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

Smith, Eve; Jorgensen, Andrea; Midgley, Angela; Oni, Louise; Goilav, Béatrice; Putterman, Chaim; Wahezi, Dawn M.; Rubinstein, Tamar; Ekdawy, Diana; Corkhill, Rachel; Jones, Caroline; Marks, Stephen D.; Newland, Paul; Pilkington, Clarissa; Tullus, Kjell; Beresford, Michael W.

doi:10.1007/s00467-016-3485-3

Cited by 46 publications

(38 citation statements)

References 46 publications

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“…NGAL has been demonstrated as a marker of renal damage in LN (4,29), which may explain why our patients with a history of biopsy-proven LN had higher serum NGAL levels. In contrast with these studies, Smith et al could not find a significant change in uNGAL levels between patients with active LN and those with non-LN in two international juvenile-onset SLE cohorts (25). Moreover, Kiani et al could not detect a relationship between uNGAL and LN in adult SLE patients (36).…”

Section: Discussionmentioning

confidence: 87%

“…In a mouse model of LN, NGAL level in the kidney, urine, and serum is elevated in connection with disease severity (20). Likewise, human studies have displayed that urinary NGAL (uNGAL) levels can reflect the decline of renal function and the disease activity in LN (5,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Furthermore, it may predict poor response after induction therapy (31).…”

Section: Introductionmentioning

confidence: 99%

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The importance of serum neutrophil gelatinase-associated lipocalin level in patients with lupus nephritis

et al. 2019

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Introduction: The neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a biomarker of renal damage. Objectives: The aim of this study was to assess the serum levels of NGAL (sNGAL) as a marker of disease activity in individuals with lupus nephritis (LN). Patients and Methods: This study contained 50 systemic lupus erythematosus (SLE) individuals with (n = 25) and without (n = 25) nephritis, and 39 healthy controls. The sNGAL levels were measured by ELISA. Renal function test, urinary parameters, lupus serology activity, and also calculated SLE disease activity index (SLEDAI) were analyzed to determine their associations with sNGAL. Results: The results revealed that the SLE individuals with or without nephritis had a raised serum NGAL levels as compared to control subjects (P<0.001). Additionally, sNGAL levels in LN individuals were meaningfully higher compared to those in non-LN patients (P<0.001). Serum NGAL showed a significant correlation with the SLEDAI, serum creatinine, and 24-h urinary protein (P<0.05). More importantly, sNGAL had a significant positive correlation with the activity index of LN (r = 0.616, P=0.001). In the ROC curve analysis, the measurement of sNGAL level showed a good diagnostic performance for distinguishing individuals with LN from SLE patients without renal involvement with AUC=0.902 (P<0.001), 72% sensitivity, and 99% specificity. Moreover, sNGAL could identify all of SLE patients from controls with high accuracy, AUC= 0.99, P<0.001, with 99% sensitivity, and 97% specificity. Conclusion: Serum NGAL had an association with clinical parameters and could discriminate LN from SLE patients without renal involvement. Our result suggests that serum NGAL can be used for early diagnosis of LN and identifying active LN.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

The importance of serum neutrophil gelatinase-associated lipocalin level in patients with lupus nephritis

et al. 2019

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“…Although the plasma AGP level rises under stress conditions, this endogenous production is considered insufficient to rival consistent pathological stress. While urinary AGP secretion in healthy people is usually very low, it is detected in patients with a variety of renal diseases including nephrotic syndrome 25 and active lupus nephritis 26 . Specifically, urinary AGP is observed from the early stage in patients with diabetic nephropathy and gradually increases with the progression of the disease, correlating with the renal damage 27 .…”

Section: Discussionmentioning

confidence: 99%

A downstream molecule of 1,25-dihydroxyvitamin D3, alpha-1-acid glycoprotein, protects against mouse model of renal fibrosis

Watanabe

Fujimura

et al. 2018

Sci Rep

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Renal fibrosis, the characteristic feature of progressive chronic kidney disease, is associated with unremitting renal inflammation. Although it is reported that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D, elicits an anti-renal fibrotic effect, its molecular mechanism is still unknown. In this study, renal fibrosis and inflammation observed in the kidney of unilateral ureteral obstruction (UUO) mice were reduced by the treatment of 1,25(OH)2D3. The plasma protein level of alpha-1-acid glycoprotein (AGP), a downstream molecule of 1,25(OH)2D3, was increased following administration of 1,25(OH)2D3. Additionally, increased mRNA expression of ORM1, an AGP gene, was observed in HepG2 cells and THP-1-derived macrophages that treated with 1,25(OH)2D3. To investigate the involvement of AGP, exogenous AGP was administered to UUO mice, resulting in attenuated renal fibrosis and inflammation. We also found the mRNA expression of CD163, a monocyte/macrophage marker with anti-inflammatory potential, was increased in THP-1-derived macrophages under stimulus from 1,25(OH)2D3 or AGP. Moreover, AGP prevented lipopolysaccharide-induced macrophage activation. Thus, AGP could be a key molecule in the protective effect of 1,25(OH)2D3 against renal fibrosis. Taken together, AGP may replace vitamin D to function as an important immune regulator, offering a novel therapeutic strategy for renal inflammation and fibrosis.

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“…Several proteins highlighted in this study have been previously reported to have biomarker utility in LN or other renal diseases, primarily as markers of renal histology or for diagnostic purposes. 17,18,24,26,37,40 For example, one study found urinary Figure 5. Comparison of quantitative proteomic approaches (A) Heat map of all proteins quantified in both DIA and TMT experiments.…”

Section: ■ Discussionmentioning

confidence: 99%

Discovery and Qualification of Candidate Urinary Biomarkers of Disease Activity in Lupus Nephritis

Anania¹,

Yu²,

Pingitore³

et al. 2018

J. Proteome Res.

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Lupus nephritis (LN) is a severe clinical manifestation of systemic lupus erythematosus (SLE) associated with significant morbidity and mortality. Assessment of severity and activity of renal involvement in SLE requires a kidney biopsy, an invasive procedure with limited prognostic value. Noninvasive biomarkers are needed to inform treatment decisions and to monitor disease activity. Proteinuria is associated with disease progression in LN; however, the composition of the LN urinary proteome remains incompletely characterized. To address this, we profiled LN urine samples using complementary mass spectrometry-based methods: protein gel fractionation, chemical labeling using tandem mass tags, and data-independent acquisition. Combining results from these approaches yielded quantitative information on 2573 unique proteins in urine from LN patients. A multiple-reaction monitoring (MRM) method was established to confirm eight proteins in an independent cohort of LN patients, and seven proteins (transferrin, α-2-macroglobulin, haptoglobin, afamin, α-1-antitrypsin, vimentin, and ceruloplasmin) were confirmed to be elevated in LN urine compared to healthy controls. In this study, we demonstrate that deep mass spectrometry profiling of a small number of patient samples can identify high-quality biomarkers that replicate in an independent LN disease cohort. These biomarkers are being used to inform clinical biomarker strategies to support longitudinal and interventional studies focused on evaluating disease progression and treatment efficacy of novel LN therapeutics.

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

Cited by 46 publications

References 46 publications

The importance of serum neutrophil gelatinase-associated lipocalin level in patients with lupus nephritis

The importance of serum neutrophil gelatinase-associated lipocalin level in patients with lupus nephritis

A downstream molecule of 1,25-dihydroxyvitamin D3, alpha-1-acid glycoprotein, protects against mouse model of renal fibrosis

Discovery and Qualification of Candidate Urinary Biomarkers of Disease Activity in Lupus Nephritis

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