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NDT Advance Access originally published online on May 21, 2008
Nephrology Dialysis Transplantation 2008 23(11):3521-3526; doi:10.1093/ndt/gfn270
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Glomerular expression of monocyte chemoattractant protein-1 is predictive of poor renal prognosis in paediatric lupus nephritis

Stephen D. Marks1,2, Sue J. Williams3, Kjell Tullus1,2 and Neil J. Sebire3

1 Nephro–Urology Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH 2 Department of Paediatric Nephrology 3 Department of Paediatric Pathology, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, UK

Correspondence and offprint requests to: Stephen D. Marks, Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, UK. Tel: +44-20-7405-9200, Ext: 0292; Fax: +44-20-7829-8841; E-mail: s.marks{at}ich.ucl.ac.uk



   Abstract
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 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Monocyte chemoattractant protein-1 (MCP-1) is upregulated and it recruits and activates inflammatory cells in murine lupus nephritis (LN).

Methods. Clinical outcomes of children with LN were examined in relation to glomerular expression of MCP-1 and macrophage infiltration, as determined by immunohistochemical staining of renal biopsy sections with MCP-1 and CD68. Sections were analysed using a modified histological score (H-score; maximum of 300) based on both percentage of positively stained cells and intensity of staining.

Results. Renal biopsies were examined from 34 children [27 (79%) female] aged 7.7–17.3 (median 13.7) years with 50% ISN/RPS Class IV LN. Renal dysfunction and proteinuria at follow-up of 2.2–15.4 (median 6.5) years were analysed with estimated glomerular filtration rates (eGFR) of 11.2–124.1 (median 93.6) ml/min/1.73 m2 and urine albumin:creatinine ratios of 1–535 (median 63) mg/mmol. There was a correlation between glomerular expression of MCP-1 and CD68 (r = 0.98, P = 0.04; median modified H-score of 219.7 and 230.8, respectively). Patients with Class III and IV LN had increased glomerular expression of both MCP-1 and PGM1 compared to the other classes (P = 0.01) with Class IV-G LN patients having the most glomerular expression of MCP-1 (median of 227.3) and PGM1 (median of 237.5) and the worst renal prognosis (with proteinuria and reduced eGFR).

Conclusions. There is a correlation between glomerular expression of MCP-1 and PGM1 and worsening renal prognosis in paediatric LN. Larger prospective studies of paediatric LN are required to further evaluate MCP-1 and other markers of disease progression.

Keywords: histopathology; lupus nephritis; MCP-1 (monocyte chemoattractant protein-1); outcomes; paediatric



   Introduction
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Subjects and methods
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Systemic lupus erythematosus (SLE) is an unpredictable multi-systemic autoimmune life-long disease whose aetiology and pathogenesis are incompletely understood. Clinical features are diverse and episodic with differing immunological manifestations. Both adults and children with SLE have a significant morbidity and mortality, which is closely related to renal involvement [1–6]. Children with SLE have an increased incidence, severity and morbidity of lupus nephritis (LN) compared to adult-onset disease [7–10]. The histopathological lesion of LN that is characterized by intra-renal inflammation and lymphocyte activation cannot be accurately predicted from clinical or serological information.

Chemotactic factors, such as monocyte chemoattractant protein-1 (MCP-1), appear to play a pivotal role in leucocyte entry into the kidney, enhancing endothelial and leucocyte adhesiveness and endothelial permeability in murine and human LN. This has been proven by previous immunohistochemical and in situ hybridization analyses of renal tissue from patients (or experimental animals) that have demonstrated local renal expression of chemotactic factors in association with inflammatory disease [11]. Renal parenchymal cells produce chemotactic factors in response to proinflammatory stimuli in cell culture studies [12]. Proteinuria can contribute to chronic kidney disease by stimulating renal tubular epithelial cells to produce cytokines such as MCP-1.

The International Society of Nephrology/Renal Pathology Society (ISN/RPS) Working Group revised the histopathological classification of LN in 2003 in order to provide a clear and unequivocal description of the various lesions and classes of LN [13,14]. Adult [15–17] and paediatric [18] studies to date have shown this to be worthwhile in allowing a better standardization and lending a basis for further clinicopathological studies.

As organ involvement is variable in SLE, the ideal site for investigating the local immunopathogenesis of LN is examining the renal tissue itself which has not been previously performed in children. Our aim was to evaluate MCP-1 in the inflammatory component of LN and the clinicopathological correlations of paediatric LN in relation to glomerular expression of MCP-1 and macrophages.



   Subjects and methods
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 Subjects and methods
Results
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Patients
SLE patients with LN were identified through searches in the Paediatric Nephrology and Histopathology databases at Great Ormond Street Hospital for Children NHS Trust. Patients with stored samples from their percutaneous renal biopsies from 1 January 1995 to 31 December 2005 were included. All the patients fulfilled at least 4 of the 11 revised American College of Rheumatology classification criteria for the diagnosis of SLE [19,20] with histopathological diagnosis and confirmation of LN.

Renal biopsy
Percutaneous renal biopsies were scored according to the 2003 ISN/RPS classification of LN [13,14] with additional studies on paraffin sections. Immunohistochemical staining was carried out using a commercially available monoclonal mouse antihuman MCP1/CCL2 antibody (R&D Systems, Oxon, UK) at a dilution of 1 in 40, which was selected for its documented efficacy in paraffin-embedded specimens and its ability to detect human MCP-1 in immunohistochemistry experiments without cross-reactivity with other chemokines. Glomerular expression of macrophage activity was detected using a monoclonal mouse antihuman CD68 antibody clone [phosphoglucomutase 1 (PGM1); Dako, Cambs, UK] at a dilution of 1 in 250. Both antibodies required antigen retrieval using ‘pressure cooking’ and pH 6.2 EDTA/citrate buffer. The detection Ultra Vision One horseradish peroxidase (HRP) polymer (Lab Vision Corporation, Cheshire, UK) was applied and the antigenic sites visualized with Dako REAL DAB+ Chromogen (Dako, Cambs, UK). Biopsies were scored by an observer (S.M.) blinded to patient identification and labelled as study number only. Glomerular staining of biopsies was analysed using a modified histopathology score (H-score of 100–300) based on both percentage of positively stained cells and a semi-quantitative scale of immunointensity as previously described [21] (0 = negative, 1 = intermediate, 2 = positive; Figure 1). Renal biopsy samples from nine children with minimal change nephrotic syndrome without any immunoglobulin deposition were used as controls (Figure 1).


Figure 1
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  		Fig. 1 Control specimens and cases with negative, intermediate and positive immunohistochemistry staining of glomeruli with MCP-1 and PGM1 (original magnification x250 with haematoxylin counterstain).

 
Clinical data
Renal function [plasma creatinine and estimated glomerular filtration rates (eGFR) from the standard Schwartz formula] [22] serum albumin and urine albumin:creatinine ratios (UA:UC) from early morning urine samples were obtained at the time of biopsy and at follow-up.

Statistical methods
Statistical analysis was performed with SPSS for Windows software version 14.0 (SPSS Inc., Chicago, IL, USA). Statistical significance was derived using non-parametric tests (Wilcoxon, Mann–Whitney and Kruskal–Wallis tests). Relationships between MCP-1, PGM1, eGFR and UA:UC were analysed using Spearman's rank correlation coefficient. P values of <0.05 were considered as statistically significant.

Ethics
Ethical approval was obtained for this study from the Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust Research Ethics Committee.



   Results
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 Subjects and methods
 Results
Discussion
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Clinical data
Thirty-four children aged 7.7–17.3 (median 13.7) years of whom 79% (27 of 34) were female were followed up for 2.2–15.4 (median 6.5) years after the biopsy. The patient and renal survival were 97% (33 of 34) and 94% (32 of 34), respectively, with one patient dying of infective complications due to hypocomplementaemia and immunosuppression and another patient requiring end-stage renal failure management with dialysis at follow-up. Renal dysfunction and proteinuria were analysed at follow-up with eGFR of 11–124 (median 94) ml/min/1.73 m2 and urine albumin:creatinine ratios of 1–535 (median 63) mg/mmol (Table 1).


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  		Table 1 Patients’ laboratory data at the time of biopsy (with modified H-score for MCP-1 and PGM1) and clinical follow-up data

 
Biopsy data
Renal biopsy specimens were analysed and scored according to the 2003 ISN/RPS classification of LN [13,14] with the biopsies containing 10–76 (median 23) glomeruli. Fifty percent of cases were ISN/RPS Class IV LN with 3%, 6%, 21%, 9% and 12% being Class I, II, III, V and overlap cases, respectively (Figure 2). Glomerular staining of MCP-1 and PGM1 was assessed using a modified histopathology score (maximum of 300) based on both percentage of positively stained cells and a semi-quantitative scale of immunointensity (0 = negative, 1 = intermediate, 2 = positive; Figure 1) compared to minimal change nephrotic syndrome controls.


Figure 2
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  		Fig. 2 ISN/RPS classification of all 34 lupus nephritis renal biopsies.

 
There was a paucity of glomerular expression of MCP-1 and PGM1 in ISN/RPS Classes I, II and V. However, patients with Class III and IV LN had increased glomerular expression of both MCP-1 and PGM1 compared to the other classes (P = 0.01) that was related to the degree of albuminuria (P = 0.03 and 0.04, respectively) but not the plasma creatinine (P = 0.22 and 0.28, respectively) or albumin levels (P = 0.78 and 0.81, respectively) at the time of the renal biopsy. The most significant glomerular expression of MCP-1 was in patients with Class IV-G LN (median of 227.3 compared to 133.3 and 208 for Class III and IV-S, respectively). This trend was mirrored by glomerular expression of PGM1 (median of 237.5 compared to 135.7 and 200 for Class III and IV-S, respectively; Table 1). There was a correlation not only between increased glomerular expression and the worst renal prognosis (with proteinuria and reduced eGFR), but also between glomerular expression of MCP-1 and PGM1 (r = 0.98, P = 0.04; Figure 3). Patients with more active LN (especially crescentic glomerulonephritis and proliferative lesions) had increased glomerular expression of MCP-1 (P = 0.03), PGM1 (P = 0.02), proteinuria (P = 0.005) and renal dysfunction (P = 0.03).


Figure 3
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  		Fig. 3 Relationship between modified histopathology scores of glomerular expression of MCP-1 and PGM1 (r = 0.98, P = 0.04).

 


   Discussion
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 Subjects and methods
 Results
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References
 
Paediatric LN occurs in up to 82% of children with SLE, of whom half will have features of Class IV LN, which carries the worst prognosis of renal dysfunction and proteinuria [8].

Our study has shown a correlation between increased glomerular expression of MCP-1 and PGM1 (anti-CD68), and albuminuria at the time of renal biopsy in addition to adverse renal prognosis in childhood LN. These findings suggest upregulation of MCP-1 with increasing intra-renal inflammation and LN disease severity, highlighting the possible pathogenic role of MCP-1 in the inflammatory process. This relationship has previously been demonstrated in both murine [23] and adult [24] LN models and suggests its possible use as a prognostic marker, but the present study is the first reporting on a series of childhood LN. Since children with SLE generally have more disease activity and damage, with increased incidence and severity of LN, studies of childhood LN are essential to delineate whether their developing immune system reacts differently with respect to various aetiopathogenic factors. This may be important in considering different treatments of SLE and LN with potentially differing pathophysiological responses in children.

MCP-1 attracts monocytes and memory T lymphocytes to the exclusion of other white blood cells, such as neutrophils. MCP-1 has a possible pathogenic role in a variety of diseases having a monocyte inflammatory component. There is an attenuation of inflammatory infiltrates and a decrease in indices of renal damage in experiments designed to neutralize the chemoattractant activity of specific chemotactic factors in models of renal injury in murine and human glomerulonephritis. Proteinuria stimulates renal tubular epithelial cells to produce cytokines such as MCP-1 that can contribute to chronic kidney disease [25] with increasing proteinuria correlating with PGM1 staining in adult LN [26]. Recent evidence has shown that the expression of target genes can be associated with LN activity and scarring. Intra-glomerular expression of IL-12, IL-18, IL-10 and MCP-1 was shown to correlate with the severity of systemic and histological activity of LN. Tubulointerstitial expression of other target genes correlated with the degree of chronic kidney scarring [11].

Interestingly, we have demonstrated increased glomerular expression of MCP-1 in children with ISN/RPS Class IV-G LN that in our previous paediatric study was also associated with the worst renal prognosis [18], unlike in adult LN where outcomes are similar to Class IV-S LN [16,17,27]. This is interesting as our differences in both glomerular expression of MCP-1 and PGM1 and renal prognosis may be due to different aetiopathogenetic mechanisms in children with less immune complex deposition in Class IV-S LN than Class IV-G LN [28]. In addition, there was no glomerular expression of MCP-1 in our paediatric cohort of Class V LN; this is not surprising, as most clinicians feel that lupus membranous nephropathy in children has a different clinical course and prognosis [29,30]. However, some critics feel that although the ISN/RPS classification is helpful in showing differences in presenting clinical and pathological features (which may underpin different aetiopathogenesis), there are not consistent differences in clinical outcomes in some of the subgroups [27,31].

Children with more active LN with crescentic glomerulonephritis and proliferative lesions had increased expression of both MCP-1 and PGM1. These findings are similar to those from a previous study showing that there was increased staining for MCP-1 in glomerular and interstitial cells in human crescentic glomerulonephritis [32]. In this cohort, urinary MCP-1 was a useful non-invasive technique for the assessment of renal involvement and monitoring the response to therapy in adults with ANCA-associated vasculitis. In a previous study of adults with crescentic glomerulonephritis, urinary MCP-1 levels correlated with the percentage of both total and fibrocellular/fibrous crescents and the number of CD68-positive infiltrating cells with the distribution of MCP-1 in the interstitium, in contrast to macrophage inflammatory protein (MIP)-1-alpha, which was detected within the crescentic lesions [33].

Furthermore, it is possible that genetic polymorphisms of the MCP-1 gene may predispose to the development of SLE, with certain genotypes at higher risk of developing LN through modulating MCP-1 expression [34,35]. This would suggest its possible role in aetiopathogenesis of LN with the useful monitoring of MCP-1 as a marker of disease activity. However, other authors have failed to show an association between MCP-1 genetic polymorphisms and the histological phenotype of LN [36].

There is evidence of the role of MCP-1 in the development of renal injury in animal and human LN. MCP-1 is upregulated and it recruits and activates inflammatory cells in murine LN [37]. If MCP-1 is involved in the aetiopathogenesis of SLE, therapeutic strategies with MCP-1 antagonists to ameliorate the initiation and progression of disease would be beneficial as future possible treatments. This has been demonstrated in murine (MRL lpr mice) LN [38]. In addition, anti-MCP-1 gene therapy in murine LN offers protection against renal injury due to reduced infiltration of leucocytes by significantly reducing glomerular IL-12 mRNA production and interstitium-infiltrating cell production of IL-12 and IFN-gamma mRNA [39]. Therefore, anti-MCP-1 gene therapy may also be an effective adjunct in the management of LN [40].

The future management of children with SLE and LN may be through monitoring of urinary biomarkers [41,42], which has been shown to be as reliable as in adult LN [43,44]. MCP-1 may be useful in clinical practice in monitoring the disease activity, although further longitudinal studies of these biomarkers are required in childhood LN. Larger prospective studies of paediatric LN are required to evaluate aetiopathogenesis, activity, chronicity and progression of disease mirrored with urinary, plasma and intra-renal biomarkers to guide physicians on treatment.



   Acknowledgments
 
S.M. received a grant from the Peel Medical Research Trust to carry out this research and would like to express his gratitude to them.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 17. 7.07
Accepted in revised form: 17. 4.08


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