Anemia In Renal Patients Research Articles

Renoprotective Effects of Daprodustat in Patients with Chronic Kidney Disease and Renal Anemia.

Many large-scale studies revealed that exogenous erythropoietin, erythropoiesis-stimulating agents, have no renoprotective effects. We reported the renoprotective effects of endogenous erythropoietin production on renal function in ischemic reperfusion injury (IRI) of the kidney using the prolyl hydroxylase domain (PHD) inhibitor, Roxadustat. The purpose of this study was to investigate the effects of daprodustat on the progression of chronic renal failure. We retrospectively investigated the effects of daprodustat on the progression of chronic renal failure and renal anemia in patients with stages 3a-5 chronic kidney diseases (estimated glomerular filtration rate, eGFR < 60 mL/min/1.73 m2). The results show that daprodustat largely slowed the reduction in eGFR. The recovery of renal function was observed in some patients. Daprodustat is useful not only for renal anemia but also for the preservation of renal function. The renoprotective effect of daprodustat was small in patients with serum creatinine larger than 3-4 mg/dL because of low residual renal function. The appearance of renal anemia would be a sign of the time to start using daprodustat.

#2070 Associations of fecal and plasma levels of SCFAs with gut microbiota and clinical characteristics in non-dialysis renal anemia patients

Abstract Background and Aims Renal anemia is one of the most common complications of Chronic Kidney Disease (CKD). The gut-kidney axis hypothesis has led to numerous studies showing that patients with CKD have a distinct gut microbiota structure compared with controls and that changes in gut microbiota correlate with disease severity and progression. The short-chain fatty acids (SCFAs) are speculated to be pivotal in the gut-kidney crosstalk. However, the role of SCFAs in renal anemia has not been elucidated. This study aimed to explore and compare the fecal and plasma levels of SCFAs in non-dialysis renal anemia patients and healthy controls to reveal the potential interactions among SCFAs, gut microbiota, and clinical features of renal anemia, which may provide new light on further studies. Method A cohort of 30 non-dialysis renal anemia patients and 20 healthy controls were recruited from the First Affiliated Hospital of Zhengzhou University. Gut microbiota was analyzed using 16S rRNA gene amplification sequencing. Fecal and plasma concentrations of SCFAs were measured using GC-MS/MS platform. The clinical characteristics of patients with renal anemia and controls were evaluated. Results Renal anemia patients displayed altered microbiota composition compared to healthy subjects. The relative abundance of Enterobacterales, Enterobacteriaceae, Escherichia-Shigella, and Escherichia-coli were higher in patients with renal anemia, and the Lachnospiraceae family decreased in renal anemia patients. In contrast, the relative abundance of Lachnospirales, Lachnospiraceae, and Bacteroides vulgatus was higher in the control group. Patients with renal anemia had higher fecal and plasma concentrations of SCFAs compared to controls. The fecal and plasma concentrations of SCFAs were significantly different not only between the patients with renal anemia and controls but also in the different severity of renal anemia. Moreover, different types of SCFAs are intimately associated with clinical characteristics. The applications of medications may exert effects on the fecal and plasma SCFAs. A positive correlation was obtained between Lachnospirales and the plasma SCFAs. The levels of acetic acid and caproic acid in fecal and the levels of acetic acid, propionic acid, and butyric acid in plasma were all positively correlated with the abundance of Cyanobacteria. Conclusion The gut metabolites SCFAs are tightly linked to the alterations of gut microbiota and clinical characteristics of renal anemia. Further studies are warranted to elucidate the relationships more in-depth.

#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.

#1174 Prevalence and factors contributing to erythropoietin hyporesponsiveness in CKD patients on hemodialysis: a single center, cross sectional study

Abstract Background and Aims Anemia, one of the most frequent early complications of CKD is associated with a reduced QOL, cardiovascular morbidity, accelerated CKD progression, and it is an independent predictor of mortality. The successful management of anemia is a vital part of patient care, that improves clinical outcomes. According to the literature, 90% of renal anemia patients responded in a dose-dependent manner to rHu EPO, whereas the remaining 5–10% of patients had either a blunted or absent response to this agent, despite high-dose therapy. Erythropoietin hyporesponsiveness is a strong, independent predictor of mortality risk. Various factors have been associated with ESA hypo responsiveness in different studies. Both the inability to achieve a target hemoglobin and administration of high dose epoetin -alpha are associated with increased risk of CVD complications. AIMS AND OBJECTIVES Method STUDY PERIOD: December 2021 to DECEMBER 2022 STUDY DESIGN: Observational cross sectional study. SAMPLE SIZE: N = 144: Patients older than 18 years old undergoing hemodialysis for at least 3 months before the study were enrolled. History of inpatient treatment, infection, bleeding or transfusion within the last month, hematologic disorders sickle cell disease, MDS and active malignancies were excluded. Required parameters were recorded on every month follow up;Demographic data, Cause of ESRD, Dialysis vintage, ESAs dose (Unit/week), type, Medications history; Dose (mg/week) of iron preparation &amp; use of medication like ACEi, ARBs, dialysis adequacy(Kt/V), haemogram, Liver function test, Kidney function test Iron profile, Serum parathyroid hormone, Serum calcium &amp; phosphorus, CRP, Anti EPO antibodies(if required). We used the European Best Practice Guideline (EBPG) II definition to define ESA hyporesponsiveness for our study purpose(Increase in erythropoietin dose ≥25% to maintain the same Hgb level or &amp;lt; 1 mg/dL gain in Hgb after 4 weeks. EHRI was calculated by dividing weekly ESA dose per kilogram of body weight (IU/Kg/W) by hemoglobin level (g/dL). Based on EHRI, patients were assigned or divided into 2 groups. Group I (EHRI&amp;lt;16) and Group II (EHRI ≥ 16). Patients in the Group II were labeled as erythropoietin hyporesponsive patients and they were compared with others in order to identify the impact of different factors on ESA. Results Among 144 patients, 80 were male and 64 females and 28.4% were diabetic. Mean EHRI were calculated for all patients and based on EHRI pts were divided into two study groups, Gr-I (EHRI&amp;lt;16) &amp; Gr-II(EHRI ≥16). EHRI ≥16 group was considered as ESA hyporesponsive groups. The study parameters were compared between the groups and its statistical significance measured. The overall prevalence of ESA hyporesponsive in our study was 26.3%. Conclusion The overall prevalence of ESA hyporesponsive in our study was 26.3%. Iron deficiency anemia, inadequate dialysis, chronic inflammation, malnutrition, secondary hyperparathyroidism and increased dialysis vintage were the factors associated with ESA hyporesponsiveness.

The drug-specific properties of hypoxia-inducible factor-prolyl hydroxylase inhibitors in mice reveal a significant contribution of the kidney compared to the liver to erythropoietin induction

AimsKidney disease often leads to anemia due to a defect in the renal production of the erythroid growth factor erythropoietin (EPO), which is produced under the positive regulation of hypoxia-inducible transcription factors (HIFs). Chemical compounds that inhibit HIF-prolyl hydroxylases (HIF-PHs), which suppress HIFs, have been developed to reactivate renal EPO production in renal anemia patients. Currently, multiple HIF-PH inhibitors, in addition to conventional recombinant EPO reagents, are used for renal anemia treatment. This study aimed to elucidate the therapeutic mechanisms and drug-specific properties of HIF-PH inhibitors. Methods and key findingsGene expression analyses and mass spectrometry revealed that HIF-PH inhibitors (daprodustat, enarodustat, molidustat, and vadadustat) alter Epo gene expression levels in the kidney and liver in a drug-specific manner, with different pharmacokinetics in the plasma and urine after oral administration to mice. The drug specificity revealed the dominant contribution of EPO induction in the kidneys rather than in the liver to plasma EPO levels after HIF-PH inhibitor administration. We also found that several HIF-PH inhibitors directly induce duodenal gene expression related to iron intake, while these drugs indirectly suppress hepatic hepcidin expression to mobilize stored iron for hemoglobin synthesis through induction of the EPO-erythroferrone axis. SignificanceRenal EPO induction is the major target of HIF-PH inhibitors for their therapeutic effects on erythropoiesis. Additionally, the drug-specific properties of HIF-PH inhibitors in EPO induction and iron metabolism have been shown in mice, providing useful information for selecting the proper HIF-PH inhibitor for each renal anemia patient.

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.

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.

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.

Changes in Metabolomic Profiles Induced by Switching from an Erythropoiesis-Stimulating Agent to a Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor in Hemodialysis Patients: A Pilot Study.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of medications for managing renal anemia in patients with chronic kidney disease (CKD). In addition to their erythropoietic activity, HIF-PHIs exhibit multifaceted effects on iron and glucose metabolism, mitochondrial metabolism, and angiogenesis through the regulation of a wide range of HIF-responsive gene expressions. However, the systemic biological effects of HIF-PHIs in CKD patients have not been fully explored. In this prospective, single-center study, we comprehensively investigated changes in plasma metabolomic profiles following the switch from an erythropoiesis-stimulating agent (ESA) to an HIF-PHI, daprodustat, in 10 maintenance hemodialysis patients. Plasma metabolites were measured before and three months after the switch from an ESA to an HIF-PHI. Among 106 individual markers detected in plasma, significant changes were found in four compounds (erythrulose, n-butyrylglycine, threonine, and leucine), and notable but non-significant changes were found in another five compounds (inositol, phosphoric acid, lyxose, arabinose, and hydroxylamine). Pathway analysis indicated decreased levels of plasma metabolites, particularly those involved in phosphatidylinositol signaling, ascorbate and aldarate metabolism, and inositol phosphate metabolism. Our results provide detailed insights into the systemic biological effects of HIF-PHIs in hemodialysis patients and are expected to contribute to an evaluation of the potential side effects that may result from long-term use of this class of drugs.

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.

#3258 MECHANISMS OF HEMOGLOBIN CYCLING IN ANEMIC END-STAGE RENAL DISEASE PATIENTS TREATED WITH ERYTHROPOIESIS-STIMULATING AGENTS

Abstract Background and Aims A considerable fraction of renal anemia patients treated with erythropoiesis-stimulating agents (ESAs) experience hemoglobin ‘cycling’ periods during which hemoglobin levels periodically over- and undershoot a specified target range [1]. This is an undesired condition, which also necessitates frequent adjustment of the drug dose. The causes of hemoglobin cycling are not understood on a fundamental level. Through a combination of biomedical simulations and quantitative data analysis, we aimed at identifying mechanisms of hemoglobin cycling and the physiological and treatment-related factors contributing to cycling. Method We developed a biomedical modeling and simulation scheme that captures the essential features of ESA therapy involving a minimal feedback model for the delayed hemoglobin response after ESA administration and a stereotypic ESA dosing algorithm [2]. In this model, hemoglobin cycling emerged as a consequence of the delayed feedback between a patient's physiological response to ESA administrations and the resulting dose adjustments, which mutually maintain themselves in a causal loop. Guided by this model, we developed a set of statistical indicators that can detect this type of self-sustained hemoglobin cycling in clinical time series, including the Pearson cross correlation between hemoglobin levels and given ESA doses and hemoglobin standard deviation. Results A model analysis showed that physiological and treatment-related delays in hemoglobin response and ESA dose adjustment and administration were a major driver of hemoglobin cycling. Such delays are caused, e.g., by the cell cycle and maturation times of erythroid progenitors in response to ESA administration on one hand and restrictions in ESA dose changes and typical administration intervals on the other hand. In clinical time series, this was reflected by a systematic delay between bursts of ESA administrations and hemoglobin cycles. We quantified 1134 such datasets from hemodialysis patients and found that more persistent cycling was associated with negative correlation coefficients between hemoglobin levels and ESA doses. Using model simulations with similar behavior, we found that many patient- and therapy-related factors affect the hemoglobin dynamics in several (sometimes competing) ways, obfuscating their overall effect. For example, a larger RBC lifespan generally both entails higher hemoglobin levels but also prolongs the effect of ESA misdosings. However, model simulations suggested that longer RBC lifespans generally have a favorable effect in requiring less ESA on average and preventing hemoglobin cycling. Moreover, the model showed that for a given patient, ESA-specific properties such as its half-life may have a ‘sweet spot’ range of values within which hemoglobin cycling was suppressed while still showing a desired effect on the hemoglobin dynamics. Furthermore, the choice of the hemoglobin target window had an impact on hemoglobin stability. If the window was chosen too small, more frequent dose adjustments could initiate and maintain a cycling behavior. Conclusion Hemoglobin cycling in renal anemia patients often emerges from a complex interplay of multiple physiological and ESA treatment-related factors, with delays between ESA administration, hemoglobin response and subsequent ESA dose adjustment being a key driver of cycling. Biomedical modeling and simulation can aid in systematically exploring these interplays and find improved dosing strategies.

The treatment effects and cardiovascular events of high-dose intravenous iron for hemodialysis patients with renal anemia: A systematic review and meta-analysis.

Hemodialysis patients are common to have renal anemia in the nephrology practice. For the renal anemia, the high-dose iron from the intravenous route is an important treatment option. We can understand the treatment effects and cardiovascular events of high-dose intravenous iron reviewing the randomized clinical trials. We compared the high-dose and low-dose iron treatments to find if the high-dose intravenous iron can influence the hematological parameters more significantly than the low-dose iron. The cardiovascular events were also analyzed for the high-dose iron treatment. Six studies with a total of 2422 renal anemia patients under hemodialysis were enrolled. We focused the outcomes of hemoglobin, transferrin saturation percentage, ferritin, erythropoietin dose, and cardiovascular events. The high-dose intravenous iron might be associated with a greater number of ferritin, transferrin saturation percentage, and hemoglobin. In addition, the erythropoietin dose was less needed to maintain the ideal hemoglobin range in the high-dose intravenous iron group. In current meta-analysis, the high-dose intravenous iron might show the superior effects on the ferritin, transferrin saturation percentage, and hemoglobin levels and needed dose of erythropoietin when compared to low-dose iron treatment.

Physician Compliance With a Computerized Clinical Decision Support System for Anemia Management of Patients With End-stage Kidney Disease on Hemodialysis: Retrospective Electronic Health Record Observational Study.

Previous studies on clinical decision support systems (CDSSs) for the management of renal anemia in patients with end-stage kidney disease undergoing hemodialysis have previously focused solely on the effects of the CDSS. However, the role of physician compliance in the efficacy of the CDSS remains ill-defined. We aimed to investigate whether physician compliance was an intermediate variable between the CDSS and the management outcomes of renal anemia. We extracted the electronic health records of patients with end-stage kidney disease on hemodialysis at the Far Eastern Memorial Hospital Hemodialysis Center (FEMHHC) from 2016 to 2020. FEMHHC implemented a rule-based CDSS for the management of renal anemia in 2019. We compared the clinical outcomes of renal anemia between the pre- and post-CDSS periods using random intercept models. Hemoglobin levels of 10 to 12 g/dL were defined as the on-target range. Physician compliance was defined as the concordance of adjustments of the erythropoietin-stimulating agent (ESA) between the CDSS recommendations and the actual physician prescriptions. We included 717 eligible patients on hemodialysis (mean age 62.9, SD 11.6 years; male n=430, 59.9%) with a total of 36,091 hemoglobin measurements (average hemoglobin and on-target rate were 11.1, SD 1.4, g/dL and 59.9%, respectively). The on-target rate decreased from 61.3% (pre-CDSS) to 56.2% (post-CDSS) owing to a high hemoglobin percentage of >12 g/dL (pre: 21.5%; post: 29%). The failure rate (hemoglobin <10 g/dL) decreased from 17.2% (pre-CDSS) to 14.8% (post-CDSS). The average weekly ESA use of 5848 (SD 4211) units per week did not differ between phases. The overall concordance between CDSS recommendations and physician prescriptions was 62.3%. The CDSS concordance increased from 56.2% to 78.6%. In the adjusted random intercept model, the post-CDSS phase showed increased hemoglobin by 0.17 (95% CI 0.14-0.21) g/dL, weekly ESA by 264 (95% CI 158-371) units per week, and 3.4-fold (95% CI 3.1-3.6) increased concordance rate. However, the on-target rate (29%; odds ratio 0.71, 95% CI 0.66-0.75) and failure rate (16%; odds ratio 0.84, 95% CI 0.76-0.92) were reduced. After additional adjustments for concordance in the full models, increased hemoglobin and decreased on-target rate tended toward attenuation (from 0.17 to 0.13 g/dL and 0.71 to 0.73 g/dL, respectively). Increased ESA and decreased failure rate were completely mediated by physician compliance (from 264 to 50 units and 0.84 to 0.97, respectively). Our results confirmed that physician compliance was a complete intermediate factor accounting for the efficacy of the CDSS. The CDSS reduced failure rates of anemia management through physician compliance. Our study highlights the importance of optimizing physician compliance in the design and implementation of CDSSs to improve patient outcomes.

Effects of hypoxia-inducible factor-prolyl hydroxylase inhibitors vs. erythropoiesis-stimulating agents on iron metabolism in non-dialysis-dependent anemic patients with CKD: A network meta-analysis.

To compare the effects of five hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs), two erythropoiesis-stimulating agents (ESAs), and placebo on iron metabolism in renal anemia patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). Five electronic databases were searched for studies. Randomized controlled clinical trials comparing HIF-PHIs, ESAs, and placebo in NDD-CKD patients were selected. The statistical program used for network meta-analysis was Stata/SE 15.1. The main outcomes were the change in hepcidin and hemoglobin (Hb) levels. The merits of intervention measures were predicted by the surface under the cumulative ranking curve method. Of 1,589 original titles screened, data were extracted from 15 trials (3,228 participants). All HIF-PHIs and ESAs showed greater Hb level-raising ability than placebo. Among them, desidustat demonstrated the highest probability of increasing Hb (95.6%). Hepcidin [mean deviation (MD) = -43.42, 95%CI: -47.08 to -39.76], ferritin (MD= -48.56, 95%CI: -55.21 to -41.96), and transferrin saturation (MD = -4.73, 95%CI: -5.52 to -3.94) were decreased, while transferrin (MD = 0.09, 95%CI: 0.01 to 0.18) and total iron-binding capacity (MD = 6.34, 95%CI: 5.71 to 6.96) was increased in HIF-PHIs versus those in ESAs. In addition, this study observed heterogeneity in the ability of HIF-PHIs to decrease hepcidin. Compared with darbepoetin, only daprodustat (MD = -49.09, 95% CI: -98.13 to -0.05) could significantly reduce hepcidin levels. Meanwhile, daprodustat also showed the highest hepcidin-lowering efficacy (84.0%), while placebo was the lowest (8.2%). For NDD-CKD patients, HIF-PHIs could ameliorate functional iron deficiency by promoting iron transport and utilization, which may be achieved by decreasing hepcidin levels. Interestingly, HIF-PHIs had heterogeneous effects on iron metabolism. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=242777, Identifier CRD42021242777.

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.

Integrated proteomic and metabolomic profiling of urine of renal anemia patients uncovers the molecular mechanisms of roxadustat.

Roxadustat (FG-4592) is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) prescribed to patients with low hemoglobin associated with chronic kidney disease. Due to the various HIF-mediated adaptive responses, FG-4592 has attracted significant interest for therapeutic use against various diseases. However, the clinical application of Roxadustat remains limited due to a lack of understanding of its underlying mechanisms. Herein, we performed label-free quantitative liquid chromatography with tandem mass spectrometry (LC-MS-MS) proteomics and un-targeted metabolomics to study the protein and metabolite alterations in the urine of renal anemia patients before and after Roxadustat therapy. The results were validated by parallel reaction monitoring (PRM). A total of 46 proteins (including 15 upregulated and 31 downregulated proteins) and 207 metabolites were significantly altered after Roxadustat treatment in urine samples obtained from renal anemia patients. Then, the altered proteins were further validated by PRM. Finally, proteomics combined with metabolomics analysis revealed that the Ras signalling pathway, cysteine and methionine metabolism, arginine and proline metabolism, and cholesterol metabolism were the main pathways altered by Roxadustat treatment. The multi-omics analysis revealed that Roxadustat could alter the protein expression and reverse the potential metabolic changes to exert hypotensive, lipid metabolic regulation, and renoprotective effects in clinical practice.

Efficacy of oral ferric citrate hydrate treatment for anemia caused by niraparib: a case report

BackgroundMaintenance therapy using poly(adenosine diphosphate-ribose)polymerase inhibitors may have adverse events, including hematological toxicity, and may limit therapeutic potential in patients with cancer. Niraparib-induced anemia negatively impacts one’s quality of life. Its amelioration by ferrous iron (for example, sodium ferrous citrate), folic acid, or vitamin B12 has not been supported. Oral ferric citrate hydrate increases circulating levels of iron and hepatic iron accumulation, improving renal anemia in patients with kidney failure receiving hemodialysis. The uptake of ferric iron is considered to be much higher than that of ferrous iron.Case presentationThe admitted patient was a 57-year-old Japanese woman with stage IIIB ovarian cancer who underwent primary debulking surgery and standard carboplatin–paclitaxel chemotherapy combined with bevacizumab, followed by niraparib (200 mg/day) maintenance therapy. The patient started oral SFC (100 mg/day) to treat niraparib-related anemia. However, she required two units of packed red blood cell transfusions three times within 3 months after starting niraparib treatment. The patient was diagnosed with niraparib-related anemia. The blood test results after 1 month from the start of niraparib treatment were as follows: red blood cells, 211 × 104/μL; hemoglobin, 7.0 g/dL; hematocrit, 20.8%; reticulocyte, 0.2%; platelet count, 18.0 × 104/μL. She was switched to oral ferric citrate hydrate with a dose of 500 mg per day and resumed niraparib treatment. She did not experience grade 3 niraparib-related hematological toxicity and achieved blood transfusion independence.ConclusionsFerric citrate hydrate may be a safe, effective, and well-tolerated oral drug for treating patients with niraparib-related anemia.

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.

Comparison of efficacy of roxadustat and erythropoietin for the treatment of renal anemia in patients with chronic kidney disease: a retrospective study.

Renal anemia is a common complication in patients with end-stage renal disease (ESRD). Both roxadustat and recombinant human erythropoietin (rhEPO) are alternative option for patients with renal anemia. However, the adverse events of rhEPO limited the wide use of it and the concrete difference of real clinical efficacy of rhEPO and roxadustat was still uncertain. This study aimed to assess the clinical efficacy of roxadustat for improving renal anemia in patients with chronic kidney disease. A retrospective cohort study of 790 consecutive patients with renal anemia treated with roxadustat and rhEPO was conducted at the Zhejiang Provincial People's Hospital. Patients were classified into two groups: roxadustat (n=95) and rhEPO (n=695). Baseline characteristics were compared in two groups. After propensity-score matching at a 1:3 ratio, we compared the efficacy of roxadustat and rhEPO in improving anemia, mainly using the Mann-Whitney U test. The follow-up period lasted 24 weeks. The baseline characteristics were comparable between the two groups after propensity-score matching. There were no significant differences in the hemoglobin levels and estimated glomerular filtration rates (eGFRs) of the two groups before roxadustat or rhEPO treatment (P>0.05). The hemoglobin level after 4 weeks of treatment was 96 g/L in the roxadustat group, and the increase from baseline was 10 g/L; in the rhEPO group, these values were 87 and 6 g/L, respectively (P<0.001). After 12 weeks of treatment, the hemoglobin level and change from baseline were 105 and 15 g/L in the roxadustat group and 94 and 11 g/L in the rhEPO group, respectively (P<0.001). Similar results were observed after 24 weeks of treatment; the hemoglobin level and change from baseline were 105 and 17 g/L in the roxadustat group and 97 and 14 g/L in the rhEPO group (P=0.001). This retrospective study demonstrated that orally administered roxadustat improved hemoglobin levels more than rhEPO in patients with CKD and anemia.

Comparison of risk of peritoneal dialysis-associated peritonitis between roxadustat and recombinant human erythropoietin in peritoneal dialysis patients: a retrospective comparative cohort study

Roxadustat and recombinant human erythropoietin (rhuEPO) have been approved for the treatment of renal anemia in patients undergoing dialysis. The comparison of risk of peritoneal dialysis (PD)-associated peritonitis between roxadustat and rhuEPO in PD patients remains uncertain. We aimed to compare the risk of PD-associated peritonitis between roxadustat and rhuEPO and examine possible modifiers for the comparison in PD patients. A total of 437 PD patients with renal anemia (defined as hemoglobin ≤10.0 g/dL) from 4 centers were selected. Participants were scheduled for follow-up every 1-3 months at each center. We compared differences in baseline characteristics by medication group and 1:1 matching group based on propensity scores. PD-associated peritonitis was defined according to the International Society for Peritoneal Dialysis guidelines. Univariable and multivariable Cox proportional hazard analyses were performed to compare the risk of PD-associated peritonitis between roxadustat and rhuEPO in PD patients. Propensity score matching method was used to examine the robustness of results. A total of 437 participants, including 291 in roxadustat group and 146 in rhuEPO group, were included in the current study, respectively. During a median follow-up of 13.0 (25th-75th, 10.0-15.0) months, PD-associated peritonitis occurred in 68 patients, including 26 of 291 (0.10 episodes per patient-year) patients in the roxadustat group and 42 of 146 (0.27 episodes per patient-year) patients in the rhuEPO group. Overall, compared to patients in the rhuEPO group, the roxadustat group (hazard ratio, 0.345; 95% confidence interval: 0.202-0.589) was associated with a lower risk of PD-associated peritonitis with adjustment of use of roxadustat medication, age, sex, hypertension status, diabetes status, dialysis vintage, serum potassium, hemoglobin, and albumin. Furthermore, the results were consistent with the propensity score analysis. None of the variables, including age, sex, body mass index, PD vintage, presence of residual renal function, hemoglobin, albumin, serum potassium, and C-reactive protein levels, significantly modified the associations. Our study demonstrated that compared with rhuEPO, roxadustat may reduce the risk of PD-associated peritonitis in PD patients, highlighting the importance of roxadustat for the prevention of PD-associated peritonitis in PD patients.