Anemia Of Chronic Kidney Disease Research Articles

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in Kidney Disease

BackgroundHypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors are an oral treatment for anemia of chronic kidney disease (CKD). In this systematic review and meta-analysis, we assessed long-term safety of HIF prolyl hydroxylase inhibitors.MethodsWe searched MEDLINE, Embase, and Cochrane databases for randomized trials comparing HIF prolyl hydroxylase inhibitors with an erythropoiesis-stimulating agent (ESA) or placebo with greater than or equal to 48 weeks of follow-up. The primary outcome was major adverse cardiovascular event (MACE), defined as a composite of all-cause death, myocardial infarction, or stroke. Treatment effects were pooled using random-effects models.ResultsTwenty-five trials involving 26,478 participants were included. Of these, 13 trials enrolled 13,230 participants with dialysis-dependent CKD, and 12 trials enrolled 13,248 participants with nondialysis-dependent CKD. There was no evidence that HIF prolyl hydroxylase inhibitors and ESA had different effects on MACE in people with dialysis-dependent CKD (risk ratio, 0.99; 95% confidence interval [CI], 0.92 to 1.08) or people with nondialysis-dependent CKD (risk ratio, 1.08; 95% CI, 0.95 to 1.22). Similarly, there was no evidence that HIF prolyl hydroxylase inhibitors and placebo had different effects on MACE (risk ratio, 1.10; 95% CI, 0.96 to 1.27) in people with nondialysis-dependent CKD. The lack of difference between HIF prolyl hydroxylase inhibitors and ESA or placebo was observed for individual components of MACE and cardiovascular death. Safety of HIF prolyl hydroxylase inhibitors for other outcomes was comparable with ESA in dialysis-dependent CKD. In nondialysis-dependent CKD, dialysis access thrombosis, venous thromboembolism, infections, and hyperkalemia occurred more frequently with HIF prolyl hydroxylase inhibitors in placebo-controlled trials but not in ESA-controlled trials.ConclusionsThere was no evidence of a difference in the long-term cardiovascular safety profile of HIF prolyl hydroxylase inhibitors and ESA in adults with dialysis-dependent CKD and adults with nondialysis-dependent CKD. (PROSPERO registration number, CRD42021278011.)

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors as a New Treatment Option for Anemia in Chronic Kidney Disease.

Anemia plays an important role in chronic kidney disease (CKD) progression because it worsens the quality of life and increases the risk of cardiovascular complications in CKD patients. In such cases, anemia is mainly caused by endogenous erythropoietin (EPO) and iron deficiencies. Therefore, KDIGO and ERBP guidelines for anemia treatment in CKD patients focus on recombinant EPO and iron supplementation. A recent new treatment option for anemia in CKD patients involves blocking the hypoxia-inducible factor (HIF) system with prolyl hydroxylase inhibitors (PHIs), what causes increasing endogenous EPO production and optimizing the use of iron. Clinical studies have shown that the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) covered in this manuscript-roxadustat, vadadustat, daprodustat, and molidustat-effectively increase hemoglobin (Hb) levels in both non-dialyzed and dialyzed CKD patients. Moreover, these medicines reduce blood lipid levels and do not accelerate CKD progression. However, blockage of the HIF system by HIF-PHIs may be associated with adverse effects such as cardiovascular complications, tumorogenesis, hyperkalemia. and retinopathy. More extensive and long-term clinical trials of HIF-PHIs-based anemia treatment in CKD patients are needed, and their results will indicate whether HIF-PHIs represent an effective and safe alternative to EPO and iron supplementation for anemia treatment in CKD patients.

Jian-Pi-Yi-Shen formula ameliorates renal fibrosis-induced anemia in rats with chronic kidney disease

Ethnopharmacological relevanceJian-Pi-Yi-Shen (JPYS) formula is an effective herbal therapy against renal injury, and JPYS has been clinically applied to ameliorate chronic kidney disease (CKD) and CKD-associated anemia. Increasing evidence supports the link between renal fibrosis and anemia in CKD. JPYS possessed anti-fibrosis effects in experimental CKD. Nevertheless, research on the mechanisms of JPYS in ameliorating renal anemia (RA) through suppressing renal fibrosis remains to be clarified. Aim of the studyOur study here was carried out to investigate the mechanisms of JPYS in protecting against RA. Materials and methodsAn adenine-induced anemia model in rats with CKD at three different time points was established, and bio-samples taken from each group were analyzed. Biochemical analysis was employed to detect kidney function and hematological parameters. Masson staining was used to evaluate renal fibrosis of rats. Western blot and immunohistochemistry were utilized to evaluate the expressions of fibrotic markers, erythropoietin (EPO) and hypoxia inducible factor-2α (HIF-2α) in the kidneys of rats. Subsequently, transcriptomic analysis was conducted to disclose the possible mechanisms of JPYS in treating RA. Finally, the expression levels of key targets were analyzed and validated by using Western blot and enzyme-linked immunosorbent assay (ELISA). ResultsJPYS treatment improved kidney function, suppressed renal fibrosis and enhanced hematological parameters in CKD rats. Moreover, JPYS treatment restored the increased expression levels of fibrotic markers and the declined EPO with time dependence. In parallel, data indicated JPYS treatment stimulated the translocation of HIF-2α into nucleus in the renal interstitium and thus promoted the expression of EPO. Transcriptomic profiling disclosed that activations of both nuclear factor kappa B (NF-κB) and transforming growth factor-β (TGF-β)/Smad pathways were closely associated with RA. Ultimately, experimental validation results presented that the increased expressions of target proteins from the above-mentioned two pathways in the kidneys were decreased significantly after JPYS treatment. ConclusionOur findings suggest that JPYS may improve RA by alleviating renal fibrosis, and the mechanisms of which involve in inhibiting the NF-κB and TGF-β/Smad pathways.

Hypoxia-inducible factor-prolyl hydroxylase inhibitors for treatment of anemia in chronic kidney disease: a systematic review and network meta-analysis.

To review current evidence on the efficacy and safety outcomes of HIF-PHIs in chronic kidney disease (CKD) populations with an emphasize on the safety profile. A systematic search was conducted in the Medline, Embase, and Cochrane Central databases. Randomized controlled trials that had assessed the efficacy and safety of HIF-PHIs for anemia in CKD were included. The efficacy outcome included change of hemoglobin and the safety outcomes any adverse events, severe adverse events, major adverse cardiovascular events, and mortality. The qualities of studies were assessed using the Cochrane ROB tool. 47 studies encompassing 55 RCTs for the study outcomes were included in this study. All six commercially available HIF-PHIs had direct comparisons to ESA and placebo, yet lacked direct comparisons among each other. The network analysis demonstrated all six HIF-PHIs were able to effectively elevate hemoglobin in the general CKD patients compared to placebo. All HIF-PHIs did not differ among each other in the efficacy of correcting anemia. Roxadustat and daprodustat had the largest number of reports in terms of adverse events. The overall risk of each safety outcome did not increase in comparison to erythropoiesis stimulating agent (ESA) or placebo, and did not differ among different types of HIF-PHIs. HIF-PHIs can effectively elevate hemoglobin without causing higher risk of safety concerns in CKD patients with anemia. Further evidence from long-term studies and the ongoing post-market surveillance is necessary.

Physician and Patient Preferences for Treatment of Anemia Associated with Chronic Kidney Disease in Japan: A Survey Including Best-Worst Scaling.

Several treatment options are available for anemia associated with chronic kidney disease (CKD); however, there remains a lack of awareness of physician and patient preferences regarding these treatments. We aimed to explore physicians' and patients' perceptions and preferences regarding the management of anemia of CKD in Japan. A web-based survey, including best-worst scaling (BWS), was conducted with physicians who had treated ≥1 patient with anemia of CKD in the preceding year, and with patients with CKD who self-reported a clinical diagnosis of anemia of CKD or low hemoglobin levels. A three-step approach was used comprising cognitive interviews, a pilot survey, and a main survey. The BWS survey results were analyzed using multinomial logit and hierarchical Bayesian models. The survey was completed by 906 participants: 103 patients (average age 60.6 years; 77.7% male) and 803 physicians (166 nephrologists, 214 cardiologists, 137 diabetologists, and 286 general internists). Almost all (96.0%) physicians surveyed considered anemia of CKD to be an important condition to treat. Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors had the highest treatment satisfaction among physicians, whereas patients had the highest satisfaction with both erythropoietin-stimulating agent therapy and HIF-PH inhibitors. Approximately one-third (35.9%) of patients surveyed indicated that they were receiving treatment. When comparing the relative importance of attributes and levels, physicians favored efficacy (particularly improvement in hemoglobin levels), whereas patients favored safety (particularly a lower rate of severe adverse events). Although a majority of physicians consider treatment of CKD-related anemia important, differences in the perceptions and usage of medications exist between medical specialties. Preferences for the management of anemia of CKD vary between physicians and patients; therefore, patient involvement in treatment decisions may help optimize outcomes.

Comparative Analysis of Real-World Efficacy and Safety of Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors in Kidney Transplant Recipients Versus Nontransplant Individuals: A Single-Center Study

ObjectivesTo compare the efficacy and safety of hypoxia-inducible factor prolyl-hydroxylase inhibitors (HIF-PHis), a novel agent for management of anemia in chronic kidney disease (CKD), between transplant recipients and nontransplant individuals. MethodsA retrospective analysis was conducted on nondialysis-dependent CKD stage 3 to 5 patients treated with the HIF-PHi roxadustat or daprodustat at a single institution. Patients were categorized as kidney transplant recipients (KTRs) and non-KTRs. Efficacy outcomes (hemoglobin and creatinine levels) and safety profiles (rate of adverse events [AEs], descriptions, and discontinuations due to AEs) were assessed 3 months before and 6 months after HIF-PHi initiation within and then between the groups. ResultsThe study comprised 82 patients (KTR: 43, non-KTR: 39). Median ages significantly differed between the KTR (52.7 years) and non-KTR (82.9 years) groups (P < .001). Roxadustat was predominantly used in the KTR group (88.4%), while daprodustat was used in the non-KTR group (94.9%, P < .001). Both groups exhibited significant increases in Hb levels at 1, 3, and 6 months post-HIF-PHi initiation (P for trend, <.001), with a relative increase in Hb level at 6 months of 16% for KTRs and 13% for non-KTRs. Creatinine levels showed no significant changes over 6 months. Although no difference was observed in drug discontinuation due to AEs, the KTR group experienced a significantly higher rate of thrombotic events (18.6 vs 2.6%, P = .049). ConclusionsHIF-PHis demonstrate comparable efficacy for managing anemia in CKD, regardless of transplant status. However, heightened vigilance for thrombosis events is necessary during follow-up for KTRs.

Pharmacokinetics, Pharmacodynamics, and Safety of Vadadustat in Healthy Volunteers and Patients with Chronic Kidney Disease.

Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia in chronic kidney disease (CKD). Single ascending dose (SAD) and multiple ascending dose (MAD) studies assessed pharmacokinetics (PK), pharmacodynamics (PD), and safety of vadadustat in healthy volunteers. A single-dose, open-label study was conducted in patients with CKD stages 3 and 4 not on dialysis. In the SAD study, 48 healthy adult men (n = 8/cohort) received single doses of vadadustat (80-1,200 mg) or placebo. In the MAD study, 34 healthy adult men (n = 8-9/cohort) received daily vadadustat (500-900 mg) or placebo for 10 days. In the single-dose CKD study, 22 male and female patients with CKD (stage 3: n = 10; stage 4: n = 12) received single doses of vadadustat (500 mg). PK parameters included plasma vadadustat; PD biomarkers were measured, including erythropoietin (EPO) levels, reticulocytes, and others. Plasma vadadustat peaked 3-4 hours after single or multiple dosing in healthy volunteers, with a mean t1/2 of approximately 4.5 hours. In patients with CKD, plasma vadadustat peaked at 5-6 hours, with a mean t1/2 of 7.2 (stage 3) and 8.5 (stage 4) hours. Vadadustat AUC∞ and Cmax increased dose proportionally in SAD and MAD trials. In all trials, EPO concentrations increased in a dose-related manner and returned approximately to baseline by 24 hours. Adverse events were mild and considered not study drug related. The PK and PD results of these studies were utilized for further clinical development of vadadustat for treatment of anemia in CKD patients.

Assessment of the safety of Roxadustat for cardiovascular events in chronic kidney disease-related anemia using meta-analysis and bioinformatics.

This study compares the cardiovascular risk in anemic chronic kidney disease patients treated with Roxadustat versus erythropoietin stimulating agents (ESAs). It also explores the cardiovascular impact of Roxadustat. We searched PubMed, EMBASE, Cochrane, Scopus, and Web of Science databases up to 13 August 2023, using terms such as "ESA," "Roxadustat," "MACE," "stroke," "death," "myocardial infarction," and "heart failure." Two researchers independently selected and extracted data based on predefined criteria. We assessed the risk of bias with the Cochrane tool and analyzed statistical heterogeneity using the Q and I2 tests. We conducted subgroup analyses by geographical region and performed data analysis with Stata 14.0 and RevMan 5.4 software. Data were sourced from the NCBI database by filtering for "Roxadustat" and "human," and differentially expressed genes were identified using R software, setting the significance at p < 0.01 and a 2-fold logFC, followed by GO enrichment analysis, KEGG pathway analysis, and protein interaction network analysis. A total of 15 articles encompassing 1,43,065 patients were analyzed, including 1,38,739 patients treated with ESA and 4,326 patients treated with Roxadustat. In the overall population meta-analysis, the incidences of Major Adverse Cardiovascular Events (MACE), death, and heart failure (HF) were 13%, 8%, and 4% in the Roxadustat group, compared to 17%, 12%, and 6% in the ESA group, respectively, with P-values greater than 0.05. In the subgroup analysis, the incidences were 13%, 11%, and 4% for the Roxadustat group versus 17%, 15%, and 5% for the ESA group, also with p-values greater than 0.05. Bioinformatics analysis identified 59 differentially expressed genes, mainly involved in the inflammatory response. GO enrichment analysis revealed that these genes are primarily related to integrin binding. The main pathways identified were the TNF signaling pathway, NF-κB signaling pathway, and lipid metabolism related to atherosclerosis. The protein interaction network highlighted IL1B, CXCL8, ICAM1, CCL2, and CCL5 as the top five significantly different genes, all involved in the inflammatory response and downregulated by Roxadustat, suggesting a potential role in reducing inflammation. The meta-analysis suggests that the use of Roxadustat and ESA in treating anemia associated with chronic kidney disease does not significantly alter the likelihood of cardiovascular events in the overall and American populations. However, Roxadustat exhibited a safer profile with respect to MACE, death, and heart failure. The bioinformatics findings suggest that Roxadustat may influence integrin adhesion and affect the TNF and NF-κB signaling pathways, along with lipid and atherosclerosis pathways, potentially reducing inflammation.

Updates in Chronic Kidney Disease.

Chronic kidney disease (CKD) affects approximately 14% of adults in the United States and is present in at least 10% of the population worldwide. Blood glucose and blood pressure control are imperative to adequately manage CKD as they are the only primary prevention measures for the condition. Recent changes in CKD evaluation and medication therapies that modify disease progression and aid in managing complications such as anemia of CKD have emerged, including a newly approved mineralocorticoid receptor antagonist and hypoxia-inducible factor-prolyl hydroxylase inhibitor, respectively. This focused update on CKD evaluation and management will review the most recent evidence and approved agents to support patients with CKD, including a review of glomerular filtration rate measurement methods such as CKD-EPI 2021 and utilization of cystatin C, Kidney Disease Improving Global Outcomes (KDIGO) guidelines, American Diabetes Association (ADA) guidelines, and primary literature supporting the use of newer agents in CKD. Checklists for managing blood pressure and blood glucose, CKD-mineral bone disorder, and anemia of CKD targeted for pharmacists are also provided. Additionally, a discussion of Centers for Medicare & Medicaid (CMS) coverage of agents approved for managing complications of CKD is included.

Iron Deficiency Anemia in Patients with Chronic Renal Insufficiency at Tertiary Care Hospital in Northern Punjab

Anemia is a frequently encountered complication of chronic kidney disease (CKD) leading to worse outcomes in terms of quality of life and premature death. However, the current prevalence of iron deficiency anemia (IDA) in CKD is understudied in Pakistan. Objective: To assess the frequency of IDA in patients with CKD at Bewal International Hospital, Gujar Khan, Pakistan. Methods: A cross-sectional was executed at the Department of Nephrology, Bewal International Hospital, Pakistan from January 1, 2022, to June 30, 2022. The study comprised 97 patients aged &gt;13 years of either gender having CKD (GFR &lt;60 ml/min/1.73m²) for at least 90 days. All patients were tested for serum creatinine, ferritin, and hemoglobin levels. IDA was considered if hemoglobin was ≤12 mg/dL in women and ≤13 mg/dL in men. Results: Among 97 patients, there were 57(58.7%) males and 40(41.3%) females. The mean age was 51.23 ± 12.99 years while the mean disease duration was 6.01 ± 1.610 years. 57(58.7%) patients had IDA. IDA was more frequent in women with CKD (67.5%), compared to men (52.64%). However, this association was statically insignificant (p&gt;0.05). When data was stratified, a substantial association was found between IDA and the stage of CKD (p=0.007). There was no significant association between IDA and disease duration (p&gt;0.05). Conclusions: It was concluded that anemia is common in CKD patients, with a high prevalence in females. Stage 3–5 CKD is significantly associated with developing iron deficiency anemia. Early identification and timely management can avoid unfavorable outcomes in these patients.

#2815 Single center, single arm, prospective, observational study of desidustat in chronic kidney disease-induced anemia

Abstract Background and Aims Anemia in chronic kidney disease (CKD) is multifactorial. Relative deficiency of erythropoietin is one of the key reasons for decreased RBC production. This anemia is associated with poor quality of life and increases morbidity in CKD patients. Injectable erythropoietin is the standard of care for CKD-anemia, which has safety concerns. Desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), stimulates endogenous erythropoiesis and is approved for CKD anemia treatment. Hence, the present study identifies the real-world clinical efficacy and safety of the desidustat treatment for a short duration in CKD anemia. Method This is an open-label, single-center, prospective study. We analyzed the data of 130 patients who are currently in follow-up and received Desidustat as treatment for CKD-anemia. The study is for the duration of 24 weeks. We followed up on patent at 1 month, 3 months, and the end of the study (6 months). Patients were given a 100-mg Desidustat tablet orally three times in a week. The primary outcome is to assess the change in Hb from baseline, and the secondary outcome is the safety of the therapy. Results In this study, we enrolled 130 patients. Of these 130 patients, 58.4% (n = 76) were male and 41.5% (n = 54) were female. The mean age of the study population was 53.6 ± 12.3 years. The majority of the study population was in the pre-dialysis category; 80% (n = 104) and 20% (n = 26) were on dialysis. All the dialysis patients were on three times per week on Dialysis. Diabetes (68%) and hypertension (75%) are the most common co-morbid conditions in patients with CKD anemia. All the patients received desidustat at a 100 mg, three-weekly dose. During each follow-up visit, a significant rise in hemoglobin was observed (p&amp;lt;0.001), as shown in the figure. With desidustat therapy, adverse drug reactions were seen in 5.3% (n = 7) cases: three cases of abdominal pain, two cases of vomiting, and two cases of diarrhea. Conclusion Oral HIF-PHIs and Desidustat showed significant improvement in hemoglobin in CKD anemia patients. More studies require for safety and efficacy in Dialysis dependent CKD - Anemia patients.

#708 Retrospective analysis of the real-world experience of desidustat in the treatment of chronic kidney disease induced anemia

Abstract Background and Aims Chronic kidney disease (CKD) is commonly associated with an increased risk of anemia, which significantly impacts patients' quality of life and increases morbidity and mortality. Current treatment options for anemia in CKD, such as injectable erythropoiesis-stimulating agents (ESAs) have limitations and safety concerns. Desidustat, a novel oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) has shown promise in stimulating endogenous erythropoiesis and addressing anemia in CKD. Therefore, the present study assesses the real-world clinical efficacy and safety of the desidustat treatment for a short duration of 6 months (24 weeks) in CKD patients with anemia. Method This is a retrospective analysis of 140 patients at our center who received Desidustat as a treatment for CKD anemia. Desidustat was initiated in all patients at 100 mg three times a week. Dose adjustment was done every 4 weeks as per the Hb level of the patient. The duration of the study was 6 months. The primary endpoint of the present study was a change in Hb from baseline with desidustat therapy and the secondary endpoint was safety of the treatment. Results The majority of the patients were Pre-dialysis 74.28% (n = 104) and 25.72% (n = 36) were dialysis-dependent patients. Of 36 dialysis-dependent patients; 75% (n = 27) were on dialysis three times a week, rest were on twice-a-week dialysis. In the current study, the majority of patients had Hypertension (95.7%) and diabetes (68.57%) as co-morbidities. All the patients in the current study were maintained with 100 mg Desidustat, however, 9.2% (n = 13) required dose reduction, and 11.42% (n = 16) required an increased dose of desidustat on the follow-up visit. In both Pre-Dialysis and dialysis-dependent patients, there was a sustainable rise in the mean Hb levels at the end of 24 weeks from baseline (1.05 g/dL; p &amp;lt; 0.05) All the patients tolerated desidustat well. In the present study, we didn't observe significant side effects related to the therapy apart from 2.41% (n = 3) cases of Diarrhoea and Vomiting. Conclusion Desidustat is effective in increasing Hb in CKD Anemia patients in the short run. However, Long-term studies are required to establish the efficacy and safety of this novel therapy.

#1171 Effect of methoxy polyethylene glycol-epoetin beta on delaying dialysis in anemic patients with Stage 4-5 chronic kidney disease

Abstract Background and Aims The optimal hemoglobin (Hb) target for treating anemia in pre-dialysis chronic kidney disease (CKD) remains controversial. This study investigates the efficacy and safety of methoxy polyethylene glycol-epoetin beta, in delaying the initiation of kidney replacement therapy (KRT), all-cause mortality, CKD progression, and quality of life in stage 4-5 CKD patients. It compares outcomes between patients targeting an Hb level of 10.5-11.5 g/dL versus 8.5-9.5 g/dL. Method This was a single-center, open-label, parallel-group randomized controlled trial. Patients with estimated glomerular filtration rates (eGFR) of 8-15 ml/min/1.73 m2, who had not yet started dialysis, were randomized into two groups based on different Hb targets (Group A: 10.5-11.5 g/dL, Group B: 8.5-9.5 g/dL). Methoxy polyethylene glycol-epoetin beta (MIRCERA®) was prescribed by a pre-specified protocol to achieve these Hb targets. Iron supplements were administered to maintain transferrin saturation &amp;gt;20% or serum ferritin &amp;gt;200 ng/ml. Primary outcomes included a composite of all-cause death and KRT initiation, with secondary outcomes encompassing eGFR slope, hospitalization incidence, blood transfusion necessity, and quality of life measured by the 36-Item Short Form Health Survey (SF-36). Results A total of 62 participants were randomized. The mean age was 64.0 years (SD ±16.0), with 51.6% being female. The mean estimated Glomerular Filtration Rate (eGFR) at enrollment was 12.1 ml/min/1.73 m2 (SD ±3.1). Group A had a significantly higher time-averaged Hemoglobin (Hb) level (10.5 g/dL, SD ±1.2) compared to 8.5 g/dL (SD ±0.9) in the control group (p &amp;lt; 0.001). There was no significant difference in the composite endpoint of all-cause death and Kidney Replacement Therapy (KRT) initiation between the two groups (Hazard Ratio [HR] 0.69; 95% Confidence Interval [CI] 0.32-1.50; p = 0.35, as shown in the Figure). The eGFR slope was similar in both groups (−2.54 vs. −2.53 ml/min/1.73 m2 per year, p = 0.9). Time-averaged ferritin, transferrin saturation, blood pressure, and dietary sodium/protein intake showed no significant differences. Participants in the lower Hb target group required more blood transfusions (11 vs 1 unit, Incidence Rate Ratio [IRR] = 0.075, 95% CI 0.002-0.517, p = 0.001). Rates of hospital admissions, and changes in SF-36 quality of life domains were comparable between the groups, as detailed in the Table. Conclusion The study indicates that using methoxy polyethylene glycol-epoetin beta to maintain a higher Hb target in anemic patients with stage 4-5 CKD does not significantly alter the rate of all-cause mortality, the initiation of KRT, and rate of eGFR decline compared to a lower Hb target. However, a higher Hb target may reduce the need for blood transfusions without adversely affecting the progression of CKD, hospitalization rates, or quality of life. These findings suggest that while higher Hb targets may not dramatically alter key clinical outcomes, they could offer benefits in reducing transfusion requirements, thus providing a more nuanced approach to managing anemia in late-stage CKD.

#1122 Anaemia in CKD and cardiovascular risk; all cut from the same cloth?

Abstract Background and Aims Anaemia in chronic kidney disease (CKD) has been repeatedly associated with increased cardiovascular morbidity and mortality, but most studies have not investigated its longitudinal association by sex and age. Our aim was to study the association between haemoglobin (Hb) current value and the hazard of major adverse cardiovascular event (MACE) in specific subgroups of CKD patients defined by age and sex. Because erythropoiesis-stimulating agents (ESA) are incriminated to modify the effect of Hb level on the hazard of event for high level of Hb, we have here only focused in non-ESA users CKD patients. Method We used data from the CKD-REIN cohort, which included 3033 patients with moderate to severe CKD from 40 nationally representative nephrology clinics in France between 2013 and 2016. We included patients with at least one Hb, estimated glomerular filtration rate (eGFR), transferrin saturation (TSAT) or ferritin measurement. We studied all Hb measurements available until a first MACE defined as the first event among cardio-vascular death, myocardial infarction, stroke or hospitalization for acute heart failure; initiation of kidney replacement therapy; death from other causes; or initiation of ESA therapy, whichever came first. First, we estimated the individual trajectories of Hb, eGFR, TSAT, ferritin using multivariate share random effect joint model. Then, we estimated the association between Hb current value and MACE using a cause specific multivariate Cox model in 4 specific subgroups separately: women ≤ and &amp;gt;70 years, men ≤ and &amp;gt;70 years. All models were adjusted on current value of eGFR, TSAT, Ferritin, and baseline value of albumin-to-creatinine ratio, age, CKD aetiology, heart failure past history, alcohol consumption, iron treatment, antithrombotic and anticoagulant. When appropriate, spline functions were used for continuous variables to account for potential non-linear effects. Reference value of Hb for computing hazard ratio was 12 g/dL in women, and 13 in men according to current definition of anaemia. Results A total of 2742 patients were included in the analysis (median eGFR 33 ml/min/1.73 m2, median age at inclusion 69 years) together with 28423 Hb measurements (median of 13 per patient) collected during a median follow-up of 5.0 years. There were 551 women ≤70 (median Hb 12.4 g/dL, 34 (6.2%) MACE), 349 women &amp;gt; 70 (12.2 g/dL, 61 (17.5%) MACE), 1009 men ≤ 70 (13.4 g/dL, 104 (10.3%) MACE) and 833 men &amp;gt; 70 (13.0 g/dL, 163 (19.6%) MACE). No statistical significant association was found in males whatever their age (Hazard ratio of MACE for each 1 g/dL increase in Hb 1.0 (95% CI 0.9-1.1) in men &amp;lt; 70 and 0.9 (95% CI 0.8-1.1) in men &amp;gt; 70). For women, the hazard of MACE raised as the Hb values decreased, with a more pronounced increase in women &amp;gt; 70 (Fig. 1). For example, the hazard ratio for a Hb value of 10 g/dL compared to the reference was 2.0 (95% CI 0.9-4.7) in women &amp;lt; 70 and 3.3 (95% CI 1.5-7.2) in women &amp;gt; 70. Conclusion In non-ESA users CKD patients, anaemia is associated with the occurrence of MACE in females, especially those older than 70 years. These results raise question about a one-size-fits-all approach in the interpretation of low values of haemoglobin and anaemia management. It also suggests to evaluate the effect of anaemia therapies in men and women separately.

#1194 Roxadustat in ESA converted patients with anemia of chronic kidney disease on dialysis: a secondary analysis of ROXSTAR Registry

Abstract Background and Aims Anemia is associated with increased morbidity &amp; mortality in chronic kidney disease (CKD) patients. Around 20% of patients experience erythropoiesis-stimulating agent (ESA) hypo-responsiveness and can't achieve hemoglobin (Hb) treatment target even with a high dose. Higher ESA dose is associated with undesirable outcomes. Roxadustat has demonstrated efficacy and safety in ESA converted CKD anemia patients. We conduct this secondary analysis of ROXSTAR registry (ChiCTR2100046322) to evaluate the Hb response to roxadustat in ESAs converted dialysis-dependent (DD) patients with prior weekly ESA dose ≥10000 U and &amp;lt;10000 U respectively. Method This study used existing data collected in the ROXSTAR Registry. DD patients converted from ESA treatment who received at least one dose of roxadustat, and had at least one post baseline Hb were included. We described the Hb response to roxadustat treatment in patients converted from higher ESA dose (≥10,000 U per week) and from lower ESA dose (&amp;lt;10,000 U per week) at enrollment. The changes from baseline to week 12 &amp; week 24 in Quality of Life (QoL) assessed by SF-36 Vitality &amp; Physical Function subscales, and Rapid Assessment of Physical Activity (RAPA) Strength &amp; Flexibility scores were also analyzed respectively. Results Total 666 ESA converted DD patients were included. For the higher ESA dose group, there were 426 patients (257 male [60.3%]) with a mean (standard deviation [SD]) age of 49.5 [13.1] years, the median (mix, max) dialysis duration was 31.7 (0.2, 307.8) months. For the lower ESA dose group, 240 patients (141 male [58.8%]) with a mean age of 49.7 [13.0] years were enrolled, and median dialysis duration was 36.4 (0.4, 266.1) months. The mean baseline Hb was 98.0 (14.5) g/L in the higher ESA dose group and 102.2 (12.6) g/L in the lower ESA dose group. The median prior weekly ESA dose was 10000 (10000, 50000) U and 6000.0 (300, 9000) U in higher &amp; lower ESA dose groups (Table 1). Mean weekly roxadustat dose during the first 12 weeks (correction phase) was maintained around 300 mg and then decreased to around 260 mg during 12-52 weeks (maintenance phase) for the higher ESA dose group; the dose started from around 300 mg and decreased to 270 mg during the correction phase and then gradually decreased to around 230 mg during the maintenance phase in the lower ESA dose group. The mean Hb change from baseline averaged over weeks 24-36 &amp; 36-52 was 12.1 [95% CI: 10.5, 13.7] g/L &amp; 12.3 [95% CI: 10.7, 13.9] g/L for the higher ESA dose group and 9.9 [95% CI: 8.0, 11.8] g/L &amp; 10.2 [95% CI: 8.3, 12.1] g/L for the lower ESA dose group, respectively. The proportion (%) of patients with mean Hb ≥100 g/L at the same period were 82.3% [95% CI: 78.1%, 86.6%] &amp; 83.6% [95% CI: 79.3%, 87.9%] in the higher ESA dose group and 88.4% [95% CI: 83.6%, 93.1%] &amp; 89.0% [95% CI: 84.3%, 93.7%] in the lower ESA dose group. There was no clinical meaningful change of QoL observed in either group. Conclusion ESA-converted DD patients responded well to roxadustat in terms of anemia correction and Hb maintenance to treatment target, regardless of prior ESA dose. Similar starting doses of roxadustat were used for both groups and then gradually decreased during the maintenance phase (week 12-52) compared to the correction phase (week 1-12) while the magnitude of dose decrease was greater in the lower ESA dose group.

#511 Inadequate diagnostic investigations and low treatment rates in CKD anemia: an inertia that can only change with long-term follow-up

Abstract Background and Aims Anemia is observed from the early stages in the course of chronic kidney disease (CKD), and as the stage progresses, the severity of anemia and its impact on quality of life increase. Early diagnosis of anemia in chronic kidney disease, assessments related to its etiology, and treatment are therefore crucial. There is no comprehensive and long-term study in Turkey addressing the diagnostic and therapeutic management of anemia seen in the course of chronic kidney disease. The aim of this study is to investigate the frequency of anemia in different stages of CKD in patients diagnosed with Stage 3 and more advanced stages, to evaluate the effectiveness of diagnostic approaches, and management of iron parameters and anemia, and to investigate the effect of anemia on patient survival. We aim to present “real-life” data from this study to guide clinical practice and correct errors or deficiencies in anemia management. Method This study is a single-center, observational-descriptive retrospective study. 1321 outpatients with Stage 3A and advanced CKD and anemia who admitted to Hacettepe University Faculty of Medicine Nephrology Clinic between 2014 and 2018 were included in the study. Data for demographics, CKD etiologies and stages, anemia severities, comorbid diseases were collected from electronic health system (Table 1). Diagnostic investigations for anemia evaluation and therapeutic interventions such as administration of iron, folic acid, vitamin B12, erythropoiesis stimulating agents (ESA) were assessed. The long-term yield of diagnostic and therapeutic approaches and their effects on survival were also evaluated. The study investigated whether the severity of anemia and improvement in anemia had an effect on survival. Results Ferritin is the most commonly performed test for the etiology of anemia (76.4%). Request rates for tests such as B12, folic acid, transferrin saturation and reticulocyte are below 20%. More than half of the patients with anemia (59.4%) have not received any form of anemia treatment. Even among those whose ferritin test was checked and the value was &amp;lt;100 µg/dL, only 41.4% were given iron treatment. As the clinical follow-up period of the patients increased, it was observed that anemia treatment was applied better and target values were reached more frequently (p &amp;lt; 0.001). More than one third of the patients (34.8%) died during follow-up. The overall survival in patients whose anemia improved was 79.8%, and it was 62.8% in patients whose anemia did not improve the overall survival was (p = 0.002) (Fig. 1). When examining the relationship between survival status and anemia severity for the non-dialysis-dependent CKD Stage 3-5 group, there was a statistically significant survival difference between the Hb group of 10-11.9 g/dL to Hb group of &amp;lt;10 g/dL (p = 0.004). Conclusion This study has shown that diagnostic tests for etiology of anemia were insufficiently ordered. It was also found that a significant majority of anemic patients who underwent etiological evaluation were not even adequately treated. Long-term follow up improved anemia treatment, and patients with improved anemia had better survival. In conclusion, we recommend an optimal evaluation of CKD patients with anemia and initiating treatment as early as possible.

#2505 PTEN ablation in osteocytes exacerbates anemia in mice with subtotal nephrectomy

Abstract Background and Aims The identification of novel roles for bone as a principal endocrine organ has grown in recent decades, being now recognized for its contribution to the regulation of numerous systemic functions. In previous studies, we observed that 5/6Nx mice with osteocytic deletion of phosphatase and tensin homolog (PTEN), exhibited higher bone volume in 5/6Nx mice, consistent with studies under normal renal conditions. However, we also noted a decrease in blood hemoglobin levels, prompting further exploration. This study aims to elucidate the causative actions by which specific PTEN deletion in osteocytes influences red blood cell (RBC) homeostasis and to identify its possible involvement in anemia development. Method To achieve this goal, we used mice with targeted PTEN deletion in osteocytes (PTEN Ocy-cKO) by crossing DMP1-Cre ± and PTENflox/flox mice, subjected to subtotal nephrectomy (5/6Nx) at 2 months of age. Two weeks post-surgery, bone and blood samples were collected for plasma biochemistry, blood count, RBC membrane integrity, and preliminary bone+bone marrow proteomic analysis. Cre-negative mice and animals with normal renal function were included as controls. Results Our findings revealed that PTEN Ocy-cKO mice, under both normal and reduced renal function conditions, showed higher bone volume than corresponding controls. In terms of blood homeostasis, PTEN Ocy-cKO mice with normal renal function showed splenomegaly and a lower number of circulating RBCs. Notably, PTEN Ocy-cKO mice undergoing 5/6Nx experienced a profound decrease in RBC number in only two weeks, independent of renal erythropoietin expression. Further exploration ruled out bone marrow failure as a cause, as the erythroid progenitor (CD45-CD71+Ter119+) population remained similar in both groups. Extramedullary hematopoiesis was observed in the spleen, in addition to increased circulating reticulocyte number in the PTEN Ocy-cKO mice. Finally, altered RBC membrane protein patterns in PTEN Ocy-cKO mice suggested reduced mechanical/osmotic resistance. Preliminary proteomic analysis identified downregulation of Slc4a1 (Band3) and Phosphofructokinase (Pfkm), whose deficiencies have been previously linked to anemia. Conclusion In conclusion, our results propose that osteocytes contribute to RBC homeostasis through a pathway downstream of PTEN, and open a new avenue for understanding anemia in chronic kidney disease and a potential target for future treatments.

#1912 Assessment of the dynamics of renal anemia in patients with atrial fibrillation and chronic kidney disease stage IIIb-V during anticoagulant therapy

Abstract Background and Aims Therapy with oral anticoagulants prevents the development of most ischemic strokes and systemic embolisms in patients with atrial fibrillation (AF) and chronic kidney disease (CKD), and also helps to increase life expectancy, improving its quality. It should be emphasized that with CKD, the risk of hemorrhagic complications also increases, which in turn can lead to the progression of renal anemia and deterioration in the patient's general condition. The main complication of anticoagulants is an increased risk of major bleeding, including intracranial, life-threatening bleeding. The purpose of the study is to assess the benefits and risks of anticoagulant therapy in patients with renal anemia in AF and stage IIIb-V CKD. Method From February 2022 to July 2023, 2983 patients with AF were admitted to cardiology departments. The majority of patients with AF had hypertension (94%), chronic heart failure (71%), coronary heart disease (65%), and type 2 diabetes mellitus (23%). CKD was diagnosed according to KDIGO criteria, glomerular filtration rate (GFR) was calculated using the CKD-EPI formula. Indications for anticoagulant therapy (ACT) were determined according to European guidelines for AF using the scales for assessing the risk of thromboembolic complications (TEC)—CHA2DS2-VASc and the risk of bleeding—HAS-BLED. Results GFR up to 45 ml/min/1.73 m2 was detected in 2189 (73%) patients with AF, GFR less than 45 ml/min/1.73 m2 in 794 (27%) patients with AF (CKD stages IIIb–V in 516 (65%) cases, for the first identified sustained decrease in glomerular filtration rate (FISD in GFR) of less than 45 ml/min/1.73 m2 was detected in 278 (35%) cases). Among patients with AF and CKD, renal anemia was diagnosed in 23% of cases, in 63% (n = 505) of cases with AF and GFR &amp;lt;45 ml/min/1.73 m2. With a GFR of 45-30 ml/min/1.73 m2, renal anemia was detected in 59%, with a GFR of 30-15 ml/min/1.73 m2—in 89%, with a GFR &amp;lt;15 ml/min/1.73 m2—in 97%, with FISD in GFR &amp;lt;45 ml/min/1.73 m2—in 51%. When stratifying thromboembolic risk according to the CHA2DS2-VASc scale in patients with AF and CKD stages IIIb–V, 0-1 points were scored by 1% (n = 11), 2-5 points by 53% (n = 420), ≥6 points by 46% (n = 363) patients. The results of the analysis of the risk of bleeding according to the HAS-BLED scale showed the following data: 0-1 point—8% (n = 64), 2 points—15% (n = 118), ≥3 points—77% (n = 612). When studying the frequency of ACT prescription, it was revealed that rivaroxaban was prescribed in 21%, apixaban—22%, dabigatran—10%, warfarin—25%, low molecular weight heparins—3%, ACT not recommended—9%, ACT of choice—10% of cases (Table 1). In mild renal anemia (in 39% of patients), taking ACT led to a reduction in the risk of developing TEC—RR 0.55 with 95% CI 0.38-0.79; in case of moderate renal anemia (in 47.3% of patients), the risk of TEC did not decrease RR 1.03 with 95% CI 0.69-1.58; with severe renal anemia (in 13.7% of patients), the risk of TEC was also not reduced—RR 1.6 with 95% CI 1.17-2.2). Conclusion Every fourth patient in the cardiology department with AF showed a decrease in GFR &amp;lt;45 ml/min/1.73 m2, while 1/3 of them had FISD in GFR &amp;lt;45 ml/min/1.73 m2, and it is in these patients that the most common the dose of the prescribed anticoagulant did not correspond to the GFR; 50% of patients with GFR &amp;lt;45 ml/min/1.73 m2 and 32% with GFR &amp;lt;30 ml/min/1.73 m2 are recommended to use direct oral anticoagulants. Patients with stage V CKD were not prescribed direct oral anticoagulants; in 50% of cases, none of the anticoagulants was recommended.

#2898 Exposure response model describing hematologic changes with chronic treatment of CKD anemia with vadadustat

Abstract Background and Aims Vadadustat (VADA) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate endogenous erythropoietin production, increasing iron mobilization and red blood cell production. VADA is approved in 36 countries globally and is indicated in the European Union for the treatment of symptomatic anaemia associated with chronic kidney disease (CKD) in adults on chronic maintenance dialysis and is an alternative to treatment with erythropoiesis-stimulating agents (ESAs). The aim of this work was to develop a predictive, semi-mechanistic model to understand the effects of VADA and erythropoiesis-stimulating agents (ESAs) on hemoglobin response and to evaluate the impact of intrinsic and extrinsic patient characteristics on that response for non-dialysis dependent (NDD) and dialysis-dependent (DD) patient populations. Method A predictive semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for VADA and ESA treatment was developed using nonlinear mixed effects methods. The model describes changes in reticulocyte count (RETICs), mature erythrocytes (RBCs) and hemoglobin (Hb) as a function of drug exposure and subject-specific characteristics. The dataset was based on data from 7 Phase 1 to Phase 3 studies (Table 1; N = 894 for VADA; N = 560 for ESA modeling) in healthy volunteers and subjects with NDD- or DD-CKD who were either ESA-naïve or ESA experienced but not receiving treatment at screening. Prior population PK modeling of VADA provided estimated drug exposures for VADA-treated subjects, while dose normalized to standard units (IU/kg/wk) was used as the exposure metric for subjects on ESA. Each of these exposure metrics could vary with time, as the dose was adjusted according to observed Hb response. This work evaluated alternative model structures, as well as covariate effects affecting Hb individual response. Results A predictive semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for VADA and ESA treatment was developed using nonlinear mixed effects methods. The model describes changes in reticulocyte count (RETICs), mature erythrocytes (RBCs) and hemoglobin (Hb) as a function of drug exposure and subject-specific characteristics. The dataset was based on data from 7 Phase 1 to Phase 3 studies (Table 1; N = 894 for VADA; N = 560 for ESA modeling) in healthy volunteers and subjects with NDD- or DD-CKD who were either ESA-naïve or ESA experienced but not receiving treatment at screening. Prior population PK modeling of VADA provided estimated drug exposures for VADA-treated subjects, while dose normalized to standard units (IU/kg/wk) was used as the exposure metric for subjects on ESA. Each of these exposure metrics could vary with time, as the dose was adjusted according to observed Hb response. This work evaluated alternative model structures, as well as covariate effects affecting Hb individual response. A similar model structure was found to describe early changes in RETICs and longer-term changes in Hb for both VADA and ESAs. In each case, the magnitude of response increases with increased drug exposure up to a maximum value (Emax), and the Emax values were similar between VADA and ESAs. Subject intrinsic predictors of response included eGFR, subject age, BMI, and serum albumin, while extrinsic factors affecting response included geographic region, limits on acceptable Hb values (which also differ by geographic region) and the presence of previous ESA treatment. Interestingly, Hb responses were also correlated with changes in serum hepcidin, a key regulator of iron homeostasis, following both VADA and ESA treatment. Differences between the response to VADA and ESA were also described, including differences in temporal changes in RETICs and Hb. Conclusion This model showed an exposure-response relationship between VADA or ESA treatment and changes in RETICs and Hb for ESA naïve or ESA-experienced CKD subjects. The model will be used to inform dosage recommendations for VADA based on patient characteristics.

#3026 Uncovering the potential of HIF-PH inhibitors to treat renal anemia

Abstract Background and Aims Hypoxia-inducible factor prolyl hydroxylase enzyme inhibitors (HIF-PHis) are a novel class of agents that were developed for the treatment of renal anemia. The agents work by stabilizing the HIF complex and stimulating endogenous erythropoietin production. This research aims to gauge the potential utilization and impact of HIF-PHis based on the perspectives of nephrologists who are based in the EU5. Method Data were collected via an independent online survey of 204 nephrologists based in the EU5 (UK, Germany, Italy, France, and Spain) in November 2023. Results EU5 nephrologists report that most dialysis and CKD non-dialysis patients with renal anemia who are on ESA therapy have an optimal response to treatment; however, a substantial proportion of patients experience a suboptimal response to treatment and up to 13% of patients across dialysis modalities are classified as ESA hypo-responders. Regardless of their geographic location, EU5 nephrologists position HIF-PHis to offer the most value in the CKD non-dialysis patient setting, with a perceived high level of opportunity (80%) for roxadustat to improve renal anemia outcomes among non-dialysis patients. Not surprisingly, the perceived advantages of an oral agent over an injectable medication for the treatment of renal anemia are more substantial for dialysis patients who are receiving home therapies (peritoneal and home hemodialysis) compared to those receiving in-center hemodialysis treatment. EU5 nephrologists also tend to believe that roxadustat represents a high level (64%) of opportunity to improve renal anemia outcomes in dialysis patients, with similar ratings observed for vadadustat (63%) in the same patient population. Specific to the use of HIF-PH inhibitors in the CKD non-dialysis setting, nephrologists are most concerned about patient compliance (51%), followed by safety compared to ESAs in general and as they relate to cardiovascular events (36%). When considering the use of HIF-PH inhibitors in the dialysis setting, nephrologists express similar concerns compared to the non-dialysis setting, with patient compliance (50%) ranked as the top concern, followed by safety compared to ESAs (38%), and the potential for off target effects (33%). Most EU5 nephrologists agree that HIF-PH inhibitors represent a more physiologic way of treating anemia of CKD compared to ESAs (70%) and many would like gain more clinical experience with the class of medications (63%). Current roxadustat treatment rates in dialysis are slowly increasing across the EU5 region, with slightly higher adoption in peritoneal dialysis patients (10%) compared to in-center hemodialysis patients (8%). Meanwhile, their self-reported uptake of roxadustat in CKD non-dialysis patients is also increasing over time, with the largest increase observed in CKD Stage 4 patients (9%). There is little consensus among EU5 nephrologists regarding their expected time to trial vadadustat once it is available, as nearly the same proportion of prescribers project that they will prescribe the agent to their dialysis patients within three months (36%), six months (23%), and within one year (28%). Conclusion With HIF-PHis having more of a physiologic mechanism of action, oral administration, and a similar safety profile compared to ESAs, broader adoption of the novel agents will potentially help address unmet needs and improve patient outcomes in the treatment of renal anemia for both CKD non-dialysis and dialysis patients.