodialysis patients receiving ESAs was equal to 1.19 (95% CI: 1.16-1.23, P ≤ 0.001). The RR of mortality in patients aged 60 years and under was equal to 1.33 (1.15-1.55, P ≤ 0.001), in the age group over 60 years was equal to 1.13 (1.10-1.16, P ≤ 0.001), in randomized clinical trial studies was equal to 1.06 (0.80-1.40, P = 0.701), in cohort studies was equal to 1.20 (1.16-1.25, P ≤ 0.001), in American countries was equal to 1.19 (1.10-1.29, P ≤ 0.001), in Asian countries was equal to 1.15 (1.10-1.19, P ≤ 0.001), and in European countries was equal to 1.18 (1.05-1.34, P = 0.007). CONCLUSION: The results of the study show that receiving ESAs is associated with a 19% increase in the risk of overall mortality in hemodialysis patients.

[New Therapeutic Strategies in the Treatment of CKD Anemia: Hypoxia-Induced Factor Prolyl-Hydroxylase Inhibitors].

The link between chronic renal failure and anemia has been known for more than 180 years, negatively impacting the quality of life, cardiovascular risk, mortality, and morbidity of patients with chronic kidney disease (CKD). Traditionally, the management of anemia in CKD has been based on the use of replacement martial therapy, vitamin therapy, and the use of erythropoiesis-stimulating agents (ESAs). In recent years, alongside these consolidated therapies, new molecules known as hypoxia-induced factor prolyl-hydroxylase inhibitors (HIF-PHIs) have appeared. The mechanism of action is expressed through an increased transcriptional activity of the HIF gene with increased erythropoietin production. The drugs currently produced are roxadustat, daprodustat, vadadustat, molidustat, desidustat, and enarodustat; among these only roxadustat is currently approved and usable in Italy. The possibility of oral intake, pleiotropic activity on martial and lipidic metabolism, and the non-inferiority compared to erythropoietins make these drugs a valid alternative to the treatment of anemia associated with chronic kidney disease in the nephrologist practice.