Exploring molecular pathology of chronic kidney disease in systemic sclerosis by analysis of urinary and serum proteins.

Edward P Stern,Christopher P Denton,Robert Unwin,Voon H Ong,Aine Burns

doi:10.1093/rap/rkaa083

Abstract

Objective.Renal involvement is common in systemic sclerosis (scleroderma; SSc) and includes chronic kidney disease (CKD). We have performed analysis of urinary proteins to gain insight into local molecular pathology of CKD in SSc and identify candidate markers for use in clinical trials.Methods.To evaluate urinary proteins that might specifically reflect SSc-related CKD, patients were recruited with confirmed SSc and stratified for the presence or absence of CKD. Controls included patients with CKD and no SSc, in addition to healthy volunteers. Candidate markers were measured in serum and urine by multiplex immunoassay testing for IL6, IL18, TNF-α, monocyte chemoattractant protein 1 (MCP1), monocyte chemoattractant protein 3 (MCP3), VEGF and the soluble adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1). Results.One hundred and two subjects were examined, including patients with SSc with no evidence of CKD (n = 40), SSc with CKD (n = 39), non-SSc CKD (n = 11) and healthy volunteers (n = 12). Urinary levels of IL6, MCP1, TNF-α, MCP3, IL18 and ICAM-1 were elevated in SSc patients compared with healthy controls. The most significant differences were for MCP1 and ICAM-1 (both P < 0.0001), and these analytes also showed the most significant differences between groups overall (P = 0.003 for MCP1 and P < 0.0001 for ICAM-1). These markers showed a trend (MCP1, P = 0.0868) or a significant difference (ICAM-1, P = 0.0134) between SSc–CKD and SSc with normal renal function.Conclusion.Urinary levels of candidate molecular markers appear to reflect SSc–CKD more than serum markers. MCP1 and ICAM-1 are promising molecular markers for SSc–CKD and might be potential biomarkers of SSc renal involvement. This might be explored in future prospective analyses.

Highlights

Systemic sclerosis is a multi-system disease with high mortality owing to the involvement of vital organs, including the heart, lungs, gut and the renal tract [1]
Urinary levels of IL6, monocyte chemoattractant protein 1 (MCP1), TNF-a, monocyte chemoattractant protein 3 (MCP3), IL18 and intercellular adhesion molecule 1 (ICAM-1) were elevated in SSc patients compared with healthy controls
The most significant differences were for MCP1 and ICAM-1, and these analytes showed the most significant differences between groups overall (P 1⁄4 0.003 for MCP1 and P < 0.0001 for ICAM-1)

Summary

Introduction

Systemic sclerosis (scleroderma; SSc) is a multi-system disease with high mortality owing to the involvement of vital organs, including the heart, lungs, gut and the renal tract [1]. Recovery from the acute kidney injury of SRC is often excellent, SRC remains an important mechanism leading to chronic kidney disease (CKD) in SSc. In addition, CKD occurs in a large proportion of SSc patients because of systemic vasculopathy, fibrosis and other mechanisms, such as overlap CTD, including SLE and vasculitis. CKD occurs in a large proportion of SSc patients because of systemic vasculopathy, fibrosis and other mechanisms, such as overlap CTD, including SLE and vasculitis Other pathologies, such as interstitial nephritis or drug toxicity, can contribute to CKD in SSc. Previous studies of sequential unselected patients suggested that CKD is present in 50% of SSc cases [5]. Often presenting as mild renal impairment that is not of immediate clinical importance, CKD has implications for long-term renal and patient outcomes and is a major determinant of the long-term outcome after SRC

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