ROLE OF IRON STORES IN ANEMIA

1. ROLE OF IRON STORES IN ANEMIA ANNA – Long Island Chapter May 7th, 2014 Naveed Masani, MD Winthrop University Hospital

2. 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

3. “INGREDIENTS” • Iron • Vitamin B12 • Folate • Erythropoietin (EPO) • Bone marrow • Hemoglobin

4. 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

5. IRON (cont) • Organ storage • 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

6. 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”

8. 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

9. PERCENT HYPOCHROMIC RED CELLS (%HYPO) • Early marker of functional iron deficiency • Outperforms Tsat & Ferritin • Blood samples need to be run within 10-12 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

10. 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

11. 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

12. 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

13. IRON ABSORPTION • Acidity favors absorption • Conversly, proton-pump inhibitors reduce/prevent absorption • Inflammation prevents absorption • Vitamin C (ascorbic acid) helps absorbs iron

14. 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

15. 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

16. 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

17. 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

18. 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

19. IRON DELIVERY • PO • 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

20. IV IRON LOADING - ESRD • Iron sucrose • 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. ESA RESISTANCE • Iron deficiency • Iron deficiency • Iron deficiency • Uremia/Inadequate HD (Kt/V, URR) • Tunneled Dialysis Catheter • Bacteremia, PVD/ulcers • Clotted AV grafts • Severe Hyperparathyroidism (PTH > 800) • Malnutrition

27. 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”