The Official Journal of the

National Kidney Foundation

VOL 38, NO 1, JULY 2001

AJKD
IN-DEPTH REVIEW
American Journal of
Kidney Diseases

Erythropoietin and Transferrin Metabolism in Nephrotic Syndrome

Nosratola D. Vaziri, MD

● Nephrotic syndrome is characterized by marked urinary excretion of albumin and other intermediate-size plasma
proteins. This results in a profound alteration of the metabolism of many plasma proteins and protein-bound
substances, as well as certain cellular and tissue proteins. This review summarizes available data on the effect of
nephrotic syndrome on the metabolism and regulation of erythropoietin (EPO) and transferrin, which are essential
for erythropoiesis. Studies of humans and animals have documented significant urinary losses of both EPO and
transferrin in nephrotic syndrome. Urinary losses of EPO have been shown to cause EPO-deficiency anemia and
prevent the normal increase in plasma EPO level in response to anemia and hypoxia in nephrotic syndrome.
Similarly, transferrinuria and increased transferrin catabolism have been shown to cause hypotransferrinemia and,
in some cases, iron-deficiency anemia. In addition, dissociation of iron from filtered transferrin, occasioned by a
reduction in tubular fluid pH, can promote tubulointerstitial injury through the iron-catalyzed generation of oxygen
free radicals. This can account in part for the role of proteinuria as a risk factor for the progression of renal disease.
Subcutaneous administration of recombinant EPO has been successfully used in the management of EPO-
deficiency anemia in nephrotic syndrome. Similarly, iron supplementation and nutritional support are indicated in
nephrotic patients with severe transferrinuria and iron-deficiency anemia. However, correction or amelioration of
the underlying proteinuria, when possible, is the ideal approach to reversal of these complications.
© 2001 by the National Kidney Foundation, Inc.

INDEX WORDS: Nephrotic syndrome; proteinuria; iron deficiency; anemia; erythropoietin (EPO); transferrin.

H EAVY GLOMERULAR proteinuria is the

defining feature of nephrotic syndrome. In
addition to albumin, many other intermediate-
size proteins are lost in the urine of humans and
animals with nephrotic syndrome. Excessive uri-
nary losses can potentially reduce plasma concen-
trations and produce a deficiency of the given
proteins. In addition, the associated salt and
water retention and volume expansion can signifi-
cantly alter the volume of distribution of most
proteins in nephrotic syndrome. In this regard,
the volume of distribution of small- to intermedi-
ate-size proteins that have substantial extravascu-
lar distributions increases, whereas that of macro-
molecular species with minimal extravascular
distribution can diminish or remain unchanged.
Moreover, rates of biosynthesis and catabolism
may increase for some proteins and decline for
others. Thus, nephrotic syndrome can potentially
change plasma concentrations of proteins by
causing urinary losses, as well as altering their
distribution, catabolism, and biosynthesis. For
example, urinary losses and depressed plasma
concentrations of various hormones, hormone-
binding proteins, coagulation proteins, fibrino-
lytic factors, immunoglobulins, enzymes, and
metal-binding proteins have been shown in ne-
phrotic humans or animals.1-14 This article re-
views available data on the effects of nephrotic
From the Departments of Medicine, Physiology, and Bio-
physics, Division of Nephrology and Hypertension, Univer-
sity of California, Irvine, CA.
Received September 19, 2000; accepted in revised form
December 22, 2000.
Address reprint requests to Nostratola D. Vaziri, MD,
Division of Nephrology and Hypertension, UCI Medical
Center, 101 The City Dr, Orange, CA 92868. E-mail:
ndvaziri@uci.edu
© 2001 by the National Kidney Foundation, Inc.
0272-6386/01/3801-0001$35.00/0
doi:10.1053/ajkd.2001.25174

American Journal of Kidney Diseases, Vol 38, No 1 (July), 2001: pp 1-8 1

2 NOSRATOLA D. VAZIRI
syndrome on the metabolism of erythropoietin
(EPO) and transferrin, which have a vital role in
erythropoiesis.
EPO
Production, Regulation, and Actions of EPO
EPO is a glycoprotein (molecular weight, 30.4
kd) that consists of a single strand of 165 amino
acids and a large carbohydrate moiety. EPO is
the product of the EPO gene, which resides on
chromosome 7.15 EPO production is markedly
increased by hypoxia, anemia, ascent to high
altitudes, and certain hemoglobinopathies, condi-
tions known to limit oxygen delivery to EPO-
producing cells.16 Upregulation of EPO produc-
tion by hypoxia recently has been shown to be
mediated by a hypoxia-inducible factor (HIF-1)
produced by many different cell types after expo-
sure to hypoxia. HIF-1 serves as a general tran-
scription factor for a number of hypoxia-induced
genes, including vascular endothelial growth fac-
tor, platelet-derived growth factor, and numerous
glycolytic enzymes.17 HIF-1 binds to an oxygen-
sensitive enhancer sequence located immedi-
ately downstream from the EPO gene.18,19 Thus,
HIF-1 serves as a transcription factor for EPO.
EPO messenger RNA (mRNA) has been found
in interstitial cells (possibly transformed fibro-
blasts) located near the base of proximal tubular
epithelial cells in the renal cortex.20 EPO gene
transcription in these cells occurs in an all-or-
none manner. Consequently, the rate of EPO
production at any given time depends on the
number of cells expressing EPO mRNA.21 The
precise manner by which hypoxia is sensed and
the EPO gene is activated is not certain. How-
ever, the localization of EPO-producing cells in
close vicinity to proximal tubular epithelial cells,
which are highly dependent on oxygen, suggests
that these cells generate the signal for transmis-
sion to the adjacent EPO-producing interstitial
cells. It should be noted that small amounts of
EPO are produced in nonrenal tissues, ie, hepato-
cytes, macrophages, and possibly erythroblasts,
approximating 10% of total-body EPO produc-
tion.22
Multipotential stem cells can replicate to pro-
duce either multipotential stem cells or commit-
ted unipotential progenitor cells. Accordingly,
stem cells are capable of replenishing their own
pool, as well as the pools of committed unipoten-
tial progenitor cells. Replication of stem cells is
primarily initiated by lineage-nonspecific growth
factors, including stem-cell factor, interleukin-3,
insulin growth factor, and granulocyte monocyte
colony-stimulating factor. Erythroid progenitor
cells appear to lose their self-renewal capac-
ity. However, they gain EPO receptor, which
promotes their replication and maturation to
erythroblasts. By acquiring EPO receptor, ery-
throid progenitor cells lose their capacity for
self-renewal, and their proliferation is directed
toward a generation of readily distinguishable
erythroid precursor cells. The earliest progenitor
cells, ie, burst-forming erythroid cells, possess
both lineage-nonspecific growth factor receptors
and erythropoietin receptor. Thus, in the pres-
ence of sufficient quantities of EPO and nonspe-
cific growth factors, they show massive prolifera-
tion, leading to the formation of many colonies
of nucleated red cells.23
However, maturation of these cells to the late
progenitor cells, known as colony-forming ery-
throid units, is coupled with a substantial loss of
nonspecific growth factor receptors. Conse-
quently, continued replication of these cells and
their transformation to precursor cells primarily
depends on the presence of EPO. Binding of
EPO to EPO receptors (a 55-kd transmembrane
protein belonging to the cytokine receptor super-
family) triggers a cascade of protein phosphory-
lation events that lead to the release of second
messengers and cell proliferation.24 Recent in
vitro studies have shown that unless EPO is
present, colony-forming erythroid progenitor cells
die of apoptosis. Thus, survival of these progeni-
tor cells and their transformation to erythroid
precursor cells are EPO dependent.25 After a
level of maturation has been reached, the surviv-
ing colony-forming erythroid cells become acti-
vated and transform to erythroid precursor cells
(erythroblasts) that are capable of synthesizing
hemoglobin. In the presence of sufficient sup-
plies of vitamin B12, folate, and iron, erythro-
blasts proliferate at a fixed rate and subsequently
extrude their nuclei to become reticulocytes,
which eventually transform to mature erythro-
cytes. Replication and maturation of erythro-
blasts appear to be independent of EPO.
ERYTHROPOIETIN AND TRANSFERRIN IN NEPHROSIS
EPO Metabolism in Nephrotic Syndrome
In an earlier study, we found marked urinary
excretion of EPO in a group of patients with
nephrotic syndrome. Urinary losses of EPO in
this population were coupled with an inappropri-
ately low plasma EPO concentration.1 This was
accompanied by a significant reduction in hemat-
ocrit in a number of patients who did not show
evidence of blood loss, hemolysis, or hematopoi-
etic factor deficiencies. We therefore concluded
that the observed anemia must be caused by EPO
deficiency in those instances. Thus, nephrotic
syndrome was identified as a potential cause of
EPO-deficiency anemia.1
In an attempt to gain further insight into the
effects of nephrotic syndrome, we subsequently
performed a comprehensive study of EPO metab-
olism, regulation, and pharmacokinetics in ne-
phrotic and control rats.2 The study showed
marked urinary EPO excretion and significant
reduction of plasma EPO concentration, coupled
with a mild reduction of hematocrit in nephrotic
animals compared with the normal control group.
Plasma EPO concentrations in the study animals
were inversely related to urinary EPO excretion.
Glomerular filtration rates in nephrotic animals
were normal and similar to those of control rats,
thus excluding renal insufficiency as a possible
contributor to the associated EPO deficiency.
Moreover, control animals were pair-fed with
their nephrotic counterparts and maintained un-
der identical experimental conditions to obviate
possible differences in dietary intake and other
conditions. Thus, the observed reduction in
plasma EPO concentrations in nephrotic rats
could be attributed solely to nephrotic syndrome.
Results of baseline studies of nephrotic animals
confirmed our earlier observations in nephrotic
humans. We then compared the changes in plasma
EPO concentration in response to hypobaric hyp-
oxia and experimental anemia of different severi-
ties produced by phlebotomy and volume replace-
ment. The experiments showed an expected
robust increase in plasma EPO levels and no
detectable quantities of EPO in the urine of
control animals after exposure to hypobaric hyp-
oxia. Conversely, nephrotic animals showed only
a slight and insignificant increase in plasma EPO
concentration, coupled with a substantial in-
crease over baseline in urinary EPO excretion
3
after a 6-hour exposure to hypobaric hypoxia. As
with hypoxia, the plasma EPO response to experi-
mentally induced anemia (hematocrits, 35%,
30%, 25%, 20%, and 15%) was negligible in
nephrotic animals that instead showed progres-
sive increases in urinary EPO excretion. Con-
versely, control animals showed a dramatic in-
crease in plasma EPO concentration in response
to the reduction in erythrocyte mass with no
detectable urinary excretion of EPO.2
Pharmacokinetic studies performed after the
intravenous injection of recombinant EPO (rEPO;
100 U/kg) showed a marked reduction in plasma
EPO half-life, significant increase in rEPO clear-
ance, and significant expansion of rEPO distribu-
tion volume in nephrotic animals compared with
control animals. Moreover, urinary EPO excre-
tion increased significantly after intravenous
rEPO injection. These findings clearly showed
the role of urinary excretion as a major reason for
the inability of nephrotic animals to sufficiently
increase plasma EPO concentration with either
endogenous release or exogenous intravenous
administration of EPO. We calculated the rate of
endogenous EPO biosynthesis from steady-state
plasma EPO level and EPO clearance data ob-
tained from pharmacokinetic studies of animals
rendered anemic by phlebotomy. Data showed a
significantly lower rate of EPO biosynthesis in
nephrotic animals compared with equally ane-
mic controls. However, no significant difference
was found when anemia was either absent or less
severe. Thus, animal studies showed heavy uri-
nary EPO losses, depressed plasma EPO concen-
trations, expanded EPO distribution (edema),
increased EPO clearance, reduced plasma EPO
half-life, and possibly diminished EPO biosynthe-
sis in nephrotic syndrome.2
Treatment of EPO-Deficiency Anemia
in Nephrotic Syndrome
The definitive treatment of EPO-deficiency
anemia in nephrotic syndrome is correction of
the underlying proteinuria. This is clearly exem-
plified by the reported simultaneous correction
of severe EPO-deficiency anemia with remission
of proteinuria after a course of steroid therapy in
a man with minimal change glomerulopathy.26
However, in many instances, proteinuria is unre-
sponsive to currently available therapeutic mo-
dalities. When present, EPO-deficiency anemia
4 NOSRATOLA D. VAZIRI
can be treated successfully with the regular ad-
ministration of rEPO in such patients. rEPO
should be administered subcutaneously to allow
gradual and sustained release of the drug. Be-
cause of the short plasma half-life and rapid
clearance and urinary losses of EPO, intravenous
administration of rEPO is not recommended in
patients with nephrotic syndrome. In an earlier
report, we showed the efficacy of subcutaneous
rEPO therapy in the treatment of severe dis-
abling EPO-deficiency anemia caused by ne-
phrotic syndrome.27 The reported efficacy of
rEPO therapy in this setting was subsequently
confirmed by other investigators.28 Because of
the paucity of published data, established guide-
lines concerning rEPO therapy in patients with
nephrotic syndrome have not yet been formu-
lated. However, existing guidelines in place for
rEPO therapy in patients with chronic renal fail-
ure can be used with the understanding that
greater dosages may be required to cope with
urinary losses of the administered rEPO.
Chronic rEPO therapy can cause de novo
hypertension or aggravation of preexisting hyper-
tension29 in patients and animals with renal insuf-
ficiency. Chronic nephrotic syndrome is fre-
quently accompanied by varying degrees of renal
insufficiency, which can increase the risk for
EPO-induced hypertension. Therefore, blood
pressure should be monitored and hypertension
should be controlled in such patients. Because
nephrotic syndrome is the prototype of acquired
hypercoagulable states,30 nephrotic patients
should be monitored for thromboembolic compli-
cations. In this regard, rEPO therapy can in-
crease platelet production, enhance platelet adhe-
sion,31,32 and cause rheological modifications
without significantly affecting plasma levels of
coagulation factors or fibrinolytic proteins in
uremic patients.32 It therefore is unlikely that
EPO therapy would significantly aggravate co-
agulation and fibrinolytic cascade disturbances
in nephrotic syndrome. Nonetheless, it is prudent
to watch patients with severe nephrotic syn-
drome for the occurrence of thromboembolism,
particularly renal vein thrombosis, regardless of
the therapeutic regimen used.
TRANSFERRIN
In solution, iron can serve as either an electron
donor (ferrous or Fe2⫹) or electron acceptor
(ferric or Fe3⫹) element. Convenient interconvert-
ibility of this element between the two redux
states, together with its overabundance in nature,
has made iron a key player in a wide array of
biochemical reactions. For example, iron has an
important part in numerous vital reactions, such
as oxygen transport, electron transfer, DNA syn-
thesis, and nitrogen fixation. Consequently, iron
is an essential and indispensable element for life.
Paradoxically, the same redox reactions respon-
sible for the vital role of iron in various biochemi-
cal functions can be a potential source of serious
cytotoxicity and tissue injury. For example, if not
properly chelated, iron can serve as a powerful
catalyst in single-electron redox reactions that
produce cytotoxic free radicals and tissue dam-
age. In addition, at physiological oxygen tension
and pH, ferrous iron (Fe2⫹) is oxidized to ferric
iron (Fe3⫹), which is readily hydrolyzed to pro-
duce insoluble products, namely, ferric hydrox-
ide [Fe(OH)3] and oxohydroxide polymers. How-
ever, a group of highly specialized chelating
molecules and sophisticated handling processes
have evolved for the absorption, transport, and
storage of iron to preserve solubility and prevent
iron-mediated free radical generation under nor-
mal conditions. Accordingly, under normal con-
ditions, these iron-complexing compounds virtu-
ally eliminate free iron from intracellular and
extracellular compartments. Ferritin and hemo-
siderin (probably made of denatured ferritine)
serve as the principal compounds for iron storage
in various tissues. Conversely, apotransferrin
serves as the primary vehicle for the transport of
iron as transferrin between the sites of absorp-
tion, storage, and utilization.33 As a circulating
protein, transferrin metabolism can be directly
affected by proteinuria and is discussed here.
Transferrin is an 80-kd monomeric glycopro-
tein (⬃6% carbohydrate) consisting of two ho-
mologous domains, each possessing a binding
site for a ferric iron atom. Transferrin belongs to
the iron-binding protein family, which includes,
in addition to transferrin, the following proteins:
a-lactoferrin, which is present intracellularly and
secreted in milk, tears, and semen and serves as a
natural bacteriostatic factor; b-ovotransferrin,
present in egg white; and finally, c-melanotrans-
ferrin, a membrane-bound homologue of trans-
ERYTHROPOIETIN AND TRANSFERRIN IN NEPHROSIS
ferrin that transports iron to intracellular low-
molecular-weight ligands.
Transferrin is synthesized by the liver and
secreted into the circulation and extravascular
space. In addition, small amounts of transferrin
are produced in testicles, spleen, brain, and kid-
neys.34-37 Transferrin was first isolated from
plasma by Schade and Caroline,38 who described
it as an iron-binding component of human plasma
and noted its bacteriostatic property. It has a
half-life of 8 to 12 days and can bind up to two
ferric iron atoms at a very high affinity (dissocia-
tion constant [Kd] ⫽ 10–23 mol/L) in a pH-
dependent manner.34,39-41 Binding of ferric iron
to each of the two apotransferrin domains leads
to a conformational change from the open to
closed position. Transferrin, usually present in
plasma as a mixture of diferric, monoferric, and
iron-free (apoferritin) forms, is normally approxi-
mately 30% saturated with iron.33 Plasma trans-
ferrin concentrations range between 2 and 4 g/L
in the healthy population. Transferrin production
is upregulated by hypoxia (through HIF-1), iron
deficiency, pregnancy, and estrogen and down-
regulated by malnutrition, inflammation, and iron
overload.33 With regard to the latter, hepatic
transferrin mRNA expression is inversely related
to body iron stores.
The primary function of transferrin is the safe
transport of iron between sites of absorption,
storage, and use. Accordingly, iron absorbed from
the gastrointestinal tract or released from iron
stores contained in macrophages is rapidly bound
by transferrin in extracellular fluid. Transferrin-
borne iron then is delivered to the target cells for
storage as ferritin or use for incorporation in
heme and nonheme proteins. This phenomenon
is mediated by a transferrin receptor, a 180-kd
transmembrane glycoprotein homodimer consist-
ing of two subunits linked by a disulfide bond.
Transferrin receptor is expressed by all cells
(except mature erythrocytes) and has the greatest
affinity for diferric transferrin; it is 30-fold greater
than monoferric transferrin and 500-fold greater
than iron-free apotransferrin. Each transferrin
receptor subunit binds one transferrin molecule
on the cell surface. Subsequently, the ligand-
receptor complex is internalized within the newly
formed endosome, which is created from inver-
sion of the coated pit in the plasma membrane.
5
This is followed by acidification (pH ⬃5.3) of
the endosomal cavity occasioned by active secre-
tion of H⫹ by proton adenosine triphosphate
pump. Endosomal pH reduction and receptor
binding work in concert to facilitate the dissocia-
tion of iron from transferrin and release of free
iron to the cell cytoplasm for binding by low-
molecular-weight ligands before use or storage.
The iron-free transferrin-transferrin receptor com-
plex is then returned to the cell surface and
apotransferrin is released into the extracellular
space.33
The amount of transferrin-borne iron (⬃3 to 4
mg) is an extremely small fraction (⬃0.1%) of
total-body iron content. However, transferrin iron
turnover is remarkably fast, averaging 30 mg/d
or 8 to 10 times plasma iron content.33
Transferrin Metabolism in Nephrotic Syndrome
Serum transferrin levels frequently are re-
duced in humans and animals with nephrotic
syndrome.42-44 This is accompanied by and largely
caused by urinary losses of this protein.12,13,45
Serum transferrin concentration is inversely re-
lated to the degree of transferrinuria in nephrotic
syndrome.45 Urinary losses of transferrin can
reduce serum iron concentrations and occasion-
ally cause iron-deficiency and microcytic ane-
mia.12,13 However, it should be noted that pre-
sumption of iron deficiency in the reported cases
was based on plasma iron indices and peripheral-
blood investigations and not confirmed by mea-
suring stainable iron in bone marrow or ferritin
values. Because transferrin is the primary ve-
hicle for iron delivery to erythroid cells for
hemoglobin synthesis, severe hypotransferrine-
mia per se can cause microcytic anemia in the
absence of true iron deficiency in nephrotic syn-
drome.
In addition to adversely affecting iron metabo-
lism, transferrinuria can potentially contribute to
renal injury by promoting iron-catalyzed genera-
tion of hydroxyl radicals in renal tubules. In this
regard, iron can disassociate from the filtered
transferrin when luminal fluid pH decreases to
approximately 6. In addition, enzymatic break-
down of the reabsorbed transferrin can liberate
iron in the proximal tubular epithelial cells. The
free iron released within the lumen of renal
tubules or cytoplasm of tubular epithelial cells
can catalyze the generation of hydroxyl radical,
6 NOSRATOLA D. VAZIRI
leading to tubulointerstitial injury and progres-
sive renal disease.46,47 To my knowledge, studies
correlating the degree of transferrinuria with
severity of renal parenchymal injury are lacking.
However, the relationship between severity of
albuminuria and progression of renal disease is
well established. Because urinary excretion of
transferrin closely correlates with that of albu-
min,45 the proportional nephrotoxicity of protein-
uria may be related in part to the associated
transferrinuria. Specific studies are required to
explore this issue. In addition to urinary losses,
transferrin catabolism is significantly increased
and can contribute in part to hypotransferrinemia
in nephrotic syndrome.48
Although transferrin biosynthesis is frequently
increased in nephrotic syndrome,48 the increase
in transferrin synthesis is usually insufficient to
maintain a normal plasma concentration. In-
creased transferrin biosynthesis in nephrotic syn-
drome is transcriptionally regulated and confined
to the liver, with no change in transferrin expres-
sion in extrahepatic tissues.49 Malnutrition and
inflammation, commonly present in nephrotic
syndrome, can downregulate transferrin biosyn-
thesis.50-52 Thus, transferrin biosynthesis may be
reduced in nephrotic patients with pronounced
malnutrition and/or inflammatory disorders.
Treatment of Hypotransferrinemia
and Iron Deficiency
The definitive treatment of nephrotic syn-
drome–induced transferrin deficiencies is correc-
tion or amelioration of the underlying protein-
uria. In addition, iron replacement and improved
nutrition are required in malnourished iron-
depleted patients. When iron deficiency is com-
bined with EPO deficiency, iron repletion and
rEPO therapy should be instituted simulta-
neously. This may help reduce the theoretical
risk for augmenting iron-mediated renal injury
by diverting circulating transferrin toward ery-
throid tissue for hemoglobin synthesis as op-
posed to increasing the available pool of trans-
ferrin for filtration in the kidney. As noted,
hypochromic microcytic anemia and reduced se-
rum iron concentration may occur in nephrotic
syndrome as a result of hypotransferrinemia as
opposed to true iron deficiency. In such cases,
iron supplementation may be unnecessary and
ineffective.
CONCLUSION
Nephrotic syndrome can cause massive uri-
nary losses and altered metabolism of EPO and
transferrin. This can occasionally lead to EPO-
and/or transferrin-deficiency anemia in nephrotic
patients. Measurements of plasma EPO, trans-
ferrin, and iron concentrations, transferrin satura-
tion, and urinary excretion of EPO and trans-
ferrin are necessary to confirm the diagnosis. In
addition, patients should be evaluated for other
causes of anemia, including hemolysis, blood
loss, other hematopoietic factor deficiencies, and
bone marrow disorders. EPO-deficiency anemia
can be effectively treated with the regular subcu-
taneous administration of rEPO. Transferrin and
iron deficiencies can be treated with iron supple-
mentation and nutritional support. When pos-
sible, the underlying proteinuria should be con-
trolled.
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