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Multicenter Study
. 2017 Feb;32(2):283-295.
doi: 10.1007/s00467-016-3485-3. Epub 2016 Sep 3.

International validation of a urinary biomarker panel for identification of active lupus nephritis in children

Eve Mary Dorothy Smith  1 , Andrea Lyn Jorgensen  2 , Angela Midgley  3 , Louise Oni  3 , Beatrice Goilav  4 , Chaim Putterman  5 , Dawn Wahezi  6 , Tamar Rubinstein  6 , Diana Ekdawy  3 , Rachel Corkhill  3 , Caroline Ann Jones  7 , Stephen David Marks  8 , Paul Newland  9 , Clarissa Pilkington  10 , Kjell Tullus  8 , Michael William Beresford  3   11
Affiliations
Multicenter Study

International validation of a urinary biomarker panel for identification of active lupus nephritis in children

Eve Mary Dorothy Smith et al. Pediatr Nephrol. 2017 Feb.

Abstract

Background: Conventional markers of juvenile-onset systemic lupus erythematosus (JSLE) disease activity fail to adequately identify lupus nephritis (LN). While individual novel urine biomarkers are good at detecting LN flares, biomarker panels may improve diagnostic accuracy. The aim of this study was to assess the performance of a biomarker panel to identify active LN in two international JSLE cohorts.

Methods: Novel urinary biomarkers, namely vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein 1 (MCP-1), lipocalin-like prostaglandin D synthase (LPGDS), transferrin (TF), ceruloplasmin, alpha-1-acid glycoprotein (AGP) and neutrophil gelatinase-associated lipocalin (NGAL), were quantified in a cross-sectional study that included participants of the UK JSLE Cohort Study (Cohort 1) and validated within the Einstein Lupus Cohort (Cohort 2). Binary logistic regression modelling and receiver operating characteristic curve analysis [area under the curve (AUC)] were used to identify and assess combinations of biomarkers for diagnostic accuracy.

Results: A total of 91 JSLE patients were recruited across both cohorts, of whom 31 (34 %) had active LN and 60 (66 %) had no LN. Urinary AGP, ceruloplasmin, VCAM-1, MCP-1 and LPGDS levels were significantly higher in those patients with active LN than in non-LN patients [all corrected p values (p c) < 0.05] across both cohorts. Urinary TF also differed between patient groups in Cohort 2 (p c = 0.001). Within Cohort 1, the optimal biomarker panel included AGP, ceruloplasmin, LPGDS and TF (AUC 0.920 for active LN identification). These results were validated in Cohort 2, with the same markers resulting in the optimal urine biomarker panel (AUC 0.991).

Conclusion: In two international JSLE cohorts, urinary AGP, ceruloplasmin, LPGDS and TF demonstrate an 'excellent' ability for accurately identifying active LN in children.

Keywords: BILAG; Glomerulonephritis; Lupus nephritis; Systemic lupus erythematosus; Urine biomarkers.

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Conflict of interest statement

Compliance with ethical standards All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Patient assent/consent and parental consent was obtained to participate in the studies. Full ethical approvals were in place from the National Research Ethics Service North West, Liverpool East, UK (reference 06/Q1502/77) and the Institutional Review Board at Einstein-Montefiore (IRB 2000–154). Conflicts of interest There has not been any financial support or other benefits from commercial sources for the work reported on in this manuscript. The authors do not have any financial interests that could create a potential conflict of interest or the appearance of a conflict of interest with regard to the work. Funding This work was supported by the Alder Hey Children’s Kidney Fund through a training fellowship [UOG10065 to ES]. Lupus UK also provides financial support for co-ordination of the UK JSLE Cohort Study. TR is supported by the Lupus Foundation of America Career Development Award, and the NIH (National Institutes of Health) Loan Repayment Program for Pediatric Research. BG is supported by the Children’s Hospital at Montefiore Young Investigator Award. CP and BG are supported by NIH/NCI 1U19CA179564 and NIH/NCI 1UH2/3TR000933. The funding bodies detailed above were not involved in the design, collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.

Figures

Fig. 1
Fig. 1
Distribution of biomarker concentrations in active-/non-lupus nephritis (LN) patients with juvenile-onset systemic lupus erythematosus (JSLE) from Cohorts 1 (UK JSLE Cohort) and 2 [Einstein Lupus Cohort (ELC)]. Horizontal line Median value for each group. Mann–Whitney U tests were used to compare the distribution of biomarker concentrations between patient groups within each cohort. A Bonferroni adjustment was applied to account for multiple testing. Corrected p values (p c) are reported. Vascular cell adhesion molecule-1 (VCAM-1) biomarker data were not available from one active-LN patient from Cohort 1; neutrophil gelatinase-associated lipocalin (NGAL) data were not available from three active-LN and 15 non-LN patients from Cohort 1. AGP Alpha-1-acid glycoprotein, CP ceruloplasmin, LPGDS lipocalin-like prostaglandin D synthase, TF transferrin, MCP-1 monocyte chemoattractant protein 1, Cr creatinine. See section Urine sample selection for definition of active-/non-LN
Fig. 2
Fig. 2
Urine biomarker concentrations in active-/non- lupus nephritis (LN) patients with/without extra-renal juvenile-onset systemic lupus erythematosus (JSLE) activity. Biomarker concentrations were standardised to urinary creatinine and expressed as median values. Horizontal line Median value for each group. Mann–Whitney U tests were used to compare biomarker concentrations between patient groups. A Bonferroni adjustment was applied to account for multiple testing. Corrected p values (p c) are reported. Vascular cell adhesion molecule-1 (VCAM-1) measurement is missing from one patient; neutrophil gelatinase-associated lipocalin (NGAL) data were not available from three active-LN and 15 non-LN patients
Fig. 3
Fig. 3
The receiver operating characteristic (ROC) cure generated from the optimal binary logistic regression model when data from both cohorts were combined. Optimal model includes Alpha-1-acid glycoprotein (AGP), ceruloplasmin, lipocalin-like prostaglandin D synthase (LPGDS), transferrin (TF) and vascular cell adhesion molecule-1 (VCAM-1) [area under the ROC curve (AUC) 0.952]
Fig. 4
Fig. 4
Urine biomarker concentrations in Cohort 2 patients with LN and no recent biopsy (BILAG-defined active LN; n = 11) versus patients with biopsy-defined active LN (n = 12). Closed symbols Median, Whiskers interquartile range. British Isles Lupus Assessment Group (BILAG), lupus nephritis (LN)
See this image and copyright information in PMC

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