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Pumping Iron:
Revisiting Risks, Benefits and Strategies in Treatment of Iron Deficiency in End Stage Renal Disease
Neeraj Singh MD
Anil K. Agarwal MD
Corresponding Author:
Anil K. Agarwal MD
Professor of Medicine
Division of Nephrology
The Ohio State University
395 W 12th Avenue, Ground Floor
Columbus, Ohio 43210
Email: [email protected]
Tel: 614 293 4997
Fax: 614 293 3073
Words: 4236 (including abstract and references
Key Words: Iron deficiency, anemia of CKD, End stage renal disease,
intravenous iron
Conflict of interest: Dr. Singh- None. Dr. Agarwal- ad hoc advisor to Amgen,
Amag, Hospira.
Abstract
Iron deficiency is a common cause of anemia in patients with end stage renal
disease (ESRD). Intravenous iron administration, especially in those requiring
treatment with erythropoiesis stimulating agents (ESA) is an essential component
of the management of anemia in ESRD patients. Iron improves hemoglobin,
reduces ESA dose requirement and also has non-erythropoietic effects including
improvement in physical performance, cognition and amelioration of restless leg
syndrome. However, iron can promote oxidative stress, cause endothelial
dysfunction, inflammation and tissue injury, and has a potential to cause
progression of both CKD and cardiovascular disease. In this review, we discuss
the benefits and risks associated with IV iron and the practical aspects of iron
administration that can minimize the complications related to iron therapy in
ESRD.
Anemia of chronic kidney disease (CKD) affects a majority of patients with End
Stage Renal Disease (ESRD) and results from a multitude of factors, primarily a
combination of decreased production of erythropoietin and low levels of iron or its
poor utilization. Although administration of erythropoiesis stimulating agents
(ESA) is remarkably effective in improving hemoglobin levels, iron deficiency
produces a state of hyporesponse to this therapy, which is frequently associated
with adverse outcomes.
Iron is a trace element that plays an essential role in a number of physiologic
processes among which the most evident is its role in oxygen transport as a
component of hemoglobin. Apart from this, iron also contributes to energy
production, immune function, cell growth and inflammation. Iron is stored in the
body as ferritin and is transported in the blood by transferrin to make it available
to bone marrow. A small concentration of non-transferrin bound iron is present in
blood normally, but can increase in presence of iron overload and cause
production of reactive oxygen species and tissue damage. Control of iron
absorption, primarily through hepcidin, is the most important mechanism of
regulating iron stores in the body.
Iron deficiency in ESRD
Iron deficiency is common in patients with ESRD and is multifactorial, resulting
from loss of blood left in the dialyzer circuit, frequent blood sampling, low-grade
gastrointestinal bleeding, multiple vascular access surgeries and decreased oral
iron absorption because of dietary restrictions and loss of taste for iron-rich
foods. Absolute iron deficiency is generally defined by transferrin saturation
(Tsat) < 20 % and ferritin < 100 ng/ml)1. However, assessment of adequacy of
iron remains an imperfect and controversial science and is a frequent topic of
debate. Common evaluation of iron stores utilizes measurement of such
biomarkers as serum iron, ferritin, transferrin saturation, and percentage of
hypochromic red cells. All these biomarkers have independent variability and are
not always reliable (Table 1)2. Soluble transferrin receptor levels may sometimes
help, but their use has not been widespread. Although bone marrow iron content
is considered the gold standard for evaluation of iron stores, it is not practical or
routine to perform. Further, while iron deficiency can be defined based on these
measurements, it is even more difficult to predict a safe and optimal level of iron
to maintain hemoglobin, making subclinical deficiency of iron an even more
difficult clinical issue.
To make the issues even more confusing, while absolute or subclinical iron
deficiency is prevalent in patients with ESRD, it is all too common to find anemic
patients with ‘adequate’ iron stores indicating poor utilization of iron. This
functional iron deficiency (TSat < 20%; ferritin > 200-500 ng/ml) happens
because iron stored in reticuloendothelial system (RES) gets “locked up” and is
not released to transferrin. As a result, transferrin-bound iron that represents
functionally available pool of iron for erythropoiesis (reflected by Tsat) remains
low despite a normal or elevated ferritin. This RES blockade is mediated by
hepcidin, a key iron regulatory hormone produced by liver in response to
inflammatory cytokines. Hepcidin reduces release of iron from macrophages and
hepatocytes and blocks ferroportin to decrease uptake of iron in enterocytes.
Additionally, inflammatory cytokines such as TNF-alpha, interferon gamma and
IL-6 increase iron uptake and upregulate ferroportin to cause retention of iron.
Benefits of iron replacement
Iron is essential to support erythropoiesis. Iron deficiency is the most common
cause of a suboptimal response to ESA therapy in ESRD patients. Not only
optimal levels of iron in patients with ESRD are difficult to define, iron therapy
can enhance the response to ESA, even in ‘iron-replete’ patients resulting in
better hemoglobin levels, decrease in ESA dosages and significant cost savings3-
4.
Higher doses of ESA administered to increase hemoglobin to higher targets have
recently been implicated in worse clinical outcomes5-6. Use of ESA eventually
depletes iron stores leading to iron deficient erythropoiesis. Such clinical situation
is commonly associated with an increased platelet count (thrombocytosis), which
in turn is believed to contribute to the increased mortality seen with high
hemoglobin targets. Hence, optimal ESA therapy requires concurrent iron
administration to prevent this phenomenon from occurring. Intravenous (IV) iron
administration has been shown to not only decrease hemoglobin variability and
ESA hyporesponsiveness, it may also reduce the risk of ESA-driven
cardiovascular events7. Additionally, IV iron has been shown to improve New
York Heart Association functional class, cardiac and renal function, quality of life
and exercise capacity in CKD patients with heart failure8.
Iron also has benefits that are independent of the correction of anemia. Both iron
and ESA cause a significant fall in hemoglobin A1C values without a change in
glycemic control in patients with diabetes and CKD9. Iron deficiency is commonly
associated with effort intolerance, fatigability, cold intolerance and failure to
concentrate. The benefits of iron supplementation, independent of increasing
hemoglobin, also include better immune function, physical performance,
thermoregulation, cognition, and improvement in restless leg syndrome 10.
Safety concerns related to iron therapy
There are a number of concerns related to use of iron in patients with ESRD,
who require intravenous (IV) iron supplementation, frequently on a regular basis.
These include hypersensitivity reactions, infections, immune dysregulatoin,
oxidative injury, inflammation and iron overload.
Hypersensitivity reactions
Intravenous (IV) iron preparations have been associated with hypersensitivity
reactions (e.g., pruritus, rash, urticaria, or wheezing) and/or hypotension. These
reactions were more common with older iron preparations. Hence most IV iron
preparations require a test dose except for the newer IV iron preparations
ferumoxytol (Feraheme) and ferric carboxymaltose (Ferniject). The risk of
adverse events and anaphylactoid reactions seem to be highest with high
molecular weight iron dextran and least with iron sucrose11-13. Low molecular
weight iron dextran and ferric gluconate fall in between these two for risk of
adverse drug events11 .
Infections
Most common infectious agents in ESRD patients require iron for their growth
and virulence. Staphylococcus epidermidis requires free iron, staphylococcus
aureus requires transferrin bound iron and E coli and klebsiella secrete
siderophores to bind iron. Transferrin bound iron is unavailable to most bacteria.
Free iron suppresses polymorphonuclear leukocyte function, impairs T cell
development and facilitates growth of bacteria by adversely affecting cell-
mediated immune effector mechanisms against invading microorganisms14. Free
iron also inhibits phagocytosis and cell lysis. Therefore in patients with sepsis,
treatment with IV iron should be avoided. Iron Overload with ferritin >1000
microgram/l in haemodialysis patients has also been shown to increases the risk
of bacteremia15 although another surveillance study of 998 patients in France did
not show worsening effect of IV iron on infection16.
Oxidative injury
Chronic kidney disease (CKD) is a pro-oxidant state, and the concern exists that
iron excess may exacerbate oxidative stress17-18. In one study, IV iron sucrose
was shown to increase the level of inflammatory chemokine monocyte
chemoattractant protein which can potentially lead to progression of CKD19.
Additionally, increased ferritin level has been linked to acute renal failure20. Some
evidence suggests that IV iron sucrose could be associated with proteinuria and
tubular damage21-22. This is supported by the fact that renal hemosiderosis
secondary to both chronic repetitive hemolytic episodes and transfusion-related
iron overload in patients with paroxysmal nocturnal hemoglobinuria can lead to
Fanconi syndrome and chronic kidney disease23. Despite the above evidence
suggesting harmful effects of iron overload on kidneys, no study has shown
evidence of direct acute kidney injury with IV iron.
Iron Overload
Iron overload may induce insulin resistance and metabolic alterations which may
promote cardiovascular adverse outcomes24. One study found correlation
between increased serum ferritin levels and severity of stroke25. Cases of
hemochromatosis have been reported with serum ferritin levels >2000 ng/ml2.
Parenteral iron has also been reported to suppress renal tubular phosphate
reabsorption and 1-alpha-hydroxylation of vitamin D resulting in
hypophosphatemic osteomalacia, an action mediated by an increase in fibroblast
growth factor 23 (FGF23)26-28.
How to replace iron in ESRD?
Iron deficiency in ESRD patients is easily corrected by intravenous iron. Indeed,
intravenous iron can raise levels of hemoglobin even without the use of ESAs
and enhance the efficacy of ESAs. A meta-analysis of studies in CKD and ESRD
showed that patients on hemodialysis therapy have better Hb level response
when treated with IV iron as compared to oral iron 29-30. It is estimated that
patients requiring maintenance hemodialysis treatments may lose up to 3 g of
iron each year and hence intravenous iron is routinely used either weekly to
monthly in dialysis patients. Regular iron infusion of 50 to 100 mg per week is
able to cover the basic needs of most hemodialysis patients. The 2006 K/DOQI
guidelines however suggest that oral iron be administered in peritoneal dialysis
as well as for initial iron therapy in hemodialysis patients1.
Available IV Iron Formulations
The most desirable iron supplement should have ease of administration, freedom
from side effects, no toxicity, efficacy and economy. No such iron preparation is
currently available. Iron is inherently toxic and all preparations of iron- oral or IV-
are ionic and have side effects. IV iron preparations are colloidal nanoparticles
consisting of a core of iron and outer carbohydrate shell to protect from toxicity of
free iron. The size and shape of core and shell determine biologic characteristics
of iron preparation- such as iron release, uptake, clearance, bioactivity, tolerance
and rate of infusion. Acute reactions to iron seem to be related to free iron toxicity
and amount of labile iron released is inversely proportional to the size of the
molecule. The amount of labile iron released also increases with the increase in
the dose and limits the maximum tolerated dose and rate of infusion. The
currently available preparations have limitations due to side effects or dose
limitations.
The carbohydrate shell of currently available IV iron preparations is composed of
dextran, sucrose, dextrin or gluconate molecule31(Table 2). Iron dextrans (INFeD-
molecular weight 96-165Kd, Dexferrum molecular weight 265Kd) - deliver iron to
RES receptors from where it is transferred to transferrin, precluding generation of
free iron. These have a half-life of 40-60 hours and a volume of distribution of 6
liters. There is no renal elimination32. Major advantage of iron dextran is the
ability to administer a full gram of iron over one session. However, dextrans are
the only IV iron preparations with reported deaths due to allergic reactions (much
more with Dexferrum than with InFeD). In one study of 573 dialysis patients,
1.7% incidence of anaphylactoid reaction was noted with IV iron33.
Low-molecular-weight iron dextran, which is approved for total dose infusion in
the United Kingdom, has been shown to be safe and efficacious compared to
iron sucrose34.
Ferric gluconate in sucrose (Ferrlecit) has a lower molecular weight (29-44Kd),
half-life of 1 hour and is devoid of direct transfer of iron to transferrin. It has a
volume of distribution of 6 L and does not have renal elimination. However, it has
low dissociation constant releasing iron quickly35.
IV iron saccharate used to replenish and maintain iron stores in stable EPO
treated HD patients is safe and effective. It results in achieving target hemoglobin
with significantly lower doses of EPO36. Iron sucrose has a molecular weight of
34-60 Kd and is also taken up by RES with some direct transfer to transferrin. It
has a half-life of 6 hours and has <5% renal elimination with volume of
distribution of 3.2-7.3 liter37.
Ferumoxytol, a recently approved preparation for treatment of anemia of CKD,
can be rapidly administered as two IV boluses of 510 mg each to replenish iron
stores38. It is a semisynthetic, ultrasmall superparamagnetic iron oxide coated
with polyglucose sorbitol carboxymethylether and is formulated with mannitol.
Each 17ml vial contains 30mg/ml iron and 44mg/ml mannitol and has molecular
weight of 750 kd and osmolality of 270-330 mOsm/kg, It has no preservative and
has very little bleomycin detectable iron (1.15 ± 0.46 µmol) amounting to only
0.001 percent free iron.
Another new formulation, ferric carboxymaltose which can be rapidly
administered in a total dose of 1000 mg also has been shown to be an effective
and well-tolerated option39-40. It is currently being tested in phase III clinical trials.
A novel iron preparation for use as intradialysate supplement is Soluble Ferric
Pyrophosphate that complexes iron tightly not to allow free iron generation. It is
claimed to enhance iron transfer directly to ferritin, RES tissues and transferrin to
transferrin. It is water soluble with a molecular weight of 745 Kd. In conrolled
studies of HD patients on erythropoeitin (and iron dextran in controls), it has been
found to be safe and effective41. Phase III trials of this compound are in planning.
Target goals for I.V iron replacement
The 2006 K/DOQI guidelines recommend transferrin saturation >20 percent and
serum ferritin concentration >200 ng/mL as the goals of iron therapy in patients
undergoing hemodialysis1. However, the desirable upper targets of ‘iron indices’
that should be used as goals to guide iron therapy remain undefined. Serum
ferritin and transferrin saturation are often confounded by non-iron-related
conditions. For instance, serum ferritin is also elevated in the setting of
inflammation, latent infections, malignancies, or liver disease7. Hence moderate-
range hyperferritinemia (500 to 2000 ng/ml) has been shown to be a misleading
marker of iron stores in dialysis patients2. In fact, serum ferritin is increased
above 500 ng/ml in almost half of all hemodialysis patients and in the range of
500-1,200 ng/ml it does not increase risk of death42. Additional IV iron given to
dialysis patients in this ferritin range increases Hgb4 and may even increase
survival2.
KDOQI recommends that when serum ferritin level is > 500 ng/ml, decision on IV
iron administration should weigh several factors including erythropoietin
responsiveness, hemoglobin and transferrin saturation level, and the patient's
clinical status. However no upper limit of serum ferritin at which to withhold IV
iron is defined.
An increased erythropoietic response to iron supplementation is also widely
accepted as a good reference standard of iron-deficient erythropoiesis43.
However, a recent study showed that both peripheral-iron indices and
erythropoietic response had equivalent, but limited, utility in identifying depletion
of bone marrow iron stores44.
In absence of clear strategies to assess iron status and arbitrary goals guiding
I.V iron therapy, concern exists that excessive IV iron may lead to iron overload
and toxicity in the long term. Iron overload itself stimulates hepcidin45 , which by
blocking release of iron from the RES, may cause further buildup of iron in tissue
stores.
Long-term outcomes with IV iron
While it is clear that IV iron could be a 'two-edged sword' with both benefits and
potential concerns in short-term, less remains known about the overall clinical
safety and risk to benefit ratio of iron supplementation in the long-term. Further
prospective research should address the optimal amount of iron
supplementation, ideal therapeutic approach and long-term safety of IV iron,
especially of the newer IV iron preparations.
Minimizing iron overload/toxicity
Iron acts as a catalyst in the generation of oxygen-free radicals and thereby
increases oxidative stress. As catalytically active iron is potentially toxic, some
authors have recommended using dosage regimens that would not release iron
into plasma in amounts exceeding the iron binding capacity of transferrin46. Use
of certain IV iron preparations like ferumoxytol that release less free iron could
potentially be less nephrotoxic47. Iron chelators with their role in binding labile
iron may provide a new modality of prevention and treatment of kidney disease48.
However oxidative stress can develop even when transferrin is not completely
saturated suggesting that free iron independent mechanisms could also be
important22. In addition, nephrotoxicity of iron may depend upon type of IV iron. A
study examined the differences in proteinuria between two IV iron preparations
and reported that in contrast to ferric gluconate, which produced only mild
transient proteinuria, iron sucrose produced a consistent and persistent
proteinuric response that was on average 78% greater49. As both serum ferritin
and TSat can be altered by a number of non-iron-related factors, it is important to
draw upon additional data when necessary such as patient’s clinical condition,
percentage of hypochromic red blood cells, and/or the reticulocyte hemoglobin
concentration. This may be helpful in correctly assessing patient's iron status and
avoiding iron overdose.
Conclusion
Iron is necessary to optimize ESA therapy in patients on dialysis. It is essential to
correctly ascertain precise cause of anemia and prudently consider iron status to
optimally supplement iron and minimize iron overload. Quest for an accurate
marker of iron stores and a safe and effective iron preparation will need to
continue. Clinicians should carefully consider the benefits and hazards of iron
therapy before using intravenous iron in the management of renal anemia until
better data is available regarding the long-term safety of iron use in dialysis
patients.
References
