ANEMIA IN CHRONIC KIDNEY

CHAPTER 19

DISEASE
Jay B. Wish

1. What causes anemia in patients with kidney disease?

The anemia of chronic kidney disease (CKD) is primarily caused by deficiency of erythropoietin (EPO).
The kidneys are the major source of EPO, and as kidney function declines, production of EPO declines
proportionately. Several other factors decrease red blood cell (RBC) life span from the normal 120 days
to approximately 70–80 days in patients with CKD. These include:
• RBC trauma due to microvascular disease from diabetes or hypertension
• Blood loss from hemodialysis (HD)
• Increased incidence of gastrointestinal bleeding from peptic ulcer disease and angiodysplasia of
the bowel
• Increased oxidative stress
2. What are the adverse effects of anemia?
Anemia leads to decreased oxygen-carrying capacity of the blood and decreased delivery of
oxygen to tissues. This results in fatigue (both with exercise and at rest), decreased cognitive
function, loss of libido, and decreased sense of well-being. The increased workload on the heart
may lead to left ventricular hypertrophy. Observational studies of dialysis patients in the 1990s
demonstrated decreased hospitalizations and mortality among patients with higher hemoglobin
(Hb) levels, but these may have been confounded by comorbidities that decreased Hb levels and
also led to poorer outcomes. Randomized controlled trials (RCTs) of erythropoiesis-stimulating
agents (ESAs) to raise Hb levels have not led to improved outcomes or consistently improved
quality-of-life (QOF; Table 19.1 and question 17).
3. How does one evaluate anemia in a patient with CKD?
EPO deficiency is a diagnosis of exclusion, and checking EPO levels in patients with CKD is generally
not indicated. The routine evaluation of such patients should include:
• Measurement of RBC indices
• Reticulocyte count
• Transferrin saturation (TSAT)
• Serum ferritin
• Stool for occult blood testing
If these tests reveal no alternative cause of anemia, it can be presumed that the anemia is
primarily due to EPO deficiency.
4. How does one interpret TSAT?
TSAT is calculated by dividing the serum iron level by the total iron-binding capacity. The total
iron-binding capacity reflects circulating transferrin, the major iron-binding protein in plasma. TSAT
correlates with the amount of iron available for erythropoiesis, because only circulating iron is
available to the bone marrow for incorporation into RBC. Patients with TSAT ,20% have decreased
iron delivery to the erythroid marrow, but supplemental iron can only correct this if the iron is
effectively released from storage sites to the transferrin carrier protein.
5. How does one interpret the serum ferritin?
The serum ferritin level correlates with storage iron, located primarily in the reticuloendothelial
system. Interpretation of serum ferritin levels is confounded by ferritin being an acute-phase
reactant and rising with acute or chronic inflammation. In patients with CKD, serum ferritin level
,100 ng/mL correlates with a deficiency in storage iron; such patients almost invariably respond to
supplemental iron therapy.

130
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 ANEMIA IN CHRONIC KIDNEY DISEASE  131

Table 19.1.  Large Randomized Studies in Patients With Anemia and Chronic
Kidney Disease Not Receiving Dialysis
CHOIR CREATE TREAT
Location United States Europe International
ESA Epoetin alfa Epoetin beta Darbepoetin alfa
Number of patients 1432 603 4038, type 2 diabetics
High Hb target g/dL 13.5 13–15 13
Low Hb target g/dL 11.3 10.5–11.5 Placebo control, ESA rescue
for Hb ,9
Cardiovascular Higher in high No difference No difference except higher
endpoints Hb group stroke and lower coronary
revascularization in high
Hb group
Progression of CKD No difference More in high Hb group No difference
Cancer deaths Not noted Not noted Higher in high Hb group
among patients with prior
cancer
Quality of life No difference Better in high Hb group No difference except less
fatigue in high Hb group
CHOIR, Correction of Hemoglobin and Outcomes in Renal Insufficiency; CKD, chronic kidney disease; CREATE,
Cardiovascular Risk Reduction of Early Anemia Treatment with Epoetin Beta; ESA, erythrocyte-stimulating
agent; Hb, hemoglobin; TREAT, Trial to Reduce Cardiovascular Events with Aranesp Therapy.

6. What is functional iron deficiency?

Functional iron deficiency is a bone marrow iron supply-demand mismatch in a patient with normal or
elevated iron stores. It can occur in the setting of inflammation when elevated hepcidin levels impair
the release of storage iron to circulating transferrin. It can also occur in patients treated with
pharmacologic doses of ESAs when the bone marrow is stimulated to produce RBCs faster than the
transferrin carrier protein can deliver adequate iron substrate. In such patients, TSAT tends to be low
or low-normal, whereas serum ferritin level may be normal or even high. The operative definition of
functional iron deficiency is based on a response to intravenous (IV) iron supplementation
characterized by either an increase in Hb or a decrease in ESA requirements to achieve the same Hb.
7. What is the role of IV iron?
Studies have demonstrated that functional iron deficiency is common in patients with end-stage kidney
disease (ESKD) who are treated with ESAs and that IV iron supplementation decreases ESA requirements
by 20% to 25%. In CKD patients with iron deficiency anemia not receiving ESAs, 1 gm IV iron generally
raises the Hb 1 gm/dL. For iron-deficient, non-hemodialysis patients who fail oral iron therapy, IV iron
can be given in larger doses over fewer treatments for patient convenience and vein sparing. In HD
patients, IV iron is generally administered in smaller, more frequent doses through the dialysis circuit.
8. What are the adverse effects of IV iron?
IV iron may be associated with acute reactions such as nausea/vomiting and hypotension, which are
likely related to free iron in the preparation. IV iron may be associated with allergic or anaphylactic
reactions to the carbohydrate that binds the iron. There have been concerns regarding the long-term
effects of IV iron administration, including iron accumulation in tissues, oxidative damage to
endothelial cells, and increased susceptibility to infection. Retrospective studies in HD patients have
shown an association with adverse clinical outcomes and monthly IV iron doses over 400 mg, but it is
impossible to exclude confounding by indication. In a prospective study comparing IV and oral iron in
patients with nondialysis patients with iron deficiency anemia, patients receiving IV iron had a 2.51
higher incidence of cardiovascular events and a 2.12 increased risk of hospitalization due to infection
over a 2-year follow-up period. This supports the Kidney Disease Improving Global Outcomes
recommendation that in patients with nondialysis CKD and iron deficiency anemia, a 1- to 3-month
trial of oral iron therapy be considered prior to initiating IV iron therapy.

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 132  CHRONIC KIDNEY DISEASE

9. Why are oral iron supplements ineffective in treating the iron deficiency in patients receiving
chronic HD?
Increasing the Hb from 8 g/dL to 11 g/dL in a 70-kg patient requires the incorporation of 600 mg
elemental iron into newly synthesized RBC. Daily iron losses in HD patients are approximately 4 to
7 mg (averaged over dialysis and nondialysis days). Thus the 2 to 4 mg of oral iron absorbed daily
from conventional oral supplements in dialysis patients with elevated hepcidin levels could barely
keep pace with ongoing iron losses, and would not allow the patient to repair the accumulated deficit.
Compounding this problem is the phenomenon of functional iron deficiency, which often results in the
need for high levels of storage iron to facilitate the release of iron to transferrin and delivery of that
iron to the erythroid marrow.
10. Are there other options for iron supplementation in HD patients?
Oral ferric citrate, a phosphate binder, has absorbable iron that has been shown to increase serum
ferritin and TSAT and decrease IV iron requirements in HD patients. Unlike other oral iron
supplements, ferric citrate is associated more with diarrhea than with constipation. Sodium ferric
pyrophosphate added to the hemodialysate solution can replace 5 to 7 mg iron per treatment,
decreasing IV iron requirements by 48%. Dialysate sodium ferric pyrophosphate has a similar safety
profile to placebo.
11. What is hepcidin?
Hepcidin is a protein synthesized by the liver in the setting of inflammation, which is usually present
in patients with CKD. Hepcidin decreases iron absorption from the gastrointestinal tract and
movement of iron from the reticuloendothelial system to the circulation. Hepcidin causes an increase
in serum ferritin levels, a decrease in TSAT, and contributes to functional iron deficiency.
Investigational drugs that decrease hepcidin activity improve ESA responsiveness.
12. How are ESAs administered?
Human recombinant erythropoietin (epoetin) is a polypeptide hormone that, like insulin, must be given
through a subcutaneous or IV route. Subcutaneously administered epoetin, because of its slower
absorption and longer half-life, is more effective than a comparable dose administered through IV.
Epoetin dose can be reduced 20% to 30% by switching patients from IV to subcutaneous dosing
while achieving the same Hb.
13. What is the recommended dose of epoetin?
For patients receiving epoetin IV on HD, the recommended starting dose is 50 units/kg of body weight
three times weekly. For patients receiving epoetin therapy subcutaneously, the recommended starting
dose is 30 units/kg administered three times weekly (as is typically done in HD facilities) or
100 units/kg/week administered weekly or biweekly (which is typical for predialysis and peritoneal
dialysis patients). Dose should be titrated at monthly intervals, depending on the Hb response.
14. What is the recommended dose of darbepoietin?
Darbepoetin alfa is an analog of human EPO, with two extra carbohydrate side chains and a longer
duration of action when compared with both native and recombinant hormone. The recommended
starting dose for darbepoetin alfa is 0.45 mcg/kg administered weekly or 0.75 mcg/kg administered
biweekly in dialysis and patients with CKD for both IV and subcutaneous administration, with
subsequent titration based on the Hb concentration. Success with longer dosing intervals for both
epoetin and darbepoetin has been reported.
15. What is the target Hb for patients with CKD receiving ESA therapy?
After considering the results of several RCTs of higher versus lower Hb targets in patients with CKD
receiving ESA therapy, the Food and Drug Administration (FDA) changed the product information for
epoetin and darbepoetin in 2011. In these RCTs patients experienced greater risks for death, major
adverse cardiovascular events, and stroke when administered ESAs to target Hb level .11 g/dL (per
the FDA; see the next section). No trial has identified a Hb target level, ESA dose, or dosing strategy
that does not increase these risks. Therefore it is recommended that the lowest ESA dose be used
that is sufficient to reduce the need for RBC transfusions.
16. What is the evidence on which the FDA based its recommendations regarding target Hb level?
The Normal Hematocrit Cardiovascular Trial, published in 1998, demonstrated a tendency toward
more cardiovascular events among patients undergoing HD and receiving epoetin who were
randomized to a target hematocrit to 42% versus 30%. Three additional studies comparing high
versus low Hb targets for ESA therapy in patients with nondialysis CKD are summarized in Table 19.1.

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 ANEMIA IN CHRONIC KIDNEY DISEASE  133

Retrospective analyses of these studies suggest that the risk of adverse outcomes is correlated with
the ESA dose received, rather than the Hb level achieved. A patient who achieves an Hb of 13 g/dL
using a low dose of ESA is at lower risk than a patient who requires a large dose of ESA to increase
the Hb level from 9 to 11 g/dL. It should be noted that the target Hb level in the high Hb arm of
all the principal trials was at least 13 g/dL, and the FDA’s statement that the risk for adverse
outcomes occurred when ESAs were administered to a target Hb .11 g/dL is a very cautious,
non-evidence-based interpretation of the studies’ results.
17. Are ESAs toxic?
ESAs are administered to more than 95% of patients receiving dialysis in the United States. Like any
other pharmacologic agent, ESAs have risks that must be weighed against their benefits. The most
compelling benefit of ESA therapy is transfusion avoidance. A pre- versus posttreatment QOL benefit
of ESA therapy was reported in patients receiving dialysis whose baseline Hb in the pre-ESA era was
7–8 g/dL, and the Hb level was increased with ESA to 10–11 g/dL; however, no significant QOL
benefit has been shown in the RCTs comparing Hb targets of 9–11.5 and 13–15 g/dL. None of the
randomized clinical trials of ESA therapy has ever shown a mortality benefit, and the three large trials
in patients with CKD who are not receiving dialysis summarized in Table 19.1 suggest that caution
must be used when treating patients with ESAs to minimize the risk of adverse outcomes. Data
demonstrating an improvement in the rates of stroke, venous thromboembolism, and heart failure (but
not mortality) among dialysis patients following a reduction in mean Hb levels from a change in ESA
reimbursement also suggest that ESAs and/or higher Hb levels have adverse effects in this vulnerable
population.
18. What is pure red cell aplasia (PRCA)?
PRCA is caused by antibodies produced against an exogenous ESA cross-reacting with endogenous
EPO. This results in the complete loss of RBC precursors from the bone marrow and severe anemia.
Most reported cases of PRCA have been associated with alterations of the ESA protein due to
manufacturing, packaging, or distribution issues, and PRCA is almost exclusively associated with
subcutaneous ESA administration. Most patients with PRCA recover after withdrawal of the ESA and
the use of immunosuppressive agents. PRCA is very rare in industrialized countries with robust
regulatory and pharmacovigilance systems.
19. Do ESAs promote cancer?
The increased number of cancer deaths noted in the high Hb arm of the TREAT study, coupled with data
from the oncology literature demonstrating increased tumor progression or recurrence among patients
treated with ESAs, suggests that ESAs should be used with caution in patients with CKD with existing
malignancies. The recommendation is that ESA treatment and dosing should be individualized in the
patient with CKD to weigh benefit versus risk and that very high doses of ESAs should be avoided.
20. Are there newer ESAs?
Methoxy-pegylated epoetin beta (Mircera) was approved by the FDA in 2008, but its introduction into
the U.S. market was delayed until 2015 because of patent infringement issues. Methoxy-pegylated
epoetin beta is effective when administered once monthly and has the same FDA recommendations
regarding dosing and target Hb levels as epoetin and darbepoetin. Its long duration of action may
make it attractive to non-hemodialysis patients who require subcutaneous ESA administration.
21. What are biosimilars?
Since ESAs are complex proteins with side chains, not every molecule is identical to each other, and
therefore it is impossible to develop a “generic” version that is identical to the originator molecule. For
biologic drugs whose patents have expired, the FDA has developed an approval pathway for biosimilar
agents whose safety, efficacy, and potency is sufficiently similar to the originator molecule that it can
be used as a therapeutic alternative. The advantage of biosimilar agents is that they are expected to
be 20% to 30% less expensive than the originator molecule. Biosimilar ESAs have been used
successfully in Europe since 2008, and at least two biosimilar ESAs are under development in the
United States as of 2016.
22. What are hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors?
Several agents are under development that potentiate the activity of HIF, the substance in the kidney
and other tissues that senses decreased delivery of oxygen (from hypoxemia or anemia) and
stimulates the production of EPO. In the absence of hypoxia, HIF is rapidly degraded by an enzyme,
prolyl hydroxylase (HIF-PH). By inhibiting HIF-PH, these agents increase HIF and endogenous EPO
activity. These agents are orally active and effective, even in patients with ESRD, suggesting that
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 134  CHRONIC KIDNEY DISEASE

significant EPO production can be induced in nonrenal tissues This is supported by the observation
that HIF-PH inhibitors are effective in anephric patients with ESRD.
23. Are there special considerations for patients with CKD and sickle cell disease?
There are no evidence-based guidelines regarding whether the anemia of patients with CKD and
sickle cell disease should be treated differently from other patients with anemia and CKD. Because of
ongoing RBC destruction, patients with sickle cell disease have lower Hb levels and higher ESA
requirements than their anemic CKD counterparts. Transfusions are more often required in patients
with sickle cell disease than in other patients with anemia and CKD, so attention must be paid to the
potential for iron overload and sensitization for future kidney transplantation. As in all patients, ESA
and transfusion therapy in patients with sickle cell disease should carefully weigh risk versus benefit.
24. What is the role of transfusions in the treatment of CKD-associated anemia?
RBC transfusion therapy for the anemia of CKD in the pre-ESA era was associated with the
transmission of bloodborne infections, iron overload, and sensitization for future kidney
transplantation. Despite the controversies regarding the risk versus benefits of ESA therapy, there is
no dispute that ESAs decrease RBC transfusion requirements, and far fewer patients receiving ESAs
require RBC transfusions than patients not receiving ESAs. Nonetheless, RBC transfusions are
occasionally required in patients with anemia and CKD, despite the use of ESA and iron therapy,
especially in the setting of acute blood loss.
25. What Hb level should trigger transfusion in a CKD patient?
Because RBC transfusions carry the risk of sensitization for future kidney transplantation, they should
be used judiciously in patients with CKD, especially those who are transplant candidates. There is no
single Hb or Hb range that is considered a trigger for RBC transfusions in patients with CKD based on
current practice guidelines, although most practitioners will transfuse patients with Hb ,7 g/dL. It
should be pointed out that the Hb target/trigger for transfusion is not the same as the Hb target range
for ESA therapy.

KEY PO I N T S
1 . The anemia of chronic kidney disease (CKD) is primarily caused by deficiency of erythropoietin.
2. Many patients with CKD not receiving hemodialysis and most patients receiving hemodialysis are
iron deficient and require iron supplementation.
3. Because higher target hemoglobin levels and higher erythropoiesis-stimulating agent (ESA) doses
have been associated with adverse outcomes, the FDA recommends using the smallest ESA dose
sufficient to reduce the need for red blood cell transfusions.
4. Biosimilar ESAs and hypoxia-inducible factor prolyl hydroxylase inhibitors may be promising alter-
natives to anemia treatment with “originator” ESAs.

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