US Pharm. 2013;8(38):22-26.
ABSTRACT: A prevalent complication of chronic kidney disease (CKD),
especially in dialysis patients, iron deficiency anemia (IDA) continues
to be underdiagnosed and undertreated. The main causes of IDA in this
population are reduced intake and impaired intestinal absorption of
dietary iron, blood losses, chronic inflammation, and increased iron
requirements during therapy with erythropoiesis-stimulating agents
(ESAs). The addition of IV iron can relieve iron-restricted
erythropoiesis and improve ESA response, as well as balance the risks of
ESA therapy. Clinical guidelines for anemia of CKD include
recommendations for the use of IV iron. There are a number of factors to
consider when managing anemia of CKD, and the various forms of iron are
A prevalent complication of chronic kidney disease (CKD),
particularly in dialysis patients, iron deficiency anemia (IDA) remains
underdiagnosed and undertreated. This article presents an update on the
diagnosis of IDA and the management of IDA with various forms of IV
The World Health Organization defines anemia as a hemoglobin (Hgb) level of <13 g/dL in men and <12 g/dL in women.1
In the United States, iron deficiency is the most common cause of
anemia. A deficiency of iron in RBCs reduces tissue oxygen delivery,
increases cardiac output, and may result in ventricular dilation and
hypertrophy, if left untreated.2 The main causes of
iron deficiency are increased demand for iron, iron loss, and—frequently
the case in CKD—decreased iron stores, reduced iron absorption, or
inflammatory iron block.
Anemia of CKD may be due to insufficient production of erythropoietin
by diseased kidneys, diminished RBC survival, iron or vitamin
deficiencies, bleeding diathesis, hyperparathyroidism, chronic
inflammation, or comorbidities.2,3 Iron deficiency also can
develop in hemodialysis (HD) patients receiving
erythropoiesis-stimulating agents (ESAs), which cause an increased
demand for iron; blood loss from dialysis is another cause of iron
deficiency.4 Diabetic patients are at increased risk for anemia, and anemia itself is an independent risk factor for CKD.5,6
Symptoms of iron deficiency include fatigue, weakness, anorexia,
insomnia, angina, tachycardia, dyspnea, decreased mental and physical
performance, and possibly heart failure. Although anemia correction in
CKD has been shown to slow the progression of renal disease and improve
overall quality of life, IDA remains underdiagnosed and undertreated.2,7,8
Because both early-stage CKD and anemia are usually asymptomatic,
renal and hematologic laboratory values should be monitored annually in
patients at risk.2,3,8 As glomerular filtration rate (GFR)
decreases with progressive CKD, the risk of anemia increases from
approximately 27% in stage 1 CKD to 76% in stage 5 (GFR <15 mL/min).5,9
Transferrin saturation (TSAT) and ferritin values help determine the presence of IDA (TABLE 1). Absolute IDA—in
which TSAT is <20% and ferritin is <100 ng/mL—refers to the
depletion of iron stores that occurs when there is insufficient iron to
produce Hgb. Functional IDA (elevated ferritin and TSAT <20%)
may develop during ESA therapy owing to inadequate mobilization despite
sufficient stores to keep up with RBC production during erythropoiesis.10,11 Failure to reach target Hgb levels may occur despite large ESA dosages.
Ferritin, a nonspecific acute-phase reactant, is elevated in chronic
inflammation. In the presence of CKD, ferritin cutoff values for both
predialysis and HD are higher in functional IDA, at >100 ng/mL and
>200 ng/mL, respectively. See TABLE 1 for other monitoring parameters (e.g., complete hematologic response) used during iron therapy.5,11
Iron and ESA Therapy
Despite its benefits, ESA therapy is associated with an increased
risk of adverse drug events (ADEs) such as cardiovascular (CV)
complications, hypertension, RBC aplasia, and development of
antierythropoietin antibodies. Three trials (CHOIR, CREATE, and TREAT)
raised concerns about ESA therapy and its associated CV and mortality
risks because of the higher Hgb levels in, and/or higher ESA doses
administered to, hyporesponders.12-14 IV iron as an adjunct
to ESA therapy has become standard treatment for optimizing Hgb status
and reducing ESA dosing requirements. Up to a 70% reduction in required ESA dosage has been noted in patients receiving IV iron.15,16 However, iron underutilization has been reported in anemic CKD patients receiving ESA therapy.17
ADEs, drug interactions, and lack of adherence limit the use of oral
iron therapy. For HD-dependent patients, who often have limited
absorption of oral iron, IV supplementation is preferred.18
The 2006 and 2007 updates to the National Kidney Foundation Kidney
Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines
for anemia of CKD recommend that HD patients on ESA therapy receive IV
iron supplementation to maintain a target Hgb of 11 g/dL to 12 g/dL (not
to exceed 13 g/dL). The guidelines also recommend that
non–dialysis-dependent and peritoneal dialysis–dependent patients
receive iron either orally or IV.19,20
Iron repletion should begin before initiation of ESA therapy. Iron
levels should initially be monitored monthly until iron stores are
replenished, then monitored quarterly. Smaller maintenance doses may be
necessary after repletion, because Hgb optimization can occur in
patients whose ferritin is >500 ng/mL. Overall clinical status,
degree of ESA responsiveness, and other causes of increased ferritin
(infection, inflammation) should be considered. Data are lacking
regarding cessation of IV iron therapy. An increase in Hgb >1 g/dL
over 1 month indicates a therapeutic response to iron therapy when IDA
diagnosis in complex situations is unclear. Monitoring of iron levels
also is important to avoid iron overload or toxicity and to prevent
hemochromatosis from developing.5
Pharmacokinetics of IV Iron Formulations
IV iron formulations contain an iron core stabilized by a
carbohydrate outer shell that maintains iron in a colloid form and
controls its release. Formulations differ in iron core size and in the
type and density of the surrounding carbohydrate shell. Pharmacokinetics
differs across iron agents, with an inverse relationship between the
strength of the iron complex and the rate of iron release. The stronger
the complex, the more slowly bioactive iron is released, which may lead
to free iron toxicity because of its lower potential to saturate
transferrin.20 Iron-carbohydrate complexes in plasma
are phagocytosed by the reticuloendothelial system, which degrades the
carbohydrate shell; iron is stored as ferritin or transported out of the
cell by an export protein. The exported iron binds to free sites on
plasma transferrin, which delivers iron to transferrin receptors, and is
then utilized in the formation of Hgb. Unutilized iron gets stored and,
when needed, is released from the cell to undergo transferrin
Comparison of IV Iron Products
IV iron products (see TABLE 2 for a comparison) are either dextran-containing or non–dextran-containing.21
ADE profiles of the various IV iron formulations are based on
differences in molecular size, degradation kinetics, and
bioavailability.22 There are concerns surrounding iron’s safety.
Iron dextran (ID) formulations carry a black box warning about fatal
anaphylactic reactions, likely because of antibodies to the
iron-carbohydrate or ID complex or the dextran component, particularly
with high-molecular-weight ID (HMW-ID). The introduction of
low-molecular-weight ID (LMW-ID) substantially reduces the risk of
anaphylaxis. With ID therapy, test doses are required, along with an
observation period for antibody reactions.23,24
Newer IV irons—ferric gluconate and iron sucrose—do not contain dextran and have a better safety profile. Chertow et al compared absolute rates of life-threatening ADEs reported by the FDA from 2001 to 2003. 25
For four different parenteral iron preparations (iron sucrose, ferric
gluconate, LMW-ID, and HMW-ID), ADEs were 0.6, 0.9, 3.3, and 11.3 per
million patients, respectively.
Vasoactive reactions, which are due to the appearance of
nontransferrin-bound or free (labile) iron in the circulation, include a
drop in blood pressure, acute edema of extremities, and acute onset of
diarrhea when large IV iron doses are administered rapidly.26
Small undiluted or infusion doses of LMW-ID are recommended; a total
dose infusion (TDI) of 1,000 mg is possible, but it must be infused over
4 to 6 hours to avoid vasoactive reactions.27 Also, IV steroid premedication has successfully prevented these reactions.
TDI of iron sucrose and ferric gluconate is not recommended because
the potential for vasoactive reactions and gastrointestinal symptoms
increases with large doses. Smaller undiluted or infusion doses are
recommended. Iron sucrose has broader FDA-labeled indications than does
ferric gluconate (TABLE 2).28-31
Ferumoxytol is the newest IV iron formulation to enter the U.S.
market. The total dose is administered undiluted in two separate
injections. Although it contains dextran derivatives, no test dose is
required. Comparative safety data with other IV iron formulations are
lacking. Life-threatening anaphylactic-type reactions,
cardiac/cardiorespiratory arrest, syncope, tachycardia/rhythm
abnormalities, angioedema, ischemic myocardial events, congestive heart
failure, absent pulse, and cyanosis have been reported for ferumoxytol.32,33 On July 25, 2013, the FDA approved ferric carboxymaltose (Injectafer), a new single-dose preparation.34,35 Soluble ferric pyrophosphate delivered via hemodiasylate is a new iron formulation in phase III development.36
There is concern about the increased risk of infection with IV iron
use. Iron may serve as a growth factor for bacteria, inhibit
phagocytosis, and increase oxidative stress. Withholding IV iron therapy
in cases of acute infection may be prudent.37 If iron
release exceeds binding capacity or if transferrin is oversaturated,
toxic unbound iron acts as a catalyst in the formation of free
radicals—believed to lead to coronary artery inflammation—and the
development of atherosclerosis and long-term CV risk. Iron may also
cause LDL oxidation, which is more damaging to the coronary arteries.
Myocardial infarction occurring with the use of IV iron, hypothesized to
be caused by elevated serum ferritin levels, also has been reported.38,39
Iron is a treatment option for anemia of CKD that can successfully
balance the risks of ESA therapy. The KDOQI guidelines were updated in
2007 to reflect this. Pharmacists should be aware that there are a
variety of factors to consider when managing anemia of CKD, and the
various types of iron are not identical.
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