CASE STUDY

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Polycythemia and increased erythropoietin

in a patient with chronic kidney disease
Simone Stark, Bjrn Winkelmann, Christof Kluthe, Jan Roigas, Uwe Querfeld and Dominik Mller*

Vanderbilt Continuing Medical Education online

S U M M A RY
This article offers the opportunity to earn one Category 1
Background A 16-year-old white male with a history of obstructive credit toward the AMA Physicians Recognition Award.
uropathy presented to a pediatric outpatient clinic with a first syncope. At
presentation, he had a hemoglobin level of 220 g/l, a serum erythropoietin
level of 27.4 U/l and a serum creatinine level of 200.7 mol/l (2.27 mg/dl). THE CASE
Investigations Physical examination, serum laboratory analysis, renal A 16-year-old white male presented to a pedi-
ultrasound, MRI, and 99mTc-MAG3 scintigraphy of the kidneys. atric outpatient clinic with a first syncope. His
Diagnosis Chronic renal insufficiency caused by obstructive physical examination was normal: there were
hydronephrosis and accompanied by increased erythropoietin levels of no symptoms of cardiac, cerebral or pulmonary
renal origin and polycythemia. abnormalities. At admission, the patient had
Management Serial phlebotomies and laparoscopic removal of the right an elevated blood pressure of 140/120 mmHg.
hydronephrotic kidney. His red blood cell count showed erythrocytosis
(7.0 1012/l), a raised hemoglobin level of 220 g/l
KEYWORDS children, chronic kidney disease, erythropoietin, hydronephrosis,
polycythemia and an increased erythropoietin level of 27.4 U/l
(normal: 1.515.2 U/l), but he had normal values
CME for platelet and leukocyte counts. The patient
had a history of obstructive uropathy that had
necessitated repeated urological intervention.
Soon after birth, he had been diagnosed with
bilateral vesicoureteral reflux grade IVV. At the
age of 2 months, the patient underwent his first
ureteral reinsertion on the left side; this proce-
dure was repeated at 1.5 years of age and again at
8 years of age. Ureteral reinsertions on the right
side were performed at the ages of 1.5 years and
2 years. Despite these interventions, the patient
developed bilateral hydronephrosis as shown by
renal ultrasound and MRI (Figure 1). A 99mTc-
MAG3 (technetium-99m-labeled mercapto-
acetyltriglycine) scintigraphy of the kidneys at
S Stark is a Resident in the Department of Neonatology, B Winkelmann is a initial presentation at the age of 16 years demon-
Senior Resident in the Department of Urology and Pediatric Urology, strated a nonfunctioning right kidney (Figure 2).
C Kluthe is a Resident in the Department of Neonatology, J Roigas is
Professor of Urology and Head of the Pediatric Urology and Childhood Renal Two years before presentation to the outpatient
Transplantation Unit, U Querfeld is Full Professor of Pediatrics and Head of clinic, the patients red blood cell count had
the Pediatric Nephrology Department, and D Mller is Assistant Professor been normal (5.76 1012/l); however, at the
in the Department of Pediatric Nephrology, all at the University Hospital current presentation, it had increased to 7.0
Charit of Berlin, Germany. 1012/l. On admission to the outpatient clinic,
the patients creatinine level was 200.7 mol/l
Correspondence
*Department of Pediatric Nephrology, Charit, Campus Virchow Klinikum, Augustenburger Platz 1,
(2.27 mg/dl) and his estimated glomerular
13353 Berlin, Germany filtration rate was 45 ml/min/1.73 m2 (Schwarz
dominik.mueller@charite.de formula). Primary pulmonary disorders, cardiac
disorders and tumors were ruled out by chest
Received 12 September 2006 Accepted 16 January 2007
www.nature.com/clinicalpractice
X-ray, echocardiography, electrocardiogram,
doi:10.1038/ncpneph0437 abdominal ultrasound and confirmation of

222 NATURE CLINICAL PRACTICE NEPHROLOGY APRIL 2007 VOL 3 NO 4

 CASE STUDY
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normal differential leukocyte count and normal A C

serum concentrations of lactate dehydrogenase,
alanine aminotransferase, aspartate amino-
transferase, gamma-glutamyltransferase, alka-
line phosphatase, electrolytes and platelets. The
isolated increased erythropoietin level and subse-
quent clinical course also excluded polycythemia
vera. Serial phlebotomies were performed on B
days 3, 7 and 9 after admission and resulted in
a transient fall in red blood cell count and an
increase in erythropoietin levels to 80.9 U/l. The
patients arterial hypertension was controlled
with ramipril, nifedipine, hydrochlorothiazide
and amlodipine. A ureteral stent was placed Figure 1 Magnetic resonance image of the urogenital tract at presentation,
9 days after admission to drain the urine of demonstrating massive hydronephrosis of both kidneys. (A) Transverse
the left (functioning) kidney, and 13 days after T2-weighted image. (B) Frontal T1-weighted image. (C) Frontal T2-weighted image.
admission, laparoscopic nephrectomy of the
right (nonfunctioning) kidney was performed.
During surgery, massive hydronephrosis of the
right kidney bulging into the right lobe of A B High

the liver (Figure 1) was confirmed. At this time, Patients total ERPF: 10 minutes after injection
the patients serum erythropoietin level was 284.7 ml/min/1.73 m2 of 99mTc-MAG3
(normal ERPF for a 16-year-old
83.7 U/l in the right renal vein; a few minutes later

Level of tracer
male: 464696 ml/min/1.73 m2)
it was 41.9 U/l in the peripheral brachial vein.
The difference in erythropoietin levels between Left kidney ERPF:
275.0 ml/min/1.73 m2 (96.6%)
these veins indicated that the right kidney was
the area of the excessive erythropoietin produc- Right kidney ERPF:
9.7 ml/min/1.73 m2 (3.4%)
tion. One day after surgery, the patients serum
erythropoietin levels and hemoglobin values Left Right
had decreased; 2 days after surgery, they were kidney kidney Low
normal (Figure 3). Hemoglobin levels remained
C
normal over 3 months of follow-up. 100 Left kidney
Percentage of remaining tracer activity

DISCUSSION OF DIAGNOSIS
Renal anemia is common in chronic kidney 80
disease and usually results from insufficient
renal production of erythropoietin.1 Although 60
they have not yet been identified, it has been
reported that dialyzable inhibitors of erythro- 40 Retention curve
poiesis are present in the sera of patients with
uremia.2 Erythropoietin, a glycoprotein growth
factor, is the primary stimulus for erythropoiesis, 20
and promotes the proliferation and terminal Right kidney
differentiation of erythrocyte precursor cells into 0
normoblasts and, subsequently, erythrocytes.3 0 5 10 15 20 25 30
Erythropoietin is produced by the kidney and to Time in minutes after tracer injection
a much lesser extent by extrarenal tissue, mainly Figure 2 Renal clearance with 99mTc-MAG3 scintigraphy demonstrating
the liver. The primary source of erythropoietin the absence of function in the right kidney. (A) The distribution of the ERPF in the
synthesis seems to be renal interstitial fibro- right and left kidneys of this patient. (B) Dorsal image showing reduction of tracer
blasts, although some studies have indicated that activity in the right kidney 10 minutes after 99mTc-MAG3 injection. The color scale
to the right of the image indicates the amount of tracer of the region of interest (red:
proximal tubular cells also have an important highest; purple: lowest). (C) Time course of tracer uptake and tracer wash-out by
role.46 Kidney cells expressing erythropoietin the kidneys. Intravenous furosemide administration (32 mg; 0.5 mg/kg) at minute
messenger RNA are limited to the deep cortex 19 did not increase tracer elimination. Abbreviations: 99mTc-MAG3, technetium-
and outer medulla of the kidney under normal 99m-labeled mercaptoacetyltriglycine; ERPF, effective renal plasma flow.

APRIL 2007 VOL 3 NO 4 STARK ET AL. NATURE CLINICAL PRACTICE NEPHROLOGY 223
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Phlebotomies at days 3, 7 and 9 Nephrectomy
90
Erythropoietin (U/l) and hemoglobin
80 Hemoglobin
70 Erythropoietin, right renal vein
Erythropoietin,
60
peripheral brachial vein
(g/dl) levels
50
40
30
20
10
0 elevated levels of insulin-like growth factor 1
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Days after admission
Figure 3 Follow-up of the patients hemoglobin levels and erythropoietin
concentrations in the serum before and after nephrectomy of the right kidney.
physiological conditions. Erythropoietin produc-
tion is regulated by alterations in tissue oxygen
tension.1 Decreased oxygen delivery, most often
a result of anemia or hypoxia, is the primary
stimulus for erythropoietin production and
release.3 As there is no significant store of erythro-
poietin,1 the rate of de novo protein synthesis
and its control are crucial. Events downstream
of the oxygen-sensitive transcription factors
are involved in erythropoietin gene expres-
sion, including the production of specific trans-
cription factors such as hypoxia-inducible
factor 1 (HIF1) comprising both alpha and beta
subunits.7 The regulation of the HIF1 subunit
occurs through oxygen-dependent degradation
mediated by the von Hippel-Lindau protein
(pVHL). In the presence of oxygen, pVHL binds
to the HIF1 protein and targets HIF1 for
proteasomal destruction.8 When local oxygen
tension is low, HIF1 cannot be hydroxylated
and binds to an enhancer sequence region on
the erythropoietin gene, leading to an increase in
the erythropoietin production.7 During anemia,
cells expressing erythropoietin messenger RNA
increase in number and their prevalence increases
in the superficial cortex.5 In severe anemia, the
serum erythropoietin level can be elevated to
as much as one thousand times the normal
level. A hypoxic stimulus increases the number
of erythropoietin-producing cells in the cortex of
the kidney, but not the amount of erythropoietin
produced per cell.9
Secondary polycythemia, as occurred in the
present case, is caused by an increased serum
224 NATURE CLINICAL PRACTICE NEPHROLOGY
erythropoietin level. This disorder is most often a
result of a compensative, oxygen-sensitive erythro-
poietin response to either hypoxia (e.g. cardiac or
pulmonary diseases, exposure to high altitude)
or high oxygen affinity hemoglobinopathies,10,11
but it can also result from the presence of an
erythropoietin-secreting tumor (e.g. Cushings
syndrome), self-injection of erythropoietin or
hormonal stimulation of erythropoiesis (e.g.
therapy with corticosteroids or androgens).
In rare cases, dysregulated reninangiotensin
system feedback mechanisms, such as those
seen in patients after renal transplantation, and
have also been shown to stimulate erythropoiesis
and cause secondary polycythemia.1214
In patients with renal insufficiency asso-
ciated with increased hemoglobin levels and
polycythemia, the possibilities of recombinant
erythropoietin overdosing and disorders such
as neoplasms and polycythemia vera must
be excluded.
The present case and others in the literature
indicate that the presence of hydronephrosis, even
if associated with no apparent glomerular filtra-
tion rate (i.e. nonfunctioning kidneys), must be
added to this list of differential diagnoses.
Table 1 summarizes the published reports on
patients with erythrocytosis, elevated erythro-
poietin levels and hydronephrosis. One retro-
spective study evaluated 355 patients with
hydronephrosis (150 males and 205 females),
and showed that 11.8% of patients had erythro-
cytosis. Red blood cell counts decreased to
normal levels in 10 cases following nephrec-
tomy.15 Another retrospective study found that
6 of 50 patients (12%) had hydronephrosis-
associated polycythemia.16 Jaworski et al.
reported a case in which drainage of the hydro-
nephrotic kidney caused an immediate drop in
hemoglobin concentration.17
In the present case, erythropoietin levels were
determined simultaneously in the right renal
vein (83.7 U/l) and in a peripheral brachial vein
(41.9 U/l). The difference between these erythro-
poietin serum levels indicated that the right
kidney was the source of the excessive erythro-
poietin production. Some case reports have
found no erythropoietin activity in the renal vein
or in venous or arterial blood,17 but it has been
suggested that such findings were a result of assays
employed by older studies lacking sensitivity to
detect erythropietin.18 In the case presented here,
the erythropoietin level was determined by the
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Table 1 Overview of reported cases of resolution of polycythemia before and after treatment of hydronephrosis by nephrectomy.
Referencea Age Sex Hemoglobin before/ Hematocrit before/ Erythropoietin before/
after nephrectomy after nephrectomy after nephrectomy
(grams per liter) (%)
Present case (2007) 16 Male 220/180 61/50 /
Bailey et al. (1995)21 33 Male 200/160 ?/? /
Castleman et al. (1959)22 62 Male 220/? 67/? ND
Cooper and Tuttle (1957)23 55 Male 190/130 68/44 ND
Donati et al. case 1 (1963)18 62 Male 240/150 71/46 ND/
Donati et al. case 2 (1963)18 42 Male 200/170 61/51 /ND
Ellis (1961)24 53 Male 150/110 ?/? ND
Frick (1961)25 52 Female 180/? 57/? ND
Gardner and Freyman (1958)26 65 Male 210/140 68/40 ND
Gouraud et al. (1987)27 17 Male 210/? 60/? /ND
Hirsch and Leiter (1983)28 69 Male 200/150 58/45 /
Jaworski and Hirte (1961)29 50 Male 200/? 60/? ND
Jaworski and Wolan (1963)17 21 Male 220/160 68/49 ND/
Jones et al. (1960)30 57 Male 220/130 62/40 /
Lawrence and Donald (1959)31 37 Male 230/150 ?/? ND
Madeb et al. (2006)32 24 Male ?/? 64/41 ND
Martt et al. (1961)33 62 Male 240/160 71/48 ND/
Meulman et al. (1992)34 19 Male 220/? 67/? ND
Narayana et al. case 1 (1976)35 51 Male 190/130 ?/? ND
Narayana et al. case 2 (1976)35 43 Male 190/120 ?/? ND
aSee Supplementary References 1 online for details of references 2135. Abbreviations: , high; , low; , normal; ?, unknown; ND, not done.

IMMULITE 1000 (Cirrus Diagnostics Inc., Los
Angeles, CA, USA), a solid-phase chemiluminescent
immunometric assay.
Our case and others reported in the literature
indicate that pressure on the renal tissue develops
slowly in hydronephrosis, leading to the local
ischemia that stimulates erythropoietin produc-
tion. In this condition, the tissue is compressed
or stretched but not destroyed. As a result,
the affected area becomes ischemic, stimula-
ting an increase in erythropoietin-producing
cells. This explanation is in line with the find-
ings in a range of animal models of experimental
hydronephrosis. In rabbits, erythropoietic
response is most pronounced with low pressure
or intermittent hydronephrosis rather than high
pressure hydronephrosis.19
Thus, ureteral obstruction with slowly
progressive hydronephrosis (as in the patient
described here) can compress the renal tissue and
reduce its blood and oxygen supply, resulting in
increased erythropoietin production secondary
to local renal ischemia. At present, it is unknown
which cells in the damaged organ are respon-
sible for increased erythropoietin production in
a hydronephrotic kidney. In patients with cystic
renal diseases (in whom mild or no anemia
with elevated erythropoietin levels can occur),
however, interstitial cells have been shown to
express erythropoietin messenger RNA, even
in advanced chronic kidney disease; cysts
derived from proximal tubules, but not those
derived from distal tubules, contained increased
concentrations of bioactive erythropoietin.20
Since hydronephrosis is more common than
hydronephrosis-associated erythrocytosis,
however, it seems unlikely that the distension
and compression of renal parenchyma are the
only factors responsible for erythrocytosis.
Elucidation of the roles of additional factors,
especially local hypoxia-inducible factors such
as HIF1 and pVHL, might give new insights into

APRIL 2007 VOL 3 NO 4 STARK ET AL. NATURE CLINICAL PRACTICE NEPHROLOGY 225
 CASE STUDY
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Competing interests
The authors declared
they have no competing
interests.
226 NATURE CLINICAL PRACTICE NEPHROLOGY
renal erythropoietin regulation and ultimately
lead to innovative pharmacological manipu-
lations of erythropoietin production in the
native kidneys.
DISCUSSION OF TREATMENT
The case described here demonstrates a preserved
feedback mechanism, as phlebotomies were
followed by increased erythropoietin production.
An autonomous mechanism, as seen in malig-
nancy-associated polycythemia, could therefore
be excluded. Erythropoietin measurements in
the renal vein showed that the nonfunctioning
kidney was the source of the excessive erythro-
poietin production. Removal of this kidney,
therefore, terminated polycythemia. This finding
is consistent with cases described in the literature
in which removal of a kidney was followed by a
significant drop in erythropoietin levels and the
disappearance of polycythemia (Table 1).
CONCLUSION
In rare cases, hydronephrotic kidney disease can be
the cause of erythropoietin-associated secondary
polycythemia, even in nonfunctioning kidneys.
Supplementary information, in the form of
an additional reference list, is available on the
Nature Clinical Practice Nephrology website.
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