Dataset Information

Discovery of SERPINA3 as a candidate urinary biomarker of lupus nephritis activity.

ABSTRACT:

Objectives

We used an unbiased proteomics approach to identify candidate urine biomarkers (CUBMs) predictive of LN chronicity and pursued their validation in a larger cohort.

Methods

In this cross-sectional pilot study, we selected urine collected at kidney biopsy from 20 children with varying levels of LN damage (discovery cohort) and performed proteomic analysis using isobaric tags for relative and absolute quantification (iTRAQ). We identified differentially excreted proteins based on degree of LN chronicity and sought to distinguish markers exhibiting different relative expression patterns using hierarchically clustered log10-normalized relative abundance data with linked and distinct functions by biological network analyses. For each CUBM, we performed specific ELISAs on urine from a validation cohort (n = 41) and analysis of variance to detect differences between LN chronicity, with LN activity adjustment. We evaluated for CUBM expression in LN biopsies with immunohistochemistry.

Results

iTRAQ detected 112 proteins in urine from the discovery cohort, 51 quantifiable in all replicates. Simple analysis of variance revealed four differentially expressed, chronicity-correlated proteins (P-values < 0.05). Further correlation and network analyses led to selection of seven CUBMs for LN chronicity. In the validation cohort, none of the CUBMs distinguished LN chronicity degree; however, urine SERPINA3 demonstrated a moderate positive correlation with LN histological activity. Immunohistochemistry further demonstrated SERPINA3 staining in proximal tubular epithelial and endothelial cells.

Conclusion

We identified SERPINA3, a known inhibitor of neutrophil cathepsin G and angiotensin II production, as a potential urine biomarker to help quantify LN activity.

SUBMITTER: Turnier JL

PROVIDER: S-EPMC6343468 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

Discovery of SERPINA3 as a candidate urinary biomarker of lupus nephritis activity.

Turnier Jessica L JL Brunner Hermine I HI Bennett Michael M Aleed Ashwaq A Gulati Gaurav G Haffey Wendy D WD Thornton Sherry S Wagner Michael M Devarajan Prasad P Witte David D Greis Kenneth D KD Aronow Bruce B

Rheumatology (Oxford, England) 20190201 2

<h4>Objectives</h4>We used an unbiased proteomics approach to identify candidate urine biomarkers (CUBMs) predictive of LN chronicity and pursued their validation in a larger cohort.<h4>Methods</h4>In this cross-sectional pilot study, we selected urine collected at kidney biopsy from 20 children with varying levels of LN damage (discovery cohort) and performed proteomic analysis using isobaric tags for relative and absolute quantification (iTRAQ). We identified differentially excreted proteins b ...[more]

PMID: 30285245

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Project description:ObjectiveThere is an urgent need to identify novel biomarkers of LN to reflect renal histological changes. This study aims to investigate urinary G3BP levels in LN patients and their association with renal disease activity both clinically and pathologically.MethodsThis is a cross-sectional study. A total of 119 lupus nephritis patients were recruited. Thirty patients with chronic kidney diseases (CKD) and 27 healthy volunteers were also recruited as controls. Urinary G3BP was tested by ELISA. Renal histopathology was reviewed by an experienced renal pathologist. Other clinical variables were collected through chart review.ResultsThe levels of uG3BP were significantly increased in active LN patients compared to those in inactive LN (p<0.001), CKD patients (p=0.01), and healthy controls (p<0.001). ROC analysis indicated a good discrimination ability of uG3BP to differentiate active LN from CKD patients (AUC=0.7), inactive LN (AUC=0.76), or healthy controls (AUC=0.87). uG3BP was positively correlated with SLEDAI (ρ=0.352, p<0.001), rSLEDAI (ρ=0.302, p<0.001), and SLICC RAS (ρ=0.465, p<0.001), indicating a role as a biomarker of disease activity. It also correlated with clinical parameters, including 24-h urine protein, ESR, and serum C3 levels. In patients with 24-h urine protein > 3.0 g/24h, uG3BP levels were higher in proliferative LN than in membranous LN (p=0.04). They could discriminate the two pathogenic types of LN (AUC=0.72), and they also positively correlated with AI (ρ=0.389, p=0.008) and scores of hyaline deposits (ρ=0.418, p=0.006). While in patients with 24-h urine protein ≤ 3.0 g/24h, uG3BP levels were not significantly different between proliferative and membranous LN, and there was no apparent relationship between uG3BP levels with AI or with scores of hyaline deposits, but they correlated positively with scores of cellular/fibrocellular crescents (ρ=0.328, p=0.04).ConclusionuG3BP is a non-invasive biomarker for clinically and histologically reflecting disease activity. It is associated with active histological changes and can be used as a surrogate biomarker when the renal biopsy is impractical.

Project description:IntroductionSystemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease, and kidney involvement with SLE, a.k.a. lupus nephritis (LN), is a frequent and severe complication of SLE that increases patient morbidity and mortality. About 50% of patients with SLE encounter renal abnormalities which, if left untreated, can lead to end-stage renal disease. Kidney biopsy is considered the criterion standard for diagnosis and staging of LN using the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification, which was developed to help predict renal outcomes and assist with medical decision-making. However, kidney biopsy-based classification of LN is highly invasive and impractical for real-time monitoring of LN status. Here, nuclear magnetic resonance (NMR) spectroscopy-based metabolic profiling was used to identify urinary metabolites that discriminated between proliferative and pure membranous LN as defined by the ISN/RPS classification, and between LN and primary focal segmental glomerulosclerosis (FSGS).MethodsMetabolic profiling was conducted using urine samples of patients with proliferative LN without membranous features (Class III/IV; n = 7) or pure membranous LN (Class V; n = 7). Patients with primary FSGS and proteinuria (n = 10) served as disease controls. For each patient, demographic information and clinical data was obtained and a random urine sample collected to measure NMR spectra. Data and sample collection for patients with LN occurred around the time of kidney biopsy. Metabolic profiling analysis was done by visual inspection and principal component analysis.ResultsUrinary citrate levels were 8-fold lower in Class V LN compared to Class III/IV patients, who had normal levels of urinary citrate (P < 0.05). Class III/IV LN patients had > 10-fold lower levels of urinary taurine compared to Class V patients, who had mostly normal levels (P < 0.01). Class V LN patients had normal urinary hippurate levels compared to FSGS patients, who completely lacked urinary hippurate (P < 0.001).ConclusionsThis pilot study indicated differences in urinary metabolites between proliferative LN and pure membranous LN patients, and between LN and FSGS patients. If confirmed in larger studies, these urine metabolites may serve as biomarkers to help discriminate between different classes of LN, and between LN and FSGS.

Dataset Information

Discovery of SERPINA3 as a candidate urinary biomarker of lupus nephritis activity.

Objectives

Methods

Results

Conclusion

Publications

Discovery of SERPINA3 as a candidate urinary biomarker of lupus nephritis activity.

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