Iron Repletion in ESRD
Saleem Bharmal
2/9/10
Case
• ESRD on maintenance hemodialysis who is
noted to have a Hgb 10.6/TSAT 19%/Ferritin
617/iron 46/TIBC 238/on EPO 4000U/week
• What would you do in this situation in terms
of ESA and iron?
• Patient EPO decreased to 3000U and started
on Ferrilicit 125mgx8 doses(1000mg total)
• 1 month later Hgb 11.1 (iron not checked)
Case
• 2 months later: Hgb 10.8/iron 36/TIBC
225/TSAT 16%/Ferritin 1075/on EPO
3000U/week
• What would you do in now?
• Kept patient on current dose of EPO no IV iron
given
• One month later Hgb 10.7
Case
• 2 months later: Hgb 9.9/iron 54/TIBC
230/TSAT 17%/Ferritin 706/on EPO
3000U/week
• What would you do now?
• Ferrilicit 125mgx8(total 1gram) given and kept
on EPO 3000U
• 1 month later: Hgb 10.4
• 2 month later: Hgb 10.2/TSAT 31%/Ferritin
1120/EPO 3000U/week
Anemia in ESRD
• According to the National Health and Nutrition
Examination Survey (NHANES) and the
Prevalence of Anemia in Early Renal Insufficiency
(PAERI) study the suggested incidence of anemia
in stage 5 CKD is more than 70%
• The most well-known causes are inadequate
erythropoietin (EPO) production and iron
deficiency.
Iron Deficiency in Hemodialysis
Patients
• Dialysis patients commonly suffer iron loss
from gastrointestinal bleeding, blood
drawing, and/or, most important with
hemodialysis, the dialysis treatment itself.
• Hemodialysis patients lose an average of 1 to
2 g of iron per year.
Type of Iron Dysfunction in HD
patients
• Absolute iron deficiency
• Functional iron deficiency
• Inflammatory Block
Absolute Iron Deficiency
•
•
TSAT falls below 20% (plasma iron divided by total iron binding capacity x 100)
Serum ferritin concentration is less than 200 ng/mL among hemodialysis patients.
Fishbane S., J. Am. Soc. Nephrol.
1996 2654-2657
Functional Iron Deficiency
• Characterized by the presence of adequate iron stores as
defined by conventional criteria, but an inability to
sufficiently mobilize this iron from the liver and other
storage sites to adequately support erythropoiesis with the
administration of erythrocyte stimulating agents (ESA).
• Serum ferritin level is either normal or elevated, but the
TSAT typically is about 20% or less.
• The hallmark of functional iron deficiency is that it
responds to iron supplements with an increase in
hemoglobin and/or decrease in ESA requirements.
Inflammatory Block or
Reticuloendothelial Blockade
• Inflammatory iron block occurs among patients with
refractory anemia due largely to an underlying
inflammatory state.
• Also characterized with TSAT < 20% and elevated Ferritin
100-800+ ng/ml
• Hepcidin, an acute phase reactant may play a role by
preventing the release of iron from macrophages to
circulating transferrin.
• Usually does not respond to iron therapy
Functional Iron Deficiency vs.
Inflammatory Block
• With functional iron deficiency iron administration will
usually increase in hemoglobin and/or decrease in ESA
requirements.
• With increasing dose of ESA ferritin levels may
decreased with functional but not inflammatory block
• Inflammatory block is most likely present if the weekly
administration of intravenous iron fails to result in
increased erythropoiesis; instead results in progressive
increase in ferritin concentrations.
DRIVE Study
JASN (18) 2007
• Study to help answer the question of what is the efficacy of IV iron
administration in HD patient with low TSAT and high ferritin levels.
• 134 patients with anemia (hgb < 11 g/dL), elevated ferritin (500 to 1200
ng/mL), low TSAT levels (≤25 %), and high ESA requirements (≥225 U/kg
per week or ≥22,500U/week)
• Randomly assigned to ferric gluconate (125 mg with 8 consecutive dialysis
sessions) or placebo.
• Patients with known infections or recent significant blood loss were
excluded.
• At randomization, epoetin was increased 25% in both groups; further
dosage changes were prohibited
• At 6 wk, hemoglobin increased significantly more (P
0.028) in the intravenous iron group (1.6 1.3 g/dl) than
in the control group (1.1 1.4 g/dl).
• More patients responded (Hgb increase > 2) after
intravenous iron than in the control group (P 0.041).
• Ferritin <800 or >800 ng/ml had no relationship to the magnitude or likelihood of
responsiveness to intravenous iron relative to the control group.
• Superiority of intravenous iron compared with no iron was similar whether baseline
TSAT was above or below the study median of 19%.
• Ferritin decreased in control and increased after intravenous.
• Intravenous iron resulted in a greater increase in TSAT than in control subjects
CHOIR, CREATE and TREAT
Alternative measures of iron status
• The percentage of hypochromic cells (%HYPO)
• Hepcidin Levels: Can help distinguish functional
iron deficiency form Inflammatory block and may
help determine when iron stores adequately
replete.
• The reticulocyte hemoglobin content (CHr)
• The proper role for these alternative measures of
iron status, which are not widely available in the
United States, in the dialysis patient is uncertain.
Reticulocyte Hemoglobin Content
(CHr)
•
The reticulocyte Hb content (CHr) is a measure of the amount of Hb in the
reticulocytes.
•
The CHr is a reasonably good reflection of how much iron was available to the
bone marrow for incorporation into new red blood cells a few days before.
Reticulocytes are released into the circulation about two days prior to maturation
into red blood cells.
•
It has been shown that CHr compares favorably with serum ferritin and TSAT in
predicting a response to intravenous iron.
•
Fishbane S. et al (KI 2001) showed a cutoff of >32 pg had a much greater utility
compared to >29pg, and a majority of the patients who received intravenous iron
therapy on the basis of a CHr >32 pg had an average of 23% reduction in their
erythropoietin requirements. Also showed in randomized trial that CHr was
equivalent to TSAT/Ferritin in maintaining Hgb and ESA dosing but used less IV iron
IV Iron Preparations for HD patients
•
Adequate iron stores are essential for achieving maximum benefit from erythropoietic agents
•
Decreased iron stores or decreased availability of iron are the most common reasons for resistance
to the effect of ESAs.
•
Patients with percent transferrin saturation ≤20 percent and ferritin between 200 and 500 ng/mL,
administer iron therapy prior to the use of ESAs if an underlying infection has been excluded.
•
The most common cause of resistance to ESA is iron deficiency, which can be present at the time of
initiation of ESA treatment or can develop as the result of exhaustion of iron stores due to the
increase in erythropoiesis caused by ESA treatment.
•
To ensure an adequate response with erythropoietic agents, most dialysis patients will require
supplemental iron on a continuing basis.
•
For hemodialysis patients use of parenteral iron rather than oral iron therapy should be used.
IV Iron Preparations for HD patients
• Iron dextran (INFeD)
• Iron sucrose (Venofer)
• Sodium ferric gluconate (Ferrlecit)
• Ferumoxytol (Feraheme)
Iron Dextran
•
Composed of a mixture of synthetic polymers of glucose, is highly effective when
given for loading or maintenance therapy.
•
Anaphylaxis to intravenous iron dextran therapy may occur in both nonuremic and
uremic patients, occasionally resulting in death. It is thought to be due to the highmolecular weight dextran moiety, which may share carbohydrate antigens with
gastrointestinal organisms.
•
Study (Fishbane et al AJKD 1996) that reviewed 573 hemodialysis patients treated
with intravenous iron dextran: 4.7% had adverse reactions most common being
itching, dyspnea or wheezing. 1.7% had reaction classified as anaphylactoid.
Among the 10 anaphylactoid reactions, 6 occurred with doses other than test
dose.
•
Administration: Test dose: 25mg mixed with 50ml NS given over 5 minutes. If
tolerated than can give up to 500 to 1gram as slow IV infusions.
Sodium Ferric Gluconate
• Has fewer life-threatening and fatal adverse
reactions than iron dextran. In addition, its
relative efficacy and adverse reaction profile
are as good or better than iron dextran.
• Administration: 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).
IV Iron Sucrose
• This formulation is effective and well-tolerated
for either loading or maintenance therapy.
Studies found that iron sucrose and sodium ferric
gluconate complex were equally effective and
safe.
• Administration: 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).
Ferumoxytol
• Approved by the FDA in June 2009, is an iron
dextran nanoparticle.
• Ferumoxytol appears to be safe and effective
when given as a rapid infusion of up to 510 mg
in patients with CKD and patients on dialysis.
• Administration: 510 mg of ferumoxytol can be
administered intravenously at a rapid rate (up
to 30 mg/sec) and be given as 3-8 days apart.
Maintenance Therapy: Intermittent vs
Continuous
• With intermittent regimens, provides a total dose of 1000 mg
whenever iron indices fall below the target levels of a transferrin
saturation of ≥20 percent and a serum ferritin concentration of
≥200 ng/mL.
• A continuous dosing regimen consists of the regular administration
of low doses of parenteral iron, which is designed to prevent the
development of iron deficiency once adequate iron stores have
been established.
• With intermittent therapy, iron is only given when iron indices are
clearly inadequate; such regimens are likely to result in less than
ideal delivery of iron to the marrow, which then results in an
inadequate amount of iron available for continued effective
erythropoiesis.
Evidence for use of Continuous
Therapy
• Study #1
• 24 patients were randomly assigned to either a regimen in which an
initial iron dextran dose of 300 to 500 mg was followed by 25 to 100
mg every one to two weeks (to maintain a transferrin saturation
between 30 and 50 percent) or an intermittent dosing regimen (to
maintain a transferrin saturation >20 percent or a ferritin level >200
ng/mL).
• A hemoglobin level of 10 to 11 g/dL was achieved in both groups.
• However, the amount of EPO required in the maintenance group
was significantly less than that utilized in the intermittent group
(1569 versus 3527 units).
Evidence for use of Continuous
Therapy
• Study #2
• 26 hemodialysis patients with adequate iron indices (serum
ferritin level >100 ng/mL and transferrin saturation >20
percent) were randomly assigned to receive intravenous
sodium ferric gluconate either in a continuous (6.25 to 21.3
mg in every hemodialysis session) or an intermittent
regimen (62.5 mg every 1 to 4 weeks).
• At 16 weeks, the continuous group had a significant
increase in serum hemoglobin level versus baseline values
(11.8 versus 11.0 g/dL, respectively), whereas no
differences were obtained in intermittent group (baseline
and 16 weeks were 11.2 and 11.1 g/dL, respectively)
TSAT goal 20-30% or 30-50%
• Study by Besarab et al. (JASN 2000): “Optimization of
Epoetin Therapy with Intravenous Iron Therapy in
Hemodialysis Patients”
• Examines the effects of a maintenance intravenous iron
dextran (ivID) protocol that increased TSAT in ESRD
hemodialysis patients from conventional levels of 20 to
30% (control group) to those of 30 to 50% (study group) for
a period of 6 months
• 42 HD patients 16- to 20-wk run-in period, during which
maintenance ivID and rhEPO were administered in amounts
to achieve average TSAT of 20 to 30% and baseline levels of
hemoglobin of 9.5 to 12.0 g/dl
• After the run-in period, 19 patients randomized
to the control group received ivID doses of 25 to
150 mg/wk for 6 months
• 23 patients randomized to the study group
received four to six loading doses of ivID, 100 mg
each, over a 2-wk period to achieve a TSAT .30%
followed by 25 to 150 mg weekly to maintain
TSAT between 30 and 50% for 6 months
• Erythropoietin (EPO) dosage was adjusted every 4
wk to maintain hemoglobin at the same value
Progressive increase in
serum ferritin to 658
ng/ml in the study group
Epoetin dose requirements for the study group decreased by the third
month and remained 40% lower than for the control group
Closing
• Given the negative evidence with high dose ESA:
• Should we aim for TSAT of 30-50%?
• Should we give IV iron even if ferritin > 800ng/ml if no
signs of active infection?
• What are the long term effects of iron loading,
oxidative stress, WBC dysfunction, vascular damage?
• Are TSAT and Ferritin good enough markers? Should we
be using CHr?
• Should we keep our ESRD on continuous maintenance
IV iron instead of intermittent? Check iron levels every
few weeks instead of every few months.