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ROLE OF IRON STORES IN ANEMIA
ANNA – Long Island ChapterMay 7th, 2014
Naveed Masani, MDWinthrop University Hospital
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
OBJECTIVES
Iron Vitamin B12 Folate Erythropoietin (EPO) Bone marrow Hemoglobin
“INGREDIENTS”
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
IRON
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
IRON (cont)
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”
IRON PARAMETERS
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
RETICULOCYTE Hgb CONTENT (CHr)
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
PERCENT HYPOCHROMIC RED CELLS (%HYPO)
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
TARGET IRON VALUES - ESRD
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
TARGET IRON VALUES - CKD
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
IRON DEFICIENCY ANEMIA (IDA)
Acidity favors absorption Conversly, proton-pump inhibitors
reduce/prevent absorption Inflammation prevents absorption Vitamin C (ascorbic acid) helps absorbs iron
IRON ABSORPTION
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
HEPCIDIN
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
VITAMIN C (ASCORBIC ACID)
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
CKD/ESRD & IRON
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
IRON THERAPIES
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
IV IRON ADVERSE EFFECTS
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
IRON DELIVERY
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
IV IRON LOADING - ESRD
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
IRON LOSSES
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
IRON OVERLOAD
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
IRON & INFECTION
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
ANEMIA
“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
ANEMIA TARGETS
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
ESA RESISTANCE
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”
DOPPS