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ROLE OF IRON STORES IN ANEMIA
ANNA – Long Island Chapter May 7th, 2014 Naveed Masani, MD Winthrop University Hospital
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OBJECTIVES Describe the iron deficiency seen in CKD/ESRD patients
Develop an understanding of iron parameters Review of the available iron therapies Define the balance between ESA dosing & iron therapy
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“INGREDIENTS” Iron Vitamin B12 Folate Erythropoietin (EPO) Bone marrow
Hemoglobin
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IRON Most abundant trace element 2/3 in heme
20-25 mg/day needed for RBC production Diet: 1 mg/day Increased need Pregnancy Childhood/adolescence Blood loss
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IRON (cont) Organ storage Total body iron content: approx 3-4 gm Liver
Spleen Bone marrow Total body iron content: approx 3-4 gm Hgb: 2gm Iron containing proteins: 400 mg Bound Iron in “transport” form: 3 – 7 milligrams Remainder in “storage” form: 500 mg – 1.5 gm
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IRON PARAMETERS Serum Iron (Fe) Tsat – percent iron saturation
TIBC – Total Iron Binding Capacity Transferrin – “transport” Rises with inflammation Falls with poor nourishment/chronic diseases Ferritin – “storage” VERY USEFUL IF LOW; HOWEVER, IF HIGH…. Provides information on storage, but not on “usability”
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RETICULOCYTE Hgb CONTENT (CHr)
Promising lab test to measure ability of red cells to use iron Measures the hemoglobin content in premature red cells (reticulocytes) Single point evaluation of iron availability for red cell production Did not make it to every day use despite clearly being superior to current standards
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PERCENT HYPOCHROMIC RED CELLS (%HYPO)
Early marker of functional iron deficiency Outperforms Tsat & Ferritin Blood samples need to be run within hours of being drawn Gives information as to the actual availability of iron to the maturing red blood cell Used in Europe on a regular basis ? If the combination of CHr & %HYPO would be better than current standards
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TARGET IRON VALUES - ESRD
Iron parameters drop significantly with initiation of ESA therapy TSAT – 20 – 50% Suggested value: 30% FERRITIN – 200 – 800 ng/mL Suggested value 500 ng/mL Acute Phase Reactant – the sicker the patient, the higher the Ferritin value, regardless of the iron stores The above parameters are frequently inadequate to diagnose anemia, esp in the CKD/ESRD population We don’t know the optimal levels of iron parameters
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TARGET IRON VALUES - CKD
TSAT – 20% FERRITIN – 100 ng/mL Start with oral iron supplementation Readily available Inexpensive Does not require IV access If can’t tolerate, then use IV therapy
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IRON DEFICIENCY ANEMIA (IDA)
Blood loss GI bleed GYN losses Destruction of blood cells Inability to absorb iron Functional deficiency (have iron, can’t access it) Almost all hemodialysis patients will develop iron deficiency anemia due to the dialysis treatment itself
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IRON ABSORPTION Acidity favors absorption
Conversly, proton-pump inhibitors reduce/prevent absorption Inflammation prevents absorption Vitamin C (ascorbic acid) helps absorbs iron
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HEPCIDIN Produced in liver Has inherent antimicrobial properties
Prevents iron absorption in the GI tract Prevents “unlocking” of iron Cleared by dialysis…..though consistent production leads to rebound levels Ferritin & Hepcidin values tend to run in parallel
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VITAMIN C (ASCORBIC ACID)
Helps “unlock” circulating iron – making it available for red blood cell production Acts to “chelate” or “splice” the iron from the circulating complex Helps the maturing red blood cell use the iron more efficiently May have an anti-oxidant mechanism Insufficient evidence in ESRD population for routine use
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CKD/ESRD & IRON Lower Iron Transport Capacity (TIBC reduced)
Decreased Absorption (Hepcidin) Ineffective Mobilization of Iron Stores (Hepcidin) Optimizing iron stores & availability leads to lower doses of ESA use
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IRON THERAPIES Iron Dextran- cheap, BUT risk of anaphylaxis
Test dose REQUIRED Iron sucrose – perhaps the safest of available therapies Ferric gluconate – shorter half-life Ferumoxytol – rapid injection; high dose delivered Ferric Carboxymaltose – concern for adverse reactions Soluble Ferric Pyrophosphate – NOT YET APPROVED Ferric citrate – NOT YET APPROVED Prior to ESA therapy, dialysis patients were generally iron OVERLOADED due to blood transfusions
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IV IRON ADVERSE EFFECTS
ALL IV Iron therapies have the potential to cause: Anaphylactic-like reactions Hypotension Chest Pain Rash Abdominal Pain “Oxidative Stress” injury Increased mortality in sepsis - ? Hurts immune response & “feeds” bacteria
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IRON DELIVERY PO IV Dialysate
Take on empty stomach; consider bedtime dosing Absorption Affected by other meds, including phosphate binders Efficacy Tolerability IV Direct access to bloodstream Highly efficacious Long-term safety NOT established Dialysate Soluble ferric pyrophosphate
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IV IRON LOADING - ESRD Iron sucrose Ferric gluconate Ferumoxytol
100 mg each treatment x 10 – total 1000 mg Ferric gluconate 125 mg each treatment x 8 – total 1000 mg Ferumoxytol 510 mg each treatment x 2 – total 1020 mg Strongly consider maintenance dosing Iron dextran generally NOT used due to relatively higher rates of anaphylactoid- reactions
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IRON LOSSES HD Blood loss via discarded filters – up to 1.5 – 3 gm/year Frequent blood draws Hidden/unrecognized GI bleeding In-center Requirements: 6-8 mg/day Home HD May have increased requirement due to daily filter losses PD Significantly less iron loss Some may even respond to oral iron
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IRON OVERLOAD An “unmeasured risk” Enlarged, stiff heart Liver disease
Pancreas damage (leading to diabetes) Pituitary damage NO correlation with Ferritin levels We don’t know the optimal levels of iron parameters
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IRON & INFECTION Bacteria feed off available, unlocked iron
Risk of bacteremia Risk of existing infections not healing/resolving When administered IV, free iron is excessively available Think of how nature looked at iron and it’s availability compared to how we administer it at dialysis
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ANEMIA When anemia NOT responsive to IV Iron and ESA – consider other causes Avoid transfusions Can “pre-sensitize” pt to potential transplants Improve Symptoms Even when hemoglobin values are appropriate, iron deficiency can result in symptoms of fatigue, memory impairment, lack of energy, decreased exercise tolerance Restless leg syndrome
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ANEMIA TARGETS “As the hemoglobin value approach or exceeds 11 g/dL, ESA dose must be reduced or interrupted” The “right” combination of ESA and IV iron is NOT known Both therapies carry benefit & risk Individualize treatment
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ESA RESISTANCE Iron deficiency Uremia/Inadequate HD (Kt/V, URR)
Tunneled Dialysis Catheter Bacteremia, PVD/ulcers Clotted AV grafts Severe Hyperparathyroidism (PTH > 800) Malnutrition
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DOPPS 70-75% of HD patients in US receiving IV Iron
Median ferritin levels: 795 ng/mL 15% over 1200 ng/mL IV Iron use has increased since CMS introduced Bundled Prospective Payment System Resulted in ESAs becoming a “cost center” as opposed to “profit drivers”
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