Background/Purpose:  Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune disease that disproportionately effects women and children of minorities. Renal Involvement (lupus nephritis, or LN) with SLE occurs in up to 80% of children with SLE and is a major determinant of poor prognosis. We have developed a non-invasive pediatric Renal Activity Index for Lupus (p-RAIL) that consists of laboratory measures that accurately reflect histologic LN activity. These markers are neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), monocyte chemotactic protein (MCP-1), adiponectin (APN), ceruloplasmin (CP) and hemopexin (HPX). A major gap in the knowledge base and a barrier to clinical utility is how these markers behave in healthy children. We set out to establish a reference range for for the p-RAIL markers in a population of healthy children, and to determine if levels of these markers fluctuate with age or sex.

Methods:  : Urine was collected from 368 children from the Cincinnati Genomic Control Cohort (healthy kids presenting to Cincinnati Children’s primary care clinic for well child visits) and assayed for NGAL, KIM-1, MCP-1, APN, CP and HPX using commercially available kits or assay materials.

Results:  Specimens were grouped by age (0-5 years (n=94); 5-10 (n=89); 10-15 (n=93); 15-20 (n=91)) and sex (M = 184, F=184). For age and gender comparisons, values for log transformed prior to analysis. The 95% CI for the means of each marker in the combined population were as follows: NGAL (12.9-20.1 ng/ml), KIM-1 (474.6-558.4 pg/ml), MCP-1 (240.9-293.4 pg/ml), APN (7.6-10.0 ng/ml), CP (480-589.8 ng/ml), HPX (814.3-1163.5 ng/ml). All p-RAIL biomarkers but adiponectin had weak but significant positive correlations with age, with NGAL being the strongest (r=0.33, p <0.001). Adiponectin had a weak negative correlation with age (r=-0.12, p=0.04). For gender comparisons, CP and HPX were elevated in females vs males (CP = 3% higher log transformed mean in females, p = 0.007; HPX = 5% higher log transformed mean in females, p = 0.0005). Consistent with previous findings, NGAL was greatly elevated in females vs males (86% higher log transformed mean in females, p<0.0001). No other gender differences were found.

Conclusion: We have established a reference range for the p-RAIL biomarkers and have highlighted age and gender differences. This information is essential for rational interpretation of studies and clinical trials utilizing the p-RAIL algorithm.