Additional information
Venofer® (iron sucrose injection, USP) can be given as a bolus injection into the
venous limb of the patient’s vascular access. This mode of administration avoids
the need for filter needles, infusion pumps, bags of normal saline, and IV sets. No
test dose is required. (In two US clinical trials, some physicians administered a test
dose at their discretion.) Venofer® is packaged in vials rather than ampules to
decrease the risk of injury from broken glass to the healthcare professional administering
the dose. This simple, user-friendly method of administration helps reduce
the physician and nursing time required for intravenous iron therapy.
Optimization of Anemia Management in NDD-CKD Without Erythropoietin
Therapy
Iron deficiency commonly complicates anemia in patients with non dialysis-dependent
chronic kidney disease (NDD-CKD). As many as 25 to 40% of males and 35
to 85% of females with anemia and NDD-CKD show evidence of iron deficiency.143
IV iron therapy can provide effective anemia management, even in the absence of
an erythropoietin, in a substantial fraction of these patients. A randomized, controlled,
multicenter trial examined response to iron therapy in patients with NDDCKD
Stage 3-5, anemia and moderately low iron indices (TSAT < 25%, ferritin 300
ng/mL). Among 47 patients who did not receive erythropoietin therapy, 18 (38%)
achieved a Hb increase of > 1.0 g/dl and 28 (60%) achieved a K/DOQI-recommended
Hb level of > 11 g/dl after administration of 1,000 mg of IV iron sucrose in
divided doses.1 Thus, IV iron sucrose alone can be effective in the management of
CKD-associated anemia in non-dialysis patients, even in the absence of erythropoietin
therapy.
Optimization of Erythropoietin Therapy
Aggressive intravenous iron therapy with products such as Venofer® (iron
sucrose injection, USP) is increasingly recognized as a means of optimizing
the response to erythropoietin. Evidence from ten studies5-7,144-151 conducted
since 1992, including a total of more than 450 patients, shows that intensive
intravenous iron supplementation (iron dextran, iron sucrose, or sodium ferric
gluconate in sucrose complex) allows a reduction in erythropoietin dose of
19% to 70%.152
Nyvad O et al.6 Data was collected from 34 end-stage renal failure patients
(26 on hemodialysis, 8 on other types of dialysis) to measure the effect of
iron sucrose on erythropoietin usage in a dialysis center in Denmark. All
patients were receiving erythropoietin (median weekly dose 5,300 IU) for
anemia. Oral iron had not resulted in a significant rise in ferritin (ferritin
ranges from 10-120 ng/L). All patients received an initial cumulative dose of
1,150 mg iron sucrose (1,000 mg iron sucrose is the FDA-approved cumulative
dose). Adjustment of erythropoietin dose was based on assessment of
clinical and lab data. Data was collected from 3 months before to 3 months
after the first dose of iron sucrose. None of the patients had very low ferritin
or TSAT values, yet IV iron sucrose therapy permitted a 27% reduction in the
dose of erythropoietin with unchanged hematocrit and hemoglobin after 3
months.
Macdougall et al.16 Macdougall et al examined the effects of adopting an
aggressive IV iron policy in the United Kingdom. Data was collected from
116 patients attending a single hemodialysis center. All patients with a serum
ferritin between 150 and 1,000 ng/mL received regular weekly IV iron supplementation
(100 mg of iron sucrose as a bolus injection). Intravenous iron
was only withheld if the serum ferritin level exceeded 1,000 ng/mL at any
stage. Patients whose serum ferritin levels were less than 150 ng/mL were
given a more aggressive regimen of IV iron until the levels reached above
this threshold. Among 116 patients included in the study, ferritin and hemoglobin
levels increased, while there was a dramatic reduction in mean erythropoietin
dose from 13,227 IU/wk to 8976 IU/wk.
26
Bioactive Iron and Labile Iron
All IV iron preparations are colloids. IV iron agents are distinguished by colloid particle
size, core size, and the nature of the carbohydrate shell.122 Particles consist a
core of ferric oxide/oxyhydroxide surrounded by a shell of carbohydrate. The
generic name of each agent derives from the carbohydrate, for example, sucrose,
dextran, or gluconate for iron sucrose, iron dextran, and iron gluconate, respectively.
There is no unbound iron in the agents themselves: neither free iron nor intact
iron compounds are found in dialysate.1,138,139,156 However, all iron agents show evidence
of iron bioactivity after exposure to blood, cells or other tissues. Evidence of
the bioactivity of IV iron agents may take several forms: including oxidative
stress,154-156 direct donation of iron to transferrin,143,145-146 and alteration of neutrophil
function.158-160 Manifestations of the bioactivity of IV iron agents are taken to be evidence
that all agents contain a bioactive or labile iron fraction.
Oxidative stress is manifested by indirect measures of the oxidation of lipid membranes
and plasma protein. Not all reports show oxidative stress related to IV iron
agents. How much, if any, oxidative stress occurs after exposure to IV iron agents
depends on the specific test used, the type of IV iron agent, and the concentration
of the IV iron agent itself. Many causes of oxidative stress in chronic kidney disease
patients receiving IV iron are unrelated to iron administration.161-162 It is theorized
that oxidative stress may contribute to the pathogenesis of atherosclerosis
and, in particular, coronary artery disease (CAD). CAD is a leading cause of death
in patients with chronic kidney disease. Although iron is a known and potent cause
of oxidative stress, experimental163 and clinical evidence that IV iron causes CAD or
contributes to atherogenesis or heart disease in renal failure is lacking. More generally,
most experts agree that naturally-occurring causes of iron excess do not lead
to higher rates of CAD.164
Infection is the other leading cause of death in patients with CKD. Since iron is an
essential nutrient for bacterial growth and IV iron agents provide iron in abundance,
the potential role of IV iron administration in the pathogenesis of infection in
patients has been explored. Despite evidence that IV iron agents may enhance
bacterial growth in vitro; prospective, multicenter clinical trials and large scale retrospective
studies in chronic kidney disease patients have found no discernible relationship
between the incidence of infection and either IV iron dosing or levels of
iron status tests.165 An analysis by Aronoff et. al. found that the mortality rate from
infection or sepsis among patients receiving iron sucrose in this trial compared
favorably with that of the overall United States hemodialysis population. They also
found that the hospitalization rate from infection among patients receiving iron
sucrose in the trial was significantly lower than that of the general US hemodialysis
population.23
Labile or bioactive iron in IV iron agents also plays a role in immune defense.
Evidence on the effect of IV iron on neutrophil function is mixed. Since part of the
neutrophil's killing potential stems from oxidative destruction of bacteria, some iron
is needed for optimum neutrophil function. Too much iron, however, impairs phagocytosis
of bacteria by neutrophils in vitro. Carefully designed, prospective studies
have shown no relationship between IV iron treatment and risk of infection.165
Finally, labile iron in IV iron agents may be manifested by a rise in the transferrin
saturation.166 Transferrin is the sole extracellular iron-binding protein. Since the
entire iron-binding capacity of transferrin in the bloodstream of an adult is less than
17 mg, rapid administration of large doses of IV iron may lead to sudden oversaturation
or supersaturation of transferrin. Non-transferrin-bound iron (NTBI) is a theoretical
mechanism to explain increased oxidative stress or bacterial growth.155 NTBI
may contribute to hypotension and cramping, symptoms which limit the dose and
rate of IV iron administration. Difficulty in detecting supersaturation and the observation
that NTBI is found in renal failure patients without IV iron therapy153,167 render
the clinical relevance of this phenomenon uncertain, however.
Markers of oxidative stress include levels of lipid peroxidation (often measured indirectly
by determining levels of malonyldialdehyde (MDA))154,168 or protein oxidation,
including advanced oxidation protein products (AOPP),169 and carbonylated fibrinogen.
170 Markers of neutrophil function include in vitro neutrophil killing capacity,159
neutrophil oxidative burst,160 and neutrophil phagocytosis. Markers of iron donation
to transferrin, of course, include the transferrin saturation (TSAT),166 bleomycindetectable
iron (BDI),170 and NTBI.153-155
In short, while no IV iron agent contains “free” iron, all IV iron agents (including
sodium ferric gluconate complex in sucrose injection, iron dextran and iron sucrose)
have biologically active or labile iron. Labile iron is manifested by several test
results that may be related to CAD and infection; CAD and infection are common
causes of death and hospitalization in dialysis patients, but there is no evidence
linking IV iron agents or IV iron administration to an increased risk of CAD or infection
in patients with chronic kidney disease.
Venofer® (iron sucrose injection, USP) can be given as a bolus injection into the
venous limb of the patient’s vascular access. This mode of administration avoids
the need for filter needles, infusion pumps, bags of normal saline, and IV sets. No
test dose is required. (In two US clinical trials, some physicians administered a test
dose at their discretion.) Venofer® is packaged in vials rather than ampules to
decrease the risk of injury from broken glass to the healthcare professional administering
the dose. This simple, user-friendly method of administration helps reduce
the physician and nursing time required for intravenous iron therapy.
Optimization of Anemia Management in NDD-CKD Without Erythropoietin
Therapy
Iron deficiency commonly complicates anemia in patients with non dialysis-dependent
chronic kidney disease (NDD-CKD). As many as 25 to 40% of males and 35
to 85% of females with anemia and NDD-CKD show evidence of iron deficiency.143
IV iron therapy can provide effective anemia management, even in the absence of
an erythropoietin, in a substantial fraction of these patients. A randomized, controlled,
multicenter trial examined response to iron therapy in patients with NDDCKD
Stage 3-5, anemia and moderately low iron indices (TSAT < 25%, ferritin 300
ng/mL). Among 47 patients who did not receive erythropoietin therapy, 18 (38%)
achieved a Hb increase of > 1.0 g/dl and 28 (60%) achieved a K/DOQI-recommended
Hb level of > 11 g/dl after administration of 1,000 mg of IV iron sucrose in
divided doses.1 Thus, IV iron sucrose alone can be effective in the management of
CKD-associated anemia in non-dialysis patients, even in the absence of erythropoietin
therapy.
Optimization of Erythropoietin Therapy
Aggressive intravenous iron therapy with products such as Venofer® (iron
sucrose injection, USP) is increasingly recognized as a means of optimizing
the response to erythropoietin. Evidence from ten studies5-7,144-151 conducted
since 1992, including a total of more than 450 patients, shows that intensive
intravenous iron supplementation (iron dextran, iron sucrose, or sodium ferric
gluconate in sucrose complex) allows a reduction in erythropoietin dose of
19% to 70%.152
Nyvad O et al.6 Data was collected from 34 end-stage renal failure patients
(26 on hemodialysis, 8 on other types of dialysis) to measure the effect of
iron sucrose on erythropoietin usage in a dialysis center in Denmark. All
patients were receiving erythropoietin (median weekly dose 5,300 IU) for
anemia. Oral iron had not resulted in a significant rise in ferritin (ferritin
ranges from 10-120 ng/L). All patients received an initial cumulative dose of
1,150 mg iron sucrose (1,000 mg iron sucrose is the FDA-approved cumulative
dose). Adjustment of erythropoietin dose was based on assessment of
clinical and lab data. Data was collected from 3 months before to 3 months
after the first dose of iron sucrose. None of the patients had very low ferritin
or TSAT values, yet IV iron sucrose therapy permitted a 27% reduction in the
dose of erythropoietin with unchanged hematocrit and hemoglobin after 3
months.
Macdougall et al.16 Macdougall et al examined the effects of adopting an
aggressive IV iron policy in the United Kingdom. Data was collected from
116 patients attending a single hemodialysis center. All patients with a serum
ferritin between 150 and 1,000 ng/mL received regular weekly IV iron supplementation
(100 mg of iron sucrose as a bolus injection). Intravenous iron
was only withheld if the serum ferritin level exceeded 1,000 ng/mL at any
stage. Patients whose serum ferritin levels were less than 150 ng/mL were
given a more aggressive regimen of IV iron until the levels reached above
this threshold. Among 116 patients included in the study, ferritin and hemoglobin
levels increased, while there was a dramatic reduction in mean erythropoietin
dose from 13,227 IU/wk to 8976 IU/wk.
26
Bioactive Iron and Labile Iron
All IV iron preparations are colloids. IV iron agents are distinguished by colloid particle
size, core size, and the nature of the carbohydrate shell.122 Particles consist a
core of ferric oxide/oxyhydroxide surrounded by a shell of carbohydrate. The
generic name of each agent derives from the carbohydrate, for example, sucrose,
dextran, or gluconate for iron sucrose, iron dextran, and iron gluconate, respectively.
There is no unbound iron in the agents themselves: neither free iron nor intact
iron compounds are found in dialysate.1,138,139,156 However, all iron agents show evidence
of iron bioactivity after exposure to blood, cells or other tissues. Evidence of
the bioactivity of IV iron agents may take several forms: including oxidative
stress,154-156 direct donation of iron to transferrin,143,145-146 and alteration of neutrophil
function.158-160 Manifestations of the bioactivity of IV iron agents are taken to be evidence
that all agents contain a bioactive or labile iron fraction.
Oxidative stress is manifested by indirect measures of the oxidation of lipid membranes
and plasma protein. Not all reports show oxidative stress related to IV iron
agents. How much, if any, oxidative stress occurs after exposure to IV iron agents
depends on the specific test used, the type of IV iron agent, and the concentration
of the IV iron agent itself. Many causes of oxidative stress in chronic kidney disease
patients receiving IV iron are unrelated to iron administration.161-162 It is theorized
that oxidative stress may contribute to the pathogenesis of atherosclerosis
and, in particular, coronary artery disease (CAD). CAD is a leading cause of death
in patients with chronic kidney disease. Although iron is a known and potent cause
of oxidative stress, experimental163 and clinical evidence that IV iron causes CAD or
contributes to atherogenesis or heart disease in renal failure is lacking. More generally,
most experts agree that naturally-occurring causes of iron excess do not lead
to higher rates of CAD.164
Infection is the other leading cause of death in patients with CKD. Since iron is an
essential nutrient for bacterial growth and IV iron agents provide iron in abundance,
the potential role of IV iron administration in the pathogenesis of infection in
patients has been explored. Despite evidence that IV iron agents may enhance
bacterial growth in vitro; prospective, multicenter clinical trials and large scale retrospective
studies in chronic kidney disease patients have found no discernible relationship
between the incidence of infection and either IV iron dosing or levels of
iron status tests.165 An analysis by Aronoff et. al. found that the mortality rate from
infection or sepsis among patients receiving iron sucrose in this trial compared
favorably with that of the overall United States hemodialysis population. They also
found that the hospitalization rate from infection among patients receiving iron
sucrose in the trial was significantly lower than that of the general US hemodialysis
population.23
Labile or bioactive iron in IV iron agents also plays a role in immune defense.
Evidence on the effect of IV iron on neutrophil function is mixed. Since part of the
neutrophil's killing potential stems from oxidative destruction of bacteria, some iron
is needed for optimum neutrophil function. Too much iron, however, impairs phagocytosis
of bacteria by neutrophils in vitro. Carefully designed, prospective studies
have shown no relationship between IV iron treatment and risk of infection.165
Finally, labile iron in IV iron agents may be manifested by a rise in the transferrin
saturation.166 Transferrin is the sole extracellular iron-binding protein. Since the
entire iron-binding capacity of transferrin in the bloodstream of an adult is less than
17 mg, rapid administration of large doses of IV iron may lead to sudden oversaturation
or supersaturation of transferrin. Non-transferrin-bound iron (NTBI) is a theoretical
mechanism to explain increased oxidative stress or bacterial growth.155 NTBI
may contribute to hypotension and cramping, symptoms which limit the dose and
rate of IV iron administration. Difficulty in detecting supersaturation and the observation
that NTBI is found in renal failure patients without IV iron therapy153,167 render
the clinical relevance of this phenomenon uncertain, however.
Markers of oxidative stress include levels of lipid peroxidation (often measured indirectly
by determining levels of malonyldialdehyde (MDA))154,168 or protein oxidation,
including advanced oxidation protein products (AOPP),169 and carbonylated fibrinogen.
170 Markers of neutrophil function include in vitro neutrophil killing capacity,159
neutrophil oxidative burst,160 and neutrophil phagocytosis. Markers of iron donation
to transferrin, of course, include the transferrin saturation (TSAT),166 bleomycindetectable
iron (BDI),170 and NTBI.153-155
In short, while no IV iron agent contains “free” iron, all IV iron agents (including
sodium ferric gluconate complex in sucrose injection, iron dextran and iron sucrose)
have biologically active or labile iron. Labile iron is manifested by several test
results that may be related to CAD and infection; CAD and infection are common
causes of death and hospitalization in dialysis patients, but there is no evidence
linking IV iron agents or IV iron administration to an increased risk of CAD or infection
in patients with chronic kidney disease.
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