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 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

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 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 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

20. 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

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 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”