DOCSLIB.ORG

Exploring Emerging Strategies in the Management of Anemia in Chronic Kidney Disease

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Exploring Emerging Strategies in the Management of Anemia in Chronic Kidney Disease Exploring Emerging Strategies in the Management of Anemia in Chronic Kidney Disease A Midday Symposium Conducted at the 2019 ASHP Midyear Clinical Meeting and Exhibition. Faculty Disclosures Chair & Presenter Jay B. Wish, MD Professor of Clinical Medicine Chief Medical Officer for Dialysis Indiana University Health Indianapolis, Indiana Jay B. Wish, MD, has a financial interest/relationship or affiliation in the form of: Consultant and/or Advisor for Akebia Therapeutics; AstraZeneca; Otsuka America Pharmaceutical, Inc.; Rockwell Medical; and Vifor Pharma Management Ltd. Speakers Bureau participant with Akebia Therapeutics and AstraZeneca. Faculty Disclosures Presenter Presenter Anil K. Agarwal, MD, FASN Thomas C. Dowling, PharmD, PhD, FCCP Professor of Medicine Professor and Assistant Dean, College of Pharmacy The Ohio State University College of Medicine Director, Office of Research and Sponsored Programs Columbus, Ohio Ferris State University Big Rapids, Michigan Anil K. Agarwal, MD, FASN, has a financial interest/relationship or affiliation in the form of: Thomas C. Dowling, PharmD, PhD, FCCP, has a financial interest/relationship or affiliation in the form of: Consultant and/or Advisor for AstraZeneca and Rockwell Speakers Bureau participant with AstraZeneca. Medical. Grant/Research Support from Akebia Therapeutics. Planning Committee Disclosures Teresa Haile, RPh, MBA, Lead Pharmacy Planner, MLI, has nothing to disclose. The planners from Medical Learning Institute, Inc., the accredited provider, and PeerView Institute for Medical Education, the joint provider, do not have any financial relationships with an ACCME-defined commercial interest related to the content of this accredited CPE activity during the past 12 months unless listed below. Content/Peer Reviewer Disclosures The following Content/Peer Reviewer(s) have nothing to disclose: Shelley Chun, PharmD Disclosure of Unlabeled Use This educational activity may contain discussions of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient's conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities. MasterClass #1 A Closer Look at the Burden of CKD-Associated Anemia and Rationale for HIF-PH Inhibition as a Therapeutic Strategy Anil K. Agarwal, MD, FASN Professor of Medicine The Ohio State University College of Medicine Columbus, Ohio Go online to access full [Certification Type] information, including faculty disclosures. Chronic Kidney Disease (CKD) Is Common Among US Adults: Fast Stats1 15% of US adults—37 million people—are estimated to have CKD Most (9 in 10) adults with CKD do not know they have it 1 in 2 people with very low kidney function who are not on dialysis do not know they have CKD 1. https://www.cdc.gov/kidneydisease/publications-resources/2019-national-facts.html. Accessed December 2, 2019. Chronic Kidney Disease (CKD) Is Common Among US Adults: Current Estimates1 CKD is more common in people aged 65 years or older (38%) than in people aged 45 to 64 years (13%) or 18 to 44 years (7%) CKD is more common in women (15%) than men (12%) CKD is more common in non-Hispanic blacks (16%) than in non-Hispanic whites (13%) or non-Hispanic Asians (12%) About 14% of Hispanics have CKD 1. https://www.cdc.gov/kidneydisease/publications-resources/2019-national-facts.html. Accessed December 2, 2019. Overview of Anemia in CKD1-3 Anemia remains an important complication experienced by The prevalence of anemia patients with kidney disease, depends on its definition although one that is treatable When present, it may Anemia generally cause symptoms such increases in frequency as fatigue, weakness, and severity in the more paleness, and advanced stages of CKD shortness of breath and age 1. Fishbane S, Spinowitz B. Am J Kidney Dis. 2018;71:423-435. 2. https://www.niddk.nih.gov/health-information/kidney-disease/anemia. Accessed December 2, 2019. 3. Stauffer ME, Fan T. PLoS One. 2014;9:e84943. Complications Associated With Anemia in CKD1-3 Anemia in CKD is associated with cognitive impairment, sleep disturbances, CKD progression, cardiovascular comorbidities, and higher mortality Direct healthcare costs are higher in CKD patients with anemia than in those without, and quality of life issues (eg, fatigue, reduced productivity) are common 1. Fishbane S, Spinowitz B. Am J Kidney Dis. 2018;71:423-435. 2. https://www.niddk.nih.gov/health-information/kidney-disease/anemia. Accessed December 2, 2019. 3. Stauffer ME, Fan T. PLoS One. 2014;9:e84943. Flowchart for the Evaluation of the CKD Patient With Anemia1 • CKD 3: at least annually • CKD 4: at least every 6 months • CKD 5 ND: at least every 6 months • CKD 5 PD: at least every 1 month • CKD 5 HD: at least every 1 month No Further Blood loss, CKD Yes hematology hemoglobinopathy, Check Hb workup vitamin B12, folate stages 1-5 No Iron deficiency Treat with ≤13.0 (men) Yes Yes iron ≤12.0 (women) Workup Normal? Anemia corrected, CBC, RBC indices, periodic follow-ups No iron studies, stool Treat with epoetin, for occult blood Yes if indicated Anemia No workup not corrected 1. Kidney Disease Outcomes Quality Initiative. Am J Kidney Dis. 2006;47:S1-S145. What Are the Potential Harms of ESA Therapy?1 Study Normal Hematocrit Study CHOIR TREAT ESA, N Epoetin alfa (1,265) Epoetin alfa (1,432) Darbepoetin alfa (4,038) HD patients with coexisting HF or CAD, ND-CKD patients with Hb <11 g/dL ND-CKD patient with T2DM, Population Hct 30% ± 3% on epoetin alfa not previously administered ESA Hb <11 g/dL Hb target, g/dL 14.0 vs 10.0 13.5 vs 11.3 13.0 vs ≥9.0 Median achieved 12.6 vs 10.3 13.0 vs 11.4 12.5 vs 10.6 Hb level, g/dL All-cause mortality, MI, All-cause mortality, MI, Primary endpoint All-cause mortality or nonfatal MI hospitalization for HF, or stroke myocardial ischemia, HF, and stroke HR or RR (95% CI) 1.28 (1.06-1.56) 1.34 (1.03-1.74) 1.05 (0.94-1.17) Adverse outcome for All-cause mortality All-cause mortality Stroke higher Hb group HR or RR (95% CI) 1.27 (1.04-1.54) 1.48 (0.97-2.27) 1.92 (1.38-2.68) No difference except less fatigue QOL Better in high Hb group (controversial) No difference in high Hb group ↑ cancer deaths in high Hb group among Comment ↑ VA thrombosis in high Hb group patients with prior history of cancer 1. Epogen (epoetin alfa) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103234s5363s5366lbl.pdf. Accessed December 2, 2019. Balancing Risk vs Benefit of ESA Therapy Lower target Higher target Hb Hb Balancing Risk vs Benefit of ESA Therapy: A Closer Look at Hb Distribution Impact of PPS (Bundled Payment for Dialysis) and the FDA ESA Label Change (2011)1,2 • Average ESA doses have decreased to around 40% • Mean Hb levels have decreased from 11.5 to 10.8 g/dL (DOPPS) • Observed rates of stroke, VTE, and HF have decreased1 • Transfusion rates have increased from around 2.7% to 3.0% (DOPPS) • Transfusion increase primarily among patients receiving multiple transfusions Is this an What about acceptable quality of life? trade-off? 1. Chertow GM et al. J Am Soc Nephrol. 2016;27:3129-3138. 2. Hirth RA et al. Am J Kidney Dis. 2014;64:616-621. Quality of Life/Patient-Centered Care in Anemia Management Although most RCTs have failed to demonstrate any improvement in QOL by raising target Hb from 9-11 g/dL to 13-14 g/dL with ESAs, these are population studies, and there may be individuals who benefit from higher Hb levels CREATE showed KDIGO acknowledges that some patients TREAT showed a SF-36 improvement may feel better at target Hb levels >11.5 decrease in in all domains at g/dL and recommends that target Hb levels fatigue higher target Hb be individualized for such patients, levels if they are willing to accept the risks Proposed Mechanisms for CV Events at Higher Target Hb Levels and ESA Doses: Which Is Responsible? Since randomization of the RCTs was by target Hb level, only the target Hb level can be considered cause and effect Higher ESA doses are highly associated with AEs in secondary analyses • Patients who achieved higher target Hb levels at low ESA doses had fewer AEs than patients who required high ESA doses to achieve lower target Hb levels • This is highly confounded by comorbidities that may lead to ESA resistance and poorer outcomes Proposed Mechanisms for CV Events at Higher Target Hb Levels and ESA Doses: Other Contributing Factors Increased blood viscosity because of higher Hb level Improved platelet function at higher Hb levels (more margination) Thrombocytosis because of ESA-induced functional iron deficiency Hypertension • Increased RBC volume • Decreased peripheral vasodilation at higher Hb levels
Load more

Recommended publications
  • Final Evidence Report
    Treatments for Anemia in Chronic Kidney Disease: Effectiveness and Value Final Evidence Report March 5, 2021 Prepared for ©Institute for Clinical and Economic Review, 2021 ICER Staff and Consultants University of Washington Modeling Group Reem A. Mustafa, MD, MPH, PhD Lisa Bloudek, PharmD, MS Associate Professor of Medicine Senior Research Scientist Director, Outcomes and Implementation Research University of Washington University of Kansas Medical Center Josh J. Carlson, PhD, MPH Grace Fox, PhD Associate Professor, Department of Pharmacy Research Lead University of Washington Institute for Clinical and Economic Review The role of the University of Washington is limited to Jonathan D. Campbell, PhD, MS the development of the cost-effectiveness model, and Senior Vice President for Health Economics the resulting ICER report does not necessarily Institute for Clinical and Economic Review represent the views of the University of Washington. Foluso Agboola, MBBS, MPH Vice President of Research Institute for Clinical and Economic Review Steven D. Pearson, MD, MSc President Institute for Clinical and Economic Review David M. Rind, MD, MSc Chief Medical Officer Institute for Clinical and Economic Review None of the above authors disclosed any conflicts of interest. DATE OF PUBLICATION: March 5, 2021 How to cite this document: Mustafa RA, Bloudek L, Fox G, Carlson JJ, Campbell JD, Agboola F, Pearson SD, Rind DM. Treatments for Anemia in Chronic Kidney Disease: Effectiveness and Value; Final Evidence Report. Institute for Clinical and Economic Review, March 5, 2021. https://icer.org/assessment/anemia-in-chronic-kidney-disease-2021/#timeline. Reem Mustafa served as the lead author for the report. Grace Fox led the systematic review and authorship of the comparative clinical effectiveness section in collaboration with Foluso Agboola and Noemi Fluetsch.
    [Show full text]
  • Report Supplement
    Treatments for Anemia in Chronic Kidney Disease: Effectiveness and Value Report Supplement January 28, 2021 Prepared for ©Institute for Clinical and Economic Review, 2021 Table of Contents A. Background: Supplemental Information ........................................................................................... 1 A1. Definitions .................................................................................................................................... 1 A2. Potential Cost-Saving Measures .................................................................................................. 1 B. Patient Perspectives: Supplemental Information .............................................................................. 3 B1. Methods ....................................................................................................................................... 3 C. Clinical Guidelines .............................................................................................................................. 4 D. Comparative Clinical Effectiveness: Supplemental Information ....................................................... 5 D1. Detailed Methods ........................................................................................................................ 5 D2. Supplemental Results ................................................................................................................ 13 D3. Evidence Tables ........................................................................................................................
    [Show full text]
  • Anemia in Chronic Kidney Disease : Role of Hypoxia Inducible Factor Stabilizer Bioscientia Medicina: Journal of Biomedicine &
    Bioscientia Medicina: Journal of Biomedicine & Translational Research eISSN (Online): 2598-0580 Bioscientia Medicina: Journal of Biomedicine & Translational Research Anemia in Chronic Kidney Disease : Role of Hypoxia Inducible Factor Stabilizer Emilia1* Zulkhair Ali2 1Trainee of Nephrology and Hypertension, Internal Medicine Department, Faculty of Medicine, Universitas Sriwijaya, Palembang, South Sumatera, Indonesia. 2Division of Nephrology and Hypertension, Internal Medicine Department, Faculty of Medicine, Universitas Sriwijaya, Palembang, South Sumatera, Indonesia. A R T I C L E I N F O A B S T R A C T Keywords: Chronic Kidney Disease Anemia contributes to increased morbidity and mortality in chronic kidney disease Anemia patients. The pathogenesis of anemia in these patients is multifactorial, but the Erythropoiesis-stimulating Agents contribution of erythropoietin deficiency becomes greater as glomerular filtration Hypoxia Inducible Factor Stabilizer. rate declines which related to decreased nephron mass. The current standard of care includes supplemental iron, erythropoiesis-stimulating agents (ESA), and red blood cell transfusions, although each has drawbacks. Lately, concern has arisen *Corresponding author: following randomized clinical trials showing that higher hemoglobin targets and/or high ESA doses may cause significant harm including increasing cardiovascular and Emilia thrombotic events, and even death. Recent experimental and clinical studies show the promising efficacy of hypoxia inducible factor (HIF) stabilizer which
    [Show full text]
  • Anemia of Chronic Diseases: Wider Diagnostics—Better Treatment?
    nutrients Communication Anemia of Chronic Diseases: Wider Diagnostics—Better Treatment? Michał Wici ´nski 1, Grzegorz Liczner 1, Karol Cadelski 1, Tadeusz Kołnierzak 1, Magdalena Nowaczewska 2 and Bartosz Malinowski 1,* 1 Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland; [email protected] (M.W.); [email protected] (G.L.); [email protected] (K.C.); [email protected] (T.K.) 2 Department of Otolaryngology, Head and Neck Surgery, and Laryngological Oncology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland; [email protected] * Correspondence: [email protected] Received: 24 April 2020; Accepted: 10 June 2020; Published: 16 June 2020 Abstract: Anemia of chronic diseases is a condition that accompanies a specific underlying disease, in which there is a decrease in hemoglobin, hematocrit and erythrocyte counts due to a complex process, usually initiated by cellular immunity mechanisms and pro-inflammatory cytokines and hepcidin. This is the second most common type of anemia after iron deficiency anemia in the world. Its severity generally correlates with the severity of the underlying disease. This disease most often coexists with chronic inflammation, autoimmune diseases, cancer, and kidney failure. Before starting treatment, one should undertake in-depth diagnostics, which includes not only assessment of complete blood count and biochemical parameters, but also severity of the underlying disease. The differential diagnosis of anemia of chronic diseases is primarily based on the exclusion of other types of anemia, in particular iron deficiency. The main features of anemia of chronic diseases include mild to moderate lowering of hemoglobin level, decreased percentage of reticulocyte count, low iron and transferrin concentration, but increased ferritin.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • 13, 2020 Individual
    Abstracts from the 11th American Conference on Pharmacometrics ACoP11 ISSN 2688-3953 ACoP11, November 9 – 13, 2020 Individual abstracts will be posted online post meeting. For citation purposes please use the following Citation: Author names, Abstract title, ACoP11, ISSN:2688-3953, 2020, Vol 2 TUE- 001 Updated Review of Vancomycin Population Pharmacokinetic Analyses in Adults Abdullah Aljutayli1, Amélie Marsot2,3, and Fahima Nekka1,4,5 1 Faculty of Pharmacy, Université de Montréal, Montréal, Canada 2Laboratoire de suivi thérapeutique pharmacologique et pharmacocinétique, Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada. 3Centre de recherche, CHU Sainte-Justine, Montréal, Québec, Canada 4 Laboratoire de Pharmacométrie, Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada. 5Centre de recherches mathématiques, Université de Montréal, Montréal, Québec, Canada. Background: Vancomycin is a drug of choice in the management of methicillin-resistant Staphylococcus aureus (MRSA) infections. Nonetheless, vancomycin optimal dosage regimens have, long, been controversial owing to the large between- and within-subject variability in its population pharmacokinetic (PopPK) profile. Objectives: Our primary aim was to better inform vancomycin dosing by providing a comprehensive synthesis of PopPK analyses of vancomycin to determine the most reported models, including the various sources of variability. Methods: Systematic search for vancomycin PopPK studies was conducted on PubMed and EMBASE with a time limit from January of 2011 to May of 2019. In addition, we inspected all relevant lists of references. Results: Thirty analyses met the research criteria and were included in this review. One-compartment and two- compartment models best-described vancomycin PopPK in thirteen and fourteen studies, respectively. Further, three- compartment models were implemented in three studies to account for an additional cite of administration, i.e.
    [Show full text]
  • Iron Deficiency in Chronic Kidney Disease
    REVIEW www.jasn.org Iron Deficiency in Chronic Kidney Disease: Updates on Pathophysiology, Diagnosis, and Treatment Elizabeth Katherine Batchelor,1 Pinelopi Kapitsinou,2,3 Pablo E. Pergola,4 Csaba P. Kovesdy ,5 and Diana I. Jalal6 1Department of Internal Medicine and 6Division of Nephrology, University of Iowa Hospitals and Clinics, Iowa City, Iowa; 2Feinberg Cardiovascular and Renal Research Institute and 3Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois; 4Renal Associates PA, Division of Nephrology, University of Texas Health Science Center at San Antonio, San Antonio, Texas; and 5Division of Nephrology, University of Tennessee Health Science Center, Memphis, Tennessee ABSTRACT Anemia is a complication that affects a majority of individuals with advanced CKD. which impairs the body’s ability to appro- Although relative deficiency of erythropoietin production is the major driver of ane- priately utilize the iron sequestered in the mia in CKD, iron deficiency stands out among the mechanisms contributing to the tissues.8 Repletion of iron stores is often impaired erythropoiesis in the setting of reduced kidney function. Iron deficiency necessary in patients with CKD for the plays a significant role in anemia in CKD. This may be due to a true paucity of iron treatment of IDA and to maximize the ef- stores (absolute iron deficiency) or a relative (functional) deficiency which prevents ficacy of ESAs. The traditional biomarkers the use of available iron stores. Several risk factors contribute to absolute and func- used to detect iron deficiency in CKD are tional iron deficiency in CKD, including blood losses, impaired iron absorption, and often unreliable, rendering the diagnostic chronic inflammation.
    [Show full text]
  • Anemia in Chronic Kidney Disease: from Pathophysiology and Current Treatments, to Future Agents
    REVIEW published: 26 March 2021 doi: 10.3389/fmed.2021.642296 Anemia in Chronic Kidney Disease: From Pathophysiology and Current Treatments, to Future Agents Jose Portolés 1,2, Leyre Martín 1,2*, José Jesús Broseta 3 and Aleix Cases 2,3 1 Department of Nephrology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain, 2 Anemia Working Group Spanish Society of Nephrology, Madrid, Spain, 3 Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain Anemia is a common complication in chronic kidney disease (CKD), and is associated with a reduced quality of life, and an increased morbidity and mortality. The mechanisms involved in anemia associated to CKD are diverse and complex. They include a decrease in endogenous erythropoietin (EPO) production, absolute and/or functional iron deficiency, and inflammation with increased hepcidin levels, among others. Patients are most commonly managed with oral or intravenous iron supplements and with erythropoiesis stimulating agents (ESA). However, these treatments have associated risks, and sometimes are insufficiently effective. Nonetheless, in the last years, there have been some remarkable advances in the treatment of CKD-related anemia, which Edited by: have raised great expectations. On the one hand, a novel family of drugs has been Michele Provenzano, developed: the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). These University of Catanzaro, Italy agents induce, among other effects, an increase in the production of endogenous Reviewed by: Lucia Del Vecchio, EPO, improve iron availability and reduce hepcidin levels. Some of them have already ASST Lecco, Italy received marketing authorization. On the other hand, recent clinical trials have elucidated Roberto Minutolo, Università della Campania Luigi important aspects of iron supplementation, which may change the treatment targets in Vanvitelli, Italy the future.
    [Show full text]
  • Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin
    UC Irvine UC Irvine Previously Published Works Title Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin. Permalink https://escholarship.org/uc/item/7k1593dd Journal Advances in therapy, 38(1) ISSN 0741-238X Authors Hanna, Ramy M Streja, Elani Kalantar-Zadeh, Kamyar Publication Date 2021 DOI 10.1007/s12325-020-01524-6 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Adv Ther (2021) 38:52–75 https://doi.org/10.1007/s12325-020-01524-6 REVIEW Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin Ramy M. Hanna . Elani Streja . Kamyar Kalantar-Zadeh Received: June 24, 2020 / Accepted: October 3, 2020 / Published online: October 29, 2020 Ó The Author(s) 2020 ABSTRACT complications. In particular, treatment with high doses of erythropoiesis-stimulating agents has Anemia is a frequent comorbidity of chronic been associated with increased rates of hospital- kidney disease (CKD) and is associated with a ization, cardiovascular events, and mortality. considerable burden because of decreased patient Resistance to erythropoiesis-stimulating agents health-related quality of life and increased health- remains a therapeutic challenge in a subset of care resource utilization. Based on observational patients. Hypoxia-inducible factor transcription data, anemia is associated with an increased risk factors, which regulate several genes involved in of CKD progression, cardiovascular events, and erythropoiesis and iron metabolism, can be sta- all-cause mortality. The current standard of care bilizedbyanewclassofdrugsthatactas includes oral or intravenous iron supplementa- inhibitors of hypoxia-inducible factor prolyl-hy- tion, erythropoiesis-stimulating agents, and red droxylase enzymes to promote erythropoiesis and blood cell transfusion. However, each of these elevate hemoglobin levels.
    [Show full text]
  • HIF-Α Prolyl Hydroxylase Inhibitors and Their Implications for Biomedicine: a Comprehensive Review
    biomedicines Review HIF-α Prolyl Hydroxylase Inhibitors and Their Implications for Biomedicine: A Comprehensive Review Kiichi Hirota Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka 573-1010, Japan; [email protected]; Tel.: +81-72-804-2526 Abstract: Oxygen is essential for the maintenance of the body. Living organisms have evolved systems to secure an oxygen environment to be proper. Hypoxia-inducible factor (HIF) plays an essential role in this process; it is a transcription factor that mediates erythropoietin (EPO) induction at the transcriptional level under hypoxic environment. After successful cDNA cloning in 1995, a line of studies were conducted for elucidating the molecular mechanism of HIF activation in response to hypoxia. In 2001, cDNA cloning of dioxygenases acting on prolines and asparagine residues, which play essential roles in this process, was reported. HIF-prolyl hydroxylases (PHs) are molecules that constitute the core molecular mechanism of detecting a decrease in the partial pressure of oxygen, or hypoxia, in the cells; they can be called oxygen sensors. In this review, I discuss the process of molecular cloning of HIF and HIF-PH, which explains hypoxia-induced EPO expression; the development of HIF-PH inhibitors that artificially or exogenously activate HIF by inhibiting HIF-PH; and the significance and implications of medical intervention using HIF-PH inhibitors. Keywords: hypoxia; transcription factor; hypoxia-inducible factor 1; HIF-1; hypoxia sensing; HIF- PH inhibitor Citation: Hirota, K. HIF-α Prolyl Hydroxylase Inhibitors and Their Implications for Biomedicine: A 1. Introduction Comprehensive Review. Biomedicines Chronic kidney disease (CKD), cancers, inflammatory diseases, nutritional deficiencies, 2021, 9, 468.
    [Show full text]
  • Update on Randomized Clinical Trials in Anemia of CKD KDIGO Chuan-Ming Hao Division of Nephrology, Huashan Hospital Fudan University DISCLOSURES
    Update on Randomized Clinical Trials in Anemia of CKD KDIGO Chuan-Ming Hao Division of Nephrology, Huashan Hospital Fudan University DISCLOSURES • Honoraria from FibroGen and AstraZeneca KDIGO Content • HIF-PHD as a target for CKD anemia treatment • HIF-PHI Roxadustat: data from China phase 3 trials • HIF-PHI Roxadustat: data from global phase 3 trials KDIGO PHI KDIGO Erythropoiesis Angiogenesis Glycolysis … PHD as a Target to Stabilize HIF KDIGO Holt-Martyn JP, et al. Medchemcomm. 2019,10(4):500-504 PHI as New Treatment for CKD Anemia Compound Company Development status Roxadustat FibroGen/Astra Zeneca Approved in China and Japan FG-4592 Vadadustat Akebia/Mitsubishi Tanabe Pharma AKB-6548 Expected to be approved in Japan in 2020 Daprodustat GSK/Kirin GSK-1278863 Expected to be approved in Japan in 2020 Molidustat Bayer BAY 85-3934 Phase III Enarodustat Japan Tobacco Inc JTZ-951 KDIGO Phase III Desidustat Cadila Healthcare Ltd ZYAN1 Phase III DDO-3055 Hengrui Medicine Phase I HEC53856 HEC Phase I HIF-117 3SBIO INC Phase I Content • HIF-PHD as a target for CKD anemia treatment • HIF-PHI Roxadustat: data from China phase 3 trials • HIF-PHI Roxadustat: data from global phase 3 trials KDIGO Roxadustat for NDD CKD : Study Design Phase 3, randomized, douBle-blind, placebo-controlled study • Key inclusions: • Key exclusions: − CKD Stages 3-5 − Clinically significant infection − Age 18-75 years − Uncontrolled hypertension − Screening Hb 7.0-10.0 g/dL − Renal cell carcinoma − No ESA for at least 5 weeks − GI bleeding − IV iron during the screening and KDIGO/or unwilling to withhold IV iron Non-dialysis Patients Study 808 Chen N, Hao CM, et al.
    [Show full text]
  • Alexander Stepanov1, Galina Lebedeva2 1 Insysbio, Moscow, Russia; 2 Insysbio UK Ltd, Edinburgh, UK
    Stimulation of erythropoiesis with ESA or blood donation: QSP model Alexander Stepanov1, Galina Lebedeva2 1 InSysBio, Moscow, Russia; 2 InSysBio UK Ltd, Edinburgh, UK INTRODUCTION RESULTS: PK/PD of EPO RESULTS: PK/PD of dustats Erythropoiesis-stimulating agents (ESAs) enhance the red blood cells Regulation effects of EPO were implemented via explicit description of The response of clinical outcomes such as reticulocytes count and (RBC) formation by bone marrow. They are used to manage anemic EPO binding to its receptor followed by internalization leading to erythropoietin levels to administration of HIF stabilizers (Roxadustat, states caused by chemotherapy, bleeding, bone marrow’s malfunctions. acceleration of cell proliferation and differentiation, and inhibition of Desidustat, Daprodustat and Molidustat) were described by the model. To predict the effect of pharmacological intervention on hematopoiesis- apoptosis. PK/PD parameters were calibrated against in vivo data for related clinical endpoints we propose the QSP model of erythropoiesis. single dosage regime of EPO (Fig. 2 and 3). Pharmacokinetics of Dustats MODEL: STRUCTURE Pharmacokinetics of Erythropoietin 800 Daprodustat dose: Desidustat dose: 400 Molidustat dose: 7000 Roxadustat dose: ODE model of erythropoiesis was constructed to comprehensively 10, 25 and 50 mg 2000 25 and 50 mg 25 and 50 mg 100 mg PMID: 26643993 PMID: 28508936 PMID: 29575006 6000 PMID: 27352308 describe cell dynamics from hematopoietic stem cell to circulating RBC. 600 300 1500 5000 400 EPO dose: 300 IU/kg EPO dose: 600 IU/kg EPO dose: 1200 IU/kg 1000 The model includes variables corresponding to specific stages of cell 2000 4000 400 1000 200 300 800 3000 development distinguished based on morphology and surface markers xadustat, ng/mL , IU/L , IU/L , IU/L 1500 o 600 2000 expression.
    [Show full text]