Pediatr Nephrol
DOI 10.1007/s00467-016-3555-6
EDUCATIONAL REVIEW
Anemia in nephrotic syndrome: approach
to evaluation and treatment
Franca Iorember 1 & Diego Aviles 1
Received: 5 October 2016 / Revised: 22 November 2016 / Accepted: 29 November 2016
# IPNA 2016
Abstract Nephrotic syndrome is one of the most common
glomerular diseases that affect in children. Complications
may occur in nephrotic syndrome as a result of the disease
itself as well as its treatment. Most of these complications
result from excessive urinary protein losses, and control
of proteinuria is the most effective treatment strategy.
Anemia is one of the many complications seen in patients
with persistent nephrotic syndrome and may occur as a
result of excessive urinary losses of iron, transferrin,
erythropoietin, transcobalamin and/or metals. This leads
to a deficiency of substrates necessary for effective eryth-
ropoiesis, requiring supplementation in order to correct
the anemia. Supplementation of iron and erythropoietin
alone often does not lead to correction of the anemia,
suggesting other possible mechanisms which need further
investigation. A clear understanding of the pathophysio-
logic mechanisms of anemia in nephrotic syndrome is
necessary to guide appropriate therapy, but only limited
evidence is currently available on the precise etiologic
mechanisms of anemia in nephrotic syndrome. In this re-
view we focus on the current state of knowledge on the
pathogenesis of anemia in nephrotic syndrome.
Keywords Anemia in nephrotic syndrome . Erythropoiesis .
Erythropoietin deficiency . Iron hemostasis . Proteinuria
* Diego Aviles
DAvile@lsuhsc.edu
1
Division of Pediatric Nephrology, Department of Pediatrics,
Louisiana State University Health Sciences Center, 200 Henry Clay
Avenue, Rm 4241, Now Orleans, LA 70118, USA
Introduction
Children with nephrotic syndrome are prone to a number of
complications, including infections, thromboembolism, endo-
crine, mineral and bone disorders, anemia, intravascular vol-
ume depletion, acute kidney injury and complications associ-
ated with immunosuppression therapy. Much of the morbidity
in nephrotic syndrome is due to the significant loss of plasma
proteins of various molecular weights in the urine, including
albumin, coagulation factors, immunoglobulins, transferrin,
erythropoietin and hormone-binding proteins (Table 1).
Trace minerals and micronutrients are also lost in this process.
Taken together, these losses lead to significant alterations in
the plasma concentrations of these proteins and minerals [1,
2]. Although data on the prevalence of anemia in patients with
nephrotic syndrome is limited, available information suggest
that anemia may be a frequent complication in these patients.
Feinstein and his group showed a prevalence of 59% in their
study population [3], with most of the patients with anemia
having steroid-resistant nephrotic syndrome. This result is
consistent with the experience at our center where approxi-
mately 28% of our population of patients with nephrotic syn-
drome have had anemia during the course of their disease
(unpublished data). A common denominator in these anemic
patients is the persistent or therapy-resistant nature of their
nephrotic syndrome. Although the pathophysiologic mecha-
nisms of anemia of chronic kidney disease are well established
[4, 5], the mechanisms of anemia in nephrotic syndrome in the
setting of normal renal function are complex and incompletely
understood [6]. Experience in our center has shown that the
correction of anemia in patients with persistent or therapy-
resistant nephrotic syndrome and normal kidney function
can be challenging, despite adequate iron and erythropoietin
supplementation, suggesting the involvement of multiple eti-
ologic mechanisms in these patients. While some mechanisms

Table 1 Molecular weight of
some of the proteins and Proteins/micronutrients
substances excreted in the urine of
patients with nephrotic syndrome
Albumin
Transferrin
Soluble transferrin
receptor
Ceruloplasmin
Transcobalamin I
Transcobalamin II
Vitamin B12
Erythropoietin
Immunoglobulin G
Retinol-binding protein
Beta-2 microglobulin
Alpha-1 microglobulin
have been defined and available evidence is compelling, other
proposed etiologic factors have yet to be clearly elucidated.
Currently, only limited data on the pathophysiologic mecha-
nisms of anemia in nephrotic syndrome are available, and
clearly more research needs to be done to better define these
mechanisms.
Normal iron homeostasis and erythropoiesis
Iron plays a crucial role in erythropoiesis, and its deficiency
leads to anemia. In the normal healthy adult, recycled iron
from aged erythrocytes, a process driven by macrophages, is
the major source of iron for erythropoiesis (approximately 15–
25 mg/day), with a minimal contribution from intestinal ab-
sorption [7, 8] (Fig. 1). Whole body iron is primarily regulated
at the level of absorption by enterocytes, and the major iron
storage organs in the body are the liver and spleen, where iron
is stored in macrophages and hepatocytes in the form of ferri-
tin [7–9]. Iron is released from storage cells into plasma
through an exporter called ferroportin, a transmembrane pro-
tein located on the surface of these cells [10]. The major reg-
ulator of iron transport in the body is hepcidin, a 2.7-kDa
peptide containing 25 amino acids. Hepcidin is synthesized
by hepatocytes and secreted into the plasma where it circulates
freely, eventually being excreted by the kidneys [7]. Hepcidin
regulates systemic iron homeostasis by causing internalization
and degradation of ferroportin (Fig. 2), thus inhibiting dietary
iron absorption in the small intestine, recycling of iron from
aged erythrocytes by macrophages and iron mobilization from
hepatic stores [9–11]. Of the 3–4 g of iron present in the
average adult body, only 2–4 mg is present in the plasma at
any given time, mostly bound to the iron transport protein
Pediatr Nephrol
Molecular weight Comment
(Da)
69,000 The most abundant protein in plasma
80,000 Transports iron in plasma
74,000 Plasma levels elevated in iron deficiency
132, 000 Transports copper in plasma
120,000 Binds vitamin B12 in plasma
36,000 Transports vitamin B12 in plasma
1,355 A non-protein micronutrient
30,400 Necessary for erythropoiesis
150,000 The smallest immunoglobulin
21,000 Transports vitamin A alcohol from liver to peripheral
tissues
11,000 Low molecular weight protein
26,000 Low molecular weight protein
transferrin [8, 9]. Iron is transported to the bone marrow bound
to transferrin and is then taken up by erythrocyte precursors
for erythropoiesis, a process facilitated by erythropoietin.
Erythropoietin is a glycoprotein produced mainly by
peritubular fibroblasts in the kidney, although hepatocytes
are the major sites of production in the fetus and neonate
[12]. Erythropoietin circulates in plasma with a plasma half-
life of 7–8 h and binds to high-affinity receptors present on the
surface of erythroid progenitor cells in the bone marrow. This
binding allows the maturation of these precursor cells into
erythrocytes [12, 13].
Mechanisms of anemia in nephrotic syndrome
Altered iron and transferrin homeostasis
Iron deficiency anemia has been reported in both adult and
pediatric patients with nephrotic syndrome. This type of ane-
mia has been attributed to increased urinary losses of iron and
transferrin in nephrotic syndrome, as demonstrated by several
studies [14–17]. Iron is lost into the urine bound to transferrin,
and it remains bound to transferrin in alkaline urine, eventu-
ally to be excreted in this state. In an adult case series by
Brown et al. [15], six of nine patients with nephrotic syndrome
demonstrated increased urinary losses of iron as measured by
the Ferene-S assay. Ferene-S is a chromogenic substrate
which reacts with iron in serum or urine (in its ferrous form)
to produce a stable colored complex which gives an absor-
bance at 593 nm. This assay has been shown to be sensitive for
the determination of iron [18]. Of these six patients with in-
creased urinary iron losses, only two developed iron deficien-
cy anemia, and iron supplementation resulted in resolution of
Pediatr Nephrol

Fig. 1 Major iron (Fe) flows and

their regulation by hepcidin and
ferroportin (Fpn). Blue Iron
bound to the iron transport protein
transferrin (Tf), red iron taken up
by erythrocytes. Hepcidin
controls the iron flow into plasma
by inducing endocytosis and
proteolysis of the iron exporter
Fpn (brown). Reproduced from
Ganz [7], with permission of the
American Physiological Society

the anemia. Of note, these latter two patients had long-
standing membranous nephropathy of about 4–5 years dura-
tion while the others had been nephrotic for only a few months
[15]. This result suggests that duration of disease might be an
important factor in the development of iron deficiency anemia
in nephrotic syndrome. Urinary transferrin loss by itself is a
possible mechanism for the development of anemia in patients
with nephrotic syndrome, and these losses have been shown to
correlate with total urinary protein loss in both pediatric and
adult studies [14, 19–22]. This loss is often accompanied by
low serum transferrin levels. The body’s response to low se-
rum transferrin levels is to increase the hepatic synthesis of
transferrin and to upregulate the soluble transferrin receptor.
Unfortunately, this response by the liver is inadequate to
replace urinary losses in patients with active nephrotic syn-
drome [21]. Consequently, normalization of serum transferrin
levels is only achieved with control of the proteinuria. In chil-
dren with steroid-sensitive nephrotic syndrome and increased
urinary transferrin loss, soluble transferrin receptor levels have
been shown to be elevated, similar to what occurs in iron
deficiency anemia [23]. This upregulation of the soluble trans-
ferrin receptor has been proposed as a mechanism to prevent
the development of iron deficiency anemia [24]. The role of
the soluble transferrin receptor in the prevention of iron defi-
ciency anemia in nephrotic syndrome is not clear and needs
further investigation. Increased knowledge may provide an
additional tool in aiding the diagnosis of iron deficiency ane-
mia and monitoring erythropoietic activity [25].

Fig. 2 Hepcidin downregulates

ferroportin expression on the cell
surface. Ferroportin (FPN) is
expressed on the surface of
enterocytes, hepatocytes and
tissue macrophages. The binding
of hepcidin to FPN leads to its
phosphorylation, internalization
and degradation. Low levels of
FPN expression reduce iron
absorption in the gut, lower iron
release from the liver and prevent
iron recycling by tissue
macrophages. Reproduced from
Cui et al. [10], with permission of
Elsevier

Urinary losses of erythropoietin
The role of erythropoietin in the development of anemia
in children with nephrotic syndrome and normal kidney
function was investigated by Feinstein et al. [3] who mea-
sured serum erythropoietin levels, iron status and vitamin
B12 concentrations in 32 children with nephrotic syn-
drome and compared the obtained values between ne-
phrotic children with anemia (n = 19) and nephrotic chil-
dren without anemia (n = 13). These patients were also
compared against two sets of controls comprising normal
healthy children and children with iron deficiency anemia
without kidney disease. Interestingly, nephrotic patients
with anemia were resistant to immunosuppressive therapy,
while those without anemia were steroid sensitive. In gen-
eral, nephrotic children demonstrated low erythropoietin
levels compared to children without kidney disease. In
those with nephrotic syndrome, erythropoietin levels were
more elevated in children who had anemia than in those
who did not have anemia. The erythropoietin levels in
nephrotic children with anemia were, however, inappro-
priately low compared to controls who had iron deficien-
cy anemia without kidney disease [3]. The administration
of erythropoietin to nephrotic patients with anemia (with
concomitant iron supplementation) led to significant im-
provement in hemoglobin levels, with no adverse effects
experienced by the patients. The blunted response seen in
those patients with nephrotic syndrome could partly be
attributable to the increased urinary losses of erythropoi-
etin, as has been demonstrated in both animal and human
studies [22, 26–28]. Erythropoietin has a molecular
weight of 30.4 kDa, less than half the weight of albumin
[29], and urinary losses of erythropoietin are expected to
be significant in nephrotic syndrome. Thus, erythropoietin
deficiency should always be considered to be a contribut-
ing factor to the development of anemia in nephrotic
patients.
The role of metals and drugs
Copper plays a significant role in erythropoiesis, and its
deficiency is known to be associated with anemia and
other hematological abnormalities [30, 31]. Copper serves
as a cofactor in many enzymatic reactions in the body. In
the mitochondria, it acts as a cofactor to cytochrome c
oxidase, a terminal enzyme in the mitochondrial respira-
tory chain [32]. Copper deficiency leads to the appearance
of enlarged mitochondria in erythropoietic cells, ineffec-
tive erythroid differentiation and hypochromic microcytic
anemia [33–35]. Urinary losses of ceruloplasmin, a cop-
per carrier protein in plasma, can lead to copper deficien-
cy and consequent anemia in children with nephrotic syn-
drome. Supplementation of copper in these patients leads
Pediatr Nephrol
to correction of the anemia [22, 36]. Copper deficiency
should be considered in patients with therapy-resistant
anemia, and measurement of serum copper levels should
be performed to exclude this possibility.
The association between the use of angiotensin
converting enzyme inhibitors (ACEIs) and anemia in pa-
tients with renal disease is well established. The use of
ACEIs in renal transplant recipients is known to be asso-
ciated with the development of anemia, which makes
these drugs useful for the treatment of erythrocytosis in
these patients [37, 38]. Close monitoring of hematologic
parameters in patients treated with ACEIs is advised [39].
ACEIs have an inhibitory effect on erythropoiesis by
lowering circulating erythropoietin levels, which can
cause or exacerbate anemia. The role of ACEIs as a po-
tential cause of anemia in patients with nephrotic syn-
drome with normal kidney function is unknown and
needs to be investigated. The immunosuppressant drug
mycophenolate mofetil has broad antiproliferative effects,
and its use has been linked to severe anemia as a result of
bone marrow suppression [40]. Discontinuation of this
drug in patients with nephrotic syndrome who develop
anemia should be considered if no clear etiology for the
anemia is identified.
Vitamin B12 deficiency
Vitamin B12 (also called cobalamin) is a non-protein or-
ganic compound that serves as a cofactor in the formation
of methionine from homocysteine and the interconversion
of methylmalonyl-CoA to succinyl-CoA in the body. It is
absorbed from the gut in the form of vitamin B12–intrinsic
factor complex and is transported in plasma bound to the
protein transcobalamin [41]. Cubulin, a peripheral mem-
brane protein, is a vitamin B12–intrinsic factor complex
receptor that is necessary for the gastrointestinal absorp-
tion of vitamin B12 and reabsorption of filtered proteins in
the proximal tubule of the kidney through a process driven
by endocytosis. Mutation of the cubulin gene (CUBN) has
been shown to be associated with megaloblastic anemia
and increased urinary protein excretion [42, 43]. The role
of vitamin B12 in erythropoiesis is well established, and
its deficiency is known to cause impaired DNA synthesis
and premature death of hematopoietic cells prior to their
maturation, leading to acquired megaloblastic anemia [31,
44]. Significant losses of transcobalamin and vitamin B12
in the urine of children with nephrotic syndrome concom-
itant with corresponding decreased serum levels of vita-
min B12 have been described [3, 22, 45]. How much im-
pact these urinary losses have on the development of ane-
mia in these children is not clear and needs further clari-
fication. It is also currently not known if mutation of
CUBN plays any role to play in this process.
Pediatr Nephrol

Diagnostic considerations B12 deficiency, followed by measurement of plasma

Any investigation of the cause of anemia in patients with ne-
phrotic syndrome should follow existing guidelines. The initial
evaluation should include a complete blood count, reticulocyte
count, peripheral smear, serum iron, total iron binding capacity,
transferrin saturation, transferrin and ferritin levels. The reticulo-
cyte count is the best laboratory marker of effective erythropoi-
esis, and levels are expected to be low in anemia due to deficien-
cies in erythropoietin, iron, vitamin B12, folate and copper. A
low mean corpuscular volume (MCV) would suggest iron defi-
ciency anemia, in which case serum iron, ferritin and transferrin
saturation would be expected to be low. A macrocytic anemia,
suggested by an elevated MCV, warrants laboratory testing for
vitamin B12 and folate deficiency [46]. Measurement of plasma
cobalamins is suggested as the primary analysis test for vitamin
methylmalonic acid in undetermined cases [47]. It is reasonable
to consider measuring vitamin B12 and folate levels at the initial
evaluation even in patients with normal MCV, since coexistent
iron and vitamin B12 deficiencies have been reported [48].
Although erythropoietin levels are not routinely measured in
clinical practice, it is reasonable to measure serum and urinary
erythropoietin concentrations in patients with nephrotic syn-
drome who are anemic and who do not show improvement of
anemia with iron supplementation. Serum and urine erythropoi-
etin concentrations can be measured by radioimmunoassay or
enzyme-linked assay [49]. Ceruloplasmin and copper deficiency
should also be suspected in therapy-resistant cases, and copper
levels should be measured is such patients. An algorithm is pre-
sented in Fig. 3 to assist clinicians with evaluation of anemia in
nephrotic syndrome.

Fig. 3 Algorithm for anemia Obtain serum iron, ferrin, TIBC,

management in nephrotic Transferrin, reculocyte count
syndrome. TIBC Total iron
binding capacity

Normal iron studies, low

Iron deficiency anemia reculocyte count

Iron supplementaon Obtain serum erythropoien

levels

Improvement of anemia
aer two weeks No Low serum Erythropoien
levels

Yes No
Yes

Connue management, Obtain serum

monitor reculocyte count Start Erythropoien.Assess
copper, folate and
responseinfourweeks
vitamin B12 levels

Serum copper,
folate or vitamin
B12 levels low
No

Start copper
Yes Reculocytosis aer gluconate, folate
two weeks of therapy and/or vitamin B 12
supplementaon

Treatment strategies
Successful correction of anemia in nephrotic syndrome de-
pends on the evaluation for the underlying causes being ap-
propriate. We recommend close monitoring of the reticulocyte
count as a marker of erythropoiesis and response to therapy.
Iron deficiency anemia should be treated with iron supplemen-
tation. Improvement in hemoglobin levels after 2 weeks of
iron supplementation is a good predictor of long-term treat-
ment response to oral iron therapy [50]. A trial of erythropoi-
etin therapy should be considered in patients with anemia who
demonstrate low or normal serum erythropoietin levels since
massive urinary losses are expected in persistent nephrotic
syndrome. The efficacy and safety of recombinant human
erythropoietin in the treatment of anemia in nephrotic syn-
drome is well established in both children and adults [3, 6].
An interval of 4 weeks is reasonable for assessment of re-
sponse after initiation of therapy. Persistent anemia despite
iron and erythropoietin therapy requires further evaluation
for other possible contributing factors, such as copper or vita-
min B12 deficiency. Copper deficiency should be treated by
supplementation with copper gluconate. Vitamin B12 defi-
ciency can be treated with oral multivitamins containing vita-
min B12. Subcutaneous or intramuscular injections of vitamin
B12 can be considered in severe cases or in patients with poor
response to oral therapy. Reticulocytosis after 1–2 weeks of
administration is an indication of response to copper or vita-
min B12 therapy [51, 52].
Summary
Severe anemia can occur in children with nephrotic syndrome.
Although the pathogenesis of anemia in nephrotic syndrome
is complex and incompletely understood, the mechanisms are
likely to be similar to known causes of anemia, such as iron,
erythropoietin, folate and vitamin B12 deficiency. Other
mechanisms are likely to play a role. The correction of anemia
in these patients can be challenging, and knowledge of all
possible underlying pathophysiologic mechanisms is neces-
sary to allow for adequate evaluation and successful treatment.
The role of soluble transferrin receptor upregulation as a
mechanism of anemia prevention in nephrotics with transfer-
rin deficiency also deserves further attention.
Multiple-choice questions (answers can be found
in the backmatter following the references):
1. Which of the following is the major source of iron for
erythropoiesis?
a) Iron absorbed from the gastrointestinal tract
Pediatr Nephrol
b) Iron stored in the liver and spleen
c) Iron released from aged red blood cells
d) Bone marrow
e) Newly formed erythrocytes
2. Hepcidin regulates systemic iron homeostasis by which of
the following processes?
a) Binding of iron in plasma and excretion through the
kidneys
b) Inhibition of ferritin formation
c) Inhibition of iron entry into the bone marrow
d) Internalization and degradation of ferroportin
e) Prevention of iron storage in macrophages
3. Which of the following is a pathophysiologic mechanism
of anemia in nephrotic syndrome include:
a) Increased urinary losses of transferrin and iron
b) Decreased production of transferrin
c) Downregulation of the soluble transferrin receptor
d) Increased urinary losses of free hemoglobin
e) Erythropoietin resistance
4. Which of the following is true of the role of drugs and
metals in the etiology of anemia in nephrotic syndrome?
a) Copper deficiency is not associated with any morpho-
logical changes in erythropoietic cells
b) Copper deficiency is difficult to treat in patients with
nephrotic syndrome
c) The use of ACEIs is not associated with anemia in
patients with kidney disease
d) The effect of ACEIs on erythropoiesis is unknown
e) ACEIs may cause anemia by lowering circulating
levels of erythropoietin and inhibiting erythropoiesis
in the process
5. Of anemia in nephrotic syndrome, which of the following
statements is correct?
a) Anemia is always corrected by iron and erythropoie-
tin supplementation
b) Patients with steroid-sensitive nephrotic syndrome
are more likely to develop iron deficiency anemia
c) Anemia does not occur in patients with nephrotic
syndrome and normal kidney function
d) The use of erythropoietin should be considered only
when plasma erythropoietin levels are low
e) The pathophysiologic mechanisms are likely multi-
factorial and incompletely understood
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Pediatr Nephrol
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Pediatr Nephrol
Answers to multiple-choice questions
1: c. Recycled iron from senescent erythrocytes is the major source of
iron used for erythropoiesis with little contribution from intestinal
absorption or any other sources.
2: d. Hepcidin regulates systemic iron homeostasis by causing the
internalization and degradation of ferroportin, resulting in decreased
iron absorption in the small intestine, recycling of iron from aged
erythrocytes and iron mobilization from storage sites.
3: a. Anemia in nephrotic syndrome can result from excessive urinary
losses of iron bound to transferrin and erythropoietin. This is most likely
to occur in patients with persistent or treatment-resistant nephrotic syn-
drome. Other mechanisms may also be responsible.
4: e. Copper deficiency leads to the appearance of enlarged
mitochondria in erythropoietic cells which can lead to ineffective
erythropoiesis. Copper gluconate supplementation is effective in
treating copper deficiency. The use of ACEIs has been associated with
anemia in renal transplant patients. ACEIs may cause anemia by lowering
circulating levels of erythropoietin and inhibiting erythropoiesis in the
process.
5: e. The pathophysiologic mechanisms of anemia in nephrotic
syndrome are complex and incompletely understood. Anemia is more
likely to occur in patients with therapy-resistant, long-standing nephrotic
syndrome and in the context of normal kidney function. Supplementation
of iron and erythropoietin does not always lead to resolution of the ane-
mia. Erythropoietin supplementation should be considered even in pa-
tients with normal plasma erythropoietin levels.