Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Pediatric Rheumatology
Published in: Pediatric Rheumatology 1/2017

Open Access 01-12-2017 | Research article

Effects of age and gender on reference levels of biomarkers comprising the pediatric Renal Activity Index for Lupus Nephritis (p-RAIL)

Authors: Michael R. Bennett, Qing Ma, Jun Ying, Prasad Devarajan, Hermine Brunner

Published in: Pediatric Rheumatology | Issue 1/2017

Login to get access

Abstract

Background

Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune disease that disproportionately effects women and children of minorities. Renal involvement (lupus nephritis, or LN) 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 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 the p-RAIL markers in a population of healthy children, and to determine if levels of these markers fluctuate with age or gender.

Methods

Urine was collected from 368 healthy children 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 gender (M = 184, F = 184). For age and gender comparisons, values were log transformed prior to analysis. The medians (minimums, maximums) of each marker in the combined population were as follows: NGAL 6.65 (0.004, 391.52) ng/ml, KIM-1416.84 (6.22, 2512.43) pg/ml, MCP-1209.36 (9.49, 2237.06) pg/ml, APN 8.05 (0.07, 124.50) ng/ml, CP 465.15 (8.02, 7827.00) ng/ml, HPX 588.70 (6.85, 17,658.40)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). For gender comparisons, NGAL, CP and HPX were elevated in females vs males (86%, p < 0.0001; 3%, p = 0.007, and 5%, p = 0.0005 elevation of the log transformed mean, respectively).

Conclusions

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.
Literature
1.
Faurschou M, Starklint H, Halberg P, Jacobsen S. Prognostic factors in lupus nephritis: diagnostic and therapeutic delay increases the risk of terminal renal failure. J Rheumatol. 2006;33:1563–9.PubMed
2.
Silva CA, Avcin T, Brunner HI. Taxonomy for systemic lupus erythematosus with onset before adulthood. Arthritis Care Res (Hoboken). 2012;64:1787–93.CrossRef
3.
Livingston B, Bonner A, Pope J. Differences in clinical manifestations between childhood-onset lupus and adult-onset lupus: a meta-analysis. Lupus. 2011;20:1345–55.CrossRefPubMed
4.
Hiraki LT, Feldman CH, Liu J, Alarcon GS, Fischer MA, Winkelmayer WC, Costenbader KH. Prevalence, incidence, and demographics of systemic lupus erythematosus and lupus nephritis from 2000 to 2004 among children in the US Medicaid beneficiary population. Arthritis Rheum. 2012;64:2669–76.CrossRefPubMedPubMedCentral
5.
Wenderfer SE, Ruth NM, Brunner HI. Advances in the care of children with lupus nephritis. Pediatr Res. 2017;81:406–14.CrossRefPubMed
6.
7.
Hagelberg S, Lee Y, Bargman J, Mah G, Schneider R, Laskin C, Eddy A, Gladman D, Urowitz M, Hebert D, Silverman E. Longterm followup of childhood lupus nephritis. J Rheumatol. 2002;29:2635–42.PubMed
8.
Weening JJ, D'Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, Balow JE, Bruijn JA, Cook T, Ferrario F, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 2004;65:521–30.CrossRefPubMed
9.
Greloni G, Scolnik M, Marin J, Lancioni E, Quiroz C, Zacariaz J, De la Iglesia Niveyro P, Christiansen S, Pierangelo MA, Varela CF, et al. Value of repeat biopsy in lupus nephritis flares. Lupus Sci Med. 2014;1:e000004.CrossRefPubMedPubMedCentral
10.
Bennett M, Brunner HI. Biomarkers and updates on pediatrics lupus nephritis. Rheum Dis Clin N Am. 2013;39:833–53.CrossRef
11.
Soliman S, Mohan C: Lupus nephritis biomarkers. Clin Immunol. 2016.
12.
Smith EM, Beresford MW. Urinary biomarkers in childhood lupus nephritis. Clin Immunol. 2016.
13.
Hinze CH, Suzuki M, Klein-Gitelman M, Passo MH, Olson J, Singer NG, Haines KA, Onel K, O'Neil K, Silverman ED, et al. Neutrophil gelatinase-associated lipocalin is a predictor of the course of global and renal childhood-onset systemic lupus erythematosus disease activity. Arthritis Rheum. 2009;60:2772–81.CrossRefPubMedPubMedCentral
14.
Rovin BH, Song H, Birmingham DJ, Hebert LA, CY Y, Nagaraja HN. Urine chemokines as biomarkers of human systemic lupus erythematosus activity. J Am Soc Nephrol. 2005;16:467–73.CrossRefPubMed
15.
Brunner HI, Mueller M, Rutherford C, Passo MH, Witte D, Grom A, Mishra J, Devarajan P. Urinary neutrophil gelatinase-associated lipocalin as a biomarker of nephritis in childhood-onset systemic lupus erythematosus. Arthritis Rheum. 2006;54:2577–84.CrossRefPubMed
16.
Suzuki M, Wiers KM, Klein-Gitelman MS, Haines KA, Olson J, Onel KB, O'Neil K, Passo MH, Singer NG, Tucker L, et al. Neutrophil gelatinase-associated lipocalin as a biomarker of disease activity in pediatric lupus nephritis. Pediatr Nephrol. 2008;23:403–12.CrossRefPubMed
17.
Brunner HI, Bennett MR, Mina R, Suzuki M, Petri M, Kiani AN, Pendl J, Witte D, Ying J, Rovin BH, Devarajan P. Association of noninvasively measured renal protein biomarkers with histologic features of lupus nephritis. Arthritis Rheum. 2012;64:2687–97.CrossRefPubMedPubMedCentral
18.
Gulati G, Bennett MR, Abulaban K, Song H, Zhang X, Ma Q, Brodsky SV, Nadasdy T, Haffner C, Wiley K, et al. Prospective validation of a novel renal activity index of lupus nephritis. Lupus 2017;26(9):927-36.
19.
Brunner HI, Bennett MR, Abulaban K, Klein-Gitelman MS, O'Neil KM, Tucker L, Ardoin SP, Rouster-Stevens KA, Onel KB, Singer NG, et al. Development of a novel renal activity index of lupus nephritis in children and young adults. Arthritis Care Res (Hoboken). 2016;68:1003–11.CrossRef
20.
Bennett MR, Nehus E, Haffner C, Ma Q, Devarajan P. Pediatric reference ranges for acute kidney injury biomarkers. Pediatr Nephrol. 2015;30:677–85.CrossRefPubMed
21.
Bennett M, Dent CL, Ma Q, Dastrala S, Grenier F, Workman R, Syed H, Ali S, Barasch J, Devarajan P. Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study. Clin J Am Soc Nephrol. 2008;3:665–73.CrossRefPubMedPubMedCentral
22.
23.
Cangemi G, Storti S, Cantinotti M, Fortunato A, Emdin M, Bruschettini M, Bugnone D, Melioli G, Clerico A. Reference values for urinary neutrophil gelatinase-associated lipocalin (NGAL) in pediatric age measured with a fully automated chemiluminescent platform. Clin Chem Lab Med. 2013;51:1101–5.CrossRefPubMed
24.
Cullen MR, Murray PT, Fitzgibbon MC. Establishment of a reference interval for urinary neutrophil gelatinase-associated lipocalin. Ann Clin Biochem. 2012;49:190–3.CrossRefPubMed
25.
McWilliam SJ, Antoine DJ, Sabbisetti V, Pearce RE, Jorgensen AL, Lin Y, Leeder JS, Bonventre JV, Smyth RL, Pirmohamed M. Reference intervals for urinary renal injury biomarkers KIM-1 and NGAL in healthy children. Biomark Med. 2014:1–9.
26.
Gulati G AK, Ying J, Zhang X, Song H, Ma Q, Haffner C, Wiley K, Bennett M, Rovin BH, Brunner HI. Validating the RAIL Algorithm in Adult Lupus Nephritis Patients [abstract]. Arthritis Rheumatol. 2015;67.
27.
Suzuki M, Ross GF, Wiers K, Nelson S, Bennett M, Passo MH, Devarajan P, Brunner HI. Identification of a urinary proteomic signature for lupus nephritis in children. Pediatr Nephrol. 2007;22:2047–57.CrossRefPubMed
28.
Suzuki M, Wiers K, Brooks EB, Greis KD, Haines K, Klein-Gitelman MS, Olson J, Onel K, O'Neil KM, Silverman ED, et al. Initial validation of a novel protein biomarker panel for active pediatric lupus nephritis. Pediatr Res. 2009;65:530–6.CrossRefPubMedPubMedCentral
29.
Guo Z, Zhang Y, Zou L, Wang D, Shao C, Wang Y, Sun W, Zhang L. A proteomic analysis of individual and gender variations in normal human urine and cerebrospinal fluid using iTRAQ quantification. PLoS One. 2015;10:e0133270.CrossRefPubMedPubMedCentral
30.
Schinstock CA, Semret MH, Wagner SJ, Borland TM, Bryant SC, Kashani KB, Larson TS, Lieske JC. Urinalysis is more specific and urinary neutrophil gelatinase-associated lipocalin is more sensitive for early detection of acute kidney injury. Nephrol Dial Transplant. 2013;28:1175–85.CrossRefPubMed
31.
Kaufeld JK, Gwinner W, Scheffner I, Haller HG, Schiffer M. Urinary NGAL ratio is not a sensitive biomarker for monitoring acute tubular injury in kidney transplant patients: NGAL and ATI in renal transplant patients. Journal of Transplantation. 2012;2012:8.CrossRef
32.
Varghese SA, Powell TB, Budisavljevic MN, Oates JC, Raymond JR, Almeida JS, Arthur JM. Urine biomarkers predict the cause of glomerular disease. J Am Soc Nephrol. 2007;18:913–22.CrossRefPubMedPubMedCentral
33.
Denko CW, Gabriel P. Age and sex related levels of albumin, ceruloplasmin, alpha 1 antitrypsin, alpha 1 acid glycoprotein, and transferrin. Ann Clin Lab Sci. 1981;11:63–8.PubMed
34.
Hyre AN, Kavanagh K, Kock ND, Donati GL, Subashchandrabose S. Copper Is a Host Effector Mobilized to Urine during Urinary Tract Infection To Impair Bacterial Colonization. Infect Immun. 2017;85(3).
35.
Lo DS, Shieh HH, Ragazzi SL, Koch VH, Martinez MB, Gilio AE. Community-acquired urinary tract infection: age and gender-dependent etiology. J Bras Nefrol. 2013;35:93–8.CrossRefPubMed
36.
Inadera H, Egashira K, Takemoto M, Ouchi Y, Matsushima K. Increase in circulating levels of monocyte chemoattractant protein-1 with aging. J Interf Cytokine Res. 1999;19:1179–82.CrossRef
37.
Mezzano SA, Droguett MA, Burgos ME, Ardiles LG, Aros CA, Caorsi I, Egido J. Overexpression of chemokines, fibrogenic cytokines, and myofibroblasts in human membranous nephropathy. Kidney Int. 2000;57:147–58.CrossRefPubMed
38.
Zhang X, Nagaraja HN, Nadasdy T, Song H, McKinley A, Prosek J, Kamadana S, Rovin BH. A composite urine biomarker reflects interstitial inflammation in lupus nephritis kidney biopsies. Kidney Int. 2012;81:401–6.CrossRefPubMed
39.
Barr DB, Wilder LC, Caudill SP, Gonzalez AJ, Needham LL, Pirkle JL. Urinary creatinine concentrations in the U.S. population: implications for urinary biologic monitoring measurements. Environ Health Perspect. 2005;113:192–200.CrossRefPubMed
40.
Neal RC, Ferdinand KC, Ycas J, Miller E. Relationship of ethnic origin, gender, and age to blood creatine kinase levels. Am J Med. 2009;122:73–8.CrossRefPubMed
41.
George MD, McGill NK, Baker JF. Creatine kinase in the U.S. population: impact of demographics, comorbidities, and body composition on the normal range. Medicine (Baltimore). 2016;95:e4344.CrossRef
42.
Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, Wei R, Curtin LR, Roche AF, Johnson CL. 2000 CDC growth charts for the United States: methods and development. Vital Health Stat. 2002;11:1–190.
Metadata
Title
Effects of age and gender on reference levels of biomarkers comprising the pediatric Renal Activity Index for Lupus Nephritis (p-RAIL)
Authors
Michael R. Bennett
Qing Ma
Jun Ying
Prasad Devarajan
Hermine Brunner
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Pediatric Rheumatology / Issue 1/2017
Electronic ISSN: 1546-0096
DOI
https://doi.org/10.1186/s12969-017-0202-0

Other articles of this Issue 1/2017

Pediatric Rheumatology 1/2017 Go to the issue

Research article

A single-center analysis of Henoch-Schonlein purpura nephritis with nephrotic proteinuria in children

Regular article

Pilot study comparing the Childhood Arthritis & Rheumatology Research Alliance (CARRA) systemic Juvenile Idiopathic Arthritis Consensus Treatment Plans

Research article

Pharmacokinetic and safety profile of tofacitinib in children with polyarticular course juvenile idiopathic arthritis: results of a phase 1, open-label, multicenter study

Research article

Ultrasound-guided steroid tendon sheath injections in juvenile idiopathic arthritis: a 10-year single-center retrospective study

Review

Protocols on classification, monitoring and therapy in children’s rheumatology (PRO-KIND): results of the working group Polyarticular juvenile idiopathic arthritis

Case Report

Effective induction therapy for anti-SRP associated myositis in childhood: A small case series and review of the literature