SCIENCE IN RENAL MEDICINE

www.jasn.org

Mechanisms of Anemia in CKD

Jodie L. Babitt and Herbert Y. Lin
Program in Anemia Signaling Research, Nephrology Division, Program in Membrane Biology, Center for Systems
Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

ABSTRACT
Anemia is a common feature of CKD associated with poor outcomes. The
current
management of patients with anemia in CKD is controversial, with recent
clinical
trials demonstrating increased morbidity and mortality related to
erythropoiesis
stimulating agents. Here, we examine recent insights into the molecular
mechanisms underlying anemia of CKD. These insights hold promise for the
development
of new diagnostic tests and therapies that directly target the
pathophysiologic
processes underlying this form of anemia.
J Am Soc Nephrol 23: 1631 1634, 2012. doi: 10.1681/ASN.2011111078

Anemia was rst linked to CKD

over
170 years ago by Richard Bright.
As kidney disease progresses, anemia
increases
in prevalence, affecting nearly all
patients with stage 5 CKD. Anemia
in
CKD is associated with reduced
quality
of life and increased
cardiovascular disease, hospitalizations, cognitive
impairment, and mortality.
AnemiainCKD
istypicallynormocytic,
normochromic, and
hypoproliferative.
The demonstration of a
circulating factor responsible for stimulating
eryth-

immunogenic EPO fragments,

which
do not all correlate with biologic
activity.
Anemia management was
revolutionized in the late 1980s with the
introduction of recombinant human EPO.
This
and related erythropoiesis
stimulating
agents (ESAs) greatly beneted
patients
by improving their debilitating
symptoms, and freeing them from
dependence
on blood transfusions with
theirassociated
complications (secondary iron
overload,
infections, and sensitization
impeding

analyses of these studies suggest that

elevated hemoglobin per se does not
confer the increased risk, but rather higher
doses of ESAs and relative resistance
to
ESAs, although this has not been studied directly. In addition, ESAs have
been associated with increased
progression of malignancy and death in cancer
patients.
Why would ESAs have these adverse
effects? Although relative EPO deciency may contribute to the anemia of
CKD, it is not the sole cause. Indeed,
anemia of CKD is resistant to ESAs in
approximately 10%20% of patients. It
seems likely that supraphysiologic
doses
of ESAs, especially at very high doses
or
in patients resistant to treatment, have
off-target effects in other tissues.
These
ndings have renewed interest in
understanding the molecular mechanisms of
anemia in CKD, with the hope of developing new therapies that more closely
target the underlying pathophysiology

ropoiesis, and the kidney as the transplantation). However, even of low hemoglobin.
main
in
source of erythropoietin (EPO) in the initial studies, adverse effects Aside from EPO deciency, what else
the
were
1950s engendered the hypothesis noted in patients receiving ESAs, contributes to the anemia of CKD?
that
includEPO deciency is a predominant ing worsening hypertension,
Numerous studies suggest that circucause
seizures, and
of anemia in CKD. Purication and dialysis access clotting. In
lating uremic-induced inhibitors of
addition,
cloning of EPO in the late 1970s ESAs do not reduce adverse
erythropoiesis contribute to the
and
outcomes asanemia,
1980s enabled the development sociated with anemia, such as
although this has been disputed in
of
mortality,
some
immunologic assays for
nonfatal cardiovascular events, left venquantitating
levels of circulating EPO. Althoughtricular hypertrophy, hospitalizations,
Published online ahead of print. Publication date
generally normal or slightly
and progression of kidney
available at www.jasn.org.
increased
disease, in
in anemia of CKD, EPO levels are prospective randomized
concontrolled triCorrespondence: Dr. Jodie L. Babitt or Dr. Herbert
sidered inappropriately low
als. In fact, recent trials in both
relative to
hemoY. Lin, Massachusetts General Hospital, 185 Camthedegreeofanemia,becausesimil dialysis and predialysis CKD
bridge Street, CPZN-8208, Boston, MA 02114.
arly
patients
Email: babitt.jodie@mgh.harvard.edu or lin.heranemic patients with normal
demonstrate an increased risk of
kidney funcdeath,
bert@mgh.harvard.edu
tion have 10100 times higher
adverse cardiovascular events,
EPO levand stroke
els. One important limitation of
by administering ESAs to target Copyright 2012 by the American Society of
Nephrology
such assays is that they measure hemoglobin
levels
.11
g/dl.
Secondary
all

J Am Soc Nephrol 23: 16311634, 2012

SCIENCE IN RENAL MEDICINE www.jasn.org

studies and no specic inhibitors

have
been identied. Shortened red
blood
cell survival also contributes, as
demonstrated by radioisotope labeling
studies. Although the etiology is not
entirely clear, metabolic and
mechanical
factors have been proposed.
Nutritional deciencies, such as folate
and vitamin B , due to anorexia or
dialysate
12
losses are currently uncommon
with the

ISSN : 1046-6673/2310-1631 1631

hemodialysis patients, also have

impaired dietary iron absorption.
Indeed,
oral iron was no better than
placebo and
was less effective than
intravenous iron
at improving anemia, improving
or preventing iron deciency, or
reducing ESA
dose in hemodialysis patients. In

reticuloendothelial macrophages, and

addition, many CKD patients

receive
ESAs, which deplete the
circulating
iron pool by increasing
erythropoiesis.

and anemia that are hallmarks of many

hepatocytes to inhibit iron entry into

the plasma. Inammatory cytokines
directly induce hepcidin transcription,
presumably as a mechanism to
sequester
iron from invading pathogens, leading
to
the iron sequestration, hypoferremia,

chronic diseases including CKD.

The development of assays to mea-

routine use of supplementation in Thus, CKD patients are prone to sure bioactive hepcidin in the last 23
hemotrue
dialysis patients. Whereas
iron deciency, and iron
years has ignited a profusion of studies
hemodialysis
supplementation
patients historically developed
is part of mainstay of anemia
investigating the role of hepcidin
secondary
treatment
excess
iron overload from recurrent
in CKD. Intravenous iron is
in the anemia of CKD. Numerous studblood transpreferred for
fusions, the modern era of ESA
hemodialysis patients because of ies now show that hepcidin is elevated
treatment
imin
has uncovered an increasingly
paired dietary iron absorption.
CKD patients. Mechanisms sugrecognized
role for disordered iron homeostasis In addition to true iron
gested to account for this are increased
as a
deciency,
major contributor to the anemia many CKD patients have
expression by inammatory cytokines
of CKD.
functional
Based on its ability to donate iron deciency, characterized by and reduced renal clearance.
and accept
imelectrons, iron is essential for
paired iron release from body
Studies are ongoing to determine
many imstores
whether
portant biologic reactions,
that is unable to meet the
hepcidin measurement will have
including oxdemand for
diagnosygen transport, cellular
erythropoiesis (also called
tic utility in CKD patients regarding iron
respiration, and
reticuloendoDNA synthesis. However, this
thelial cell iron blockade). These status, inammatory status, or ESA resame proppatients
erty makes excess iron toxic by have low serum transferrin
sponsiveness or resistance.
generating
saturation (a
Complicating
free radicals that can damage or measure of circulating iron) and factors are the lack of uniformity in
destroy
normal
hepcells. Systemic and cellular iron or high serum ferritin (a marker of cidin measurements by different
levels
assays,
must therefore be tightly
body iron stores). Some of these and the complex interplay of various
regulated. The
patients
facmajority of iron (2025 mg) is
are treated with intravenous iron, tors that inuence hepcidin levels in
provided
a trend
CKD
by recycling from senescent red that seems to be increasing with patients, including iron, inammation,
blood
the
cells, which are phagocytosed by recent controversy surrounding
and reduced renal clearance that tend
reticuESAs.
to
loendothelial macrophages to
However, for patients with high increase hepcidin, and anemia, ESAs,
store iron
serum
diuntil it is needed, with lesser
ferritin $500800 ng/ml,
alysis clearance, and hypoxia that tend
amounts
management
to
provided by dietary absorption in is less clear. Concerns about
reduce hepcidin.
the dutreating
odenum (12 mg) and release
these patients with iron include poor Recognition of a key role for hepcidin
from liver
efstores. Plasma iron, which
fectiveness and the potential for excess in causing the functional iron
circulates
adverse
debound to transferrin, is relatively effects, including oxidantciency and anemia of CKD has ignited
limited
mediated tisat 3 mg, and therefore must be
sue injury from excess iron
interest in targeting the hepcidinturned
deposition
ferroportin
over several times to meet the
and increased risk of infection.
axis as a new treatment strategy for
daily reOne limthis
quirements for erythropoiesis.
itation is that high serum ferritin disease. By blocking hepcidin and/or
With no
is not

regulated mechanism for iron

specic for increased body iron
removal,
stores
typical iron losses are 12mgdaily, because ferritin is also affected
by infecmainly from intestinal and skin
tion, inammation, liver disease,
cell shedand
ding and menstruation in
malignancy.
reproductiveagewomen.Systemicironbalanceis Recent data suggest that
hepcidin extherefore maintained by
cess may account for the
regulating dietary
impaired dietary
iron absorption and iron release iron absorption and
from
reticuloendothelial
storage sites in the liver and
cell iron blockade present in
reticuloendomany CKD
thelial macrophages.
patients. Discovered
independently by
CKD patients have increased
three groups in 20002001,
iron
hepcidin
losses, estimated at 13 g per
is the main hormone responsible
year in hefor
modialysis patients, due to
maintaining systemic iron
chronic
homeostableeding from uremia-associated sis. Produced by the liver and
platesecreted
let dysfunction, frequent
into circulation, hepcidin binds
phlebotomy,
and
and blood trapping in the dialysis induces degradation of the iron
appaexporter,
ratus. CKD patients, particularly ferroportin, on duodenal
enterocytes,

1632

Journal of the American Society of Nephrology

increasing ferroportin activity, these

agents could improve dietary iron absorption and iron mobilization from the
patients own body stores, thereby
minimizing the need for supraphysiologic
doses of intravenous iron and ESAs
with their potential adverse effects. Importantly, in CKD patients with hepcidin
excess, large intravenous boluses of
iron
would be predicted to have limited
effectiveness because much of the iron is
rapidly taken up by the liver and
sequestered,
and the remainder that is incorporated
into red blood cells would be recycled
ineffectively. In addition, intravenous iron
itself would further increase in hepcidin

J Am Soc Nephrol 23: 16311634, 2012