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