If G.B.’s condition does not respond to oral therapy, as indicated by either
persistent iron deficiency based on iron indices or inadequate response to what is
considered an adequate dose and duration of erythropoietic therapy, IV iron is
necessary. The IV iron preparations currently available are iron dextran (INFeD,
DexFerrum), sodium ferric gluconate complex in sucrose (Ferrlecit), iron sucrose
(Venofer), ferumoxytol (Feraheme), and ferric carboxymaltose (Injectafer).
Additionally, soluble ferric pyrophosphate citrate was approved by the FDA in
2015; this iron product is added to the dialysate used for hemodialysis. The dextran
products have caused anaphylactic reactions and, as a result, have an FDA-mandated
black box warning that requires administration of a 25-mg test dose followed by a 1-
hour observation period before the total dose of iron is infused.
component is believed to be the cause of such reactions. The dose of IV iron
recommended to correct absolute iron deficiency is a total dose of 1 g administered
in divided doses or for a prolonged period to minimize the risk of adverse effects.
For iron dextran, the approved dose is 100-mg increments, administered during 10
dialysis sessions for patients on HD to provide a total of 1 g. Larger doses of 500 mg
up to the total 1-g dose have been safely administered during a longer infusion period
Sodium ferric gluconate and iron sucrose are the most widely used iron products
in the CKD population. Both the ferric gluconate and iron sucrose products have been
used successfully in patients who have experienced allergic reactions to the dextran
products, and evidence indicates that they are safer: 8.7 adverse events per million
doses for dextran versus 3.3 adverse events for gluconate.
recommended total dose of 1 g, ferric gluconate is administered as 125 mg (10 mL)
during eight consecutive dialysis sessions for patients on HD. The dose can be
administered as a slow IV injection at a rate of up to 12.5 mg/minute or diluted in
100 mL of normal saline and infused for 1 hour. Administration of 125 mg for 10
minutes (without a test dose) was determined to be a safer alternative to dextran
preparations in patients on HD and is an approved dosing strategy. Doses up to 250
mg for 1 hour have been administered safely.
106 The flexibility of administering
larger doses of iron is an important factor in achieving efficiencies in the outpatient
setting for patients with early CKD and those receiving PD.
Iron sucrose (Venofer) is a polynuclear iron hydroxide sucrose complex. The
recommended dose of iron sucrose is 100 mg (5 mL) during 10 consecutive HD
sessions to provide the total dose of 1 g.
106 The dose can be administered by a slow
IV injection for 5 minutes or diluted in 100 mL of normal saline and infused for at
least 15 minutes. As with sodium ferric gluconate, a test dose is not required. Iron
sucrose doses of 250 to 300 mg have been safely administered for 1 hour and found
to be as effective as sodium ferric gluconate administration in maintaining
hemoglobin in patients receiving epoetin.
106 Furthermore, iron sucrose has
demonstrated the lowest anaphylaxis at first exposure and during total iron
Smaller doses of IV iron, in increments of 25 to 200 mg, can be administered on a
weekly, every 2-week, or monthly basis to patients without absolute iron deficiency.
These doses will sustain adequate iron stores, maintain target hemoglobin values,
and potentially reduce the required dose of the erythropoietic agent.
is most convenient for patients on HD who have regular IV access and increased iron
needs because of chronic blood loss. Maintenance iron therapy replaces these losses
and minimizes the need for the more aggressive 1-g total doses of IV iron required
for absolute iron deficiency. If G.B. starts on HD in the future, regular dosing of IV
iron during dialysis is the most reasonable way to maintain adequate iron required
for sustained erythropoiesis. Iron indices should be monitored at least every 3 months
to guide IV iron therapy. This strategy, however, could lead to increased exposure to
free iron, which may place the patient at an increased risk of adverse effects (e.g.,
inflammation, oxidative stress).
Ferumoxytol (Feraheme) is a semisynthetic carbohydrate-coated,
superparamagnetic iron oxide nanoparticle approved for the treatment of iron
deficiency anemia of CKD. The small content of free iron in the formulation allows
for doses of 510 mg to be administered safely for 17 seconds, followed by a second
510-mg IV injection 3 to 8 days later. Contrary to previous IV iron formulations, a 1-
g repletion regimen of ferumoxytol can be completed in two settings. Prospective,
randomized studies in patients with CKD (categories 1–5) demonstrated the
effectiveness of ferumoxytol in increasing hemoglobin levels in CKD patients
109 Ferumoxytol presents the same side effect profile as
other IV iron preparations (i.e., hypotension or hypersensitivity reactions, including
anaphylaxis or anaphylactoid reactions). The carbohydrate coating of ferumoxytol is
suggested to reduce immunologic sensitivity, potentially resulting in less risk for
anaphylactic type reactions compared with the other available high molecular weight
IV iron products (e.g., iron dextran).
110 However, ferumoxytol has an adverse drug
event rate of approximately 0.2% and the FDA has added a black box warning stating
concern for fatal and serious hypersensitivity reactions particularly with the first
111,112 Additionally, ferumoxytol can affect the diagnostic ability of magnetic
resonance imaging for up to 3 months after the last dose.
ERYTHROPOIESIS-STIMULATING AGENT THERAPY
Recombinant human EPO should be initiated for anemia of CKD in G.B. if there is no
response in her hemoglobin to IV iron. Regular dialysis may improve an anemic
condition, but it will not restore the hemoglobin concentrations to normal because the
primary cause of anemia is reduced EPO production by the kidneys. Although blood
transfusions were once the mainstay of treatment, they are now avoided, if possible,
because they are associated with a risk for viral diseases (hepatitis, human
immunodeficiency virus), iron overload, and further suppression of erythropoiesis.
symptoms of anemia (e.g., fatigue, dyspnea on exertion, tachycardia). Currently, G.B.
is not a candidate for transfusions based on her hemoglobin of 9.3 g/dL and the
absence of significant symptoms on presentation. Androgens raise EPO
concentrations and were previously used to treat the anemia of CKD. However,
inconsistent erythropoietic response, many adverse effects, and the availability of
recombinant EPO have terminated the use of androgens as a treatment of anemia.
Human Erythropoetin-Epoetin Alfa
Human EPO or epoetin, the exogenous form of EPO, is produced using recombinant
technology. Epoetin alfa is available in the United States, whereas epoetin beta is
available primarily outside the United States. Since it became available in 1989,
epoetin alfa (Epogen, Procrit) has provided an effective treatment option for anemia
and has substantially decreased the need for RBC transfusions. Epoetin alfa
stimulates the proliferation and differentiation of erythroid progenitor cells, increases
hemoglobin synthesis, and accelerates the release of reticulocytes from the bone
For patients such as G.B. who do not yet require dialysis and for patients receiving
PD, epoetin alfa is generally administered by subcutaneous (SC) injection. However,
HD patients often receive epoetin alfa by IV administration because easy IV access is
established. SC administration is preferred because lower doses can be administered
less frequently and cost is lower than with IV administration. Starting doses for
epoetin alfa administration are 50 to 100 units/kg 2 times weekly.
from IV to SC administration (half-life of epoetin alfa is 8.5 hours IV vs. 24.4
equivalent to the IV dose is recommended. Patients receiving epoetin alfa SC should
be instructed on the appropriate administration technique, which includes rotating the
sites for injection (e.g., upper arm, thigh, and abdomen).
Darbepoetin alfa (Aranesp) was approved in 2001 for the treatment of anemia of
CKD, regardless of dialysis requirements. Darbepoetin is a hyperglycosylated analog
of epoetin alfa that stimulates erythropoiesis by the same mechanism. Instead of the
three N-linked carbohydrate chains on epoetin alfa, darbepoetin has five, which
increase the capacity for sialic acid residue binding on the protein. The increased
protein binding slows total body clearance and increases the terminal half-life to
25.3 hours and 48.8 hours after IV and SC administration, respectively. Darbepoetin
alfa’s longer half-life relative to epoetin alfa offers the potential advantage of less
frequent dosing to maintain target hemoglobin values.
Studies in patients with CKD 3 and 4 determined that starting SC doses of 0.45
mcg/kg administered once per week and 0.75 mcg/kg once every other week were
effective in achieving target hemoglobin and hematocrit values in patients who had
not previously received erythropoietic therapy.
In patients on dialysis converted
from epoetin alfa to darbepoetin alfa (IV and SC), darbepoetin maintained target
hemoglobin values when administered less frequently (i.e., one dose every week in
patients previously receiving epoetin alfa 3 times/week, and one dose every other
week in patients previously receiving epoetin once weekly).
The approved starting dose of darbepoetin alfa in patients who have not
previously received epoetin therapy is 0.45 mcg/kg given either IV or SC once
115 Patients who are already receiving epoetin therapy may be converted to
darbepoetin alfa based on the current total weekly epoetin dose (Table 28-9).
patients currently receiving epoetin alfa 2 to 3 times a week, darbepoetin alfa may be
administered once weekly. Patients who are receiving epoetin alfa once weekly
should receive darbepoetin alfa once every 2 weeks. To calculate the once every 2-
week darbepoetin dose, the weekly epoetin alfa dose should be multiplied by 2 and
that value used in column 1 of Table 28-9 to find the corresponding darbepoetin dose
from column 2 in Table 28-9. For example, a patient receiving epoetin 6,000
units/week should receive 40 mcg of darbepoetin alfa once every 2 weeks (6,000
units epoetin × 2 = 12,000 units, which corresponds to a weekly darbepoetin dose of
Epoetin alfa and darbepoetin alfa are generally well tolerated, with hypertension
being the most common adverse event reported. Although elevated BP is not
uniformly considered a contraindication to therapy, BP should be monitored closely
so that changes in antihypertensive therapy and the dialysis prescription are made, if
justified. Failure to elicit a response to erythropoietic therapy requires evaluation of
factors that cause resistance, such as iron deficiency, infection, inflammation, chronic
blood loss, aluminum toxicity, malnutrition, and hyperparathyroidism. Resistance to
erythropoietic therapy has been observed in patients receiving ACEI, although data
116 Rare cases of antibody formation to epoetin therapy have been
reported primarily with one epoetin alfa product manufactured outside the United
States. Neutralizing anti-EPO antibodies were identified in 13 patients with pure
RBC aplasia who required blood transfusions after a course of therapy with epoetin
Treatment of G.B.’s anemia must be initiated, given the chronic nature of her
kidney disease and her current hemoglobin. In patients with hemoglobin values less
than 10 g/dL, it is important to identify and correct any iron or folate deficiency and
perform a stool guaiac test to rule out active GI bleeding. Iron supplementation is
indicated, not only if G.B. is iron deficient but also to maintain iron status while
receiving erythropoietic therapy (see Iron Therapy section). Although administration
of iron alone may improve her anemia, epoetin alfa or darbepoetin alfa may likely be
required, based on the severity of her anemia and the progressive nature of her
kidney disease. G.B. may start darbepoetin alfa administered at a dose of 25 mcg
(0.45 mcg/kg) SC once per week, assuming her iron status is appropriate (see Iron
Status section). Another option would be epoetin alfa at a dose of 6,000 units
(approximately100 units/kg) administered SC once per week or divided into two
weekly doses of 3,000 units. She also should be instructed on how to administer SC
epoetin alfa or darbepoetin alfa. Dose adjustments should not be made more
frequently than once every 4 weeks for either agent because of the time course for
response (i.e., the pharmacodynamic effects on RBC homeostasis). The time it takes
to reach a new steady state, when RBC production is equal to RBC destruction,
depends on the life span of the RBC, which is approximately 60 days in patients with
kidney failure. Therefore, it will take approximately 2 to 3 months to reach a plateau
in measured hemoglobin. Dose adjustments should be made on the basis of G.B.’s
hemoglobin, which should be monitored every 1 to 2 weeks after initiation of therapy
or after a dose change. If a rapid increase in hemoglobin is observed (hemoglobin
>1.0 g/dL during any 2-week period) or approaching 11.5 g/dL, then doses of either
agent should be decreased by approximately 25%. If response is inadequate
(hemoglobin increase <1 g/dL in 2–4 weeks), then the doses should be increased by
25%. Once stable, the hemoglobin should be monitored every 2 to 4 weeks. If a
response is not observed despite appropriate dose titration, G.B. should be evaluated
for possible reasons for nonresponse (i.e., iron deficiency, bleeding, aluminum
intoxication, hyperparathyroidism, infection).
Estimated Darbepoetin Alfa Starting Doses Based on Previous Epoetin Alfa
Previous Weekly Epoetin Alfa Dosage
Weekly Starting Darbepoetin Alfa Dosage
determine a darbepoetin alfa conversion dosage.
Reprinted with permission from Facts & Comparisons eAnswers.
The ESA peginesatide, a pegylated peptide, was FDA approved for anemia treatment
in dialysis patients in March 2012. However, peginesatide was withdrawn from the
market by the manufacturer after serious hypersensitivity reactions, including
Continuous EPO receptor activator (Mircera) is a long-acting ESA. CERA is
twice the molecular weight of EPO from the addition of a single 30-kDa polymer
chain into the EPO molecule that results in a considerably longer elimination half-life
compared with EPO (130 hours vs. 4–28 hours). This allows for extended-interval
dosing of biweekly and once monthly. It has an efficacy and safety profile
comparable to other available ESAs. Extended-interval dosing agents, such as
CERA, have several advantages in patients with CKD 3 and 4, including improved
patient compliance, less administration costs, reduced burden on patient from fewer
injections given, and fewer outpatient visits to receive IV administration.
QUESTION 1: H.B. is a 65-year-old white man with category 5 CKD who has just started chronic HD. He
168/90 mm Hg. A recent ECG showed evidence of LVH.
Predialysis laboratory values were as follows:
Cholesterol (nonfasting), 345 mg/dL
H.B. has a urine output of 50 mL/day. What conditions evident in H.B. place him at increased risk of
cardiovascular complications and mortality?
H.B. has uncontrolled hypertension that is not adequately managed with his current
drug therapy or HD. Hypertension is associated with LVH, ischemic heart disease,
and heart failure, all of which are contributing factors to overall mortality in patients
with CKD 5D who are undergoing dialysis.
4 H.B.’s ECG evidence of LVH should
trigger additional evaluation to determine the extent of cardiac involvement and
diagnosis of heart failure, which is associated with increased mortality in both
diabetic and nondiabetic patients (see Chapter 14, Heart Failure).
early in the course of CKD and progresses as kidney disease progresses. H.B. is in
the most severe stage of CKD and has the greatest likelihood of developing LVH.
Anemia contributes substantially to the development of LVH and heart failure as
well. H.B.’s hemoglobin of 9.0 g/dL is below the target value and requires treatment
based on evaluation of his iron indices (see Anemia section).
Additional factors that increase the risk of cardiovascular complications and
mortality in H.B. include elevated cholesterol and triglycerides levels as well as
hypoalbuminemia (serum albumin, 3.0 g/dL). Increased levels of homocysteine are
common in patients with kidney failure and have been associated with increased risk
119 Because elevated concentrations of homocysteine have
been observed in conjunction with decreased folate and vitamin B12
aggressive supplementation of these vitamins in this population has been suggested.
Because H.B.’s total corrected calcium (corrected for hypoalbuminemia; see Case
28-3, Question 2, for an explanation of this correction) is 9.4 mg/dL, his calcium and
use of a calcium-containing phosphate binder will need to be monitored frequently.
Cardiac calcification is common in patients with kidney disease and also is
associated with cardiovascular complications. It has been reported that
approximately 80% of patients with ESRD have detectable coronary artery
120 CVD and complications continue to be the leading cause of mortality
in patients with kidney failure.
CASE 28-2, QUESTION 2: What options are available to treat H.B.’s hypertension considering his other
cardiac complications and BP goal?
Hypertension is common in patients with CKD. Multiple factors are involved in the
development of hypertension in the CKD population, including extracellular volume
expansion from salt and water retention and activation of the renin–angiotensin–
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