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Anemia in CKD:Clinical point of view
This document discusses anemia in chronic kidney disease (CKD). It outlines the benefits of treating anemia, including improved quality of life and reduced cardiovascular risks. It then presents a case study of a 65-year-old CKD patient with diabetes and hypothyroidism. His lab results show hemoglobin of 8.4 g/dL, ferritin of 950 ng/mL, and TSAT of 15%. The document goes on to discuss factors contributing to anemia, methods of assessing iron status, iron replacement therapies including oral and parenteral options, ESA therapies, and guidelines around hemoglobin targets in CKD patients. Safety issues of iron treatment and limitations of ESA therapy are also reviewed.
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Overview of anemia's impact in CKD, stressing the need for decrease in hospitalization, improve cognitive function and quality of life.
Case of a 65-year-old CKD patient with lab findings indicating anemia, emphasizing management complexity.
Categorization of anemia contributing factors in CKD: non-correctable, potentially correctable, and easily correctable.
Details on iron storage types and laboratory criteria for assessing iron status in anemia patients.
Risks associated with iron treatment in CKD, including cardiovascular events, inflammation, infections, and iron overload.
Oral and parenteral iron supplements with recommended doses for anemia management.
Comparison of iron therapy efficacy, infection risk and cardiovascular risk between maintenance and bolus administration.
Details on ESA therapy types, dosing and limitations such as contraindications and associated risks.
Negative outcomes of from TREAT and other studies on aggressive ESA treatment, contrasting patient safety.
Risks of blood transfusions in CKD patients, highlighting why they should be avoided except in emergencies.
Focus on maintaining target hemoglobin levels and reducing transfusion needs, emphasizing patient quality of life.
Importance of early ESA intervention in CKD progression and quality of life, balancing hemoglobin levels for treatment.
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Anemia in CKD:Clinical point of view
- 1. Anemia in CKD ClinicalPoint of View Tamer Zaki Assistant Lecturer Mansoura Nephrology and Dialysis Unit
- 2. Why anemia Decreasebleeding tendency Quality of life Improve cognitive function Exercise capacity Decrease sleep disturbance Decrease COP, LVH and IHD Decrease depression Improve sexual & endocrinal Improve immune Improve ms metabolism Decrease hospitalization rate Decrease need for transfusion Improve nutrition Decrease nausea and vomiting
- 3. A 65-year-old patientwith stage 5D CKD presents to the nephrology office. He has a 7-year history of type 2 diabetes and hypothyroidism. On examination, patient had diabetic foot ulcer oozing pus. He was not compliant on his dialysis schedule due to recurrent intra-dialytic hypotension In routine lab Hemoglobin level (Hb) is 8.4 g/dL Serum ferritin level is 950 ng/mL Transferrin saturation ratio (TSAT) is 15%
- 5. Factors contributing toanemia Non-correctablePotentially correctable Easily correctable Hemoglobinopathy Bone marrow disorders Infection Inflamation Under-dialysis Hemolysis Bleeding Hyperparathyroidism PRCA Malignancy malnutrition Esa deficiency IDA Vit B12 and folic acid deficiency Hypothyroidism ACEI, ARBs Non-adherance
- 6. Iron Storage Transferrin FerritinHemosiderin 2 atoms 4500 atoms Much more Hepcidin
- 9. Bone marrow studies(gold standard) % of hypochromic cells > 6% Reticulocyte Hb level < 29 pg Combined TSAT (<20%) and ferritin (<100) NB: Functional iron deficiency TSAT (<20%) and ferritin (>800) Lab for Iron Status
- 11. Safety Issues inIron Treatment in CKD • Higher incidence of cardiovascular events • Carotid artery media-intima thickness and arterial stiffness • Increased ROS generation which trigger inflammation • Immune deficiency and susceptibility to infections • facilitating microbial growth and virulence • Allergy and hypersensitivity reaction • Iron overload
- 12. Iron replacement therapy Oral Fumarate65 Gluconate 35 Sulfate 60 Feredate 27 Recommended dose 150-200mg/d
- 13. Parentral (100mg/amp) Dextran Sucrose Gluconate Carboxy-maltose Ferumoxytol Isomaltoside Newer agents Heamiron Ferrous citrate Ferric pyrophosphate citrate
- 15. Maintenance vs Bolus •More efficacious • Less infection risk • Less oxidative stress (transferrin oversaturation) • Les CVD risk • Higher mortality (observational DOPPS data)
- 16.
- 17. ESA therapy • Sh-L:Zero hour • 50-100 IU/kg divided on 3 doses/w Epo α • Sh-L: 5d • 50-100 IU/kg divided on 3 doses/w Epo β • Sh-L: 7d • 0.45 IU/kg once weekly Darba-piotin α • Sh-L: 28d • 0.6 mg/kg every 2w Mer-Cera
- 18. Limitations of Esatherapy Contraindication of Esa Therapy • Malignancy exacerbation • Uncontrolled HTN (supra-physiologic serum level) • Hx of thrombo-embolic event in the past 6m • High risk for thrombosis • PRCA
- 19. • the TREATstudy failed to show any beneficial effect of Darbepoietin α compared to placebo. • The CHOIR and CREATE already indicated that an early complete correction of anemia with ESAs does not reduce the risk of cardiovascular events, on the contrary, intensified ESA therapy doubled the occurrence of stroke and those with a history of cancer had increased mortality.
- 21. Blood Transfusion Avoided exceptin emergency Risk of volume overload Iron overload Infection Transfusion reaction Barrier for Tx
- 22. Target Hb level Targetof therapy is not Hb only but: Reducing the need for transfusions and improving the quality of life and fatigue Then Hb level The target Hb of >13 g/dl might lead to increase in the risk of CVD Decreasing over years 10.5-11.5gm/dl stop Esa therapy if Hb >13 g/dl Avoid decrease Hb level below 9 g/dl Age related: the non-elderly population had poorer prognosis with Hb <10 g/dl, while the elderly population with only Hb <9 g/dl.
- 23. Pre-Dialysis with Anemia CKDprogression: early start of Epo with higher Hb level can retard progression of ckd CVD: >13 gm/dl harmful but high Hb level >11.8gm/dl may improve symptomatic HF and anemia QOL: >12gm/dl physical function, general health, social function and mental health Maintaining a high Hb of >12 g/dl without ESA is not harmful for CKD patients
Editor's Notes
- #4 Based on the laboratory values including the presented markers of iron status, this patient appears to suffer from iron deficiency. Iron deficiency in this patient is characterized by a relatively low serum ferritin value of 87 ng/mL, which is below the recommended number of 100 ng/mL for patients with CKD. [The patient's] TSAT is 15% and a TSAT below 20% is considered [to be] iron deficiency in patients with CKD, or below 16% in the general population. In addition, the Hb level is below 10 g/dL. In this patient, it's 8.4 g/dL, which is consistent with moderate-to-profound anemia. Assessment of iron status in a patient with CKD is usually done using the traditional markers of iron status including serum ferritin. It is recommended that patients with CKD should have a serum ferritin level > 100 ng/mL, as well as a TSAT level, also known as iron saturation ratio, measured. If it is < 20%, it is consistent with iron deficiency in CKD patients. It is believed that [a] TSAT level below 20% is more sensitive in terms of detecting iron deficiency in CKD patients whereas ferritin is more specific. In other words, if serum ferritin is < 100 ng/mL, then there is a high likelihood of iron deficiency in these patients whereas a normal serum ferritin level above 100 ng/mL does not necessarily rule out iron deficiency. (Enlarge Slide)The most important step at this point is to restore iron stores in this patient before starting with ESAs. There are other markers of iron deficiency that are not used commonly in individuals with CKD. The gold standard is bone marrow studies by performing bone marrow aspiration and examining the iron status in the bone marrow biopsy specimens. There are also other markers of iron deficiency or iron stores that are readily available for the CKD patient population.
- #7 Transferrin receptorsarethemainrouteofironentry into mostcells.Transferrinreceptor(TfR)1is expressed ubiquitouslyonmostcellsincludingeryth- roid tissue,26 whereas TfR2isexpressedmostlyon hepatocytes.27 Circulating iron-transferrincomplexis endocytosed whenitbindstothetransferrinreceptorat the cellsurface.28 After ironistakenup,itbindsto intracellular ferritin—the storageformofiron.Each ferritin moleculeismadeupofLandHsubunitsand can storeupto4,500ironatomsintheferricstate.29 L-rich ferritinisaniron-richferritinthatformsthecore and typicallyisfoundintissuesthatcanstoreironfor long-term use(ie,liverandspleen).H-ferritinchains have lowerironcontent,butareresponsiblefor catalyzing theoxidationofFe2þ. Thestoragepool of ironislabile,suchthatunderconditionsofiron deficiency, ironreadilyisreleasedintotheblood plasma, whereaswhenthereisanexcessofiron, ferritin canbeconvertedfurthertoanotherintracellular storage formofiron:hemosiderin.30 Although storage of excessironintheformofhemosiderinlimitsthe toxicity offreelyavailableiron,ascomparedwith ferritin, thebioavailabilityofironthatisstoredas hemosiderin ismuchworse. On the other hand,hepcidindeficiency canleadto excessive ironabsorptionandironoverloaddisorders, the basisofseveralformsofhereditaryhemo- chromatosis
- #8 absorption takes place in the proximal small intestine heme or non-heme absorbed through separate mechanisms Non-heme iron = the oxidized or ferric (Fe3) form (brush-border ferric reductase ) Divalent metal transporter 1 (DMT1) Hepcidin in cells (enterocytes, macrophages, hepatocytes) Ferroportin the only iron exporter
- #9 intheFIND–CKD studywassimilarforall treatment arms(33.1%inthehigh-ferritinferriccar- boxymaltose arm,34.0%inthelow-ferritinferric carboxymaltose arm,and30.4%intheoralironarm). Serious infectionsalsowerenearlyidenticalforthe three treatmentarms(3.9%,3.3%,and3.8%, respectively).
- #10 Use percentage of hypochromic red blood cells (%HRC; more than 6%), but only if processing of blood sample is possible within 6 hours. If using %HRC is not possible, use reticulocyte haemoglobin content (less than 29 pg) or equivalent tests – for example, reticulocyte haemoglobin equivalent. If these tests are not available or the person has thalassaemia or thalassaemia trait, use a combination of transferrin saturation (less than 20%) and serum ferritin measurement (less than 100 micrograms/litre). Do not request transferrin saturation or serum ferritin measurement alone to assess iron deficiency status in people with anaemia of CKD. Do not routinely consider measurement of erythropoietin levels for the diagnosis or management of anaemia in people with anaemia of CKD. Iron-deficient for a variety of reasons blood loss through the gastrointestinal tract Because they are more predisposed to bleeding tendencies Poor nutrition Iron loss during hemodialysis Several non–iron-dependent factorscanregulateferri- tin levelssuchasinflammation, liverdysfunction,and malnutrition.38 Proinflammatory cytokinessuchas tumor necrosisfactor α and interleukin1β increase ferritin synthesis.39,40 Inflammation andnutritional status areassociatedsignificantly withserumferritin levels (between200and2,000ng/mL)indialysis patients.41 Similar toferritin,TSAThasitsshortcomingsasa marker ofironstatus.Apartfromhavingdiurnal variation, transferrinandTSATlevelsalsoareinflu-enced bynutritionalstatusandinflammation. Trans- ferrin levelsarelowinmalnutrition,makingTSAT appear higher.Instatesofinflammation TSATmight be artificially lowgiventhattransferrinisanacute phase reactantandisincreasedwithinflammation.
- #14 Taken away from food, antacids and PO4 binders PPI decrease absorption Heam Iron forms Gastric upset Three times per day Black stool and constipation Delayed release formula (SR) the lack of clinical evidence prevents to answer the most intriguing questions, namely the optimal dose and frequency of parenteral iron, upper limit of dosing and therapy duration Oral ironisinexpensiveandthemostphysiologic treatment ofirondeficiency. Multiplepreparationsare readily availableforclinicaluseandconsistmostlyof ferrous salts.Bivalentiron(ferrous)isbelievedtobe three timesbetterabsorbedthanthetrivalentferric iron.3 Efficacy offerrousironislimitedbygastro- intestinal sideeffects,frequentadministration,and diminished enteralabsorptionasaresultofinteraction with food,phosphatebinders,andreducedgastric acidity. Heme ironisabsorbedintheintestineviaadifferent transporter thanferrousiron.Anearlyopen-labelstudy of hemeironpolypeptideindialysispatientssuggested efficacy,8 consistent withastudyshowinghigher bioavailability ofhemeironthanironsalts.9 A more recent rigorousrandomizedtrialprescribing240mgof heme ironpolypeptideor210mgofferroussulfate showed neitheragentsignificantly improvedhemoglo- bin, transferrinpercentagesaturation(TSAT),orlow- ered epoetindose
- #15 Polysaccharide coat SE and pro oxidant stress, infection, allergy Gadolinium based MRI Thrombophlebitis An alternative approach for iron substitution in dialysis patients is offered by ferric pyrophosphate citrate [65], a water-soluble iron salt preparation, which is added to prepare dialysate. The compound is able to diffuse through the dialyzer into the blood providing iron directly to transferrinwithout increasing iron stores. Although several beneficial effects including reduced IV iron and ESA requirementswere described in two recent studies [66,67], a substantial safety analysis as well as a head-to-head comparison between ferric pyrophosphate citrate and iron sucrose have not been performed yet. In certain cases such as ongoing systemic inflammation or calciphylaxis – a rare, but very severe complication of CKD – iron substitution should be completely avoided Furthermore, therapeutically induced hemochromatosis independently of other causative factors increases cardiovascular risk and mortality Retrospective analysis of the Dialysis Outcomes Practice Patterns Study (DOPPS) population database points also towards this “negative direction”, as increased mortality and more frequent hospitalization was found among patients who received N300mg/month IV iron
- #18 The reason for the greater bioavailability of iron in ferric citrate than in conventional oral iron preparations is unclear and requires further investigation. Possible mechanisms include but are not limited to differences in the nature of the accompanying anion (citrate vs others), possible vesicular or paracellular transport of ferric citrate as opposed to the tightly regulated DMT-1 (divalent metal transporter 1) pathway, extended sites of absorption beyond the duodenum/proximal jejunum, and uremia-induced changes in the structure and function of the gut epithelial barrier. Another likely mechanism for bioavailability of iron in ferric citrate is the high iron content (1,200-2,400 mg of elemental iron per day) of the prescribed dose, which far exceeds the iron content prescribed in the standard oral iron compounds (200 mg/d).
- #24 Unit of blood contain around 250 mg iron
- #25 Anemia of renal disease is common and is associated with significant morbidity and death. It is mainly caused by a decrease in erythropoietin production in the kidneys and can be partially corrected with erythropoiesis-stimulating agents (ESAs). However, randomized controlled trials have shown that using ESAs to target normal hemoglobin levels can be harmful, and have called into question any benefits of ESA treatment other than avoidance of transfusions.