Faint is not a description of color Faint is a description of LIFE

REDUCED INTAKE Poor appetite Poor G-I absorption Concurrent medication – e.g. omeprazole Food interactions Occult G-I losses Peptic ulceration Blood sampling Dialyser losses Concurrent meds. – e.g. aspirin Heparin on dialysis INCREASED LOSSES Why are CKD patients prone to develop iron deficiency ?

Iron Management WHY..? -Most common cause of an incomplete response to Epoetin Is iron Deficiency -Iron is Crucial to the success of Epoetin therapy -Allow Epoetin to be used more cost-effectively NKF-DOQI

IDS IDA

Physical performance IDS IDA

Papayannopoulou T, et al. In: Hoffman R, et al., ed. Hematology: Basic Principles and Practice. 4 th ed. 2005; SCF, GM-CSF, IL-3 SCF, IL-1, IL-3, IL-6, IL-11 Pluripotent Stem Cell Burst-Forming Unit-Erythroid Cells (BFU-E) Colony-Forming Unit-Erythroid Cells (CFU-E) ReticulocytesRBCsErythro- blasts Proerythro- blasts About 8 Days Iron Erythropoietin Erythropoiesis in CKD Erythropoiesis Transferrin Receptors Epo Vit D

Early stage Iron deficiency syndrome IDS Fatigue Difficulty concentration Depressed mood Sleeping disturbance Neck tensions Headache Dizziness Loss of hair Early stage Iron deficiency syndrome IDS Fatigue Difficulty concentration Depressed mood Sleeping disturbance Neck tensions Headache Dizziness Loss of hair Late stage Iron deficiency anemia IDA Pallor (pale skin) General malaise Muscular weakness Dyspnea Palpitation Tachycardia Low blood pressure Iron deficiency stages

What a body needs iron for Red blood cell formation 70 % of body iron Myoglobin formation Myoglobin occurs in the cells of the heart muscle and the skeletal muscles

What a body needs iron for Hormone formation formation of hormones can only occur if a biochemical impulse for their production is sent. This requires enzymes - substances, also known as catalysts these enzymes need iron to do their job

Serotonin Dopamine an endorphin, is also often referred to as the “happy hormone.” Like serotonin, dopamine is called a “happy hormone” dopamine makes it possible for a person to recognize relevant stimuli, i.e., those that are meaningful to him, and ignore unimportant ones

Melatonin DSIP (Delta Sleep Inducing Peptide) regulates the functioning of what is known as our inner clock produces the deep sleep, an important sleep phase that is responsible for the quality of our nightly recovery.

Cortisol controls all of the protein, sugar and fat metabolisms As a stress hormone, it is simultaneously responsible for our body to adapt to special stresses with appropriate reactions

Energy production Each body cell contains a large number of mitochondria We consider them our “power plants” and they use adenosine triphosphate (ATP) to produce the necessary chemical cell energy It is the iron-sulfur molecules, which are the central constituents in the cascade of chemical reactions that results in energy being released in the cells

Eicosanoid formation Eicosanoids are our organism’s iron- containing signaling molecules, which directly influence many of our bodily functions a) Effect on smooth muscle tension b) Influence on the stomach c) Effect on the immune system

Eicosanoids influence the state of tension of the smooth muscles. Depending on the impulse that the smooth muscle cells are exposed to, they change from a state of tension to a state of relaxation and vice versa These signaling molecules thereby have a direct effect on important bodily functions, such as blood pressure regulation breathing intestinal and uterine activities. a) Effect on smooth muscle tension:

b) Influence on the stomach: In the stomach, an equilibrium typically exists between the aggressive hydrochloric acid needed for digestion and the mucous membrane, a layer of cells protecting the stomach walls. Here, the iron-containing eicosanoids are co-responsible for both the acid production and for an adequate quality of the protective layer.

c) Effect on the immune system: The eicosanoids also include leukotrienes. Those are small acid particles in the white blood cells which are 1.effective in connection with allergic and inflammatory reactions. 2.It is also the function of leukotrienes to “attract” the body’s antibodies to the site of an infection.

Basic tissue formation Iron is co-responsible for the formation and regeneration of our organism’s basic tissues. These are known to include bone, cartilage, skin, connective tissue, mucous membranes, hair and nails. In these building processes, protein chains are converted to stable fibers by a biochemical process known as hydroxylation. Iron is indispensable for this process as well.

factors contribute to the development of iron deficiency in CKD Occult G-I losses Peptic ulceration Blood sampling Dialyser losses Concurrent meds. – e.g. aspirin Heparin on dialysis INCREASED LOSSES 1. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39 (2 Suppl 1):S1-266.

All CRF patients must be iron replete to achieve and maintain the target Hb. Almost all HD patients will require IV iron EBPG KEY RECOMMENDATIONS

Adequate iron status is defined as : -Serum ferritin  100mg/l  200mg/l -TSAT > 20% -Hypochromic RBCs < 10% To achieve this target, the population median will be: Serum ferritin = mg/l -TSAT = 30-40% -Hypochromic RBCs < 2.5% EBPG KEY RECOMMENDATIONS

Iron Management Do we match the standards ESAM Survey 6 month survey dialysis patients 13 Western European countries Published in Nephrology Dialysis Transplantation in 2000

ESAM Survey key findings Absolute iron deficiancy % of HD patients -41% to 45% of PD patients Iron Store monitor -41% had iron stores monitored less frequently than is recommended by the EBPG during Epoetin treatment in correction phase Cost effectiveness Patients with adequate iron status reached a higher Hgb with lower Epoetin dose

Determine patient Hemoglobin Monitor Hgb Hgb  11-12g/dl Check blood pressure (if high) control hypertension Check iron stores: -Transferrin saturation  20% -Serum ferritin  100ng/ml CKD  200ng/ml ESRD - MCH low in iron deficiency - MCV low in iron deficiency Hgb< 11-12g/dl Supplement to maintain Adequate iron levels In practice we aim for -Transferrin saturation 30-40% -Serum ferritin ng/ml Initiate Epo therapy If Serum ferritin high MCH low MCV low Check CRP for infection or inflammation Protocol for dose adjustment

Initiate Epoetin therapy - 50 IU/Kg/week for CKD Predialysis -150 IU/kg/week for ESRD DIALYSIS Optimize dose: monitor Hgb and adjust dose accordingly Withhold the Epoetin dose Monitor Hgb twice a week Maintain same dose Monitor Hgb once/month Increase weekly dose by 25-50% Monitor Hgb twice a week For 2-6 weeks after any dose adjustment Hgb g/dl Hgb > 12 g/dl & if Hgb increases >1 g/dl/in any 2 week period Hgb < g/dl & If Hgb increases < 0.7 g/dl/month

What are the most common causes for Epo resistance Common causes 4 Iron deficiency Infection/inflammation Chronic blood loss Osteitis fibrosa/hyperparathyroidism

What about Iron deficiency Most common cause of resistance Normal body Iron stores are mg

during first 3 months of Epo therapy 1000 mg What about the iron requirements For CRF patients mg of iron/3 month Once target Hgb is achieved

How can we assess the iron status Serum Ferritin ‹ 100 ng/ml ‹ 200 ng/ml In practice we aim for ng/ml

How can we assess the iron status Transferrin saturation ‹ 20 % In practice we aim for 30-40%

How can we assess the iron status Hypochromic RBCs > 10% In practice we aim for < 2.5%

Treatment options Adequate iron stores readily available for erythropoiesis are the prerequisite for the correction of anemia in all settings.

Treatment options Red blood cell transfusions in life threatening anemia

Pharmacological agents for anemia correction Treatment options

Oral iron therapy Oral iron salts - (non-compliance due to GIT upset) - Intake independent of meals is recommended Oral Heme iron - Intestinal iron absorption is times more than iron salts - Minimal GIT upset-more patient compliance

Intravenous iron preparations Structure of IV iron agents - Colloids with spheroidal iron - Carbohydrate nano particles - Each particle Consists of - Iron-oxyhydroxide core (iron (III) hydroxide) - Carbohydrate shell surrounds & stabilizes the core This particles structure resemble ferritin that protects against the toxicity of unbound inorganic ferric iron (iron (III))

Intravenous iron preparations While the core chemistry is identical in all agents Core size, shell and global size of the particles differ for each agent

Differences in core size & carbohydrate chemistry determine Pharmacological & biologic differences Clearance after injection Iron release in vitro Early evidence of iron bioactivity in vivo Maximum tolerated dose Rate of infusion

Intravenous iron forms Iron dextran (50mg/ml) Risk of life-threatening or serious acute hypersensitivity Test dose of 0.5 ml (25mg)is required prior to first therapeutic dose One hour should elapse after the test dose Can be given IV.

Intravenous iron forms Ferric gluconate Lower incidence of lethal hypersensitivity Iron sucrose (20mg/ml) No reported lethal reactions The most commonly used.

Check IRON early and often

Frequency of iron monitor in CKD patients Not on Epoetin or IV iron3-6 Month Initiation phase of EPO and No IV iron 4-6 Weeks Initiation phase of EPO and taking IV iron 3 Month Maintenance phase of EPO and taking iv iron 3-6 Month

Labile Iron Definition Defined as the fraction of total intravenous iron with early biological activity -Due to a limited pathway seen with all intravenous iron agents where iron is donated directly from the iron- carbohydrate complex to transferrin

Fraction of labile iron in (iron–carbohydrate) complexes varies from 2.5 to 5.8% iron dextran < iron sucrose < ferric gluconate 2.5%  5.8% Labile Iron

Molecular weight - Iron dextran (76 to 265KD) > iron sucrose (43 KD) > ferric gluconate (38KD) -The total surface area for iron release is likely the key factor influencing the rate of iron release. -A collection of smaller spheres offers a greater total surface area for iron release than a collection of fewer, larger spheres with an equal mass

IV iron preparations Allergic reactions Fatal anaphylactic reactions reported by FDA (FOI) database ( ) related to iron sucrose = 0%

IM&SC - IM & SC iron abandoned in many countries due to side effects Intravenous iron therapy For patients - intolerant to oral iron - oral iron supplementation is not possible - oral iron therapy fails to provide enough iron for the correction or prevention of iron-deficiency anemia despite appropriate patients compliance. Parenteral iron