Original Paper

Nephron 1998;80:401407

a
b

Departments of
Nephrology and
Microbiology, Karolinska Hospital,
Stockholm, Sweden

Soluble Interleukin-6 Receptor,

Interleukin-10 and Granulocyte
Colony-Stimulating Factor in Acute
Pyelonephritis: Relationship to
Markers of Bacterial Virulence and
Renal Function

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

Key Words
Acute pyelonephritis
Cytokines
Cytokine receptors
Interleukin-6 receptor
Interleukin-10
Granulocyte colony-stimulating
factor

Abstract
Background: Cytokines and cytokine receptors are involved in the systemic
and local inflammatory response in patients with urinary tract infections.
Methods: We examined urine and serum concentrations of soluble IL-6
receptor (sIL-6R), IL-10 and granulocyte colony-stimulating factor (G-CSF) in
29 women with acute pyelonephritis caused by Escherichia coli 2 weeks after
the infection, during the subsequent episode of cystitis or asymptomatic bacteriuria and also later when the same patients were free from bacteriuria. Concentrations of sIL-6R, IL-10 and G-CSF were related to the expression of five
virulence markers of E. coli and to glomerular filtration rate (GFR) after
pyelonephritis. Results: On admission because of acute pyelonephritis the
serum concentration of sIL-6R was similar to that of 12 healthy controls. Two
weeks after the infection when all patients had received antibiotic treatment,
the serum concentration of sIL-6R was significantly higher compared to that
on admission (p ! 0.001) and also higher compared to healthy controls (p =
0.001). Patients with increased concentrations of sIL-6R in serum 2 weeks
after infection had significantly lower GFR at follow-up (p ! 0.05). Patients
with acute pyelonephritis had higher concentrations of G-CSF and IL-10 in
serum compared to healthy subjects (p ! 0.001 and p = 0.06, respectively).
G-CSF in serum was higher in patients infected by E. coli producing cytotoxic
necrotizing factor (p ! 0.05). Patients infected by strains producing hemolysin
had lower concentrations of sIL-6R (p ! 0.001). Patients with detectable levels
of the anti-inflammatory cytokine IL-10 in serum had significantly higher concentrations of IL-6 and the soluble tumor necrosis factor receptors I and II in
serum as compared to patients in whom IL-10 was not detectable (p ! 0.001,
p = 0.001 and p ! 0.05, respectively. Conclusion: These investigations, together with our previous findings summarized in this paper, contribute to an
increased understanding of the local and systemic inflammatory response arising in response to acute pyelonephritis.

ABC

1998 S. Karger AG, Basel

00282766/98/08040401$15.00/0

Fax + 41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com

Accessible online at:

http://BioMedNet.com/karger

Stefan H. Jacobson, MD, PhD

Department of Nephrology, Karolinska Hospital
S171 76 Stockholm (Sweden)
Tel. +46 8 51773162, Fax +46 8 51772958, E-Mail staco@divmed.ks.se

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Stefan H. Jacobson a
Ying Lu b
Annelie Brauner b

Accepted: June 19, 1998

Urinary tract infections (UTIs) activate both mucosal

and systemic inflammatory responses in which cytokines
play a pivotal role. It has recently become evident that not
only cytokines but also circulating cytokine receptors and
cytokine-cytokine receptor complexes are involved in the
effects of cytokines in gram-negative infections [13].
Soluble cytokine receptors with neutralizing function
have been found for many cytokines. One function of
these receptors might be the protection of the organism
against excess activity of harmful cytokines. The soluble
IL-6 receptor (sIL-6R) is a 50- to 55-kD glycoprotein that
binds with IL-6 and this complex will associate with a
nonligand-binding membrane glycoprotein (gp130) and
induce its biological effects [4]. In contrast to the neutralizing soluble cytokine receptors, sIL-6R appears to stimulate the biologic activity of IL-6 [5]. We have recently
demonstrated increased sIL-6R levels in the dialysate of
patients on peritoneal dialysis during peritonitis [6]. sIL6R is also detectable in serum from septic patients as well
as in serum, urine and biological fluids during nonpathological conditions [4, 7].
The anti-inflammatory cytokine IL-10 is produced by
monocytes/macrophages, Th2 subset of T-helper lymphocytes and B lymphocytes. IL-10 profoundly suppresses the induced production of tumor necrosis factor
(TNF-), IL-1, IL-6 and IL-8 by monocytes [8]. Moreover, IL-10 produced in a murine model of endotoxin
shock reduced bacterial lipopolysaccharide toxicity [9].
Increased serum concentrations of IL-10 have been detected in patients with septicemia and meningitis, in the
peritoneal dialysate of patients with peritonitis as well as
in the cerebrospinal fluid of children with bacterial meningitis [1014].
Granulocyte colony-stimulating factor (G-CSF) plays a
vital role in both maintaining the normal blood neutrophil count and determining the neutrophils response in
infectious diseases. G-CSF enhances neutrophil motility,
stimulates phagocytic activity, induces a delayed but significant respiratory burst in adherent neutrophils, significantly enhances the microbicidal activity of normal neutrophils against Staphylococcus aureus, enhances neutrophil-mediated antibody-dependent cell-mediated cytotoxicity, modulates the expression of cell surface receptors
on neutrophils and reduces neutrophil apoptosis [1518].
Administration of G-CSF augments the host defense and
reduces the occurrence of fever and infections in patients
with neutropenia and is therefore considered to be a useful agent for enhancing the inflammatory response and

402

Nephron 1998;80:401407

thereby improving the outcome of a broad range of infectious diseases.

In the present investigation we studied the concentrations of the three differently acting mediators sIL-6R, IL10 and G-CSF in the serum and urine of women with nonobstructive acute pyelonephritis caused by Escherichia
coli. In addition, the relationship between the concentrations of these compounds and the expression of five bacterial virulence markers (expression of P-fimbriae, cell surface hydrophobic properties, hemolysin synthesis, production of cytotoxic necrotizing factor (CNF) and aerobactin) and renal function after pyelonephritis was studied. To our knowledge, these issues have not been examined before. Moreover, we summarize and compare the
results to the concentrations of other cytokines and cytokine receptors determined in exactly the same group of
patients [2, 3].

Material and Methods

Subjects
Blood and urine samples were collected from 29 women admitted
to the Karolinska Hospital, Stockholm, Sweden, because of clinical
and laboratory signs of acute nonobstructive pyelonephritis. The
mean age of the patients was 30 B 3 (range 1670) years. The
diagnostic criteria for acute pyelonephritis were bacteriuria (1 105
bacteria/ml urine), increased concentration of C-reactive protein
(1 20 mg/l), fever 1 38 C and clinical signs of pyelonephritis including flank pain without concurrent symptoms or signs of other infections. One of the patients had E. coli bacteremia. All patients underwent intravenous urography during the follow-up period and 5 had
signs of pyelonephritic renal scarring, i.e. calyceal clubbing in combination with a corresponding reduction in the renal parenchyma.
These 5 patients had a history of previous acute pyelonephritis. In all
cases renal infections were caused by E. coli. The patients were
treated with antibiotics (mostly cephalosporines or ciprofloxacin)
intravenously for 35 days followed by 2 weeks of oral medication.
The infection was clinically cured in all cases. If infection recurred
during the 2-year follow-up period, treatment was reinstituted with
the appropriate agent for 710 days and the patient was then usually
established on a long-term low-dose prophylactic regime.
Urine and blood samples were collected approximately 2 weeks
after the episode of acute pyelonephritis from 24 of the patients
(mean 16, range 1039 days). The patients were then encouraged to
attend the outpatient clinic at any time without appointment if they
had symptoms or signs of UTI. A mid-stream urine sample was cultured at each visit and also in connection with routine appointments
at the outpatient clinic, usually 6 months after the infection. In this
way, four recurrences of cystitis and five episodes of asymptomatic
bacteriuria (ABU) were detected in the same group of patients. Urine
concentrations of sIL-6R, IL-10 and G-CSF were analyzed in all
patients who had ABU or cystitis. Urine and serum concentrations
were also analyzed in 12 healthy women with a mean age of 44 B 1
(range 3948) years. None of these women had clinical signs of UTI
and their urine cultures showed no significant growth of bacteria.

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Introduction

Table 1. Serum and urine concentrations of cytokines and cytokine receptors in patients with acute pyelonephritis
Median concentration in serum

sIL-1ra, pg/ml
IL-6, pg/ml
sIL-6R, pg/ml
IL-8, pg/ml
IL-10, pg/ml
sTNFR I, pg/ml
sTNFRII, pg/ml
G-CSF, pg/ml

2 weeks
after
infection

2,180
55
42,500
73
n.d.
2,460
5,350
47

1,025
n.d.
57,000
47
n.d.
1,120
3,050
n.d.

!0.001
NS
!0.001
NS
NS
!0.001
!0.001
NS

Median concentration in urine

controls

350
n.d.
41,000
n.d.
n.d.
1,020
2,025
n.d.

pb

!0.001
!0.001
NS
!0.001
0.06
!0.001
!0.001
!0.001

acute
pyelonephritis

2 weeks
after
infection

40
44
n.d.
870
n.d.
2,500
6,300
n.d.

n.d.
n.d.
44
78
n.d.
1,125
2,260
n.d.

pa

NS
NS
NS
NS
NS
!0.05
!0.05
NS

controls

8,400
n.d.
1,365
87
n.d.
1,125
1,980
n.d.

pb

!0.001
!0.001
!0.01
!0.005
NS
!0.001
!0.001
NS

Summarized from the present study and previous studies on the same patients [2, 3].
n.d. = Not detectable.
Statistical analyses were done using Mann-Whitney U test, Wilcoxon signed-rank test and 2 analysis.
Acute pyelonephritis vs. 2 weeks after infection.
Acute pyelonephritis vs. controls.

Determination of sIL-6R, IL-10 and G-CSF

Cytokines were determined by enzyme immunoassay. IL-10, GCFS and sIL-6R kits were obtained from R&D systems (Abingdon,
UK). In both urine and serum the lowest limit of detection for IL-10
was 7.8 pg/ml, G-CSF at 39 pg/ml and sIL-6R at 31.3 pg/ml. The
total amount of soluble receptors present in the sample, i.e. both free
receptors and receptors bound to IL-6 were measured with the assay
employed. No cross-reactivity or interference has been observed with
other related cytokines or factors.
Virulence Characteristics of E. coli Causing Acute Pyelonephritis
Numbers of bacteria in the urine were estimated by the standard
loop technic. Isolates were identified biochemically by means of the
API 20 E-system (API, La Balme-Les Grottes, France). The following
five virulence characteristics of E. coli were sought in the present
study: expression of P-fimbriae, expression of cell surface hydrophobic properties, hemolysin synthesis, CNF and aerobactin production. These were analyzed as previously described [1921].
Renal Function
Glomerular filtration rate (GFR) was determined by the plasma
clearance 51Cr-EDTA, 23 months after the renal infection.
Statistical Analyses
Results are given as means B SEM, medians and ranges. Simple
regression analysis, the Mann-Whitney U test, Wilcoxon signed-rank
test and 2 analysis with continuity correction were used for paired
and unpaired observations.

sIL-6R, IL-10 and G-CSF in Pyelonephritis

Results
The patients were admitted to the clinic after a mean of
2 (range 15) days after the onset of subjective symptoms
of renal infection. Mean C-reactive protein on admission
was 79 B 8 mg/l, mean leukocyte count was 12.7 B 0.8 !
109/l and mean erythrocyte sedimentation rate was 34 B
3 mm/h.
Total sIL-6R in Serum and Urine during and after
Acute Pyelonephritis
The median concentration of sIL-6R in serum was
42,500 pg/ml on admission because of acute pyelonephritis. This was not significantly different from the level of
sIL-6R among healthy subjects (table 1; fig. 1). sIL-6R
was also determined 2 weeks after the episode of acute
pyelonephritis when all patients had received antibiotic
treatment and were free from symptoms. At this time
point, the serum concentration of sIL-6R was significantly higher compared to that on admission (p ! 0.001) and
also higher compared to healthy controls (p = 0.0014;
fig. 1).
The concentration of sIL-6R in urine was much lower
than in serum. sIL-6R was detected in urine from all
healthy individuals and the median concentration was
1,365 pg/ml. In contrast, sIL-6R was only detected in
urine from 13 of 29 (45%) patients with acute pyelone-

Nephron 1998;80:401407

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acute
pyelonephritis

pa

p < 0.001
p = 0.0014

60,000

40,000

20,000

0
Acute
pyelonephritis

2 weeks after
pyelonephritis

Controls

Fig. 1. Concentrations of soluble IL-6 receptor in serum during

and after an episode of acute pyelonephritis.

Table 2. Virulence characteristics of the

infecting E. coli strain
Virulence marker

Expression of P-fimbriae
Hydrophobic properties
Production of
Aerobactin
Hemolysin
CNF

69
85
67
42
20

phritis (p = 0.0032 vs. healthy controls). sIL-6R in urine

was detected in 64% of patients 2 weeks after acute pyelonephritis, in 3 of 4 patients with a subsequent episode of
cystitis, in 4 of 5 patients with ABU and in 9 of 10 patients
who had no symptoms or signs of UTI.
There was no correlation between the levels of sIL-6R
in serum and urine and the corresponding concentrations
of IL-6, IL-8, IL-1 receptor antagonist (IL-1ra) and the
soluble TNF receptors (sTNFR I and sTNFR II) which
were analyzed in exactly the same patients as in our previous studies [2, 3].
IL-10 in Serum and Urine during and after Acute
Pyelonephritis
In serum IL-10 was detected in 9 of 27 (33%) patients
with acute pyelonephritis as compared to none of the
healthy subjects (p = 0.06; table 1). Two weeks after the

404

Nephron 1998;80:401407

G-CSF in Serum and Urine during and after Acute

Pyelonephritis
G-CSF was detected in serum in 67% of patients with
acute pyelonephritis but was not detectable in any of the
healthy subjects (p ! 0.001; table 1). The median concentration of G-CSF in serum of patients with pyelonephritis
was 47 pg/ml. Two weeks after the infection when all
patients had received antibiotic treatment, G-CSF in
serum was still detected in 3 of 24 (13%) patients. G-CSF
was detected in the urine of 4 of 29 (14%) patients with
acute pyelonephritis, but was not detectable in any of the
healthy subjects (NS vs. acute pyelonephritis) or in patients with cystitis, ABU, or in patients without clinical
signs of infection at routine examinations.
Correlation between Bacterial Virulence-Associated
Traits of the Infecting E. coli Strain and sIL-6R, IL-10
and G-CSF in Serum and Urine
Virulence characteristics of the pyelonephritic E. coli
strain are presented in table 2. Patients infected by E. coli
strains producing CNF significantly more often had detectable G-CSF levels in serum (100%) compared to
patients infected by CNF-negative strains (68%, p !
0.05). Patients infected by E. coli strains producing hemolysin had significantly lower concentrations of sIL-6R in
serum (38,000 pg/ml) compared to patients infected by
hemolysin-negative strains (51,000 pg/ml, p ! 0.01). No
other significant correlations between virulence markers
and cytokine concentrations were observed in the present
study.

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pg/ml
80,000

infection IL-10 was detected in 1 of 24 (4%) patients. In

the urine IL-10 was detected in 5 of 29 (17%) patients
with acute pyelonephritis compared to 3 of 12 (25%)
healthy subjects (NS). Two weeks after renal infection IL10 was detected in the urine in 31% of patients and subsequently in 1 of 4 patients with an episode of cystitis, in 2
of 5 patients with ABU and in 1 of 10 patients without
symptoms or signs of UTI.
Patients with detectable levels of IL-10 in serum had
significantly higher concentrations of IL-6, sTNFR I and
sTNFR II in serum, analyzed in exactly the same group of
patients as in previous studies [2, 3], compared to patients
with acute pyelonephritis in whom IL-10 was not detectable in serum (p ! 0.001, p = 0.01 and p ! 0.05, respectively). The concentrations of IL-10 in urine did not correlate with the concentration of IL-6 or soluble TNF receptors in urine.

We have studied the local and systemic concentrations

of the naturally occurring soluble receptor to IL-6, the
anti-inflammatory cytokine IL-10 and G-CSF in patients
with acute pyelonephritis before and after antibiotic treatment and during subsequent episodes of cystitis or
asymptomatic bacteriuria as well as in healthy subjects.
The concentration of these compounds in serum and
urine was related to the expression of five different bacterial virulence characteristics of E. coli causing the renal
infection, to renal function 23 months after the episode
of acute pyelonephritis and to the concentrations of IL-6,
IL-8, IL-1ra, sTNFR I and sTNFR II which previously
have been determined in exactly the same group of
patients.
In the present investigation, the serum concentration
of sIL-6R increased during the episode of acute pyelonephritis despite effective antibiotic treatment. Patients
with high concentrations of sIL-6R 2 weeks after admittance had lower GFR as compared to patients in whom
the sIL-6R concentration remained stable during the
infection. To our knowledge this has not been shown
before. The mechanism is not clear but it has been postulated that circulating sIL-6R may potentiate the IL-6
response in vivo. sIL-6R has been found to be stable in
serum from patients with multiple myeloma for periods
varying from 320 to 760 days [22]. Previous studies in the
same group of patients have shown that patients with
increased urine concentration of IL-8 and serum concentrations of sTNFR II also have reduced GFR [2, 3].
The urine concentration of IL-6R was lower than in
serum and also lower during pyelonephritis as compared
to healthy subjects. This corresponds to the pattern observed for IL-1ra [3] but contrasts to the urine concentrations of soluble TNF receptors I and II which are found in
increased concentrations in patients with acute pyelonephritis [3]. The different biological activity of soluble

TNF receptors, which are antagonistic, and the agonistic

sIL-6R might be one reason for the different reaction pattern. The binding capacity of cytokines to the corresponding receptor and to uroepithelial cells, the local production and the renal clearance may also be of importance.
Increased concentrations of sIL-6R have been observed in patients with HIV infection and in sera of
patients with monoclonal gammopathy [22, 23]. In patients with sepsis syndrome, however, sIL-6R in serum
was significantly lower than in healthy individuals and a
significant negative correlation between IL-6 and sIL-6R
was observed [6]. Likewise, we have observed a negative
correlation in the dialysate of patients on peritoneal dialysis [7]. A temporal but not statistically significant negative
correlation was observed among patients with acute pyelonephritis in the present investigation. The regulation
of sIL-6R concentrations in different pathological conditions is not clear. sIL-6R is generated either by shedding
the membrane-anchored gp80, a process in which proteinkinase C seems to play an important role, or by direct production of a sIL-6R form through transcription of a specific mRNA [24, 25]. The clinical relevance of a certain
amount of circulating sIL-6R has not been established.
We have previously shown that patients infected with
E. coli-producing hemolysin had significantly higher concentrations of IL-6 in serum during acute pyelonephritis
as compared to patients infected with E. coli without such
production [2]. In the present investigation, patients infected by E. coli-producing hemolysin had significantly
lower concentrations of sIL-6R in serum as compared to
patients infected by hemolysin-negative strains. An increased turnover of membrane-anchored sIL-6R in the
presence of high levels of IL-6 might be responsible for the
decreased levels of sIL-6R seen in patients infected by
hemolysin-negative strains.
IL-10 is a potent immunosuppressant which may help
control the inflammatory response induced by bacterial
infection. In the present investigation IL-10 was more
often detected in serum from patients with pyelonephritis
than in healthy subjects. We are not aware of any other
studies in which serum and urine concentrations of IL-10
have been determined in patients with acute pyelonephritis. In patients with septicemia 5783% of the patients
had detectable IL-10 levels in serum compared to 25% of
critically ill patients [10, 11]. We observed a significant
correlation between the serum concentration of IL-10 on
admission because of acute pyelonephritis and levels of
IL-6, sTNFR I and sTNFR II in serum. This is in accordance with previous studies [11, 12]. IL-10 inhibits the
production of TNF-, IL-1, IL-6 and IL-8 and improves

sIL-6R, IL-10 and G-CSF in Pyelonephritis

Nephron 1998;80:401407

Discussion

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Renal Function in Relation to sIL-6R, IL-10 and

G-CSF in Serum and Urine
The mean GFR 23 months after the episode of acute
pyelonephritis was 98 B 4 ml/min ! 1.73 m2. Patients
with increased concentrations of sIL-6R in serum 2 weeks
after infection had significantly lower GFR at follow-up
23 months after the episode of acute pyelonephritis (r =
0.46, p ! 0.05). Both these variables were normally distributed. No other correlations to renal function were
observed in this study.

the survival of animals in experimental endotoxemia [26].

The only patient with E. coli bacteremia in the present
study had the highest concentration of IL-10 in serum.
Some patients may have had higher concentrations of
cytokines prior to admittance since the mean time from
onset of symptoms to admission to the hospital was
2 days. Kinetic IL-10 studies have shown that low concentrations are detected 7 h after activation of monocytes
and that maximal IL-10 production occurs 2428 h after
activation [8]. This is later than the production of the early acting proinflammatory cytokines which are secreted at
high levels between 4 and 8 h after activation [27]. This
might explain the lack of correlation between the secretion of IL-10 in serum and urine and the early acting
proinflammatory cytokines. Another possible explanation
is that the inflammatory response in patients with acute
pyelonephritis is much less than in patients with bacteremia and septic shock.
Serum concentrations of G-CSF have been reported to
be elevated in many inflammatory diseases with an
increase in neutrophils in the peripheral blood [28]. In the
present investigation, G-CSF was detected in the serum of
patients with acute pyelonephritis in a significantly larger
proportion than in healthy subjects. There were no significant correlations between G-CSF in serum and urine and
the degree of leukocytosis (data not shown). The span of
time from onset of infection to admission might be the
explanation. G-CSF modulates the function and activity
of developing neutrophils and induces significant alterations in the biological activity of mature neutrophils.

This may augment the host defence in response to invading pathogens such as bacteria. In the present study
patients infected by E. coli producing CNF more often
had detectable G-CSF levels in serum as compared to
patients infected with CNF-negative strains. Thus, the
cytotoxic activity in urine and kidneys seems to stimulate
the endogenous serum production of G-CSF.
We conclude that in patients with acute nonobstructive E. coli pyelonephritis serum levels of sIL-6R are higher than urine concentrations and rise during the course of
infection, especially in those patients in whom renal function is affected. Urine concentrations of sIL-6R were,
however, significantly lower in patients with acute pyelonephritis as compared to healthy individuals. This pattern is similar to that observed for IL-1ra and adults with
acute pyelonephritis, but different from what we previously observed for soluble TNF receptors in urine. This
investigation expands our previous experience in this
field and contributes to an increased understanding of the
initiation and maintenance of the local and systemic
inflammatory responses in patients with acute pyelonephritis.

Acknowledgements
This study was supported by grants from the Swedish Medical
Research Council, Ollie and Elof Ericssons Foundation and the
Karolinska Institute.

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

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