A Markov Multi-State model of lupus nephritis urine biomarker panel dynamics in children: Predicting changes in disease activity

E M D Smith; A Eleuteri; B Goilav; L Lewandowski; A Phuti; T Rubinstein; D Wahezi; C A Jones; S D Marks; R Corkhill; C Pilkington; K Tullus; C Putterman; C Scott; A C Fisher; M W Beresford

doi:10.1016/j.clim.2018.10.021

A Markov Multi-State model of lupus nephritis urine biomarker panel dynamics in children: Predicting changes in disease activity

Clin Immunol. 2019 Jan:198:71-78. doi: 10.1016/j.clim.2018.10.021. Epub 2018 Nov 2.

Authors

E M D Smith¹, A Eleuteri², B Goilav³, L Lewandowski⁴, A Phuti⁵, T Rubinstein⁶, D Wahezi⁷, C A Jones⁸, S D Marks⁹, R Corkhill¹⁰, C Pilkington¹¹, K Tullus¹², C Putterman¹³, C Scott¹⁴, A C Fisher¹⁵, M W Beresford¹⁶

Affiliations

¹ Department of Women's & Children's Health, University of Liverpool, Liverpool, UK; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK. Electronic address: esmith8@liverpool.ac.uk.
² Medical Physics and Clinical Engineering, and Department of Physics, University of Liverpool, Liverpool, UK. Electronic address: antonio.eleuteri@liv.ac.uk.
³ Department of Paediatric Nephrology, Albert Einstein College of Medicine, New York, USA. Electronic address: bgoilav@montefiore.org.
⁴ National Institute of Health, Maryland, USA. Electronic address: laura.lewandowski@nih.gov.
⁵ Paediatric Rheumatology, University of Cape Town, Cape Town, South Africa. Electronic address: trubinst@montefiore.org.
⁶ Department of Paediatric Rheumatology, Albert Einstein College of Medicine, New York, USA. Electronic address: trubinst@montefiore.org.
⁷ Department of Paediatric Rheumatology, Albert Einstein College of Medicine, New York, USA. Electronic address: DWAHEZI@montefiore.org.
⁸ Department of Paediatric Nephrology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK. Electronic address: Caroline.Jones@alderhey.nhs.uk.
⁹ Paediatric Nephrology, Great Ormond Street Hospital, London, UK. Electronic address: Stephen.Marks@gosh.nhs.uk.
¹⁰ Department of Women's & Children's Health, University of Liverpool, Liverpool, UK. Electronic address: rachel.corkhill@liverpool.ac.uk.
¹¹ Paediatric Rheumatology, Great Ormond Street Hospital, London, UK. Electronic address: Clarissa.Pilkington@gosh.nhs.uk.
¹² Paediatric Nephrology, Great Ormond Street Hospital, London, UK. Electronic address: Kjell.Tullus@gosh.nhs.uk.
¹³ Department of Rheumatology, Albert Einstein College of Medicine, New York, USA. Electronic address: Chaim.Putterman@einstein.yu.edu.
¹⁴ Paediatric Rheumatology, University of Cape Town, Cape Town, South Africa. Electronic address: chris.scott@uct.ac.za.
¹⁵ Medical Physics and Clinical Engineering, and Department of Physics, University of Liverpool, Liverpool, UK. Electronic address: clfs12@liverpool.ac.uk.
¹⁶ Department of Women's & Children's Health, University of Liverpool, Liverpool, UK; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK. Electronic address: m.w.beresford@liverpool.ac.uk.

PMID: 30391651
DOI: 10.1016/j.clim.2018.10.021

Abstract

Background: A urine 'biomarker panel' comprising alpha-1-acid-glycoprotein, ceruloplasmin, transferrin and lipocalin-like-prostaglandin-D synthase performs to an 'excellent' level for lupus nephritis identification in children cross-sectionally. The aim of this study was to assess if this biomarker panel predicts lupus nephritis flare/remission longitudinally.

Methods: The novel urinary biomarker panel was quantified by enzyme linked immunoabsorbant assay in participants of the United Kingdom Juvenile Systemic Lupus Erythematosus (UK JSLE) Cohort Study, the Einstein Lupus Cohort, and the South African Paediatric Lupus Cohort. Monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1 were also quantified in view of evidence from other longitudinal studies. Serial urine samples were collected during routine care with detailed clinical and demographic data. A Markov Multi-State model of state transitions was fitted, with predictive clinical/biomarker factors assessed by a corrected Akaike Information Criterion (AICc) score (the better the model, the lower the AICc score).

Results: The study included 184 longitudinal observations from 80 patients. The homogeneous multi-state Markov model of lupus nephritis activity AICc score was 147.85. Alpha-1-acid-glycoprotein and ceruloplasmin were identified to be the best predictive factors, reducing the AICc score to 139.81 and 141.40 respectively. Ceruloplasmin was associated with the active-to-inactive transition (hazard ratio 0.60 (95% confidence interval [0.39, 0.93])), and alpha-1-acid-glycoprotein with the inactive-to-active transition (hazard ratio 1.49 (95% confidence interval [1.10, 2.02])). Inputting individual alpha-1-acid-glycoprotein/ceruloplasmin values provides 3, 6 and 12 months probabilities of state transition.

Conclusions: Alpha-1-acid-glycoprotein was predictive of active lupus nephritis flare, whereas ceruloplasmin was predictive of remission. The Markov state-space model warrants testing in a prospective clinical trial of lupus nephritis biomarker led monitoring.

Keywords: Juvenile systemic lupus erythematosus; Lupus Nephritis; Markov Multi-State model; Urine biomarker panel.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Biomarkers / urine
Ceruloplasmin / urine*
Child
Female
Humans
Lupus Nephritis / diagnosis*
Lupus Nephritis / urine
Male
Markov Chains*
Orosomucoid / urine*

Substances

Biomarkers
Orosomucoid
Ceruloplasmin

Abstract

Publication types

MeSH terms

Substances

Grants and funding