Treatment Of Renal Anemia Research Articles

Identification of 3-aryl-5-methyl-isoxazole-4-carboxamide derivatives and analogs as novel HIF-2α agonists through docking-based virtual screening and structural modification

Hypoxia-inducible factor-2 (HIF-2) serves as the pivotal transcription factor in cellular responses to low oxygen levels, particularly concerning the regulation of erythropoietin (EPO) production. A docking-based virtual screening on crystal structures of HIF-2α inhibitors unexpectedly identified 3-phenyl-5-methyl-isoxazole-4-carboxamide derivative v19 as a hit of HIF-2α agonist. Further structural optimizations of compound v19 led to the discovery of a series of HIF-2α agonists with novel scaffolds. The most promising compounds 12g and 14d exhibited potent HIF-2α agonistic activities in vitro with EC50 values of 2.29 μM and 1.78 μM, respectively. Molecular dynamics simulations have revealed their capacity to allosterically enhance HIF-2 dimerization, which shed light on their mechanism of action. Moreover, compound 14d demonstrated a favorable pharmacokinetic (PK) profile, boasting an impressive oral bioavailability value of 68.71 %. These findings strongly suggest that compound 14d is an auspicious lead compound for the treatment of renal anemia.

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

BackgroundChronic 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.MethodsWe 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).ResultsA 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.ConclusionsOur 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 registrationCRD42023396704.

Roxadustat on Renal Anemia with Macroinflammation: A Retrospective Cohort Study

Introduction: Roxadustat, the first-in-class drug for the treatment of renal anemia, has demonstrated efficacy in renal anemia with microinflammation. Additional data are needed regarding the efficacy of roxadustat on renal anemia with systemic macroinflammation. Methods: Three cohorts of renal anemia based on the basic level of high-sensitivity CRP were included. Patients with hsCRP ≤2 mg/L were selected as non-inflammation (NI) group; 2< hsCRP ≤10 mg/L as microinflammation (MI) group; hsCRP≥10 mg/L as macroinflammation (MA) group. Patients received oral roxadustat three times per week for 52 weeks. The primary end point was the hemoglobin level over weeks 12–52. The second end point was the cumulative proportion of patients achieving hemoglobin response by the end of week 12. Results: A total of 107 patients with chronic kidney diseases (CKDs) were enrolled. Overall, the baseline hemoglobin level of patients was 79.99 ± 11.20 g/L. Roxadustat could significantly increase the hemoglobin level in all of the three groups and did not show any significant difference (p > 0.05, respectively). Meanwhile, compared with that of the NI group, there was no significant difference in hemoglobin response rate in the MA group both at week 12 (p = 0.06; 95% confidence interval [CI], 0.9531–13.75) and week 52 (p = 0.37; 95% CI, 0.5080–7.937). Moreover, the hemoglobin response was independent of baseline hsCRP level (p = 0.72, 95% CI, −0.1139 to 0.0794). More importantly, roxadustat significantly reduced ferritin and serum iron levels and increased total iron-binding capacity in the three groups, which showed no significant differences among the three groups (p > 0.05, respectively). Conclusion: Roxadustat significantly improves anemia in CKD patients with systemic macroinflammation.

Lifestyle factors associated with a rapid decline in the estimated glomerular filtration rate over two years in older adults with type 2 diabetes–Evidence from a large national database in Japan

Background The present study investigated lifestyle risk factors from metabolic syndrome-related lifestyles for a rapid decline in the estimated glomerular filtration rate (eGFR) among adults aged 40–74 years with treated and untreated type 2 diabetes. Methods and results This study analyzed data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan, encompassing the period from fiscal year (FY) 2017 to FY2020. We established FY2018 as our baseline year. The subjects of this study were adults aged 40–74 in FY2018(baseline) who had type 2 diabetes and underwent specific health checkups in FY2020. We excluded adults with a medical record of kidney dialysis between FY2017 and FY2018, records of suspected type 1 diabetes between FY2017 and FY2020, or a baseline eGFR &gt;85 mL/min/1.73 m2 or missing eGFR data as of FY2020. Eventually we analyzed 573,860 individuals. The outcome variable was a rapid decline in eGFR (≥30%) during the follow-up. Exposure lifestyle factors included skipping breakfast, late-night dinners, regular smoking, a high alcohol intake, non-refreshing sleep, and a lack of habitual exercise. Logistic regression models were stratified by age (40–59 and 60–74 years) and baseline eGFR levels (60–85, 30–59, and &lt;30 mL/min/1.73 m2). Covariates included sex, a history of heart disease, a history of stroke, a history of renal failure, anemia, low-density lipoprotein, systolic blood pressure, hemoglobin A1C, body mass index, antidiabetic medications, antihypertension drugs, lipid-lowering drugs, the oral adsorbent Kremezin, non-steroidal anti-inflammatory drugs, and drugs for the treatment of renal anemia. A rapid decline in eGFR was detected in approximately 1.3% of participants (7,683 cases). In the baseline eGFR &gt;30 subgroups (60–85 or 30–59 mL/min/1.73 m2), skipping breakfast and regular smoking were associated with a rapid decline in eGFR in both age groups, while a lack of habitual exercise and late-night dinners in the 60–74 age group and non-refreshing sleep in the 40–59 age group were identified as risk factors. Additionally, skipping breakfast was a risk factor for a rapid decline in eGFR in the 60–74 age group regardless of baseline eGFR levels. In the baseline eGFR &lt;30 mL/min/1.73 m2 subgroup, skipping breakfast and non-refreshed sleep were risk factors for a rapid decline in eGFR. Conclusions We found specific lifestyle risk factors were associated with a rapid eGFR decline among people with type 2 diabetes from a nationwide database in Japan. The associations varied by baseline eGFR level, age, and sex. Lifestyle modifications may effectively prevent the aggravation of diabetic kidney disease.

Analysis of the Short-Term Curative Effect of Roxadustat in Treating Renal Anemia in Patients with Peritoneal Dialysis

Objective: To analyze the short-term curative effect of roxadustat in the treatment of renal anemia in patients with peritoneal dialysis. Methods: 70 patients with peritoneal dialysis renal anemia admitted to the dialysis department of our hospital from March 2021–March 2023 were selected as research objects, divided into a research group and a reference group according to random number drawing method, with each group consisting of 35 cases. The patients in the research group were treated with roxadustat, and those in the reference group were treated with recombinant human erythropoietin. The total efficacy, anemia index, iron metabolism index, and occurrence of adverse reactions were compared between the two groups. Results: The total efficacy of the treatment received in the research group was significantly higher than that in the reference group (P &lt; 0.05). In terms of anemia indicators, there was no statistically significant difference between the hemoglobin (Hb), the red blood cell (RBC), and the hematocrit (HCT) of both groups (P &gt; 0.05) before treatment. After treatment, the anemia indicators of the patients in the research group were significantly better than those in the reference group, (P &lt; 0.05). In terms of iron metabolism, before treatment, there was no significant difference between the total iron-binding capacity (TIBC), the transferrin (TRF), the ferritin (FER), and iron (Fe) of both groups (P &gt; 0.05). After treatment, the research group’s iron metabolism indicators were significantly better than those of the reference group (P &lt; 0.05). The incidence of adverse reactions in the research group was significantly lower than that in the reference group (P &lt; 0.05). Conclusion: The short-term curative effect of roxadustat in the treatment of peritoneal dialysis patients was demonstrated through this study, making it a viable treatment option.

Hypoxia-inducible factor-prolyl hydroxylase inhibitor Roxadustat (FG-4592) reduces renal fibrosis in Dahl salt-sensitive rats.

Although hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors have been developed for the treatment of renal anemia, their effects on cardiac and renal dysfunction remain unknown. We previously reported on Dahl salt-sensitive rats, in a rat model of salt-sensitive hypertension, that exhibited anemia and impaired expression of duodenal iron transporters after the development of hypertensive cardiac and renal dysfunction. Therefore, we investigated the effects of Roxadustat (FG-4592), an HIF-PH inhibitor, on anemia, iron regulation, and cardiac and renal dysfunction in Dahl salt-sensitive rats. Six-week-old male Dahl salt-sensitive rats were fed a normal or high-salt diet for 8 weeks. A further subset of Dahl salt-sensitive rats, that were fed a high-salt diet, was administered Roxadustat for 8 weeks. Dahl salt-sensitive rats fed a high-salt diet developed hypertension, cardiac and renal dysfunction, and anemia after 8 weeks of feeding. Roxadustat increased hemoglobin and serum erythropoietin levels in Dahl salt-sensitive rats fed a high-salt diet. With regard to the iron-regulating system, Roxadustat lowered hepatic hepcidin gene expression and increased the gene expression of duodenal iron transporters, such as cytochrome b and divalent metal transporter 1 , in Dahl salt-sensitive rats fed a high-salt diet. Roxadustat did not affect the development of hypertension and cardiac hypertrophy in Dahl salt-sensitive rats with a high-salt diet; however, Roxadustat treatment attenuated renal fibrosis in these rats. Roxadustat ameliorated anemia with affecting the gene expression of the iron-regulating system, and did not affect cardiac hypertrophy but attenuated renal fibrosis in Dahl salt-sensitive rats fed a high-salt diet.

In-Silico Aided Screening and Characterization Results in Stability Enhanced Novel Roxadustat Co-Crystal

Roxadustat (RXD) is an approved drug substances for the treatment of renal anemia. It has poor aqueous solubility and photochemical stability. This study employs a comprehensive approach to enhance the stability and physicochemical properties RXD through coformer selection and characterization. The investigation integrates delta pKa analysis, molecular complementary assessment, molecular electrostatic potential surface analysis, and machine learning techniques to predict potential co-crystal formation and binding interactions between drug molecules and coformers. The co-crystal screening which lead to in a novel RXD-nicotinamide co-crystal (RXD-NA). Experimental characterization underscores the physical and chemical stability of the co-crystals. To elucidate the supramolecular synthons and understand the intermolecular interactions in the RXD-NA co-crystal, Hirshfeld surfaces analysis, quantum theory of atoms in molecules (QTAIM) analysis and non-covalent interaction (NCI) analysis were performed. Computational analysis of photo-isomer formation aligns with experimental observations, further enhancing our understanding of RXD-coformer interactions. RXD-NA co-crystal was found photo-chemically stable as compared to free base API drug substance. This integrated methodology provides a systematic framework for informed co-crystal design, holding promise for optimizing RXD formulations based on molecular interactions and stability considerations. Consequently, this study contributes valuable insights to the field of rational drug design and formulation optimization.

Safety and Efficacy of Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors vs. Erythropoietin-Stimulating Agents in Treating Anemia in Renal Patients (With or Without Dialysis): A Meta-Analysis and Systematic Review.

Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) are a novel group of drugs used to treat renal anemia, but their benefits vary among different trials. Our meta-analysis aims to assess the safety and efficacy of HIF-PHI versus erythropoiesis-stimulating agents (ESA) in managing anemia among patients with chronic kidney disease (CKD), regardless of their dialysis status. PubMed, Embase, and Google Scholar were queried to discover eligible randomized controlled trials (RCTs). To quantify the specific effects of HIF-PHI, we estimated pooled mean differences (MDs) and relative risks (RR) with 95% CIs. Our meta-analysis involved 22,151 CKD patients, with 11,234 receiving HIF-PHI and 10,917 receiving ESA from 19 different RCTs. The HIF-PHI used included roxadustat, daprodustat, and vadadustat. HIF-PHI yielded a slight but significant increase in change in mean hemoglobin (Hb) levels (MD: 0.06, 95% CI (0.00, 0.11); p = 0.03), with the maximum significant increase shown in roxadustat followed by daprodustat as compared to ESA. There was a significant decrease in efficacy outcomes such as change in mean iron (MD: -1.54, 95% CI (-3.01, -0.06); p = 0.04), change in mean hepcidin (MD: -21.04, 95% CI (-28.92, -13.17); p < 0.00001), change in mean ferritin (MD: -16.45, 95% CI (-27.17,-5.73); p = 0.03) with roxadustat showing maximum efficacy followed by daprodustat. As for safety, HIF-PHI showed significantly increased incidence in safety outcomes such as diarrhea (MD: 1.3, 95% CI (1.11, 1.51); p = 0.001), adverse events leading to withdrawal (MD: 2.03, 95% CI (1.5, 2.74), p = 0.00001) among 25 various analyzed outcomes. This meta-analysis indicates that HIF-PHIs present a potentially safer and more effective alternative to ESAs, with increased Hb levels and decreased iron usage in CKD patients without significantly increasing adverse events. Therefore, in these patients, we propose HIF-PHI alongside renal anemia treatment.

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

Background and objectiveStudies 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 methodsMulticentre, non-interventional, retrospective study with CKD-ND stage 3a-5 and CKD-D patients treated in Spain between 2015 and 2017 (RIKAS study). ResultsThe 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. ConclusionsThe 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.

A clinical study on roxadustat for anemia in diabetic nephropathy: a 8-week study.

The development of roxadustat is a standard treatment for renal anemia, and multiple clinical trials have proved its safety and efficacy. However, less information is available from trials of the population with diabetic nephropathy (DN). This study aimed to determine whether roxadustat is effective for treating DN. This was a single-center, retrospective, institutional review board-approved cohort study. The patients with DN were chosen and given roxadustat or erythropoietin (EPO) for 8weeks. The mean hemoglobin (Hb) level after 8weeks of treatment served as the primary outcome. Alterations in the iron index and lipid levels were considered secondary objectives. Sub-group analysis was performed to observe the impact of inflammation and glycemic status on Hb. A total of 80 patients were enrolled, 40 in each group. After 8weeks of treatment, the Hb levels in the roxadustat group were higher than those in the control group. The number of patients who achieved Hb response was higher in the roxadustat group than in the control group (77.5% versus 27.5%; P < 0.001). In addition to lowering total cholesterol and low-density lipoprotein cholesterol, roxadustat decreased ferritin and elevated total iron-binding capacity. Compared to the control group, roxadustat was more beneficial for patients with an inflammatory condition and poor glycemic control. Roxadustat treatment remarkably corrected anemia in patients with DN, and its effectiveness was unaffected by inflammation or glycemic control levels. In addition, roxadustat can also reduce a patient's blood lipid level and enhance the body's use of iron. ChiCTR2200057232.

Disproportionality Analysis on Hypothyroidism With Roxadustat Using the Japanese Adverse Drug Event Database.

Hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI) is a novel agent for the treatment of renal anemia. HIF-PHI increases endogenous erythropoietin production by inhibiting the degradation of an erythropoietin transcription factor. Although beneficial effects are expected from HIF-PHI, its novel mechanism raises concerns regarding the risk of potential adverse events. The cases of hypothyroidism, which had not been reported in clinical trials, were reported after the administration of roxadustat in a real-world setting. However, the effects of HIF-PHIs on thyroid function have not yet been fully evaluated. This study aimed to assess the clinical impact of HIF-PHIs on thyroid function using the Japanese Adverse Drug Event Report database, a spontaneous reporting system in Japan, because HIF-PHIs were made available in Japan before they were available in other countries. Although a disproportionality signal for hypothyroidism was detected with roxadustat (reporting odds ratio [ROR]:22.1, 95% confidence interval [CI]:18.3-26.7, no signals were detected with another HIF-PHI, daprodustat (ROR:1.3, 95%CI:0.3-5.4), and epoetin beta pegol (ROR:1.2, 95%CI:0.5-2.7). Signals of hypothyroidism due to roxadustat were also detected regardless of age or sex. Approximately 50% of hypothyroidism cases were reported within 50 days of starting roxadustat use. These results indicate that roxadustat use may be related to the development of hypothyroidism. The need for monitoring of thyroid function should be alerted during roxadustat administration regardless of age or sex.

Roxadustat alleviates the inflammatory status in patients receiving maintenance hemodialysis with erythropoiesis-stimulating agent resistance by increasing the short-chain fatty acids producing gut bacteria

BackgroundHypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have improved the treatment of renal anemia, especially in patients resistant to erythropoiesis-stimulating agents (ESAs). HIF facilitates maintain gut microbiota homeostasis, which plays an important role in inflammation and iron metabolism, which are in turn key factors affecting ESA resistance. The current study aimed to investigate the effects of roxadustat on inflammation and iron metabolism and on the gut microbiota in patients with ESA resistance.MethodsWe conducted a self-controlled, single-center study including 30 patients with ESA resistance undergoing maintenance hemodialysis. All patients received roxadustat without iron agents for renal anemia. Hemoglobin and inflammatory factors were monitored. Fecal samples were collected before and after 3 months’ administration and the gut microbiota were analyzed by 16S ribosomal RNA gene sequencing.ResultsHemoglobin levels increased after treatment with roxadustat for 3 months (P < 0.05). Gut microbiota diversity and abundance also changed, with increases in short-chain fatty acid (SCFA)-producing bacteria (Acidaminococcaceae, Butyricicoccus, Ruminococcus bicirculans, Ruminococcus bromii, Bifidobacterium dentium, Eubacterium hallii) (P < 0.05). Serum SCFA levels also increased (P < 0.05). Inflammatory factors, including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, interferon-γ, and endotoxin gradually decreased (P < 0.05). Serum hepcidin, ferritin, and total and unsaturated iron-binding capacities decreased (P < 0.05), while soluble transferrin receptor levels increased at each time point (P < 0.05). There were no significant differences in serum iron and transferrin saturation at each time point. The abundance of Alistipes shahii was significantly negatively correlated with IL-6 and TNF-α (P < 0.05).ConclusionsRoxadustat alleviated renal anemia in patients with ESA resistance by decreasing inflammatory factors and hepcidin levels and improving iron utilization. These effects were at least partly mediated by improved diversity and abundance of SCFA-producing gut bacteria, probably via activation of HIF.

Decorated gold nanoparticles on hydroxymethylated lignin modified magnetic composite: Introducing a novel therapeutic drug for the treatment of renal anemia

Decorated gold nanoparticles on hydroxymethylated lignin modified magnetic composite: Introducing a novel therapeutic drug for the treatment of renal anemia

#4399 ALGORITHM-MANAGED DOSING AND PHARMACIST-MANAGED DOSING OF ERYTHROPOIETIN STIMULATING AGENTS IN RENAL ANEMIA: A SYSTEMATIC REVIEW

Abstract Background and Aims In clinical practice, the treatment of renal anemia is challenging. The attainment of target levels for hemoglobin is often low, due to the high incidence of infections, hyporesponsiveness to erythropoietin stimulating agents (ESA), and suboptimal prescribing of ESA and iron. Several interventions to improve the treatment of renal anemia have been developed, two of them being algorithm-managed dosing and pharmacist-managed dosing of ESA. We performed a systematic review to identify and summarize these two types of interventions and to determine their effectiveness in improving the treatment of renal anemia. Method We followed the PRISMA guidelines for systematic reviews. Studies that explored the effect of algorithm-managed and pharmacist-managed dosing of ESA in adult patients with renal anemia were evaluated for inclusion. No restrictions were set on outcome parameters. All observational and interventional studies that included a control group and had a follow-up of at least six months, were eligible for inclusion. Only full-length articles were considered for inclusion. PubMed, Embase, Web of Science, and the Cochrane Library were searched from their inception through July 2022. All included studies were evaluated by two independent reviewers. The quality of studies was assessed by the Newcastle Ottawa Scale and the risk of bias was assessed by the ROBINS-I and RoB1 tools. Data were summarized and tabulated. Studies were grouped according to intervention type, study design, and risk of bias. The protocol of this study was registered in PROSPERO (International Prospective Register of Systematic Reviews) with ID CRD42021243678. This study was funded by the Franciscus Gasthuis and Vlietland hospital. Results A total of 120 articles were assessed for inclusion, and after screening, 16 articles were included with a total number of 3777 patients. Available evidence was scarce and generally of low to moderate quality; only two RCTs could be identified. All but one of the other studies were observational in nature. The risk of bias was serious in all but one study. Study follow-up was relatively short, varying between six and thirteen months. In six studies, ESA dosing was pharmacist-managed and in one study ESA dosing was algorithm-managed, in nine studies a combination was used. The quality of the intervention description was low to moderate and interventions generally were not reproducible. Although heterogeneity was substantial for outcome parameters, four types of outcome parameters could be determined: hemoglobin/hematocrit, ESA dose and expenditure, iron status, and iron dose. Quantitative synthesis of data was not possible due to the substantial heterogeneity in outcome parameters and the high risk of bias. Therefore, the effectiveness of algorithm-managed and pharmacist-managed dosing of ESA in renal anemia could only be qualitatively assessed for the four types of outcome parameters. In six of the fifteen studies that reported on hemoglobin or hematocrit, the percentage of patients within target levels was significantly higher for the intervention group, whereas in four studies no significant difference was found. Six of the ten studies that reported on ESA dose or ESA expenditure found a significant decrease in ESA dose or expenditure in the intervention group, whereas two studies reported no significant difference. In five of the seven studies that reported on iron status, a significantly higher iron status was found in the intervention group, whereas one non-inferiority study reported no significant difference. In three of the four studies that reported on the iron dose, no significant difference was found between the intervention and the control group, whereas in one study the iron dose was significantly higher in the intervention group. Conclusion Available evidence was scarce with a high risk of bias, and quantitative data synthesis was not possible. Therefore, no definite conclusions could be drawn on the effectiveness of algorithm-managed and pharmacist-managed dosing of ESA in renal anemia. Consequently, no recommendations on the implementation of either of the two interventions could be made.

#4740 DIFFERENT ORAL IRON PREPARATIONS IN CHRONIC KIDNEY DISEASE: A COMPARATIVE ANALYSIS

Abstract Background and Aims Anaemia is common and undertreated morbidity in chronic kidney disease (CKD). Optimal approach to treatment of renal anemia is matter of ongoing debate. This is the first comparative analysis between different oral iron preparations in CKD patients. Method This prospective observational multicentre study was performed from March 2019 to May 2021. In total, 214 non-dialysis dependent CKD stage3-5 patients with 3 months follow-up were included. Inclusion &amp; exclusion criteria are mentioned in Table 1. Primary outcome was rise in Haemoglobin at 1 month/3 months &amp; rise in Transferrin saturation (TSAT) at 3 months. Treatment adherence was also evaluated. Figure 1 depicts the study model. Results Table 2 depicts demographic data while Table 3 depicts correlation between baseline haemoglobin &amp; different modifiable/non-modifiable variables. Rise in haemoglobin &amp; TSAT with different oral iron preparations has been shown in Table 4 while the ANOVA tables for clinical significance of this rise has been shown in Figures 2 &amp; 3. Rise in haemoglobin and TSAT% was highest with Ferric Pyrophosphate &amp;gt; Ferric Fumarate &amp;gt; Ferric Saccharate. Treatment adherence was highest with Ferric Pyrophosphate (100%) &amp;gt; Heme Iron Polypeptide (91.4%) &amp;gt; Ferrous Ascorbate (88.9%). Conclusion Ferric Pyrophosphate is most effective among available oral iron preparations in rising haemoglobin level. It effectively repletes iron stores &amp; has highest treatment adherence.

Three-year safety observation of subcutaneous administration of epoetin-zeta in patients with chronic renal anemia: Results from PASCO II study.

Epoetin has been used to treat patients with renal anemia since 1988. -Anti-erythropoietin antibody-mediated pure red cell aplasia (PRCA) has been associated with epoetin usage, and a PRCA incidence of 4.5per 10,000 patient-years was observed for epoetin-α (Eprex) in 2002. The PASCO II study (post-authorization safety cohort observation of Retacrit and Silapo (epoetin-ζ) administered subcutaneously for the treatment of renal anemia) followed 6,346 patients (4,501 Retacrit (group R); 1,845 Silapo (group S)) for up to 3 years of subcutaneous treatment with the biosimilar epoetin-ζ. One PRCA in 1 (0.02%) patient in group R who tested positive for neutralizing antibodies was reported. Overall, 527 adverse events of special interest (AESI) including PRCA occurred in 418 (6.60%) patients, lack of efficacy occurred in 34 (0.54%), and thromboembolic events in 389 (6.14%) patients. 41 adverse drug reactions other than AESIs were reported in 28 (0.44%) patients. The exposure-adjusted incident rate of PRCA was 0.84 per 10,000 patient-years. This real-world study showed that among patients with renal anemia receiving subcutaneous administration of the biosimilar product epoetin-ζ, the incidence rate of PRCA was substantially below the risk observed in 2002 for Eprex and that there was no immunogenicity concern or other new safety concern.

Jian-Pi-Yi-Shen formula restores iron metabolism from dysregulation in anemic rats with adenine-induced nephropathy

Ethnopharmacological relevanceJian-Pi-Yi-Shen (JPYS) is a herbal decoction being used to relieve the symptoms of chronic kidney disease (CKD) and its complications, including anemia, for over twenty years. Nonetheless, it is unclear how JPYS influences renal anemia and iron metabolism. Aim of the studyAn analysis of network pharmacology, chemical profiling, and in vivo experiments was conducted to identify the impact of JPYS on JAK2-STAT3 pathway and iron utilization in renal anemia and CKD. Materials and methodsThe chemical properties of JPYS and its exposed ingredients were detected in vivo. And based on the aforesaid chemical compounds, the potential targets and signaling pathways of JPYS for renal anemia treatment were predicted by network pharmacology. Afterward, an adenine-feeding animal model of CKD-related anemia was developed to verify the mechanism by which JPYS modulates iron recycling to treat renal anemia. Renal injury was estimated by serum creatinine (Scr), blood urea nitrogen (BUN), histopathological examinations and fibrosis degree. Western blot, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry approaches were utilized to assess the levels of JAK2, STAT3 and iron metabolism-related factors. ResultsThere were 164 active ingredients identified in JPYS, including prototypes and metabolites in vivo were identified in JPYS, and 21 core targets were found through network pharmacology based on topological characteristics. Combined with the core targets and pathway enrichment analysis, the majority of the candidate targets were associated with the JAK2-STAT3 signaling pathways. Experimental results indicated that JPYS treatment significantly decreased the expression of BUN and Scr, restored renal pathological damage, down-regulated fibrosis degree, and improved hematological parameters such as red blood cell, hemoglobin and hematocrit in CKD rats. Furthermore, JPYS significantly restored iron metabolism from dysregulation by increasing the levels of iron and ferritin in the serum, inhibiting the production of hepcidin in liver and serum, and regulating transferrin receptor 1 in bone marrow. Meanwhile, the expression of JAK2 and STAT3 was suppressed by JPYS treatment. ConclusionsBased on these results, JPYS reduces hepcidin levels by inhibiting the activation of JAK2-STAT3 signaling, thereby protecting against iron deficiency anemia.

Enarodustat Treatment for Renal Anemia in Patients With Non-dialysis Chronic Kidney Disease.

Renal anemia is a major complication in patients with chronic kidney disease (CKD), leading to morbidity and mortality. Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHI), also called HIF stabilizers, increase endogenous erythropoietin production and are expected to be novel orally administrated agents for renal anemia in CKD. Enarodustat is being developed as an oral HIF-PHI. It was recently approved in Japan and clinical development is ongoing in the USA and South Korea. Therefore, there are only a few real-world data regarding treatment of renal anemia using enarodustat. This study evaluated the efficacy of enarodustat in patients with non-dialysis CKD. Nine patients (78±11 years old, male=6, female=3) were enrolled in this study. Patients received enarodustat as first-line therapy or changed from erythropoiesis stimulating agents (2-6 mg). The observation period was 4.8±2.0 months. Levels of hemoglobin were effectively increased and maintained with enarodustat administration. C-reactive protein and serum ferritin were significantly decreased, but no change in renal function was observed. Furthermore, no serious adverse effects were recognized in all patients during the study. Enarodustat is an effective and relatively well-tolerated agent for the treatment of renal anemia in patients with non-dialysis CKD.

Recombinant erythropoietin treatment improves serum podocyte marker levels in diabetic kidney disease

BackgroundRecombinant human erythropoietin (rHuEPO) is an effective treatment for renal anemia. Recently, there is evidence to suggest that rHuEPO may reduce podocyte injury in diabetic kidney disease (DKD). However, there is no published study on the change in podocyte injury marker levels before and after rHuEPO treatment in DKD. MethodsWe measured serum nephrin and podocalyxin level, and their corresponding plasma mRNA levels, in 49 DKD patients before rHuEPO treatment, and then 12 and 36 weeks afterward. ResultsThere were reductions in serum nephrin (p = 0.002) and podocalyxin levels (p = 0.09), as well as their corresponding plasma mRNA levels (p < 0.0001 for both) after rHuEPO treatment. The change in serum nephrin and podocin level had significant inverse correlation with the concomitant change in hemoglobin level (r = −0.670 and −0.739 respectively, p < 0.0001 for both), but not with the change in kidney function or proteinuria. ConclusionSerum nephrin and podocalyxin levels and their corresponding plasma mRNA levels were significant reduced after rHuEPO treatment in DKD patients, and the change in serum nephrin and podocalyxin levels correlated with the change in hemoglobin level. The effect of rHuEPO on podocyte injury deserves further study.

Efficacy and Safety of Roxadustat in Patients with Chronic Kidney Disease: An Updated Meta-Analysis of Randomized Controlled Trials including 6,518 Patients.

Roxadustat is a newly listed oral hypoxia-inducible factor-proline enhancing enzyme inhibitor (HIF-PHI) in recent years. There have been some studies that have proved the efficacy of roxadustat on the treatment of renal anemia in patients with chronic kidney disease (CKD), but there are still different conclusions on its safety. PubMed, Embase, Cochrane, and ClinicalTrials were searched for randomized controlled trials (RCTs) that assess efficacy and safety of roxadustat treatment for anemia in CKD patients. The Cochrane Literature Quality Evaluation Scale was used to evaluate the quality of included literature. We choose fixed-effects model or random effects model for data processing based on heterogeneity. It was considered statistically significant when p value <0.05. A total of 842 articles were retrieved, and 16 trials in the 15 articles were finally included. Roxadustat treatment significantly increased Hb levels. Iron (SMD 1.43, 95% CI 0.31 to 2.55), total iron-binding capacity (SMD 2.06, 95% CI 0.91 to 3.22), ferritin (WMD 21.33, 95% CI 3.04 to 39.62), transferrin saturation (SMD 4.17, 95% CI 3.90 to 4.45), and LDL-cholesterol (SMD -0.64, 95% CI -0.73 to -0.55) showed statistical significance in dialysis-dependent (DD) study. And hepcidin (SMD -1.56, 95% CI -2.63 to -0.50), transferrin (SMD 1.80, 95% CI 1.53 to 2.06), total iron-binding capacity (SMD 1.62, 95% CI 1.39 to 1.86), total cholesterol (SMD -0.88, 95% CI -1.68 to -0.09), ferritin (WMD -52.68, 95% CI -62.68 to -42.67), transferrin saturation (SMD -5.57, 95% CI -7.47 to -3.68), and LDL-cholesterol (SMD -0.85, 95% CI -1.37 to -0.34) showed statistical significance in not dialysis-dependent (NDD) study. In terms of safety, roxadustat treatment did not increase risk of total adverse events either in dialysis-dependent or not dialysis-dependent patients. Roxadustat can effectively improve anemia in patients with chronic kidney disease. There was no significant difference in total adverse events compared with the control group.