Anemia Of Chronic Disease Research Articles

Glioblastoma multiforme influence on the elemental homeostasis of the distant organs: the results of inter-comparison study carried out with TXRF method

Glioblastoma (GBM) is a fast-growing and aggressive brain tumor which invades the nearby brain tissue but generally does not spread to the distant organs. Nonetheless, if untreated, GBM can result in patient death in time even less than few months from the diagnosis. The influence of the tumor progress on organs other than brain is obvious but still not well described. Therefore, we examined the elemental abnormalities appearing in selected body organs (kidney, heart, spleen, lung) in two rat models of GBM. The animals used for the study were subjected to the implantation of human GBM cell lines (U87MG and T98G) characterized by different levels of invasiveness. The elemental analysis of digested organ samples was carried out using the total reflection X-ray fluorescence (TXRF) method, independently, in three European laboratories utilizing various commercially available TXRF spectrometers. The comparison of the data obtained for animals subjected to T98G and U87MG cells implantation showed a number of elemental anomalies in the examined organs. What is more, the abnormalities were found for rats even if neoplastic tumor did not develop in their brains. The most of alterations for both experimental groups were noted in the spleen and lungs, with the direction of the found element changes in these organs being the opposite. The observed disorders of element homeostasis may result from many processes occurring in the animal body as a result of implantation of cancer cells or the development of GBM, including inflammation, anemia of chronic disease or changes in iron metabolism. Tumor induced changes in organ elemental composition detected in cooperating laboratories were usually in a good agreement. In case of elements with higher atomic numbers (Fe, Cu, Zn and Se), 88% of the results were classified as fully compliant. Some discrepancies between the laboratories were found for lighter elements (P, S, K and Ca). However, also in this case, the obtained results fulfilled the requirements of full (the results from three laboratories were in agreement) or partial agreement (the results from two laboratories were in agreement).

A novel scenario in the therapeutic management of anemia of chronic kidney disease: placement and use of roxadustat.

Anemia is a frequent and early chronic kidney disease (CKD) complication. Its management is currently based on oral or intravenous iron supplements, erythropoiesis-stimulating agents, and red blood cell transfusions, when the benefits of transfusion outweigh the risks. Anemia in CKD patients is underdiagnosed and undertreated. Current standard of care is associated with challenges and therefore new treatment approacheshave been sought. Hypoxia-inducible factor-prolyl-hydroxylase enzyme inhibitors are a new class of orally administered drugs used to treat anemia associated with CKD. Small-molecule hypoxia-inducible factor-prolyl-hydroxylase inhibitors have a novel mechanism of action that activates the hypoxia-inducible factor (oxygen-sensing) pathway resulting in a coordinated erythropoietic response, leading to increased endogenous erythropoietin production, improved iron absorption and transport, and reduced hepcidin. Roxadustat is the first hypoxia-inducible factor-prolyl-hydroxylase inhibitor approved by the European Medicines Agency (EMA) and reimbursed in Italy by the Italian Medicines Agency (AIFA) for the treatment of adult patients with symptomatic CKD-related anemia. This authorization was based on the outcome of a globally-conducted phase 3 clinical trial program comprising eight pivotal multicenter randomized studies. In the absence of up-to-date guidelines, we performed a critical appraisal of the placement and use of roxadustat in this therapeutic context.

Phenome-wide association study identifies new clinical phenotypes associated with Staphylococcus aureus infections.

Phenome-Wide Association study (PheWAS) is a powerful tool designed to systematically screen clinical observations derived from medical records (phenotypes) for association with a variable of interest. Despite their usefulness, no systematic screening of phenotypes associated with Staphylococcus aureus infections (SAIs) has been done leaving potential novel risk factors or complications undiscovered. We tailored the PheWAS approach into a two-stage screening procedure to identify novel phenotypes correlating with SAIs. The first stage screened for co-occurrence of SAIs with other phenotypes within medical records. In the second stage, significant findings were examined for the correlations between their age of onset with that of SAIs. The PheWAS was implemented using the medical records of 754,401 patients from the Marshfield Clinic Health System. Any novel associations discovered were subsequently validated using datasets from TriNetX and All of Us, encompassing 109,884,571 and 118,538 patients respectively. Forty-one phenotypes met the significance criteria of a p-value < 3.64e-5 and odds ratios of > 5. Out of these, we classified 23 associations either as risk factors or as complications of SAIs. Three novel associations were discovered and classified either as a risk (long-term use of aspirin) or complications (iron deficiency anemia and anemia of chronic disease). All novel associations were replicated in the TriNetX cohort. In the All of Us cohort, anemia of chronic disease was replicated according to our significance criteria. The PheWAS of SAIs expands our understanding of SAIs interacting phenotypes. Additionally, the novel two-stage PheWAS approach developed in this study can be applied to examine other disease-disease interactions of interest. Due to the possibility of bias inherent in observational data, the findings of this study require further investigation.

Endoscopic and Colonoscopy Investigation in Anemia: Yield of these Procedures in Identifying a Gastrointestinal Cause

Introduction: Anemia is a common laboratory finding among patients and many inpatients are worked up during their hospital stay with either endoscopy and/or colonoscopy. An evidence-based approach is warranted to determine this course of action is likely to affect treatments and outcomes especially in the inpatient population in other types of anemia as well. Methods: In this retrospective analysis, charts were obtained for inpatients that underwent either endoscopy and/or colonoscopy with anemia during the period of over 5 years at a community hospital. These patient records were reviewed, and data was collected into a standardized collection tool for statistical analysis. Bonferroni method was used to correct for multiple testing parameters. Results: Out of 173 total patients, endoscopic/colonoscopy findings were positive in 6/5 with untyped anemia, 34/20 with anemia of chronic disease (ACD), 49/29 with iron deficiency anemia (IDA), and 34/26 with anemia due to other causes (ADOC) respectively. Positive findings in either endoscopy and/or colonoscopy 75.47%, 91.38%, 72.73%, and 100% with a p value of .026. Conclusion: In cases of anemia without signs of active gastrointestinal bleeding, inpatient examination by either endoscopy and/or colonoscopy found a probable cause in most patients irrespective of the type of anemia.

Efficacy of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor on Clinical Parameters in Patients with Heart Failure.

Background and Objectives: Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors have been approved as an oral drug for treating anemia in chronic kidney disease (CKD). However, the clinical effect of HIF-PH inhibitors in patients with heart failure (HF) is unclear. Thus, this study investigated the effect of HIF-PH inhibitors in patients with HF and CKD. Materials and Methods: Thirteen patients with HF complicated by renal anemia who were started on vadadustat were enrolled. Clinical parameters were compared before and 1 month after vadadustat was started. Results: The mean left ventricular ejection fraction was 49.8 ± 13.9%, and the mean estimated glomerular filtration rate was 29.4 ± 10.6 mL/min/1.73 m2. The hemoglobin level was significantly increased (9.7 ± 1.3 mg/dL vs. 11.3 ± 1.3 mg/dL, p < 0.001), and the N-terminal prohormone of B-type natriuretic peptide was significantly decreased after the introduction of vadadustat [4357 (2651-15182) pg/mL vs. 2367 (1719-9347) pg/mL, p = 0.002]. Furthermore, the number of patients with New York Heart Association functional class ≥ 3 was also decreased after the introduction of vadadustat [8 (61.5%) vs. 1 (7.7%), p = 0.008]. No thromboembolic adverse events or new tumors were observed in any patient during the study period. Conclusions: The introduction of vadadustat in patients with HF complicated by renal anemia led to improvements in anemia and symptoms of HF.

Efficacy and safety of molidustat for the anemia of chronic kidney disease: A systematic review and meta-analysis of randomized controlled trials

Objective: Anemia is a prevalent complication in chronic kidney disease (CKD) patients, necessitating effective management for improved clinical outcomes. This systematic review and meta-analysis aim to evaluate the efficacy and safety of molidustat for iron-deficient anemia in CKD patients. Methods: A comprehensive search of Ovid MEDLINE, Web of Science, PubMed, and Cochrane CENTRAL was conducted. The primary efficacy outcomes included changes in hemoglobin (Hb) levels during follow-up and at week 16. Inverse variance random effects models were used for main analysis. The overall risk of bias (RoB) was assessed using the Cochrane RoB2 tool. Results: Six randomized controlled trials (RCTs) involving 999 patients were included. The meta-analysis for Hb change during follow-up revealed a mean difference (MD) of 0.09 (95% CI, -0.49 to 0.67), p=0.071, with an I² of 81% whereas Hb change at week 16 showed an MD of 0.12 (95% CI, -0.40 to 0.64), p=0.65 with an I² of 85%. Notably, changes in hepcidin levels during follow-up (MD -16.55, 95% CI -29.54 to -3.56) favored molidustat but not changes in total iron binding capacity at week 16 (MD 2.89, 95% CI 1.74 to 4.04). However, the impact of molidustat on transferrin saturation, iron levels, and ferritin levels showed comparable results. Regarding safety outcomes, no significant differences were observed in treatment emergent adverse events (TEAE) leading to death, patients with ≥1 major adverse cardiovascular event (MACE), hyperkalemia, any TEAE, and any serious TEAE. The risk of CKD worsening was increased with molidustat (MD 1.79, 95% CI 1.03 to 3.10). Subgroup analyses for primary outcomes were consistent with main analyses. RoB for Hb change was found as high/some concerns in 5/1 RCTs, respectively. Conclusion: Molidustat exhibited noninferiority to ESAs in managing anemia in CKD patients. However, a concerning finding was the increased risk of CKD worsening associated with molidustat use. Well-designed RCTs are essential to enhance our understanding of molidustat's in CKD-related anemia.

Distinguishing Iron Deficiency Anemia from Anemia of Chronic Disease Using Hematological Measures

Anemia is a serious public health concern in today’s world which is particularly affecting young children, pregnant women, menstruating adolescent girls and women. The two most common causes of anemia are iron deficiency anemia (IDA) and anemia of chronic disease (ACD), often known as anemia of inflammation. This study aim was to assess the levels of certain hematological parameters, including Hemoglobin Estimation, Mean Corpuscular Volume (MCV), Serum Ferritin, Serum TIBC, Erythrocyte Sedimentation Rate and C - reactive protein to clearly differentiate between iron deficiency anemia and anemia of chronic disease. The study was conducted in Department of Medical Lab Technology, Riphah International University, Islamabad from September 01, 2023 to January 01, 2024. A total of 109 samples with 59 of iron deficiency anemia patients and 50 patients of Anemia of chronic disease were assessed for differentiation be these two diseases. The significant level was selected with p-value less than 0.05. Hemoglobin estimation, TIBC, and ESR were significant in our investigation as their p-values were less than 0.05. Hence, it concluded that Hemoglobin estimation, total Iron Binding Capacity and Erythrocyte Sedimentation Rate were Hematological parameters that distinguished between Iron Deficiency Anemia and Anemia of Chronic Disease.

Neutrophil-to-Lymphocyte Ratio in Adult Patients with Anemia: A Hospital-Based Cross-Sectional Study

Background: Neutrophil-to-lymphocyte ratio, a well-defined marker of immunity, is raised in many conditions which are characterized by abnormal inflammatory and immunological responses. Anemia of chronic disease, the most prevalent type in hospitalized patients, is a dominant clinical picture in protracted stimulation of immunity. This study aimed to assess the neutrophil-to-lymphocyte ratio in adult participants with anemia and to compare of the ratio with non-anemic participants. Methods: In a cross-sectional study conducted in the Department of Clinical Physiology of Karnali Academy of Health Sciences, Teaching Hospital, Jumla, Karnali Province, Nepal, in the months of August, 2023, data on clinico-demographic variables were retrieved from the laboratory information system of hospital records of February–March, 2023. From the hematological parameters retrieved, the status of anemia and the neutrophil-to-lymphocyte ratio were calculated. Results: After scrutiny of the laboratory records of 1421 adult patients, with 69.7% (N=990) female, the prevalence of anemia was 12.4% (N=176) and the median neutrophil-to-lymphocyte ratio was 2.21 (IQR: 1.41–3.75). The median neutrophil-to-lymphocyte ratio was significantly greater in the anemic participants among the overall (p&lt;0.001) participants and across the subgroups of gender (p&lt;0.001) and age (p&lt;0.05). Conclusion: The neutrophil-to-lymphocyte ratio was significantly greater in the adult anemic than in the non-anemic participants. To this end, further studies assessing the association of this ratio with the various clinical aspects of anemia, such as subtypes, severity, course, prognosis and treatment responses are needed.

Red cell parameters, iron, vitamin B12 and folate levels of pulmonary tuberculosis patients attending clinic at General Hospital, Akamkpa, Cross River State, Nigeria

Introduction: Tuberculosis caused by Mycobacterium tuberculosis, is a disease of public health importance, characterized by a chronic granulomatous inflammation in humans. In this study, red cell and iron parameters as well as vitamin B12 and folate levels were assessed with a view to investigate the presence or absence of iron deficiency and/or vitamin B12 and folate deficiency in tuberculosis disease Methods: Fifty (50) male and female tuberculosis patients within the ages of 15-60 years and attending clinic at the General Hospital, Akamkpa were enrolled in this study. Fifty apparently healthy and mantoux-negative subjects who were age and gender matched and resident in Akamkpa served as control. Ethical approval and informed consent were obtained from the Cross-River State Ministry of Health and all participants. Demographic information was obtained by face-to-face interview. Diagnosis of TB was by the Ziehl-Neelsen technique. Red cell and iron parameters, vitamin B12 and folate levels were determined by standard methods. Data were analyzed using student t-test on statistical package for social sciences version 21and a P value less than or equal to 0.05 is considered significant. Results: The mean age of TB patients (34.7±10.4 years) is comparable to that of the control (32.4±8.6 years) with more males (56%) affected than females (44%). Fifteen (30%) of the TB patients have primary level of education with 31 (62%) and 4 (8%) having attained secondary and tertiary levels. The level of education for the control was 12 (24%), 22 (44%) and 16 (32%) for primary, secondary and tertiary respectively. The TB patients were farmers 20 (40%), traders 15 (30%), students 9 (18%) and civil servants 6 (12%) while the controls consisted of 14 (28%) farmers, 16 (32%) traders, 12 (24%) students and 8 (16%) civil servants. The packed cell volume and haemoglobin concentration of TB patients (0.34±0.05 L/L and 121.4±11.3 g/L) was significantly lower (p &lt; 0.05) than 0.41±0.04 L/L and 145.2±13.1 g/L for the control. The red cell count and mean cell volume of TB patients (4.55±0.73 x 10 12/L and 79.21±2.40 fl) was comparable (p &gt; 0.05) to control values (4.84±0.54 x 10 12/L and 80.18±1.30 fl). Mean cell haemoglobin and mean cell haemoglobin concentration of TB patients was 27.58±2.12 pg and 34.37±1.43 g/dl, which was significantly lower than 29.72±2.24 pg and 35.73±1.38 g/dl obtained for control. The serum iron of TB patients (47.90±6.25µg/dl) was significantly lower (p = 0.001) than control value 109.03±8.56µg/dl. The total iron binding capacity (188.05±33.01µg/dl) and transferrin saturation with iron (28.00±4.54 %) were significantly lower (p = 0.001) for TB patients versus control (252.28±36.30µg/dl and 42.46±6.23%). Serum ferritin of TB patients (345.30±82.61 ng/ml) was significantly higher (p = 0.001) when compared to the value for control (108.62±28.50 ng/ml). Vitamin B12 and folate levels (245.37±39.62 ng/L and 353.34±57.06 µg/l) were significantly lower (p = 0.001) for TB patients when compared with control (550.20±82.33 ng/L and 681.93±97.36µg/l) though within the reference values. Conclusions: This study has shown a lower packed cell volume and haemoglobin concentration in tuberculosis disease indicating the presence of anaemia. An alteration in iron metabolism and increased iron stores has also been demonstrated ruling out iron deficiency anaemia. Vitamin B12 and folate levels though lower for TB patients, are within the reference range thus excluding megaloblastic anaemia. Tuberculosis shows a normocytic normochromic anaemia which is typical of anaemia of chronic disease and inflammation.

Inflammatory immune profiles associated with disease severity in pulmonary tuberculosis patients with moderate to severe clinical TB or anemia.

Immune control of Mycobacterium tuberculosis (Mtb) infection is largely influenced by the extensive disease heterogeneity that is typical for tuberculosis (TB). In this study, the peripheral inflammatory immune profile of different sub-groups of pulmonary TB patients was explored based on clinical disease severity, anemia of chronic disease, or the radiological extent of lung disease. Plasma samples were obtained from n=107 patients with active pulmonary TB at the time of diagnosis and after start of standard chemotherapy. A composite clinical TB symptoms score, blood hemoglobin status and chest X-ray imaging were used to sub-group TB patients into 1.) mild and moderate-severe clinical TB, 2.) anemic and non-anemic TB, or 3.) limited and extensive lung involvement. Plasma levels of biomarkers associated with inflammation pathways were assessed using a Bio-Plex Magpix 37-multiplex assay. In parallel, Th1/Th2 cytokines were quantified with a 27-multiplex in matched plasma and cell culture supernatants from whole blood stimulated with M. tuberculosis-antigens using the QuantiFERON-TB Gold assay. Clinical TB disease severity correlated with low blood hemoglobin levels and anemia but not with radiological findings in this study cohort. Multiplex protein analyses revealed that distinct clusters of inflammation markers and cytokines separated the different TB disease sub-groups with variable efficacy. Several top-ranked markers overlapped, while other markers were unique with regards to their importance to differentiate the TB disease severity groups. A distinct immune response profile defined by elevated levels of BAFF, LIGHT, sTNF-R1 and 2, IP-10, osteopontin, chitinase-3-like protein 1, and IFNα2 and IL-8, were most effective in separating TB patients with different clinical disease severity and were also promising candidates for treatment monitoring. TB patients with mild disease displayed immune polarization towards mixed Th1/Th2 responses, while pro-inflammatory and B cell stimulating cytokines as well as immunomodulatory mediators predominated in moderate-severe TB disease and anemia of TB. Our data demonstrated that clinical disease severity in TB is associated with anemia and distinct inflammatory immune profiles. These results contribute to the understanding of immunopathology in pulmonary TB and define top-ranked inflammatory mediators as biomarkers of disease severity and treatment prognosis.

KRONİK BÖBREK HASTALIĞI VARLIĞINDA HASTANEDE EDİNİLMİŞ ANEMİ GELİŞİMİNE ETKİ EDEN FAKTÖRLERİN DEĞERLENDİRİLMESİ

Kronik böbrek hastalığı (KBH) 3 aydan uzun süren, böbrekte işlevsel ya da yapısal bozukluk ve/veya glomerüler filtrasyon hızında azalma olmasıdır. Hastanede edinilmiş anemi (HEA), hastaneye yatış sonrası hastalarda etyolojik bir neden olmaksızın anemi gelişmesidir. İyatrojenik geliştiği düşünülmektedir. Çalışmamızda KBH tanısıyla hasta-neye yatırılan hastalarda HEA prevalansını ve etki eden faktörleri saptamayı amaçladık. Mart- Eylül 2014 arasında, 18 yaş ve üzerine, KBH tanılı, nefroloji servisine yatışı yapılan hastalar çalışmaya alındı. Hipervolemi, kanama, hemoliz, sepsis, hematolojik malignite varlığı, antikoagülan kullanımı olan hastalar, sıvı replasmanı planlanan ve renal replasman tedavisi alan hastalar çalışmaya dahil edilmedi. Hastaneye yatış sonrasında hemoglobin düzeyinde 0,5 g/dl ve üzerinde düşme olması HEA olarak tanımlandı. Çalışmamızda KBH hastalarında HEA sıklığı %70 saptanmıştır. HEA gelişimi, KBH evresi ve hipotiroidi varlığı ile istatiksel anlamlı olarak ilişkili saptanmıştır (KBH p=0.021, hipotiroidi p=0.002). Günlük flebotomi miktarınin (p=0,203) ve hastanede yatış süresinin (p=0,180) HEA gelişimi ile ilişkisi saptanmamıştır. HEA’nın tanınması ve gelişimi açısından risk faktörlerinin saptanarak, önlenmesinin hastaların sağlık durumuna olumlu etki edeceği düşüncesindeyiz.

Analysis of etiology and complications in children with stage 5 chronic kidney disease

Objective: To investigate the etiology, complications, and prognostic factors of stage 5 chronic kidney disease (CKD5) in children. Methods: A case series study was conducted to retrospectively analyze the general situation, clinical manifestations, laboratory tests, genetic testing, and follow-up data (until October 2022) of 174 children with CKD5 who were diagnosed and hospitalized at the Children's Hospital of Chongqing Medical University from April 2012 to April 2021. The characteristics of complications in the children were compared based on age, gender, and etiology. Based on the presence or absence of left ventricular hypertrophy (LVH), patients were divided into LVH group and non LVH group for analyzing the influencing factors of cardiovascular disease. Patients were also divided into death group and survival group, peritoneal dialysis group and hemodialysis group based on the follow-up data for analyzing the prognostic factors. The chi-square test, independent sample t-test, Fisher exact probability test, Mann-Whitney U test and Kruskal Wallis test were used to analyze data among different groups. Multivariate Logistic regression analysis was used to identify the prognostic factors. Results: A total of 174 children with CKD5 were enrolled in the study (96 boys and 78 girls), aged 11.2 (8.2, 13.0) years. Congenital kidney and urinary tract malformations (CAKUT) were the most common causes of the CKD5 (84 cases, 48.3%), followed by glomerular diseases (83 cases, 47.7%), and among which 28 cases (16.1%) were hereditary glomerular diseases. The common complications of CKD5 included anemia (98.2%, 165/168), mineral and bone disorder in chronic kidney disease (CKD-MBD) (97.7%, 170/174), lipid metabolism disorders (87.5%, 63/72), hypertension (81.4%, 127/156) and LVH (57.6%,57/99). The incidences of hypertension in primary glomerular disease were higher than that in CAKUT(93.8%(30/32) vs.73.7%(56/76),χ2=5.59,P<0.05). The incidences of hypertension in secondary glomerular disease were higher than that in CAKUT and that in hereditary kidney disease (100.0%(20/20) vs. 73.7%(56/76), 68.2%(15/22), both P<0.05). The incidence of hypocalcemia in CAKUT, primary glomerular disease, and hereditary kidney disease was higher than that in secondary glomerular disease (82.1%(69/84), 88.2%(30/34), 89.3%(25/28) vs. 47.6%(10/21), χ2=10.21, 10.75, 10.80, all P=0.001); the incidence of secondary hyperparathyroidism in women was higher than that in men (80.0%(64/80) vs. 95.0%(57/60), χ2=6.58, P=0.010). The incidence of LVH in children aged 6-<12 was higher than that in children aged 12-18 (73.5%(25/34) vs. 43.1%(22/51), χ2=7.62, P=0.006). Among 113 follow-up children, the mortality rate was 39.8% (45/113). Compared to the survival group, the children in the death group had lower hemoglobin, higher blood pressure, lower albumin, lower alkaline phosphatase and higher left ventricular mass index ((67±19) vs. (75±20) g/L, 142 (126, 154) vs. 128(113, 145) mmHg(1 mmHg=0.133 kPa), (91±21) vs. (82±22) mmHg, 32 (26, 41) vs. 40 (31, 43) g/L, 151 (82, 214) vs. 215 (129, 37) U/L, 48 (38, 66) vs. 38(32, 50) g/m2.7,t=2.03, Z=2.89, t=2.70, Z=2.49, 2.79, 2.29,all P<0.05), but no independent risk factors were identified (all P>0.05). The peritoneal dialysis group had better alleviation for anemia, low calcium, and high phosphorus than the hemodialysis group ((87±22) vs. (72±16) g/L, (1.9±0.5) vs. (1.7±0.4) mmol/L, (2.2±0.7) vs. (2.8±0.9) mmol/L, t=2.92, 2.29, 2.82, all P<0.05), and the survival rate of the peritoneal dialysis group was significantly higher than that of the hemodialysis group (77.8% (28/36) vs. 48.4% (30/62), χ2=8.14, P=0.004). Conclusions: CAKUT is the most common etiology in children with CKD 5, and anemia is the most common complication. The incidence of complications in children with CKD 5 varies with age, gender and etiology. Anemia, hypertension, hypoalbuminemia, reduced alkaline phosphatase and elevated LVMI may be the prognostic factors in children with CKD5. Peritoneal dialysis may be more beneficial for improving the long-term survival rate.

Efficacy and safety of hypoxia-inducible factor-prolyl hydroxylase inhibitor treatment for anemia in chronic kidney disease: an umbrella review of meta-analyses

The objective was to provide a comprehensive summary of existing evidence on the efficacy and safety of hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) for the treatment of anemia in chronic kidney disease (CKD). A systematic search was conducted in the Medline, Embase, and Cochrane databases. Only meta-analyses that evaluated the efficacy and safety of HIF-PHI treatment for anemia in CKD were included. The efficacy outcomes included hemoglobin levels and iron metabolism indices, while the safety outcomes were assessed by examining adverse events. The qualities of methodologies and evidence were assessed using the AMSTAR 2 system and the NutriGrade tool, respectively. Fourteen meta-analyses, comprising 105 distinct comparisons, were included. The comparisons were backed by evidence of high, moderate, and low levels, distributed in approximately equal proportions. None of the studies were deemed to possess a high level of confidence. In both the overall and individual treatment groups of HIF-PHI, there was an increase in the levels of hemoglobin, transferrin, and transferrin saturation, while the levels of hepcidin and total iron binding capacity decreased. Serum ferritin exhibited a reduction to some extent, while serum iron did not show significant alterations following HIF-PHI treatments. There were no notable disparities in safety outcomes between the HIF-PHI and erythropoietin stimulating agents or placebo groups. This umbrella review suggests that HIF-PHI treatment can effectively increase hemoglobin levels in CKD patients and enhance iron metabolism by decreasing hepcidin levels and improving iron transport. The safety profiles of HIF-PHIs were generally comparable to those of ESA therapies or placebos.

The Heparinoid Sevuparin Improves Anemia and Kidney Status in a Mouse Model of Chronic Kidney Disease

The control of systemic iron availability is essential to sustain the different needs of the body, without causing iron overload disease or deficiency (anemia) meaning that iron is highly regulated and the master regulator is hepcidin. High levels of hepcidin induce ferroportin degradation, inhibiting iron release from enterocytes and macrophages resulting in an internal iron deficiency, which underlies anemia of chronic diseases (ACD). Patients with chronic kidney disease (CKD) often have ACD due to a combination of inflammation, erythropoietin (EPO) insufficiency/unresponsiveness, elevated hepcidin levels, reduced kidney function and decreased iron availability. Treatments involve erythropoiesis-stimulating agents, that in a longer perspective often fail to ameliorate the anemia, highlighting the need for new therapeutic tools. Interestingly, it has been reported that hepcidin suppression improves anemia in rodent models of CKD, suggesting that normalising hepcidin levels may be a means to treat anemia in CKD and in general in ACD. It is known that heparins are potent hepcidin suppressors; sevuparin, a novel, clinical stage, low-molecular weight heparinoid compound with substantially reduced anticoagulant activity is a promising candidate drug to control hepcidin expression in patients with CKD. The authors previously found that sevuparin strongly suppressed basal, BMP6- and IL6-dependent hepcidin expression in vitro with a maximum effect after 6h (90% reduction) persisting for at least 16h. The hepcidin lowering effect of sevuparin was confirmed also in healthy mice. Furthermore, in healthy volunteers, a single dose of subcutaneous sevuparin caused a significant reduction of about 50% (3 mg/kg) and 80% (9 mg/kg) of serum hepcidin after 12 and 24h, respectively, providing a robust translational context to the sevuparin effects on hepcidin levels. The aim of the present work was to investigate the effect of sevuparin on hepcidin, hemoglobin and the kidney status in a CKD mouse model of high hepcidin anemia. Mice fed with “adenine rich diet” (ARD) (0.2% adenine; 0.9% phosphorus; 0.6% calcium; 20% casein) developed moderate or severe signs of kidney damage as manifested by weight loss, increased serum creatinine, high hepcidin levels, low serum iron and anemia (hemoglobin ≤ 12.5 g/dL) after 7-9 weeks. After the onset of CKD, the mice were chronically treated with PBS or sevuparin (10 mg/kg/daily) subcutaneously for 3 or 6 weeks alone or in combination with erythropoietin (EPO) administered intraperitoneally (50 U/mouse twice a week in the first 3 weeks followed by 3 weeks and then 25 U/mouse once a week to simulate EPO hypo-responsiveness). Sevuparin was provided by Modus Therapeutics AB, Sweden, whereas EPO was used in the form of the commercially available darbapoietin alfa (ARANESP ®). Sevuparin treatment alone increased hemoglobin, hematocrit and weight (Hb 11-12 g/dL; Ht 20%; 22 g vs baseline values of Hb 9-10 g/dL; Ht 18%; 14.5 g PBS) with adjoining modest decreases of serum hepcidin and creatinine. The reduction of creatinine was supported by a concomitant improvement of the kidney status visible as a reduction of collagen deposits indicative of reduced fibrosis compared to the mice treated with PBS only. The EPO/sevuparin combination showed a strong reduction from control of serum hepcidin levels (292 ng/mL vs 1382 ng/mL) after 3 weeks of treatment whereas after 6 weeks levels were increased up to 2000 ng/mL suggesting that the chronic treatment with EPO is not optimal, as observed in patients. Interestingly the concomitant benefit on anemia at 3w (about Hb 18 g/dL, Ht 54%) for the combination remained stable at 6w, further supported by the maintained high Ret-He (about 15.62 pg); suggesting a phased dependency on hepcidin in the development of CKD anemia. Furthermore, the improvement of the kidney status (histology and function) was also maintained throughout combination treatment. Our data in this mouse CKD model add new insights to the role of hepcidin in the development of CKD anemia over time. Furthermore, the results are promising and support further mechanistic and clinical studies to elucidate the therapeutic role for sevuparin as a treatment in anemia of inflammatory and/or chronic diseases in monotherapy or in combination with EPO and to explore its role in kidney protection.

Selective Inhibition of Repulsive Guidance Molecule C/Hemojuvelin (RGMc/HJV) with SRK-256 to Mobilize Iron in Functional Iron Deficiency

Functional iron deficiency is a serious condition marked by serum iron restriction in the presence of adequate iron stores that can lead to anemia, worsening quality of life, and leading to poor patient outcomes. Functional iron deficiency is characterized by abnormally high levels of hepcidin given serum iron status; it is frequently observed in diseases with chronic inflammation, such as anemia of chronic disease, chronic kidney disease, and myelofibrosis. Current treatments to address this patient population involve non-specifically targeting hepcidin and come with risks of off-target side effects. The secretion of hepcidin from the liver hepatocytes is linked to circulating serum iron levels and is controlled by the Bone Morphogenic Protein (BMP) 2/6 signaling pathway. Repulsive Guidance Molecule C or Hemojuvelin (RGMc/HJV) is a BMP 2/6 co-receptor in liver hepatocytes. Human genetic mutations in this gene result in juvenile hemochromatosis and genetic mouse studies have demonstrated that RGMc/HJV has a specific role in maintaining systemic iron homeostasis through modulation of hepcidin expression. We have generated a highly selective, fully human antibody (SRK-256) against RGMc/HJV which binds to the target with 39 pM affinity. SRK-256 has no detectable binding to RGMa or RGMb, thus avoiding potential side effects of targeting these gene family members with key physiological roles outside of iron metabolism. A high-resolution crystal structure (2.2 Å) elucidates not only the mechanism of action of SRK-256 directly competing for BMP binding to RGMc via contacts within the BMP binding domain, but also identifies binding to regions within this domain highly unique to RGMc over RGMa and RGMb, thus supporting the selectivity of the molecule. This mechanism of action is corroborated by in vitro assay data demonstrating that SRK-256 blocks signaling by BMP 2, 4, and 6. Pharmacodynamic and pharmacokinetic data supportive of a monthly subcutaneous dosing regimen in human patients has been generated in cynomolgus macaques, where SRK-256 demonstrates a dose-proportional duration of effect on suppression of hepcidin expression and elevation of transferrin saturation and achieves ~95% bioavailability via subcutaneous dosing. Furthermore, in the rat peptidoglycan-polysaccharide (PGPS) model of anemia of chronic disease, we have shown that in contrast to treatment with erythropoiesis stimulating agent alone (EPO, serum iron 47.7 ± 9.8 µg/dL), SRK-256 can restore serum iron to normal levels (Healthy control, serum iron 231.9 ± 12.0 µg/dL; SRK-256, serum iron 248.7 ± 60.9 µg/dL; and SRK-256+EPO, serum iron 277.6 ± 92.9 µg/dL) in the context of inflammation-driven, iron-restricted anemia (Figure 1). SRK-256 represents a potent and selective potential therapy for the treatment of patients with iron-restricted anemias across diseases of chronic inflammation.

Addressing Chronic Anemia in Sickle Cell Disease: Characterizing Erythropoiesis-Stimulating Agent (ESA) Utilization and Practice Patterns Among Providers

Background: Chronic anemia exerts profound impacts on the morbidity, mortality, and quality of life in individuals with sickle cell disease (SCD), but therapeutic options are limited. Erythropoietin-stimulating agents (ESAs) are the standard of care for managing anemia in chronic kidney disease (CKD). However, their utilization in SCD remains ad hoc, with limited literature and no guidelines supporting the use of ESAs in SCD. To address this knowledge gap, we present preliminary findings from a survey designed to evaluate provider practices and identify factors influencing the use of ESAs in SCD. Methods: We conducted a cross-sectional web-based survey from March-July 2023 among providers taking care of patients with SCD in the United States (US) and internationally. Survey items were developed to assess provider demographic characteristics, practice environments, and provider practices around ESA use in SCD. The data was collected and managed using REDCap electronic data capture tools hosted at the University of Pittsburgh. Descriptive statistics were used to report the data. Results: The survey has been completed by 33 providers as of a cut date of July 23, 2023. Most providers were hematologists who practiced in an academic setting (23/33, 69.7%), with an equal gender distribution (Table 1). The number of patients with SCD seen annually varied, with 101-300 patients being the most common cohort size (13/33, 39.4%). In the 12 months prior to survey completion, 15/33 (45.5%) providers treated at least 1 patient with SCD with ESAs, usually outpatient (Table 2). Commonly reported barriers to outpatient ESA therapy included lack of insurance approval/coverage or cost concerns, lack of provider experience, and patient tolerability/adherence or inability to perform self-injections. Fewer respondents reported no barriers to prescribing ESAs in the outpatient setting, compared to in the acute/inpatient setting (18.2% vs. 48.5%). The most commonly reported indications for starting ESAs in the outpatient setting were chronic anemia from end-stage renal disease or CKD, reduction of blood transfusion requirement, and chronic anemia in patients refractory to approved therapies. Less commonly reported indications include severe or symptomatic anemia alone and chronic anemia in the setting of cardiopulmonary disease. Respondents reported several contraindications to starting ESAs, including a history of venous thromboembolism (VTE), malignancy, stroke, coronary artery disease, hypertension, and frequent vaso-occlusive crises. Respondents also expressed concerns about the cost/insurance coverage, efficacy, safety, patient burden, and appropriate dosing of ESAs in patients with SCD. Only 18/33 (54.5%) respondents reported ever treating outpatients with SCD with ESAs; nearly all of them used 1 st generation ESAs, and a majority used 2 nd generation ESAs. For 1 st generation ESAs, the most common starting dose was 3500-7000 units (U) (50-100 U/kg; 22.2%) or 7001-14000 U (101-200 U/kg; 22.2 %). Once weekly was the most common dosing interval (50%), followed by three times a week (TIW; 27.8%) and twice a week (16.7%). The maximum dose used was 56001-70000 U (801-1000 U/kg) TIW. For 2 nd generation ESAs, the most common starting dose was 141-210 mcg (2.1-3.0 mcg/kg) (22.2%), and administration often occurred once every 2 weeks (44.4%) or weekly (27.8%). The maximum dose used was 211-315 mcg (3.1-4.5 mcg/kg) weekly. Outpatient ESAs were most often initiated for hemoglobin (Hb) &amp;lt; 6 g/dL (8/18, 44.4%), and Hb &amp;gt; 9 g/dL was the most common treatment target (6/18, 33.3%). ESAs were often combined with hydroxyurea, voxelotor, and simple transfusions (Table 2). Conclusion: These preliminary survey results show considerable variability in how ESAs are currently being used in people with SCD. These variations in clinical practice highlight both significant ambiguity about what works in this setting and the need for further research into the optimal use of ESAs for the management of chronic anemia in SCD (ongoing clinical trial: ACHiEvE-SCD, NCT05451940). Future directions include evaluating differences in practice patterns among adult vs. pediatric and US-based vs. non-US-based providers.

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

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

Effect of the Phosphate Binder Sevelamer Carbonate on the Bioavailability of Enarodustat, an Oral Erythropoiesis Stimulating Agent.

Enarodustat is an orally available hypoxia-inducible factor-prolyl hydroxylase inhibitor which can correct the erythropoietic capacity and improve anemia in chronic kidney disease. Sevelamer carbonate, a non-calcium-based polymeric resin, is one of the commonly prescribed agents for the management of hyperphosphatemia in patients undergoing hemodialysis. This was an open-label, crossover study in healthy male subjects (N=12) that evaluated the effect of sevelamer carbonate (2400mg) on the bioavailability of enarodustat (25mg) when the 2 drugs were administered together (Treatment B) or when enarodustat was administered 3hours after (Treatment C) or 1hour before (Treatment D) sevelamer carbonate compared to enarodustat alone (Treatment A). With coadministration of the 2 drugs (Treatment B), enarodustat Cmax and AUCinf reductions were 53% and 45%, respectively. For Treatment C, Cmax and AUCinf reductions were 11% and 6%, respectively, and for Treatment D the corresponding values were 8% and 20%. Thus, coadministration of enarodustat and sevelamer carbonate resulted in a substantial reduction (≈50%) in the oral bioavailability of enarodustat. However, the interaction was substantially mitigated by staggering the administration of enarodustat and sevelamer carbonate. Administration of 4 single oral doses of enarodustat 25mg, with or without sevelamer carbonate, were safe and well tolerated in this study.

Pathophysiology of anemic syndrome in celiac disease and its therapeutic treatment

The review presents modern ideas about the pathophysiology of the anemia syndrome associated with celiac disease. Brief information is provided about the main proteins involved in iron metabolism and their role in maintaining homeostasis. Attention is paid to the multifactorial pathogenetic mechanisms of anemia in celiac disease, the state of the duodenal mucosa and ultrastructural changes in the villi of enterocytes with signs of atrophy, which play a key role in the regulation of iron absorption, and also provides information on the mechanisms of the development of functional iron deficiency and its role in the pathogenesis of anemia of chronic diseases.

Abstract 13670: Prevalence and Long-Term Outcomes of Intravenous Iron Sucrose Therapy in Heart Failure With Reduced Ejection Fraction: A Single Institution Retrospective Cohort Study

Background: Iron deficiency (ID) is prevalent in heart failure with reduced ejection fraction (HFrEF) defined as left ventricular ejection fraction (LVEF) ≤ 40%. Most trials used in the 2022 AHA/ACC guidelines studied iron carboxymaltose; most had a short follow-up and evaluated heart failure readmissions. We explored the prevalence of iron use, long-term therapeutic benefits, and impact on all-cause readmission for patients with HFrEF. Methods: In this retrospective cohort study, we analyzed electronic medical record data from a university hospital from 2016 to 2021 with an ICD-10 code of systolic heart failure (LVEF &lt; 50%) and ID, or iron deficiency anemia (IDA) (n=619). Intravenous (IV) iron sucrose group was matched to a control group (n = 43) by propensity score matching for age and sex. Conditional logistic regression was utilized to estimate unadjusted odds ratios (uOR) with 95% confidence interval (CI), while Mann-Whitney test was utilized to compare median values of nonparametric estimates. Statistical analysis was done in SAS version 9.4. Results: 66.7% of the studied population were male and 61.1% were ≥ 65 years. The common comorbid conditions were ischemic cardiomyopathy (39.6%), chronic kidney disease (CKD) (26.2%), and gastrointestinal (GI) bleeding (12.3%). ID was present in 115 (18.6%); IDA in 95 (15.4%) and 43 (6.9%) received IV iron sucrose. IV iron administration was significantly associated with LVEF 41-49% (uOR = 2.65, 95% CI: 1.10 - 6.43), GI bleeding (uOR = 16.00, 95% CI: 2.12 - 120.65), chronic kidney disease (uOR = 3.67, 95% CI: 1.49 - 9.04), iron deficiency (uOR = 26.00, 95% CI: 3.53 - 191.60]) and iron deficiency anemia (uOR = 24.00, 95% CI: 3.23 - 177.41). LVEF ≤40% was non-significantly associated with all-cause mortality (uOR = 1.50, 95% CI: 0.61 - 3.67). The IV iron group had a higher median rate of 6-year readmissions (8 [IQR:8] vs.1 [2]; p&lt;0.001), and blood transfusions (11 [24] vs. 3.5 [2]; p=0.05). Conclusions: Patients with HFrEF were less likely to receive IV iron sucrose and more likely to die. Those with frequent blood transfusions, GI hemorrhage, and CKD were more likely to receive IV iron. The study indicates the impact of disease severity and comorbidities on management. Larger studies are needed to investigate this postulation.