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Iron Deficiency in Patients Undergoing Hemodialysis

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Agenda…

• Rationale• Diagnosis of iron deficiencyAbsolute iron deficiency

Bone marrow biopsy

Functional iron deficiency

Updates

• Target• EBM  • Trends

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Rationale…

Hemodialysis patients lose an average of 1 to 2 g of iron per year

Anemia is a common complication in patients affected by chronic kidney disease, especially patients undergoing hemodialysis.

Correction of the anemia yields numerous benefits:

• A higher tolerance for physical activity

• An improvement of cognitive and cardiovascular functions

• A better quality of life

• Reduced hospitalization

• lower mortality

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Rationale…

• In patients undergoing hemodialysis and treated with ESAs, iron-deficient erythropoiesis frequently develops.

• The iron deficiency can be absolute (eg, malnutrition, gastrointestinal bleeding, chronic blood retention in the dialysis circuit, and frequent blood collections) or functional (ie, limitation of bone marrow erythropoietic activity by inability to mobilize sufficient iron from body storage sites); in this situation the body's total iron stores may be normal.

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Rationale…

• The iron deficit limits the effectiveness of the therapy with ESAs, and, to optimize the treatment, patients must receive an intravenous (IV) iron supplement.

• Because parenteral iron administration has potential risks that are immediate (eg, toxic effects and anaphylactic reactions) and long-term (eg, decreased polymorphonuclear leukocyte function, increased risk of infections, organ damage)

• It is essential to select patients who need iron supplementation.

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DIAGNOSIS OF IRON DEFICIENCYAbsolute iron defeciency

•The percent transferrin saturation (plasma iron divided by total iron binding capacity x 100, TSAT) falls below 20 percent

•The serum ferritin concentration is less than 100 ng/mL among predialysis and peritoneal dialysis patients

•Or is less than 200 ng/mL among hemodialysis patients.

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This difference in the serum ferritin level is based upon accumulating evidence in hemodialysis patients that the maintenance of ferritin levels above 200 ng/mL is associated with decreased erythropoietin requirements.

Rocha LA et al, 2009

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DIAGNOSIS OF IRON DEFICIENCYBone marrow biopsy

Rare in CKD and ESRD•Risk of bleeding and infection

Instead any enhancement of erythropoiesis with:•Iron supplementation

++ hemoglobin

-- doses of ESAStancu S et al, 2010

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DIAGNOSIS OF IRON DEFICIENCYFunctional iron deficiency

Characterized by :

• Adequate iron stores inability to sufficiently mobilize

• Transferrin saturation ≤20 percent

• Elevated ferritin level (typically >100 to 200 ng/mL)

How to differentiate ?

•Response to ESAs and intravenous iron (50-125mg for 8-10 doses)

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DIAGNOSIS OF IRON DEFICIENCYFunctional iron deficiency

Drive study 2007

• Administration of ferric gluconate (125 mg for eight treatments) is superior to no iron therapy in anemic dialysis patients receiving adequate epoetin dosages and have a ferritin 500 to 1200 ng/ml and TSAT<or=25%.

Coyne DW et al, 2007

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DIAGNOSIS OF IRON DEFICIENCYUpdates..

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• To diagnose iron deficiency in patients undergoing hemodialysis, the percentage of hypochromic RBCs (with cellular hemoglobin concentration <280 g/L [HYPO%]) and mean reticulocyte hemoglobin content (CHret) were proposed as alternatives to biochemical tests.

Pajola R et al, 2011

• Reticulocyte Transferrin R expression reflected the changes in the Hb level and the iron availability at the cellular level, and therefore it might be useful in the assessment of iron status in patients with CRF

Soininen K et al, 2010

DIAGNOSIS OF IRON DEFICIENCYUpdates..

• A low hepcidin level in hemodialysis patients with high epoetin resistance index could be a useful marker of iron-restricted erythropoiesis, but confirmation by a therapeutical trial is necessary.

Brătescu LO et al, 2010

• Iron status should be regularly assessed for the optimal management of renal anemia. Guidelines include the hemoglobin content of reticulocytes and the percentage of hypochromic RBC as markers for functional iron deficiency.

European guidelines

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Target…

European Best Practice

Guidelines

US Kidney Disease Outcome Quality Initiative

Target hemoglobin

level, g/dL (g/L)>11.0( 110) 11.0–12.0( 110–120)

Ferritin, ng/mL (pmol/L)

>100( 225) >200( 449)

Transferrin saturation)%(

>20 ≥20

HYPO% <10 —

CHret (pg) >29 >2915

Target… 

• Approximately 1000 mg is required among hemodialysis patients to raise hemoglobin levels from approximately 8 g/dL to 11 to 12 g/dL with the initiation of ESA therapy.

• After target hemoglobin levels are achieved, approximately 500 mg of iron is required every three months to maintain target levels with ESA therapy.

K/DOQI Clinical practice guidelines

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Target…

The Japanese Society for Dialysis Therapy Guidelines 2011

•propose that a minimal amount of iron should be given to chronic kidney disease patients with anemia and only in cases of evident iron deficiency.

•Japanese clinicians believe that the risk/benefit ratio for iron supplementation is higher than that accepted in Western countries.

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Target…

The Japanese Society for Dialysis Therapy Guidelines 2011

•. When erythropoiesis-stimulating agent hyporesponsiveness exists, we should consider conditions other than iron deficiency and treat these conditions to improve iron utilization.

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 EBM

•Intravenous sodium ferric gluconate complex in sucrose or iron sucrose rather than iron dextran for hemodialysis patients because of their apparently equivalent efficacy but greater relative safety compared to iron dextran

 (Grade 1A)

•Among hemodialysis patients, the use of parenteral iron rather than oral iron therapy is recommended

(Grade 1B)

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 EBM

If iron indices indicate absolute (transferrin saturation <20 percent and the serum ferritin is <200 ng/mL) or functional iron deficiency (transferrin saturation <20 percent and the serum ferritin is between 200 to 500 ng/mL in the setting of ESA therapy)

125 mg of sodium ferric gluconate complex in sucrose can be given at each consecutive hemodialysis treatment for a total of eight doses (1000 mg in total).

OR

100 mg iron sucrose can be given at each consecutive hemodialysis treatment for a total of 10 doses (1000 mg in total)

(Grade 1B)20

EBM

Intravenous iron is not given to patients with ferritin levels above 500 ng/mL and anemia, although each patient should be individually assessed.

(Grade 2B)Among such patients, an initial trial of increased erythropoietin dose alone, without intravenous iron, may be considered if the hemoglobin level is persistently below 11 g/dL with an erythropoietin dose that is not particularly high.

(Grade 2B)

If this is not successful in raising the hemoglobin level or a further increase is desired, we suggest judicious supplemental iron with or without a further increase in erythropoietin dose

(Grade 2B)

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Trends

HD patients had impaired endothelial functions. However, in HD patients, high and repeated doses of IV iron sucrose do not have deleterious effects on endothelial functions.

Ozkurt S et al, 2012

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 Trends

This formulation, uniquely, can be administered in a large dose as a short intravenous injection of 1 min or less, markedly facilitating care.

Rosner MH et al, 2011

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Trends

In view of the ability of iron to exert direct toxic effects and to induce oxidative stress on the one hand versus its essential role in various cellular processes on the other hand, the possible role of iron in the development of vascular calcification should be considered.

Neven E et al, 201124

Trends

Iron sucrose appears to offer the most favorable safety profile when compared to iron dextran and sodium ferric gluconate in treating hemodialysis patients. Oxidative stress and hypersensitivity reactions are common problems encountered when administering intravenous iron.

Copol E et al, 2011

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Trends

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Iron isomaltoside 1000 was clinically well tolerated, safe and effective. This new intravenous iron may offer a further valuable choice in treating the anemia of CKD.

Bhandari S et al, 2011

 Trends

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Newly available iron preparations appear to be clinically promising, cost effective, and practical alternatives to current standards of iron repletion

Bhandari S 2011

THANK YOU

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