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.
| Original language | English |
|---|---|
| Pages (from-to) | 71-78 |
| Number of pages | 8 |
| Journal | Clinical Immunology |
| Volume | 198 |
| DOIs | |
| State | Published - Jan 2019 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2018 Elsevier Inc.
Funding
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): Children and CRN Research Nurses and staff in both UK 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 rheumatology and nephrology clinical teams, consultants, research nurses and clinical nurse specialists in each centre. 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, Nicole Jordan for co-ordination of the Einstein Lupus Cohort, Sandra Pienaar and Wonita Petersen for processing and storage of the urine samples at the Red Cross Hospital and Sister Caroline Nguqu/Sister Dorothy Brown for their support with sample collection. This work was supported by the Alder Hey Children's Kidney Fund (UK) through a training fellowship [grant number UOG10065 to ES ]. The laboratory, sample transfer and research nursing costs have been supported by a Medical Research Council (UK) confidence in concept grant [grant number JXR11948 , to MWB and ES]. The SA Cohort Study was funded by the Lupus Foundation of America Early Career Award (USA) , a training grant at Duke University [USA, grant number T32 AI0007217 ], a Duke Global Health Institute Fieldwork grant (USA) , and the Fogarty International Center [USA, grant number National Institutes of Health R25TW009337 ]. TR is supported by the Lupus Foundation of America Career Development Award (USA), and the National Institutes of Health Loan Repayment Program for Paediatric Research (USA). BG is supported by the Children's Hospital at Montefiore Young Investigator Award (USA) . CP and BG are supported by the following grants; National Institutes of Health/National Cancer Institute [USA, grant numbers 1U19CA179564 , 1UH2/3TR000933 ] and National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases [USA, grant number UH2/UH3AR067689 ]. 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. The study took place as part of the UK's ‘Experimental Arthritis Treatment Centre for Children’ funded by Arthritis Research UK (UK) , the University of Liverpool (UK) , Alder Hey Children's NHS Foundation Trust and the Alder Hey Charity and based at the University of Liverpool and Alder Hey Children's NHS Foundation Trust (UK) . This work was supported by the Alder Hey Children's Kidney Fund (UK) through a training fellowship [grant number UOG10065 to ES]. The laboratory, sample transfer and research nursing costs have been supported by a Medical Research Council (UK) confidence in concept grant [grant number JXR11948, to MWB and ES]. The SA Cohort Study was funded by the Lupus Foundation of America Early Career Award (USA), a training grant at Duke University [USA, grant number T32 AI0007217], a Duke Global Health Institute Fieldwork grant (USA), and the Fogarty International Center [USA, grant number National Institutes of Health R25TW009337]. TR is supported by the Lupus Foundation of America Career Development Award (USA), and the National Institutes of Health Loan Repayment Program for Paediatric Research (USA). BG is supported by the Children's Hospital at Montefiore Young Investigator Award (USA). CP and BG are supported by the following grants; National Institutes of Health/National Cancer Institute [USA, grant numbers 1U19CA179564, 1UH2/3TR000933] and National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases [USA, grant number UH2/UH3AR067689]. 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. The study took place as part of the UK's ?Experimental Arthritis Treatment Centre for Children? funded by Arthritis Research UK (UK), the University of Liverpool (UK), Alder Hey Children's NHS Foundation Trust and the Alder Hey Charity and based at the University of Liverpool and Alder Hey Children's NHS Foundation Trust (UK).
| Funders | Funder number |
|---|---|
| Alder Hey Charity | |
| Alder Hey Children | |
| Alder Hey Children's Kidney Fund | |
| Children's Hospital at Montefiore | |
| Experimental Arthritis Treatment Centre for Children? | |
| JSLE Study Group | |
| NIHR Alder Hey Clinical Research Facility for Experimental Medicine | |
| National Institute of Health Research | |
| National Institutes of Health/National Cancer Institute | |
| UK's ‘Experimental Arthritis Treatment Centre for Children | |
| National Institutes of Health | |
| National Cancer Institute | 1U19CA179564 |
| Fogarty International Center | R25TW009337 |
| National Institute of Arthritis and Musculoskeletal and Skin Diseases | UH2/UH3AR067689 |
| Lupus Foundation of America | T32 AI0007217 |
| National Center for Advancing Translational Sciences | UH2TR000933 |
| Alder Hey Children's NHS Foundation Trust | UOG10065 |
| Medical Research Council | JXR11948 |
| Arthritis Research UK | |
| University of Liverpool |
Keywords
- Juvenile systemic lupus erythematosus
- Lupus Nephritis
- Markov Multi-State model
- Urine biomarker panel