Browsing by Subject "Anemia"
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Item Anemia and FGF23 elevation in CKD: Homeostatic Interactions and Emerging Therapeutics(Wolters Kluwer, 2022) Agoro, Rafiou; White, Kenneth E.; Medical and Molecular Genetics, School of MedicinePurpose of review: Chronic kidney disease (CKD) is a progressive disorder that is associated with development of elevated fibroblast growth factor 23 (FGF23) levels and anemia. Here, we review recent literature that extends our current knowledge on the interactions between FGF23 and anemia in CKD and the impact of anemia-targeting therapeutics on FGF23 elevation in CKD. Recent findings: The anemia of CKD is primarily driven by a lack of erythropoietin (EPO) and iron deficiency. In addition to EPO and iron replacement, novel drug classes to treat anemia have been approved or are in clinical development. A recent observational study provides supportive evidence for the hypothesis that FGF23 elevation in CKD mediates adverse effects of iron deficiency on the cardiovascular system in patients with CKD. Preclinical and clinical studies revealed that ferric citrate (FC), and hypoxia-induced factor-prolyl hydroxylase inhibitor (HIF-PHI) treatment may reduce elevated FGF23 levels in CKD, suggesting that correcting anemia in CKD could potentially lower FGF23 levels. However, as we describe, HIF-PHI have context-dependent effects. Moreover, whether a reduction in FGF23 will improve patient outcomes in patients with CKD remains to be determined. Summary: With the emergence of novel therapeutics to treat oxygen and iron utilization deficits in CKD, studies have investigated the impact of these new drugs on FGF23. Several of these drugs, including FC and HIF-PHIs, alleviate iron homeostasis alterations in CKD and are associated with FGF23 reduction. Herein, we review the relationships between oxygen/iron sensing and FGF23 in CKD, recent findings which link FGF23 with cardiac dysfunction, as well as future translational and clinical avenues.Item Anemia and Iron-Deficiency Anemia in Children Born to Mothers with HIV in Western Kenya(Sage, 2021-02-22) Oyungu, Eren; Roose, Anna W.; Ombitsa, Ananda R.; Yang, Ziyi; Vreeman, Rachel C.; McHenry, Megan S.; Pediatrics, School of MedicineThe objective of this study was to determine and compare anemia and iron-deficiency anemia (IDA) rates in young Kenyan children who are HIV infected (HI), HIV exposed, uninfected (HEU), and HIV unexposed (HU). Questionnaires, anthropometrics, and blood samples were collected from HI, HEU, and HU aged 18 to 36 months. Descriptive statistics, Fisher’s exact tests, and linear regression were used for analysis. Of 137 total participants, HI (n = 18), HEU (n = 70), and HU (n = 49), 61.1%, 53.6%, and 36.7%, respectively, were anemic, with mean hemoglobin levels highest in HU (P = .006). After adjusting for covariates, HI (β = −9.6, 95% CI:−17.3 to −2.0) and HEU (β = −7.4, 95% CI: −12.9 to −1.9) had lower hemoglobin levels compared with HU. The proportion of children with IDA did not differ significantly across groups (P = .08). HEU have rates of anemia and IDA similar to HI. Anemia risk is generally higher in HEU than HU, even after adjusting for covariates.Item Are Adults Over 18 Years of Age with Anaemia More Likely to Develop Chronic Periodontitis Than Adults Without Anaemia? - A Systematic Review and Meta-Analysis(Wolters Kluwer, 2023-08-30) Roberts, Madison; Jimson, Sudha; Srinivasan, Mythily; Oral Pathology, Medicine and Radiology, School of DentistryAims and objectives: Periodontitis is a chronic disease affecting the supporting tissues of the teeth and exhibits bidirectional relation with systemic diseases. This study aims to determine the association between chronic periodontitis and erythrocyte functional measures: total red blood cells (RBCs), hemoglobin (Hb) concentration, mean corpuscular volume (MCV), and mean corpuscular hemoglobin concentration (MCHC) by systematic review and meta-analysis. Materials and methods: A systematic search of the electronic databases PUBMED, OVID, Embase, Web on Science, and Google Scholar was undertaken from inception to July 2022. English language studies that evaluated the erythrocyte functional measures in periodontitis and health were selected. Other review reports, letters/opinion articles, studies without a definition of periodontitis, and the concomitant presence of systemic conditions (diabetes, kidney disease, cancer) were excluded. Two reviewers determined full-text eligibility in a blinded process. Meta-Essentials software was used to generate forest plots and to determine heterogeneity and publication bias. Results: Twenty-six studies involving 1082 patients with chronic periodontitis and 980 healthy controls were analyzed. Pooled results showed lower Hb concentration (Hedges' g = -1.16; 95% confidence intervals [CI], -1.7 to -0.62), RBC counts (Hedges' g = -0.85; 95% CI, -1.31 to -0.38) and packed cell volume (-0.56; 95% CI, -1.02 to -0.11) in patients with chronic periodontitis. Conclusion: This meta-analysis showed a decreasing trend in the hematological parameters, including hemoglobin concentration, number of erythrocytes, and hematocrit in patients with chronic periodontitis compared to healthy controls.Item Association between admission haematocrit and mortality among men with acute ischaemic stroke(BMJ, 2018-04-24) Sico, Jason J.; Myers, Laura J.; Fenton, Brenda; Concato, John; Williams, Linda S.; Bravata, Dawn M.; Neurology, School of MedicineObjective: Anaemia is associated with higher mortality among patients with non-stroke cardiovascular conditions; less is known regarding the relationship between anaemia and mortality among patients with acute ischaemic stroke. Methods: Medical records were abstracted for n=3965 veterans from 131 Veterans Health Administration facilities who were admitted with ischaemic stroke in fiscal year 2007. Haematocrit values within 24 hours of admission were classified as ≤27%, 28%-32%, 33%-37%, 38%-42%, 43%-47% or ≥48%. Multivariate logistic regression was used to examine the relationship between anaemia and in-hospital, 30-day, 6-month and 1-year mortality, adjusting for age, medical comorbidities, modified Acute Physiology and Chronic Health Evaluation-III and stroke severity. Impact factors were calculated to standardise comparisons between haematocrit tier and other covariates. Results: Among n=3750 patients included in the analysis, the haematocrit values were ≤27% in 2.1% (n=78), 28%-32% in 6.2% (n=234), 33%-37% in 17.9% (n=670), 38%-42% in 36.4% (n=1366), 43%-47% in 28.2% (n=1059) and ≥48% in 9.1% (n=343). Patients with haematocrit ≤27%, compared with patients in the 38%-42% range, were more likely to have died across all follow-up intervals, with statistically significant adjusted ORs (aORs) ranging from 2.5 to 3.5. Patients with polycythaemia (ie, haematocrit ≥48%) were at increased risk of in-hospital mortality (aOR=2.9; 95% CI 1.4 to 6.0), compared with patients with mid-range admission haematocrits. Pronounced differences between patients receiving and not receiving blood transfusion limited our ability to perform a propensity analysis. Impact factors in the 1-year mortality model were 0.46 (severe anaemia), 0.06 (cancer) and 0.018 (heart disease). Conclusions: Anaemia is independently associated with an increased risk of death throughout the first year post stroke; high haematocrit is associated with early poststroke mortality. Severe anaemia is associated with 1-year mortality to a greater degree than cancer or heart disease. These data cannot address the question of whether interventions targeting anaemia might improve patient outcomes.Item Association of Plasma Tau With Mortality and Long-term Neurocognitive Impairment in Survivors of Pediatric Cerebral Malaria and Severe Malarial Anemia(American Medical Association, 2021-12) Datta, Dibyadyuti; Bangirana, Paul; Opoka, Robert O.; Conroy, Andrea L.; Co, Katrina; Bond, Caitlin; Zhao, Yi; Kawata, Keisuke; Saykin, Andrew J.; John, Chandy C.; Biostatistics and Health Data Science, School of MedicineImportance: Cerebral malaria (CM) and severe malarial anemia (SMA) are associated with persistent neurocognitive impairment (NCI) among children in Africa. Identifying blood biomarkers of acute brain injury that are associated with future NCI could allow early interventions to prevent or reduce NCI in survivors of severe malaria. Objective: To investigate whether acutely elevated tau levels are associated with future NCI in children after CM or SMA. Design, setting, and participants: This prospective cohort study was conducted at Mulago National Referral Hospital in Kampala, Uganda, from March 2008 to October 2015. Children aged 1.5 to 12 years with CM (n = 182) or SMA (n = 162) as well as community children (CC; n = 123) were enrolled in the study. Data analysis was conducted from January 2020 to May 2021. Exposure: CM or SMA. Main outcomes and measures: Enrollment plasma tau levels were measured using single-molecule array detection technology. Overall cognition (primary) and attention and memory (secondary) z scores were measured at 1 week and 6, 12, and 24 months after discharge using tools validated in Ugandan children younger than 5 years or 5 years and older. Results: A total of 467 children were enrolled. In the CM group, 75 (41%) were girls, and the mean (SD) age was 4.02 (1.92) years. In the SMA group, 59 (36%) were girls, and the mean (SD) age was 3.45 (1.60) years. In the CC group, 65 (53%) were girls, and the mean (SD) age was 3.94 (1.92) years. Elevated plasma tau levels (>95th percentile in CC group; >6.43 pg/mL) were observed in 100 children (55%) with CM and 69 children (43%) with SMA (P < .001). In children with CM who were younger than 5 years, elevated plasma tau levels were associated with increased mortality (odds ratio [OR], 3.06; 95% CI, 1.01-9.26; P = .048). In children with CM who were younger than 5 years at both CM episode and follow-up neurocognitive testing, plasma tau levels (log10 transformed) were associated with worse overall cognition scores over 24-month follow-up (β = -0.80; 95% CI, -1.32 to -0.27; P = .003). In children with CM who were younger than 5 years at CM episode and 5 years or older at follow-up neurocognitive testing, plasma tau was associated with worse scores in attention (β = -1.08; 95% CI, -1.79 to -0.38; P = .003) and working memory (β = -1.39; 95% CI, -2.18 to -0.60; P = .001). Conclusions and relevance: In this study, plasma tau, a marker of injury to neuronal axons, was elevated in children with CM or SMA and was associated with mortality and persistent NCI in children with CM younger than 5 years.Item ATP-Binding Cassette Transporter of Clinical Significance: Sideroblastic Anemia(MDPI, 2024-06-14) Ogunbileje, John O.; Harris, Neil; Wynn, Tung; Kashif, Reema; Stover, Brian; Osa-Andrews, Bremansu; Pathology and Laboratory Medicine, School of MedicineThe ATP-binding cassette (ABC) transporters are a vast group of 48 membrane proteins, some of which are of notable physiological and clinical importance. Some ABC transporters are involved in functions such as the transport of chloride ions, bilirubin, reproductive hormones, cholesterol, and iron. Consequently, genetic or physiological disruption in these functions is manifested in various disease processes like cystic fibrosis, Tangier disease, and sideroblastic anemia. Among other etiologies, primary sideroblastic anemia results from a genetic mutation in the ATP-binding cassette-7 (ABCB7), a member of the ABC transporter family. There are not many articles specifically tackling the disease processes caused by ABC transporters in detail. Some testing methodologies previously reported in the available literature for investigating sideroblastic anemia need updating. Here, we expound on the relevance of ABCB7 as a clinically important ABC transporter and a rare participant in the disease process of Sideroblastic anemia. The other genetic and secondary etiologies of sideroblastic anemia, which do not involve mutations in the ABCB7 protein, are also described. We review the pathophysiology, clinical course, symptoms, diagnosis, and treatment of sideroblastic anemia with a focus on modern technologies for laboratory testing.Item Biosimilars—Emerging Role in Nephrology(American Society of Nephrology, 2019-09-01) Wish, Jay B.; Medicine, School of MedicineThe Food and Drug Administration (FDA) defines a “biosimilar” agent as a biologic that is highly similar to the reference or originator biologic product notwithstanding minor differences in clinically inactive components with no clinically meaningful differences in terms of the safety, purity, and potency. The advantage of biosimilars is that they are usually about 15%–30% less expensive than the reference product, which results in system-wide cost savings and increased patient access. Because biologic drugs are produced by living organisms, they are by nature heterogeneous and identical copies cannot be made, unlike generic versions of small-molecule drugs. Proposed biosimilars must undergo a rigorous evaluation process to demonstrate a high degree of structural and functional similarity with the reference biologic. Once that is confirmed, a stepwise process of comparison with the reference agent with regard to animal trials, pharmacokinetics/pharmacodynamics, immunogenicity, and human efficacy/safety is conducted. The experience with biosimilars in other highly regulated markets where patent protection for originator biologics is not as robust as in the United States has been favorable in terms of safety, efficacy, and cost savings. An FDA approval pathway was created in 2009 to expedite the approval of biosimilars; as of early 2018 nine agents had been approved through that pathway, none in nephrology. The first United States biosimilar epoetin was approved on May 15, 2018, but does not have an interchangeability designation, meaning that prescribers must specifically write for the biosimilar product for patients to receive it. Given the unfamiliarity of biosimilars within the nephrology community it is recommended that educational programs be developed to address this unmet need and for research to be conducted addressing the perceptual, clinical, and economic effect of biosimilars on our patients.Item Effects of Iron Isomaltoside vs Ferric Carboxymaltose on Hypophosphatemia in Iron-Deficiency Anemia: Two Randomized Clinical Trials(American Medical Association, 2020-02-04) Wolf, Myles; Rubin, Janet; Achebe, Maureen; Econs, Michael J.; Peacock, Munro; Imel, Erik A.; Thomsen, Lars L.; Carpenter, Thomas O.; Weber, Thomas; Brandenburg, Vincent; Zoller, Heinz; Medicine, School of MedicineImportance Intravenous iron enables rapid correction of iron-deficiency anemia, but certain formulations induce fibroblast growth factor 23–mediated hypophosphatemia. Objective To compare risks of hypophosphatemia and effects on biomarkers of mineral and bone homeostasis of intravenous iron isomaltoside (now known as ferric derisomaltose) vs ferric carboxymaltose. Design, Setting, and Participants Between October 2017 and June 2018, 245 patients aged 18 years and older with iron-deficiency anemia (hemoglobin level ≤11 g/dL; serum ferritin level ≤100 ng/mL) and intolerance or unresponsiveness to 1 month or more of oral iron were recruited from 30 outpatient clinic sites in the United States into 2 identically designed, open-label, randomized clinical trials. Patients with reduced kidney function were excluded. Serum phosphate and 12 additional biomarkers of mineral and bone homeostasis were measured on days 0, 1, 7, 8, 14, 21, and 35. The date of final follow-up was June 19, 2018, for trial A and May 29, 2018, for trial B. Interventions Intravenous administration of iron isomaltoside, 1000 mg, on day 0 or ferric carboxymaltose, 750 mg, infused on days 0 and 7. Main Outcomes and Measures The primary end point was the incidence of hypophosphatemia (serum phosphate level <2.0 mg/dL) between baseline and day 35. Results In trial A, 123 patients were randomized (mean [SD] age, 45.1 [11.0] years; 95.9% women), including 62 to iron isomaltoside and 61 to ferric carboxymaltose; 95.1% completed the trial. In trial B, 122 patients were randomized (mean [SD] age, 42.6 [12.2] years; 94.1% women), including 61 to iron isomaltoside and 61 to ferric carboxymaltose; 93.4% completed the trial. The incidence of hypophosphatemia was significantly lower following iron isomaltoside vs ferric carboxymaltose (trial A: 7.9% vs 75.0% [adjusted rate difference, –67.0% {95% CI, –77.4% to –51.5%}], P < .001; trial B: 8.1% vs 73.7% [adjusted rate difference, –65.8% {95% CI, –76.6% to –49.8%}], P < .001). Beyond hypophosphatemia and increased parathyroid hormone, the most common adverse drug reactions (No./total No.) were nausea (iron isomaltoside: 1/125; ferric carboxymaltose: 8/117) and headache (iron isomaltoside: 4/125; ferric carboxymaltose: 5/117). Conclusions and Relevance In 2 randomized trials of patients with iron-deficiency anemia who were intolerant of or unresponsive to oral iron, iron isomaltoside (now called ferric derisomaltose), compared with ferric carboxymaltose, resulted in lower incidence of hypophosphatemia over 35 days. However, further research is needed to determine the clinical importance of this difference.Item Epoetin zeta in the management of anemia associated with chronic renal failure - differential pharmacology and clinical utility(Dove Press, 2014-04) Davis-Ajami, Mary; Wu, Jun; Downton, Katherine; Ludeman, Emilie; Noxon, VirginiaEpoetin zeta was granted marketing authorization in October 2007 by the European Medicines Agency as a recombinant human erythropoietin erythropoiesis-stimulating agent to treat symptomatic anemia of renal origin in adult and pediatric patients on hemodialysis and adults on peritoneal dialysis, as well as for symptomatic renal anemia in adult patients with renal insufficiency not yet on dialysis. Currently, epoetin zeta can be administered either subcutaneously or intravenously to correct for hemoglobin concentrations ≤10 g/dL (6.2 mmol/L) or with dose adjustment to maintain hemoglobin levels at desired levels not in excess of 12 g/dL (7.5 mmol/L). This review article focuses on epoetin zeta indications in chronic kidney disease, its use in managing anemia of renal origin, and discusses its pharmacology and clinical utility.Item Erythropoietic effects of vadadustat in patients with anemia associated with chronic kidney disease(Wiley, 2022) Koury, Mark J.; Agarwal, Rajiv; Chertow, Glenn M.; Eckardt, Kai-Uwe; Fishbane, Steven; Ganz, Tomas; Haase, Volker H.; Hanudel, Mark R.; Parfrey, Patrick S.; Pergola, Pablo E.; Roy-Chaudhury, Prabir; Tumlin, James A.; Anders, Robert; Farag, Youssef M.K.; Luo, Wenli; Minga, Todd; Solinsky, Christine; Vargo, Dennis L.; Winkelmayer, Wolfgang C.; Medicine, School of MedicinePatients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non-dialysis-dependent patients with CKD and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.