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

Eve Mary Dorothy Smith; Andrea Lyn Jorgensen; Angela Midgley; Louise Oni; Beatrice Goilav; Chaim Putterman; Dawn Wahezi; Tamar Rubinstein; Diana Ekdawy; Rachel Corkhill; Caroline Ann Jones; Stephen David Marks; Paul Newland; Clarissa Pilkington; Kjell Tullus; Michael William Beresford

doi:10.1007/s00467-016-3485-3

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

Eve Mary Dorothy Smith, Andrea Lyn Jorgensen, Angela Midgley, Louise Oni, Beatrice Goilav, Chaim Putterman, Dawn Wahezi, Tamar Rubinstein, Diana Ekdawy, Rachel Corkhill, Caroline Ann Jones, Stephen David Marks, Paul Newland, Clarissa Pilkington, Kjell Tullus, Michael William Beresford

Research output: Contribution to journal › Article › peer-review

42 Scopus citations

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.

Original language	English
Pages (from-to)	283-295
Number of pages	13
Journal	Pediatric Nephrology
Volume	32
Issue number	2
DOIs	https://doi.org/10.1007/s00467-016-3485-3
State	Published - 1 Feb 2017
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2016, The Author(s).

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 authors would like to acknowledge all patients and their families for participating in this study, as well as all the support given by the entire multi-disciplinary team within each of the paediatric centres. The study was supported by the National Institute of Health Research (NIHR) Clinical Research Network (CRN), with special thanks to all children and CRN Research Nurses and staff in both centres, the NIHR Alder Hey Clinical Research Facility for Experimental Medicine and all those who have supported the work of the UK JSLE Study Group to date. Specific acknowledgement goes to the clinical teams, consultants, research nurses and clinical nurse specialists in each centre, including: Yvonne Glackin, Olivia Lloyd, Susan Wadeson and Collette Hodgson. Special recognition also goes to Dr. Duncan Appleby for database and information technology support, Graham Jeffers for laboratory support, Carla Roberts for co-ordination of the UK JSLE Cohort study and Nicole Jordan for co-ordination of the Einstein Lupus Cohort.

Funders	Funder number
Alder Hey Children’s Kidney Fund	UOG10065
Children’s Hospital at Montefiore
JSLE Study Group
NIHR Alder Hey Clinical Research Facility for Experimental Medicine
National Institutes of Health
National Cancer Institute	U19CA179564
Lupus Foundation of America
Medical Research Council	MC_PC_14110, MR/M01665X/1
National Institute for Health Research

Keywords

BILAG
Glomerulonephritis
Lupus nephritis
Systemic lupus erythematosus
Urine biomarkers

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10.1007/s00467-016-3485-3

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Smith, E. M. D., Jorgensen, A. L., Midgley, A., Oni, L., Goilav, B., Putterman, C., Wahezi, D., Rubinstein, T., Ekdawy, D., Corkhill, R., Jones, C. A., Marks, S. D., Newland, P., Pilkington, C., Tullus, K., & Beresford, M. W. (2017). International validation of a urinary biomarker panel for identification of active lupus nephritis in children. Pediatric Nephrology, 32(2), 283-295. https://doi.org/10.1007/s00467-016-3485-3

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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 (pc) < 0.05] across both cohorts. Urinary TF also differed between patient groups in Cohort 2 (pc = 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 {\textquoteleft}excellent{\textquoteright} ability for accurately identifying active LN in children.",

keywords = "BILAG, Glomerulonephritis, Lupus nephritis, Systemic lupus erythematosus, Urine biomarkers",

author = "Smith, {Eve Mary Dorothy} and Jorgensen, {Andrea Lyn} and Angela Midgley and Louise Oni and Beatrice Goilav and Chaim Putterman and Dawn Wahezi and Tamar Rubinstein and Diana Ekdawy and Rachel Corkhill and Jones, {Caroline Ann} and Marks, {Stephen David} and Paul Newland and Clarissa Pilkington and Kjell Tullus and Beresford, {Michael William}",

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doi = "10.1007/s00467-016-3485-3",

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Smith, EMD, Jorgensen, AL, Midgley, A, Oni, L, Goilav, B, Putterman, C, Wahezi, D, Rubinstein, T, Ekdawy, D, Corkhill, R, Jones, CA, Marks, SD, Newland, P, Pilkington, C, Tullus, K & Beresford, MW 2017, 'International validation of a urinary biomarker panel for identification of active lupus nephritis in children', Pediatric Nephrology, vol. 32, no. 2, pp. 283-295. https://doi.org/10.1007/s00467-016-3485-3

TY - JOUR

T1 - International validation of a urinary biomarker panel for identification of active lupus nephritis in children

AU - Smith, Eve Mary Dorothy

AU - Jorgensen, Andrea Lyn

AU - Midgley, Angela

AU - Oni, Louise

AU - Goilav, Beatrice

AU - Putterman, Chaim

AU - Wahezi, Dawn

AU - Rubinstein, Tamar

AU - Ekdawy, Diana

AU - Corkhill, Rachel

AU - Jones, Caroline Ann

AU - Marks, Stephen David

AU - Newland, Paul

AU - Pilkington, Clarissa

AU - Tullus, Kjell

AU - Beresford, Michael William

PY - 2017/2/1

Y1 - 2017/2/1

N2 - 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 (pc) < 0.05] across both cohorts. Urinary TF also differed between patient groups in Cohort 2 (pc = 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.

AB - 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 (pc) < 0.05] across both cohorts. Urinary TF also differed between patient groups in Cohort 2 (pc = 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.

KW - BILAG

KW - Glomerulonephritis

KW - Lupus nephritis

KW - Systemic lupus erythematosus

KW - Urine biomarkers

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

Abstract

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Keywords

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