Abstract
BackgroundImproved, noninvasive biomarkers are needed to accurately detect lupus nephritis (LN) activity. The purpose of this study was to evaluate five S100 proteins (S100A4, S100A6, S100A8/9, and S100A12) in both serum and urine as potential biomarkers of global and renal system-specific disease activity in childhood-onset systemic lupus erythematosus (cSLE).MethodsIn this multicenter study, S100 proteins were measured in the serum and urine of four cSLE cohorts and healthy control subjects using commercial enzyme-linked immunosorbent assays. Patients were divided into cohorts on the basis of biospecimen availability: (1) longitudinal serum, (2) longitudinal urine, (3) cross-sectional serum, and (4) cross-sectional urine. Global and renal disease activity were defined using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and the SLEDAI-2K renal domain score. Nonparametric testing was used for statistical analysis, including the Wilcoxon signed-rank test, Kruskal-Wallis test, Mann-Whitney U test, and Spearman’s rank correlation coefficient.ResultsAll urine S100 proteins were elevated in patients with active LN compared with patients with active extrarenal disease and healthy control subjects. All urine S100 protein levels decreased with LN improvement, with S100A4 demonstrating the most significant decrease. Urine S100A4 levels were also higher with proliferative LN than with membranous LN. S100A4 staining in the kidney localized to mononuclear cells, podocytes, and distal tubular epithelial cells. Regardless of the S100 protein tested, serum levels did not change with cSLE improvement.ConclusionsHigher urine S100 levels are associated with increased LN activity in cSLE, whereas serum S100 levels do not correlate with disease activity. Urine S100A4 shows the most promise as an LN activity biomarker, given its pronounced decrease with LN improvement, isolated elevation in urine, and positive staining in resident renal cells.
Highlights
Improved, noninvasive biomarkers are needed to accurately detect lupus nephritis (LN) activity
These proteins represent a diverse group of calcium-binding proteins, and mainly the heterodimer S100A8/9 and S100A12 have been studied to date in inflammatory diseases
Patients in Cohort Cross-sectional serum cohort (Xs) had longer disease duration at the time of sample collection than patients in Cohort Cross-sectional urine cohort (Xu) (5–8 years compared with 2–2.5 years)
Summary
Noninvasive biomarkers are needed to accurately detect lupus nephritis (LN) activity. The purpose of this study was to evaluate five S100 proteins (S100A4, S100A6, S100A8/9, and S100A12) in both serum and urine as potential biomarkers of global and renal system-specific disease activity in childhood-onset systemic lupus erythematosus (cSLE). S100 proteins are emerging as reliable biomarkers of disease activity in a multitude of pediatric inflammatory diseases, including systemic juvenile idiopathic arthritis and inflammatory bowel disease [7, 8]. These proteins represent a diverse group of calcium-binding proteins, and mainly the heterodimer S100A8/9 ( known as MRP8/14 or calprotectin) and S100A12 have been studied to date in inflammatory diseases. S100A8/9 and S100A12 are expressed predominantly by phagocytes and serve as danger or damage-associated molecular patterns upon extracellular release, triggering continued inflammation [7].
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