Urinary and tissue monocyte chemoattractant protein1 (MCP1) in lupus nephritis patients

Abstract

Aim of the work: To assess the role of urinary and tissue monocyte chemoattractant protein-1 (MCP-1) in active lupus nephritis (LN) and to correlate the levels with disease activity and renal status.
Patients and methods: Urinary and tissue MCP-1 were determined in 42 systemic lupus erythematosus (SLE) patients with LN. 20 matched controls were considered. SLE disease activity index (SLEDAI) was recorded in all patients. Urinary and renal tissue MCP-1 was evaluated. Renal biopsy was performed in active LN patients for histopathological classification and correlation.
Results: 22 active LN patients (22.8 ± 4.7 years old) and 20 inactive (24.6 ± 4.3 years old) were studied. They were 39 female and 3 males (F:M 13:1). The urinary MCP-1 was significantly higher in active LN patients (1072.8 ± 658.4 pg/mg creatinine) compared to the inactive group (151.3 ± 103.5 pg/mg creatinine) and both were significantly higher than the level in the controls (19 ± 17.8 pg/mg creatinine) (p

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Original Article
Urinary and tissue monocyte chemoattractant protein1 (MCP1) in lupus
nephritis patients
Hanan Ali Taha
a
, Nilly Helmy Abdallah
a
, Mohamed Nabil Salem
a,
⇑
, Azza H. Hamouda
b
,
Mervat Ismail Abd Elazeem
c
, Nahla Naeem Eesa
d
a
Internal Medicine Department, Faculty of Medicine, Beni-Sueif University, Egypt
b
Histology Department, Faculty of Medicine, Minia University, Egypt
c
Rheumatology and Rehabilitation Department, Faculty of Medicine, Beni-Sueif University, Egypt
d
Rheumatology and Rehabilitation Department, Faculty of Medicine, Cairo University, Egypt
article info
Article history:
Received 17 January 2017
Accepted 29 January 2017
Available online xxxx
Keywords:
Systemic lupus erythematosus
Lupus nephritis
Urinary monocyte chemoattractant protein
Renal biopsy
Immunohistochemistry
abstract
Aim of the work: To assess the role of urinary and tissue monocyte chemoattractant protein-1 (MCP-1) in
active lupus nephritis (LN) and to correlate the levels with disease activity and renal status.
Patients and methods: Urinary and tissue MCP-1 were determined in 42 systemic lupus erythematosus
(SLE) patients with LN. 20 matched controls were considered. SLE disease activity index (SLEDAI) was
recorded in all patients. Urinary and renal tissue MCP-1 was evaluated. Renal biopsy was performed in
active LN patients for histopathological classification and correlation.
Results: 22 active LN patients (22.8 ± 4.7 years old) and 20 inactive (24.6 ± 4.3 years old) were studied.
They were 39 female and 3 males (F:M 13:1). The urinary MCP-1 was significantly higher in active LN
patients (1072.8 ± 658.4 pg/mg creatinine) compared to the inactive group (151.3 ± 103.5 pg/mg crea-
tinine) and both were significantly higher than the level in the controls (19 ± 17.8 pg/mg creatinine)
(p < 0.001). A significant correlation was present in the active LN patients between urinary MCP-1 level
and proteinuria, anti-dsDNA, renal SLEDAI and biopsy activity index and negatively with C3 and C4. There
was a significant correlation of the glomerular MCP-1 renal tissue expression score with the renal SLEDAI,
anti-dsDNA, biopsy activity index and urinary MCP-1 and negatively with C3. Tubulointerstitial MCP-1
score significantly correlated with urinary MCP-1. Urinary, glomerular and tubular MCP-1 showed a sen-
sitivity of 97%, 64% and 4% and specificity of 100%, 95% and 20% respectively in detecting LN.
Conclusion: MCP-1 could be a valuable marker for LN and disease activity.
Ó2017 Egyptian Society of Rheumatic Diseases. Publishing services provided by Elsevier B.V. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disorder
that may affect multiple organ systems. Renal damage is one of the
most serious complications of SLE. Renal involvement occurs in
40–70% of all patients [1]. Renal biopsy is the gold standard for
diagnosis of LN. However, repeated biopsies are not always practi-
cal particularly in those with associated severe haematological or
cerebral manifestations. Moreover, it is also an invasive procedure
[2].The most widely used biomarkers for early detection of chronic
kidney disease are proteinuria, serum creatinine and blood urea
nitrogen (BUN). All of these indicate later stages of involvement
[3]. Many biomarkers for renal involvement in SLE have been sug-
gested in Egyptian patients [4–7].
Monocyte chemoattractant protein-1 (MCP1) is a chemokine
that attracts monocytes/macrophages to sites of inflammation
[8]. The MCP-1 was significantly increased in Egyptian SLE patients
especially those with an increased intima media thickness [9].
MCP-1 is produced by mesangial, podocyte, and monocyte cells
in response to various proinflammatory stimuli. These inflamma-
tory cells and substances subsequently mediate tissue injury and
contribute to the development of renal dysfunction [8]. Urinary
levels of MCP-1 were found to be significantly greater in patients
with a renal flare [10,11].
The aim of the present study was to assess the role of urinary
and tissue monocyte chemoattractant protein-1 (MCP-1) in the
early diagnosis of lupus nephritis (LN) and to correlate the levels
with disease activity and renal status.
http://dx.doi.org/10.1016/j.ejr.2017.01.004
1110-1164/Ó2017 Egyptian Society of Rheumatic Diseases. Publishing services provided by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Peer review under responsibility of Egyptian Society of Rheumatic Diseases.
⇑
Corresponding author.
E-mail address: mnabil2011@yahoo.com (M.N. Salem).
The Egyptian Rheumatologist xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
The Egyptian Rheumatologist
journal homepage: www.elsevier.com/locate/ejr
Please cite this article in press as: Taha HA et al. Urinary and tissue monocyte chemoattractant protein1 (MCP1) in lupus nephritis patients. The Egyptian
Rheumatologist (2017), http://dx.doi.org/10.1016/j.ejr.2017.01.004

2. Patients and methods
This cross sectional study was performed on 42 SLE patients and
20 age and sex matched apparently healthy control subjects.
Patients were selected from the Rheumatology and Clinical
Immunology unit, Internal Medicine department as well as the
Rheumatology and Rehabilitation department, Faculty of Medicine,
Beni Sueif University in the period between January 2014 and
September 2014 and were diagnosed according to the Systemic
Lupus International Collaborating Clinics classification criteria for
SLE [12]. The study was approved by the university ethics review
committee in accordance with the 2013 revised Helsinki Declara-
tion. A written consent was provided by the patients before inclu-
sion in the study.
Disease activity was assessed with the Systemic Lupus Erythe-
matosus Disease Activity Index (SLEDAI) [13]. Renal SLEDAI score
was considered which consists of 4 kidney related items (haema-
turia, pyuria, proteinuria and urinary casts) [14].
Demographic, clinical data and medication history were
recorded. Laboratory investigations done included complete blood
count (CBC), erythrocyte sedimentation rate (ESR), serum crea-
tinine and protein quantification in 24 hour urine. Anti-double
stranded deoxyribonucleic acid (anti-ds DNA) was assessed by
indirect immunofluorescence and the complement factors (C3
and C4 levels) by radial immunodiffusion.
Urinary MCP-1 was measured (CCL2/MCP-1 Quantikine ELISA
kit, R&D Systems, USA) in random spot urine samples at the time
of renal biopsy or within 30 days of it. First morning voided mid-
stream urine was used for the analysis and values were expressed
as pg/mg creatinine.
Patients who required kidney biopsy as part of the standard
care therapy were included. Ultrasound guided renal biopsy was
performed in the internal medicine department and biopsies were
evaluated according to the revised International Society of
Nephrology/Renal Pathology Society (ISN/RPS) classification of
lupus nephritis [15]. The histological activity and chronicity indices
were calculated.
All patients were considered to have renal involvement accord-
ing to clinical, laboratory and biopsy parameters and patients were
accordingly classified into 2 groups: active and inactive LN.
Immunohistochemically staining of kidney biopsy was done
using streptavidin-biotin-immunoperoxidase technique (Dako-
cytomation CA). Glomerular and tubular staining using a
histopathological sore from 100 to 300 based on 2 variables; per-
centage of positively stained cells and a scale of immunointensity
(from 0 to 3) [16].
Statistical analysis: Data were analysed using the software,
Statistical Package for Social Science, (SPSS) version 19. The results
were presented percentage for qualitative data and as minimum,
maximum, mean and standard deviation for quantitative data.
Student t-test was used for comparison between means of two
groups and one way ANOVA for three groups. Spearman correla-
tion coefficient was used to test relations between numerical vari-
ables. P-value < 0.05 was considered significant. Receiver operating
characteristic (ROC) curves were constructed to determine the per-
formance characteristics of urinary MCP-1 levels, glomerular and
tubular MCP-1 for detection and prediction of LN activity.
3. Results
This study was performed on 42 SLE patients and 20 normal
control subjects. Group I included 22 active LN patients with mean
age of 22.8 ± 4.7 years; 20 females and 2 males with a F:M 10:1.
Group 2 included 20 patients with inactive lupus nephritis with
mean age 24.6 ± 4.3 years; 19 females and one male patient (F:M
19:1). The 20 control subjects had a matched age of
26.6 ± 4.5 years (p = 0.37) and gender (p = 0.76); 18 females and 2
males (F:M 9:1). Active LN patients were receiving pulse steroids,
cyclophosphamide (CYC) and mycophenolate mofetil while inac-
tive LN patients were maintained on immunosuppressives. The
Table 1
Demographic features, laboratory investigations, renal biopsy findings and disease activity in systemic lupus erythematosus patients with and without active lupus nephritis.
Parameter mean ± SD or n (%) Lupus nephritis (LN) patients (n = 44)
Active (n = 22) Inactive (n = 20) p
Disease duration (year) 3.4 ± 2.7 5.4 ± 2.9 0.03
Laboratory investigations
Hemoglobin (g/dl) 9.44 ± 1.69 10.87 ± 1.75 0.012
WBC (10
3
/mm
3
) 6.65 ± 3.30 7.73 ± 3.70 0.34
Platelets (10
3
/mm
3
) 246.4 ± 114.1 241.6 ± 99.3 0.89
ESR (mm/1st h) 109.3 ± 16.5 48.60 ± 26.76 <0.001
Creatinine (mg/dl) 1.6 ± 1.8 0.98 ± 0.97 0.16
Proteinuria (mg/24 h) 1866.8 ± 1260.9 996 ± 763 <0.001
C3 (mg/dl) 49.9 ± 19.4 131.9 ± 55.1 <0.001
C4 (mg/dl) 8.8 ± 5.02 30.6 ± 15.2 <0.001
Anti-dsDNA (IU/ml) 104.7 ± 15.6 24.1 ± 6.3 <0.001
Renal biopsy
LN class
Class I 0 (0) 2 (10)
Class II 4 (20) 8 (40)
Class III 8 (40) 3 (15) 0.16
Class IV 7 (35) 7 (35)
Class V 1 (5) 0 (0)
Activity index 10.5 ± 4.6 2.95 ± 1.6 < 0.001
Chronicity index 4.6 ± 2.4 3.3 ± 1.9 0.07
Disease activity
SLEDAI Total 39.6 ± 3.6 14.5 ± 4.1 < 0.001
Renal 9.4 ± 2.4 5 ± 1.8 < 0.001
Extra-renal 30.2 ± 4.1 9.5 ± 4.3 < 0.001
C3 and C4: Complement factor 3 and 4, Anti-ds DNA: Anti-double stranded deoxyribonucleic acid, SLEDAI: Systemic Lupus Erythematosus Disease Activity Index. Bold values
are significant at p < 0.05.
2H.A. Taha et al. / The Egyptian Rheumatologist xxx (2017) xxx–xxx
Please cite this article in press as: Taha HA et al. Urinary and tissue monocyte chemoattractant protein1 (MCP1) in lupus nephritis patients. The Egyptian
Rheumatologist (2017), http://dx.doi.org/10.1016/j.ejr.2017.01.004

demographic features, laboratory investigations, renal biopsy find-
ings and disease activity in the patients are presented in Table 1.
The urinary MCP-1 was significantly higher in active LN
patients (1072.8 ± 658.4 pg/mg creatinine) compared to the inac-
tive group (151.3 ± 103.5 pg/mg creatinine) and both were signifi-
cantly higher than the level in the controls (19 ± 17.8 pg/mg
creatinine) (p < 0.001). Comparison of the urinary MCP-1 in
patients and control is graphically demonstrated in Fig. 1.
A significant correlation was present in the active LN patients
between urinary MCP-1 level and proteinuria, anti-dsDNA, renal
SLEDAI and biopsy activity index and negatively with C3 and C4
as shown in Table 2.
In both nephritis groups, there was a significant correlation of
the glomerular MCP-1 renal tissue expression score with the renal
SLEDAI, anti-dsDNA level, biopsy activity index and urinary MCP-1
level and negatively with C3 level. However, the tubulointerstitial
MCP-1 score significantly correlated with urinary MCP-1 (Table 3).
Glomerular and tubular renal tissue immune-staining of MCP-1 in
lupus nephritis patients are shown in Fig. 2.
The ROC curve of the urinary, glomerular and tubular MCP-1 for
detecting activity of LN revealed an area under curve (AUC) of 0.99,
0.75 and 0.34 respectively as well as a sensitivity of 97%, 64% and
4% and specificity of 100%, 95% and 20% respectively (Fig. 3).
4. Discussion
Systemic lupus erythematosus presents many challenges for
clinicians. The onset of disease may be insidious, with many differ-
ent symptoms and signs, making early and accurate diagnosis not
easy. It is protean in its manifestations and follows a relapsing and
remitting course [17]. Renal involvement in SLE carries significant
morbidity and mortality. The 5- and 10-year renal survival rates of
lupus nephritis in the 1990s ranged between 83%–92% and 74–84%
respectively [18]. LN demonstrates a wide spectrum of glomerular
alterations reaching from mesangial through focal proliferative to
diffuse proliferative glomerulonephritis (GN) with crescent
Fig. 1. Urinary monocyte chemoattractant protein-1 (MCP-1) in the lupus nephritis
patients and control.
Table 2
Correlation of urinary monocyte chemoattractant protein-1 (MCP-1) with laboratory parameters, disease activity and renal biopsy indices.
Parameters
R (p)
Urinary MCP-1 (pg/mg creatinine)
Active LN (n = 22) Inactive LN (n = 20)
Hemoglobin (g/dl) 0.19 (0.43) 0.13 (0.58)
Creatinine (mg/dl) 0.23 (0.34) 0.25 (0.29)
Proteinuria (g/24hrs) 0.66 (0.002) 0.19 (0.45)
C3 (mg/dl) 0.12 (0.008) 0.24 (0.32)
C4 (mg/dl) 0.54 (0.015) 0.37 (0.11)
Anti-dsDNA (IU/ml) 0.24 (0.001) 0.03 (0.89)
Renal SLEDAI 0.41 (0.001) 0.22 (0.3)
Biopsy activity index 0.5 (0.001) ––
Biopsy chronicity index 0.02 (0.9) – –
C3 and C4: Complement factor 3 and 4, Anti-ds DNA: Anti-double stranded deoxyribonucleic acid, SLEDAI: Systemic Lupus Erythematosus Disease Activity Index. Bold values
are significant at p < 0.05.
Table 3
Correlation between monocyte chemoattractant protein-1 (MCP-1) renal tissue expression scores with the laboratory parameters, renal disease activity index, biopsy indices and
urinary MCP-1 in systemic lupus erythematosus patients with lupus nephritis.
Parameter
R (p)
MCP-1 renal tissue expression scores
Glomerular Tubulointerstitial
Creatinine (mg/dl) 0.11 (0.3 0.2 (0.5)
Proteinuria (g/24 h) 0.62 (<0.001) 0.4 (0.05)
C3 (mg/dl) 0.42 (0.02) 0.01 (0.8)
C4 (mg/dl) 0.39 0.05 0.22 (0.1)
Anti-dsDNA (IU/ml) 0.41 (0.04) 0.1 (0.2)
Renal SLEDAI 0.55 (0.01) 0.31 (0.07)
Biopsy activity index 0.41 (0.01) 0.39 (0.05)
Biopsy chronicity index 0.11 0.6 0.21 (0.7)
Urinary MCP-1 0.46 (0.02) 0.51 (0.01)
C3 and C4: Complement factor 3 and 4, Anti-ds DNA: Anti-double stranded deoxyribonucleic acid, SLEDAI: Systemic Lupus Erythematosus Disease Activity Index, MCP-1:
monocyte chemoattractant protein-1 (MCP-1). Bold values are significant at p < 0.05.
H.A. Taha et al. / The Egyptian Rheumatologist xxx (2017) xxx–xxx 3
Please cite this article in press as: Taha HA et al. Urinary and tissue monocyte chemoattractant protein1 (MCP1) in lupus nephritis patients. The Egyptian
Rheumatologist (2017), http://dx.doi.org/10.1016/j.ejr.2017.01.004

formation. Tubulointerstitial nephritis may also be an additional
feature [19].
The conventional laboratory markers used in clinical practice
such as serum complement levels and ds-DNA antibodies are unre-
liable indicators of LN as they lack both sensitivity and specificity
for prediction of active or relapsing LN. Moreover, serum creatinine
is also an unsatisfactory marker as significant renal damage can
occur before it rises [20]. Other laboratory tests such as proteinuria
and urinary sediments are also non-specific markers [21].
Renal biopsy remains the gold standard for the evaluation of LN
disease activity. However, it is an invasive procedure and serial
renal biopsies are not appropriate in clinical practice [22]. Hence,
it is very important to identify noninvasive new biomarkers that
are able to predict renal flares and/or reflect its activity [23]. Clin-
ical parameters are not sensitive or specific enough for detecting
ongoing disease activity in the SLE [3]. Measurement of cytokines
in urine is therefore an encouraging approach with increasing clin-
ical applications in SLE. Identifying biomarkers that identify severe
and active LN may provide a reliable alternative to the invasive
biopsy [3]. All types of renal cells (endothelial, mesangial, tubular
epithelial, interstitial cells and podocytes) can express chemokines
upon stimulation. Proinflammatory stimuli, induce MCP-1 expres-
sion, which ultimately leads to tissue injury [24]. MCP-1 plays a
major role in the pathogenesis of progression of renal disease [25].
In the present study, urinary MCP-1 levels were significantly
elevated in patients with active LN compared to those with inac-
tive disease and control. Similarly, in an early report, Noris et al.
[26] showed that in active LN patients, urinary MCP-1 was signif-
icantly higher than in inactive patients or in controls, and high
doses of IV methylprednisolone significantly lowered its levels.
Tucci et al. [27] presented evidence that urinary MCP-1 promotes
renal disease in experimental GN, also, Rovin et al. [10] have shown
that the mean level at the time of renal flares was significantly
higher than that of controls, patients with inactive renal disease
and patients with active or inactive nonrenal SLE. Li and colleagues
[28] agreed with us that the MCP-1 levels in urine of active
patients were markedly higher than in controls, but no significant
difference was found between the levels between those in remis-
sion and control. Moreover, Alharazy et al. [29] and Rovin and Song
[30] found that urinary MCP-1 of patients with renal flare was sig-
nificantly higher than that of patients with non-renal flare and con-
trol. Singh et al. [31] reported that urinary MCP-1 could distinguish
those patients with active LN from those with inactive renal dis-
ease or stable SLE and the study of Torabinejad et al. [32] and
Alharazy et al. [33] reported a higher level in active LN patients
which decreased in response to treatment while, Watson et al
[34] had confirmed that MCP-1 distinguishes patients with active
and inactive LN, regardless of previous renal involvement.
Fig. 2. Glomerular and tubular renal tissue immunohistochemical of monocyte chemoattractant protein-1 (MCP-1) in lupus nephritis patients. Positive cells are stained dark
brown and are referred to by black arrows showing: very weak cytoplasmic expression only in the macula densa cells (arrows) in (a). The expression begins to appear in the
proximal (green arrows) and distal convoluted tubules (blue arrows) in (b) and increases in (c) and (d) respectively to become deeply stained in (e) and (f). (counterstain H X
at 1000 magnification). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
4H.A. Taha et al. / The Egyptian Rheumatologist xxx (2017) xxx–xxx
Please cite this article in press as: Taha HA et al. Urinary and tissue monocyte chemoattractant protein1 (MCP1) in lupus nephritis patients. The Egyptian
Rheumatologist (2017), http://dx.doi.org/10.1016/j.ejr.2017.01.004

Furthermore, Rosa et al. [35] found the concentration of urinary
MCP-1 significantly higher in active LN patients. A significant cor-
relation between urinary MCP-1 and renal SLEDAI scores has been
found in the present study. Many authors had previously reported
these findings as Rovin and Sang [30] and Chan et al. [36] noted
that urinary MCP-1 level significantly correlated with overall SLE-
DAI and renal score.
In our study there was a significant correlation between pro-
teinuria, anti-dsDNA and urinary MCP-1 and negatively with C3
in the active LN patients, while in the inactive patients there was
no such correlation. This may suggest that urinary MCP-1 could
be added to the panel of non-invasive biomarkers used for detect-
ing renal flares. In accordance with our results Tucci et al. [27] and
Kim et al. [37] found a significant correlation between urinary
MCP-1 and proteinuria. In active LN patients, a significant correla-
tion was found between urinary MCP-1 and the biopsy activity
index which agrees with the results of Brunner et al. [38] who
studied a panel of non-invasive biomarkers including urinary
MCP-1 and correlated them with histological features.
In the current study renal biopsy was obtained from SLE
patients with active LN and MCP-1 renal tissue expression was
evaluated in relation to laboratory investigations. No relation was
noted between serum creatinine and either glomerular or tubu-
lointerstitial MCP-1 protein expression. However, a significant cor-
relation was present between the level of proteinuria and both
glomerular and tubulointerstitial MCP-1 expression. This agreed
with the results of Marks et al. [39]. Proteinuria may stimulate
renal tubular epithelial cells to produce cytokines as MCP-1 that
can contribute to chronic kidney damage. On the otherhand, Dia
et al., [40] did not find any association between the degree of pro-
teinuria and MCP-1 expression. This discrepancy may be attributed
to the degree of proteinuria i.e. heavy proteinuria may be associ-
ated with tubulointerstitial and glomerular damage. The present
results were in accordance with the results of Ghobrial et al. [3]
in proving a strong positive correlation between tissue and urinary
MCP-1 which may be due to that such chemokine starts pathogen-
esis in the kidney and is then excreted in urine. Tissue MCP-1 also
correlated with renal SLEDAI and biopsy activity index. Now we
can ask if tissue staining for MCP-1 in routine renal biopsy for
lupus patients could be beneficial.
In this work, urinary MCP-1 had a sensitivity of 97% and a speci-
ficity of 100% in detecting active lupus nephritis. Glomerular MCP-
1 had a sensitivity of 64% and specificity of 95% while tubular MCP-
1 had a sensitivity of 4% and specificity of 20% in detecting active
LN. Therefore, urinary and glomerular MCP-1 are more sensitive
and specific for detection of activity of lupus nephritis.
Certain limitations were encountered in the current study and
need to be addressed in the future. Including the small sample size.
Serial measurement of UMCP-1 together with its correlation with
disease activity and treatment response may also be useful
In conclusion, urinary and tissue MCP-1 was able to distinguish
active from inactive renal disease. It has a consistently good diag-
nostic performance with a high sensitivity and specificity for
detection of LN activity. Thus, it can be added to the panel of
biomarkers either in urine or in renal biopsy.
Conflict of interest
None.
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Rheumatologist (2017), http://dx.doi.org/10.1016/j.ejr.2017.01.004

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6H.A. Taha et al. / The Egyptian Rheumatologist xxx (2017) xxx–xxx
Please cite this article in press as: Taha HA et al. Urinary and tissue monocyte chemoattractant protein1 (MCP1) in lupus nephritis patients. The Egyptian
Rheumatologist (2017), http://dx.doi.org/10.1016/j.ejr.2017.01.004