Nephrol Dial Transplant (2010) 25: 1639–1646
doi: 10.1093/ndt/gfp670
Advance Access publication 8 January 2010
Intra-peritoneal interleukin-6 system is a potent determinant of the
baseline peritoneal solute transport in incident peritoneal dialysis
patients
Kook-Hwan Oh1,2, Ji Yong Jung7, Myeong Ok Yoon3, Aeran Song3, Hajeong Lee1, Han Ro1,2,
Young-Hwan Hwang4, Dong Ki Kim1, Peter Margetts5 and Curie Ahn1,2,6
1
Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea, 2Transplantation Research Institute, Seoul
National University, Seoul, Korea, 3Clinical Research Institute, Seoul National University Hospital, Seoul, Korea, 4Department of
Internal Medicine, Eulji General Hospital, Eulji University College of Medicine, Seoul, Korea, 5Department of Medicine, McMaster
University, Hamilton, ON, Canada, 6Cancer Research Institute, Seoul National University, Seoul, Korea and 7Department of Internal
Medicine, Gachon University of Medicine and Science, Incheon, Korea
Correspondence and offprint requests to: Curie Ahn; E-mail: [email protected]
Abstract
Background. Interleukin-6 (IL-6) is a key player in modulating inflammation. IL-6 and soluble IL-6 receptor (sIL6R) complex induces the synthesis and secretion of various
chemokines, adhesion molecules and angiogenic molecules. We hypothesized that the baseline peritoneal solute
transport rate (PSTR) early after commencing peritoneal
dialysis (PD) may depend largely on the IL-6/sIL-6R system. We also hypothesized that the dialysate concentrations of IL-6/sIL-6R could be closely related to local
inflammation or angiogenesis in the peritoneal cavity.
Methods. Fifty incident patients with a modified peritoneal equilibration test result within 3 months after commencing PD and without a previous history of peritonitis were
enrolled. Clinical parameters such as age, sex, comorbid
disease, body mass index, residual renal function and Creactive protein were assessed. Serum and dialysate markers including CA125, IL-6, sIL-6R, monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth
factor (VEGF) and angiopoietin-2 (Ang-2) were measured
and correlated with PSTR.
Results. Dialysate concentrations of IL-6 (r = 0.576, P <
0.001), MCP-1 (r = 0.408, P = 0.003) and Ang-2 (r =
0.408, P = 0.003) correlated with mass transfer area coefficient for creatinine (MTACcr), respectively. Dialysate appearance rate (AR) of albumin correlated with dialysate
concentrations of CA125 (r = 0.751, P < 0.001), IL-6
(r = 0.303, P = 0.039), sIL-6R (r = 0.497, P < 0.001),
MCP-1 (r = 0.488, P < 0.001), VEGF (r = 0.443, P =
0.004) and Ang-2 (r = 0.488, P < 0.001). Neither MTACcr
nor AR of albumin was associated with systemic markers.
Multivariate analysis showed that MTACcr is independently associated with dialysate IL-6 and serum albumin. It also showed that AR of albumin is independently predicted
by dialysate sIL-6R. Dialysate IL-6 correlated with dialysate concentrations of CA125 MCP-1, VEGF and Ang-2.
Conclusion. Our study from incident PD patients suggested that (i) dialysate the IL-6 system is a potent determinant of baseline PSTR and (ii) elevation of IL-6 in the
dialysate is associated with up-regulation of intra-peritoneal inflammatory and angiogenic molecules.
Keywords: albumin appearance rate; interleukin-6; MCP-1; peritoneal
dialysis; PSTR
Introduction
Peritoneal solute transport rate (PSTR) is measured by dialysate-to-plasma (D/P) ratios or mass transfer area coefficients (MTACcr) of low molecular weight solutes. High
PSTR reflects either a large effective peritoneal surface
area, which results from a large number of perfused peritoneal capillaries engaged in the diffusion of the solute,
or increased permeability of the peritoneal vasculature.
Some investigators have suggested that baseline PSTR,
measured early after the commencement of peritoneal dialysis (PD), is associated with comorbidity or systemic inflammation [1,2]. However, we have recently shown, from
a relatively large number of Korean patients, that the baseline PSTR is not associated with markers of systemic inflammation or comorbidity [3]. Therefore, it could be said
that these associations are somewhat context and/or population dependent [3–6]. Instead, the pathophysiologic implication of the several intra-peritoneal markers has been
investigated with diverse results.
Interleukin-6 (IL-6) is a key player in modulating inflammation. IL-6 is secreted from a variety of cells including macrophages and monocytes at inflammatory sites. It
was also shown that the human peritoneal mesothelial
cells (HPMC) can release IL-6 upon exposure to the spent
© The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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1640
dialysate or interleukin-1β (IL-1β) [7]. IL-6 not only stimulates the production of acute phase proteins in response
to various stimuli but regulates a temporal switch from
acute to chronic inflammation [8]. A soluble form of IL6 receptor (sIL-6R) is shed from neutrophils by limited
proteolysis of membrane IL-6R or translation of alternatively spliced mRNA of IL-6R [9,10]. As a result, the
complex of IL-6 and sIL6R can bind to the gp130, a signal-transducing subunit on the cell membrane, which exists on most of the cell types. This way of IL-6 signaling,
which is named trans-signaling, compared to classic signaling, enables the IL-6 system to activate cells, including
HPMCs [8], that do not normally express IL-6R on the
surface membrane. IL-6 and sIL-6R complex induces the
synthesis and secretion of CC chemokine, monocyte chemoattractant protein-1 (MCP-1), which attracts monocytes
and lymphocytes. It also induces other molecules as well,
such as chemokines (MCP-3, IL8), adhesion molecules
(ICAM-1, VCAM-1) [11,12] and angiogenic molecule
(vascular endothelial growth factor, VEGF) [13,14]. It
was shown in a few reports that dialysate IL-6 concentration is associated with PSTR either at baseline [2,15] or
among prevalent patients [16] but refuted by other investigators [17].
We have previously shown that the dialysate concentration of IL-6 closely correlates with PSTR in incident patients [15]. Our observation is supported by other
investigators as well [2,18]. However, the mechanistic significance of dialysate IL-6 in the development of high PSTR
still remains to be elucidated. IL-6 has been described as
having both pro- and anti-inflammatory effects [19,20].
IL-6 is also presumed to be a marker of cell vitality [21].
Therefore, whether elevated dialysate concentration of IL6 in association with high PSTR could represent a state of
enhanced peritoneal inflammation or a state of peritoneal
mesothelial cell integrity needs to be investigated.
Based on our previous observation that the baseline
PSTR early after commencing PD is associated with dialysate IL-6 concentration, we hypothesized that the up-regulation of intra-peritoneal IL-6 from high/fast transporter
is linked with up-regulation of downstream inflammatory
markers such as sIL-6R and MCP-1 and increased expression of angiogenic molecules. According to the three-pore
model of the peritoneal membrane function, we dissociated
the small solute transport associated with the small-pore
area from the albumin appearance rate (AR) representing
large molecular transport.
Materials and methods
Patients
Fifty incident patients starting PD between July 2005 and December 2006
were enrolled from Seoul National University Hospital, Seoul, Korea, after having given their informed consent. Approval for the study was obtained from the local ethics committee. In all these patients, the modified
peritoneal equilibration test (PET) using 3.86% glucose PD fluid was performed within 3 months after commencing PD. Patients who had peritonitis before or during the PET were excluded. Comorbidity of the patients
was assessed on the basis of the Davies comorbidity score [1], which
comprises seven comorbid conditions, leading to three risk groups, i.e.
low (no comorbid disease), intermediate (one or two comorbid diseases)
and high (three or more comorbid diseases) risk groups.
K.-H. Oh et al.
Peritoneal solute transport rate
Modified PET with 3.86% glucose PD fluid was performed as described
in our previous report [3]. The peritoneal transport type of each patient
was classified as described elsewhere [22]. Mass transfer area coefficient
for creatinine (MTACcr) was calculated by the simplified Garred equation
[23]. Dialysate-to-plasma concentrations for Cr (D/PCr) and albumin (D/P
alb) at 4 h were acquired. MTACcr and D/P cr representing small solute
transport and AR representing large molecular transport were measured.
For comparison, patients were assigned to two groups according to the D/
PCr: high/high average (H/A) and low/low average (L/A) groups.
Biochemical parameters
Dialysate glucose and creatinine concentration was measured as described
previously [3]. High sensitivity C-reactive protein (hsCRP) was measured
by immunoturbidometry (latex) with a sensitivity of 0.1 mg/l (normal
values <5 mg/l).
Determination of serum and dialysate markers
Samples for the determination of serum IL-6, sIL-6R, MCP-1, IL-1β,
TNFα, VEGF and angiopoietin-2 (Ang-2) concentrations were obtained
from the serum taken during PET test and immediately frozen at −70°C
until analysis. Serum IL-6, IL-1β and TNFα concentrations were analyzed
using Bio-Plex Multiplex Cytokine Assay according to the manufacturer’s
instructions (Biorad Laboratories, Hercules, CA, USA). The limits of
detection in the serum were defined as 0.17 pg/ml for IL-6, 0.24 pg/ml
for IL-1β and 0.70 pg/ml for TNFα, respectively. Serum VEGF concentrations were analysed with enzyme-linked immunosorbent assay (ELISA)
with a sensitivity of 4.1 pg/ml by using DuoSet ELISA Development
System (R&D Systems, Minneapolis, USA). Serum sIL-6R, MCP-1 and
Ang-2 concentrations were measured using Quantikine ELISA Kit (R&D
Systems) according to the manufacturer’s instruction.
Samples from the overnight effluent were taken and immediately frozen at −70°C until analysis for the determination of dialysate CA125,
IL-6, sIL-6R, MCP-1, TNFα, IL-1β, VEGF and Ang-2. CA125 was determined by using electrochemiluminescence immunoassay with Elecsys
CA 125 II (Roche Diagnostics, Mannheim, Germany) according to the
manufacturer’s instruction. The lower detection limit was 0.6 IU/ml. Dialysate IL-6 concentration was determined using photometric ELISA
(Boehringer Mannheim, Mannheim, Germany) with intra- and inter-assay
coefficients of variation of 2.6% and 7.1%, respectively. The sensitivity
was 7.5 pg/ml. Dialysate TNFα and VEGF concentrations were analysed
using Bio-Plex Multiplex Cytokine Assay according to the manufacturer’s
instructions (Biorad Laboratories). The limit of detection in the dialysate
was defined as 0.82 pg/ml for TNFα and 4.30 pg/ml for VEGF. Dialysate
IL-1β concentrations were analyzed with ELISA with a sensitivity of
1.1 pg/ml by using DuoSet ELISA Development System (R&D Systems).
For the determination of sIL-6R, dialysate samples were diluted five
times and were measured using Quantikine Human sIL-6R Immunoassay
Kit (R&D Systems). Intra- and inter-assay variations were 3.5% and
5.1%, respectively. Dialysate MCP-1 and Ang-2 concentrations were
measured using Quantikine ELISA Kit (R&D Systems).
Each assay is considered highly specific for the molecule with no significant cross-reactivity.
Calculations
Residual renal function was derived from the glomerular filtration rate
(GFR) calculated as the average of renal urea and creatinine clearance.
The patient’s normalized body surface area was calculated by the Du Bois
and Du Bois equation [24]. Residual renal Kt/Vurea was obtained from 24h collection of urine. Urea distribution volume was calculated using the
Watson equation [25]. Peritoneal Kt/Vurea and creatinine clearance (Ccr)
were derived from 24-h collection of the PD effluent. Total Kt/Vurea was
calculated by the sum of renal and peritoneal Kt/Vurea.
Dialysate AR of each molecule was calculated by the product of its
dialysate concentration and drained volume divided by the dwell time
and expressed as picograms per minute.
Statistical analysis
Normality of distribution for each variable was assessed by the
Kolmogorov–Smirnov test. Variables without a normal distribution were
IL-6 and PSTR in incident PD patients
1641
Table 1. Patient characteristics (n = 50)
Age (years)
Male/female
Diabetic (n, %)
BMI (kg/m2)
BSA (m2)
Time on PD (months)
High-sensitivity CRP (mg/l)
Etiology of renal failure
Diabetes mellitus
Hypertension
Glomerulonephritis
Allograft rejection
Others
Davies comorbidity score
None (0)
Intermediate (1–2)
High (3–7)
D/P creatinine
D/D0 glucose
Net UF during PET (ml)
Weekly total Kt/V
GFR (l/week/1.73 m2)
Results
46.5 ± 14.0
27:23
14 (28%)
22.9 ± 3.9
1.63 ± 0.20
1.9 ± 1.0
0.3 (0.1–2.4)
14 (28%)
12 (24%)
11 (22%)
4 (8%)
9 (18%)
31 (62%)
16 (32%)
3 (6%)
0.72 ± 0.09
0.31 ± 0.12
690 ± 233
2.35 ± 0.67
45.0 ± 27.0
BMI, body mass index; BSA, body surface area; UF, ultrafiltration; GFR,
glomerular filtration rate calculated as the mean of creatinine and urea
clearance. Data are shown as mean ± SD or median (interquartile range)
if not specified.
either transformed into logarithmic scale for correlation analysis or
compared by a nonparametric test. For continuous variables, comparison
between two groups was made by using Student’s t test or Mann–Whitney
U test. Chi square test was used for categorical variables. Correlation
between two continuous variables was analysed by Pearson correlation
test. A P value <0.05 was considered statistically significant. SPSS version
15.0 for Windows (SPSS Inc., Chicago, IL, USA) was used for the statistical analysis.
Patient characteristics
All patients (n = 50) were ethnic Koreans and older than 18
years. Among them, 27 (54%) were male and 14 (28%) were
diabetic. Patients were 46.5 ± 14.0 years old and the patients
were receiving peritoneal dialysis for 1.9 ± 1.0 months when
modified PETwas performed. The causes of ESRD were diabetes in 14 (28%) patients, hypertension in 12 (24%),
chronic glomerulonephritis in 11 (22%), allograft rejection
in 4 (8%) and other causes in 9 (18%). Only 3 patients (6%)
had 3 or more comorbid conditions and 16 patients (32%)
had 1 or 2 comorbid conditions (Table 1).
Mean D/P creatinine ratio at 4 h was 0.72 ± 0.09 and
mean dialysate-over-initial dialysate concentration ratio
(D/D0) for glucose at 4 h was 0.31 ± 0.12 for the entire
population. Mean net ultrafiltration (UF) during the PET
test was 690 ± 233 ml. The total Kt/V (peritoneal + renal)
was 2.35 ± 0.67 and GFR was 45.0 ± 27.0 l/week/1.73 m2.
Comparison between L/A vs H/A
L/A and H/A groups had similar age, sex ratio, diabetes
prevalence and the time on PD. No significant differences
were observed between the two transport types in terms of
body mass index (BMI), GFR, comorbidity assessed by
Davies comorbidity score, hsCRP and serum concentrations of various markers such as IL-6, sIL6R, MCP-1,
VEGF and Ang-2. However, dialysate IL-6 were significantly higher in the H/A group (P = 0.002). Dialysate levels of CA125, sIL-6R, MCP-1, VEGF and Ang-2 were
not different between the two groups (Table 2). IL-1β
and TNFα concentrations in the serum and dialysate were
Table 2. Comparison between L/A and H/A groups
Age (years)
Sex (male/female)
Diabetes (n, %)
Time on PD (months)
BMI (kg/m2)
GFR (l/week/1.73 m2)
Davies comorbidity score (n, %)
Low (0)
Intermediate (1–2)
High (3–7)
High-sensitivity CRP (mg/l)
Serum IL-6 (pg/ml)
Serum sIL-6R (ng/ml)
Serum MCP-1 (pg/ml)
Serum VEGF (pg/ml)
Serum Ang-2 (pg/ml)
Dialysate CA125 (IU/ml)
Dialysate IL-6 (pg/min)
Dialysate sIL-6R (pg/min)
Dialysate MCP-1 (pg/min)
Dialysate VEGF (pg/min)
Dialysate Ang-2 (pg/min)
L/A (n = 26)
H/A (n = 24)
P value
48.0 ± 15.0
13/13
8 (30.8%)
1.8 ± 0.9
22.1 ± 3.8
43.1 ± 25.9
45.0 ± 2.9
14/10
6 (25.0%)
2.0 ± 1.0
21.6 ± 4.0
47.9 ± 30.0
0.44
0.58
0.75
0.41
0.65
0.54
0.87
16 (61.5%)
8 (30.8%)
2 (7.7%)
0.1 (0.1–2.3)
2.9 (1.4–4.1)
53.9 (39.6–66.0)
413 (338–475)
38.9 (15.8–72.3)
5813 (4737–7819)
11.7 (5.5–22.2)
123 (56–300)
1558 (678–2446)
581 (249–925)
218 (157–278)
668 (343–1344)
15 (62.5%)
8 (33.3%)
1 (4.2%)
0.8 (0.1–2.5)
2.8 (1.2–7.7)
47.7 (38.3–52.3)
381 (317–512)
38.5 (19.5–66.0)
6089 (3843–7170)
15.4 (11.6–29.5)
307 (163–465)
935 (437–2831)
746 (464–1293)
249 (90–345)
635 (317–1985)
0.57
0.71
0.19
0.75
0.82
0.42
0.058
0.002
0.70
0.10
0.88
0.58
BMI, body mass index; BSA, body surface area; GFR, glomerular filtration rate calculated as the mean of creatinine and urea clearance. Data are shown
as mean ± SD or median (interquartile range) if not specified.
1642
K.-H. Oh et al.
Table 3. Correlation between peritoneal transport parameters and various dialysate markers
MTACcr
r
P
Albumin AR
r
P
CA125
r
P
Log IL-6
r
P
Log sIL-6R
r
P
Log MCP-1
r
P
Log VEGF
r
P
Log Ang-2
r
P
MTACcr
Albumin AR
CA125
Log IL-6
Log sIL-6R
Log MCP-1
Log VEGF
Log Ang-2
1
0.196
0.187
0.183
0.217
0.576
<0.001
0.020
0.894
0.408
0.003
0.062
0.694
0.408
0.003
1
0.751
<0.001
0.303
0.039
0.497
<0.001
0.488
<0.001
0.443
0.004
0.488
<0.001
1
0.346
0.017
0.433
0.003
0.351
0.015
0.440
0.004
0.351
0.015
1
0.145
0.321
0.619
<0.001
0.329
0.031
0.619
<0.001
1
0.531
<0.001
0.533
<0.001
0.531
<0.001
1
0.478
0.001
1.000
<0.001
1
0.478
0.001
1
MTACcr, mass transfer area coefficient for creatinine; AR, dialysate appearance rate; Ang-2, angiopoietin-2.
Table 4. Correlation between peritoneal transport parameters and various serum markers
MTACcr
r
P
Albumin AR
r
P
Log CRP
r
P
Log IL-6
r
P
Log sIL-6R
r
P
Log MCP-1
r
P
Log VEGF
r
P
Log Ang-2
r
P
MTACcr
Albumin AR
Log CRP
Log IL-6
Log sIL-6R
Log MCP-1
Log VEGF
Log Ang-2
1
0.196
0.187
0.058
0.690
0.067
0.664
−0.244
0.091
−0.220
0.128
−0.038
0.800
−0.215
0.138
1
−0.159
0.292
0.061
0.699
−0.248
0.096
−0.147
0.331
0.057
0.712
−0.070
0.642
1
0.530
0.001
0.003
0.983
−0.222
0.125
0.163
0.268
−0.217
0.134
1
−0.038
0.807
0.184
0.231
−0.004
0.980
0.116
0.454
1
0.269
0.061
0.143
0.333
0.355
0.012
1
0.158
0.284
0.403
0.004
1
−0.046
0.756
1
MTACcr, mass transfer area coefficient for creatinine; AR, dialysate appearance rate; Ang-2, angiopoietin-2.
under the detection limit in the majority of the patients (data not shown) and, thus, not considered for analysis.
Correlation between dialysate markers and PSTR
MTACcr correlated with dialysate IL-6 (r = 0.576, P <
0.001), MCP-1 (r = 0.408, P = 0.003) and Ang-2 (r =
0.408, P = 0.003; Table 3). However, MTACcr did not correlate with dialysate levels of CA125, sIL-6R and VEGF.
Dialysate AR of albumin correlated with CA125 (r =
0.751, P < 0.001), IL-6 (r = 0.303, P = 0.039), sIL-6R
(r = 0.497, P < 0.001), MCP-1 (r = 0.488, P < 0.001),
VEGF (r = 0.443, P = 0.004) and Ang-2 (r = 0.488, P <
0.001) in the dialysate (Table 3).
IL-6 and PSTR in incident PD patients
1643
Table 5. Multivariate regression analysis for MTACcr and dialysate
albumin appearance rate
Dependent variable: MTACcr
Log IL-6
Serum albumin
Dependent variable: Albumin
appearance rate
log AR sIL-6R
Standardized coefficient β
P value
0.517
−0.351
<0.001
0.005
0.585
<0.001
Age, gender, diabetes, Davies comorbidity grade, CRP, serum albumin,
dialysate appearance rates for IL6, sIL6R, MCP-1, VEGF, Ang-2 were
entered in a multiple linear regression analysis.
No correlation between systemic markers and PSTR
Associations between various markers in the serum and
MTACcr or dialysate AR of albumin were analysed by
Pearson correlation analysis. Neither MTACcr nor dialysate
AR of albumin correlated with the serum concentrations of
CRP, IL-6, sIL-6R, MCP-1, VEGF and Ang-2 (Table 4).
No correlation between systemic and dialysate markers
As for the molecules analysed in the present study (IL-6,
sIL-6R, MCP-1, VEGF and Ang-2), no correlation was
found between the systemic and dialysate concentrations
of each marker molecule (data not shown).
Multivariate analysis for MTACcr and albumin
appearance rate
Multivariate linear regression models for MTACcr and albumin AR are given Table 5. Higher MTACcr was independently predicted by dialysate IL-6 (P < 0.001) and
serum albumin (P = 0.005). Higher dialysate AR of albumin was independently predicted by dialysate sIL-6R (P <
0.001; Table 5).
Correlation of dialysate IL-6 with various intra-peritoneal
markers
Dialysate level of IL-6 correlated with CA125 (r = 0.346,
P = 0.017), MCP-1 (r = 0.619, P < 0.001), VEGF (r =
0.329, P = 0.031), Ang-2 (r = 0.619, P < 0.001) but not
with sIL-6R (r = 0.145, P = 0.321) (Figure 1).
Discussion
High PSTR may have two potential etiologies—a large effective peritoneal surface area resulting in a large smallpore area and inflammation (or vascular injury) resulting
in increased peritoneal permeability. In the present study,
in order to distinguish between these two processes, we
dissociated small solute transport rate represented by
MTACcr and protein leak across large pores represented
by dialysate albumin AR.
Our results showed that peritoneal small solute transport
rate represented by MTACcr strongly correlated with the
dialysate concentrations of IL-6, MCP-1 and Ang-2. Dialysate AR of albumin correlated with the dialysate concen-
trations of IL-6, sIL-6R, MCP-1, VEGF, CA125 and Ang2. Elevated concentration of dialysate IL-6 was associated
with up-regulation in the dialysate of MCP-1, VEGF, Ang2 and CA125, respectively. After adjustment, multivariate
linear regression analysis showed that MTACcr was independently predicted by dialysate IL-6 and serum albumin
concentration. Dialysate AR of albumin was independently
associated with sIL-6R in the dialysate.
Role of the intra-peritoneal markers in determining
PSTR has been suggested in several studies. Continous
ambulatory peritoneal dialysis (CAPD) associated peritonitis is usually a localized infection in the peritoneal cavity
and is associated with a transient increase in PSTR and low
UF volume, accompanied by marked elevation in the effluent fluid of inflammatory or vasoactive substances such as
IL-1β, IL-6, transforming growth factor β1 and fibroblast
growth factor [26]. In a longitudinal study [17], baseline
D/P creatinine was associated with dialysate concentration
of locally produced vasoactive substances rather than the
systemic markers. In that study, D/PCr change over time
was associated with dialysate IL-6.
The present study showed a strong correlation between
baseline PSTR with dialysate IL-6. Dialysate IL-6 correlated both with MTACcr and with albumin AR. Association
of PSTR with dialysate IL-6 has been suggested by other
researchers as well. Pecoits-Filho et al. [2] reported a
strong positive correlation between baseline D/PCr and dialysate IL-6. In their study, the association between baseline D/PCr and dialysate IL-6 was even stronger than that
between D/PCr and plasma IL-6. However, unlike ours, the
association of IL-6 with sIL-6R or with MCP-1 was not
investigated in their study.
IL-6 has been described as having both pro- and anti-inflammatory effects [19,20]. Also, HPMC is one of the
principal sources of IL-6 [27,28]. Therefore, the mechanistic meaning of elevated dialysate IL-6 level, whether it indicates a local pro- or anti-inflammatory state or enhanced
mesothelial vitality, needs to be elucidated. In our study,
elevation of dialysate IL-6 was strongly associated with
up-regulation of MCP-1, a downstream inflammatory molecule and angiogenic markers such as VEGF and Ang-2
(Table 3, Figure 1).
It was shown in a murine model that sIL-6R shed from
infiltrating neutrophils during bacterial peritonitis complexes with intra-peritoneal IL-6. The IL-6 and sIL-6R
complex regulates differential expression of chemokines
and induces transition from initial neutrophil-predominant
to the more sustained monocyte-predominant phase [8].
MCP-1(CCL2) is a potent chemoattractant and activator
of monocytes/macrophages. Release of MCP-1 was increased when HPMCs were stimulated by IL-6 and sIL6R complex [11]. Intra-peritoneal injection of lipopolysaccharide induced up-regulation of MCP-1, VEGF and other
cytokines, resulting in increased peritoneal solute transport
rate [29]. Dialysate MCP-1 concentration positively correlated with D/PCr in a cross-sectional analysis with a mixture of stable prevalent patients and new patients [31].
Therefore, correlation of PSTR with dialysate IL-6, sIL6R and MCP-1 in our study, altogether, suggests that baseline PSTR is associated with a state of pro-inflammatory
milieu in the peritoneal membrane.
1644
Fig. 1. Dialysate IL-6 correlated with dialysate CA125 (A), MCP-1 (C), VEGF (D) and Ang-2 (E) but not with sIL-6R (B).
K.-H. Oh et al.
IL-6 and PSTR in incident PD patients
In the present study, the dialysate concentration of IL-6
was 15.3 (median) times higher than the serum counterpart, which is in parallel with other reports [16,31]. This
suggests that the dialysate concentration of IL-6 reflects
local production of the molecule in the peritoneum. IL-6
was detected in the dialysate of patients without any signs
of systemic inflammation [31]. In the present study, dialysate concentrations of IL-6 did not correlate with the serum
IL-6 or with CRP (data not shown). Local peritoneal production of IL-6 may reflect chronic inflammatory state of
the peritoneum, apart from the systemic inflammation. It is
noteworthy that dialysate sIL-6R correlated with albumin
AR alone, while dialysate IL-6 correlated with both
MTACcr and albumin AR. Whether such a discrepancy implies a differential role between IL-6 trans-signaling and
classic pathway needs to be investigated in a future study.
One explanation could be derived from the large concentration gradient for sIL-6R between the serum and dialysate. Unlike other molecules analysed in our study, serum
concentration of sIL-6R was >100 times higher than its
dialysate concentration (Table 2). It is presumable, with
such remarkable concentration gradient, that the intraperitoneal concentration of sIL-6R is more heavily dependent on its transport from the systemic circulation rather
than its local production in the peritoneum.
VEGF is a potent stimulator of vascular permeability
and neoangiogenesis [32]. In our study with incident patients, VEGF in the dialysate correlated with the AR of albumin but not with MATCcr. Our data also show a positive
correlation between dialysate IL-6 and VEGF, supporting
that VEGF is up-regulated by IL-6 [13,14].
Ang-2 is one of the angiogenic factors suspected to play
a role in the peritoneal neoangiogenesis in a rat model of
experimental encapsulating peritoneal sclerosis [33]. In
our study, associations of Ang-2 with both MTACcr and
albumin AR were revealed (Table 3). This is in keeping
with a recent report elsewhere that Ang-2 plays a role in
the pathogenesis of vascular leakiness to macromolecules
[34].
Dialysate CA125 is a glycoprotein produced constitutively by mesothelial cells [35]. CA125 is considered to
reflect peritoneal mesothelial cell mass or turnover [36].
Our study showed an association of CA125 with albumin
appearance but not with MTACCcr. Dialysate CA125 correlated with dialysate IL-6, supporting the fact that HPMC
is a major source of IL-6 in the peritoneum.
In the present study, IL-1β and TNFα concentrations in
the serum and dialysate were in the lower-than-detectable
level in the majority of the patients, which is in accordance
with other reports [37,38]. Therefore, the association of
PSTR with these two markers could not be assessed in
the present study.
Our patient population had much lower comorbid conditions compared with others. Among 50 patients, only
three patients (6%) had three or more comorbid conditions
while others reported 11% [1]. Median CRP level was
0.3 mg/l (interquartile range 0.1–2.4 mg/l). These observations together suggested a much lower level of systemic
inflammation for our patient population compared with
others [39]. Differences in the baseline patient characteristics could be one explanation for our finding that systemic
1645
factors do not have much influence on the baseline PSTR,
which is in contrast with other reports [1,2].
The present study has some limitations—small number
of patients selected from a single PD unit. These might
have rendered the study to be prone to type 2 errors and
centre effect. Therefore, our observations need to be confirmed in a larger prospective study.
Our study employed modified PET using 3.86% glucose
PD fluid, although previous reports on peritoneal solute
transport rate mostly employed standard PET using
2.26% PD fluid. It was shown elsewhere that no significant differences exist between the two methods in terms
of solute transport rates for urea, creatinine and protein
[40]. Besides, 3.86% glucose solution provides better information on ultrafiltration and free water transport.
In conclusion, the results from the present study with incident PD patients suggest a dialysate IL-6 system represented by IL-6/sIL-6R/MCP-1 as a potent determinant in
baseline PSTR. It also suggests a differential role of individual intra-peritoneal markers in association with MTACcr and
albumin AR. Elevation of dialysate IL-6 was related to elevation of downstream inflammatory molecule and angiogenic factors in the peritoneum. Future studies in a larger
scale are needed to elucidate various serum and/or dialysate
markers associated with the peritoneal transport of small
molecules and macromolecules.
Conflict of interest statement. None declared.
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Received for publication: 23.6.09; Accepted in revised form: 16.11.09