Neutrophil gelatinase-associated lipocalin as a biomarker for lupus nephritis

Torres-Salido, María Teresa; Cortés-Hernández, Josefina; Vidal, Xavier; Pedrosa, Albert; Vilardell‐Tarrés, Miquel; Ordi‐Ros, Josep

doi:10.1093/ndt/gfu062

Cited by 37 publications

(50 citation statements)

References 32 publications

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“…In recent years, various studies have focused on the combination of SLE biomarkers and simple clinical indicators for improving the sensitivity and specificity of predictions regarding LN activity and disease progression (28,29). TWEAK is a novel member of the tumor necrosis factor ligand super family that is distributed in a range of organs, including the pancreas, heart, intestine, kidney, brain, ovaries, liver, spleen, lymph nodes and skeletal muscle (30).…”

Section: Discussionmentioning

confidence: 99%

Involvement of TWEAK and the NF-κB signaling pathway in lupus nephritis

Sun

Teng

et al. 2018

Exp Ther Med

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Abstract. Previous findings have identified that tumor necrosis factor-related weak inducer of apoptosis (TWEAK) is associated with lupus nephritis (LN) activity status; however, the mechanism involved remains unclear. The present study aimed to investigate the roles of TWEAK and the nuclear factor (NF)-κB signaling pathway in LN. TWEAK levels in the blood and urine of patients with LN or non-LN systemic lupus erythematosus were measured by ELISA and compared with those in healthy controls. TWEAK expression and NF-κB transcriptional activity in the kidney were detected by western blotting, and Ki-67 and cluster of differentiation (CD) 68 expression were assessed using immunofluorescence. Additionally, human mesangial cells (HMCs) were cultured in vitro and divided into five groups: Normal control, TWEAK stimulus group, TWEAK + TWEAK blocking antibody, TWEAK + NF-κB inhibitor (BAY 11-7082) and TWEAK + combined (blocking antibody + BAY 11-7082). Cell cycle activity and Ki-67 expression in the HMCs were evaluated using flow cytometry, and cell induction of macrophage chemotaxis was determined by a Transwell assay. Levels of the inflammation-associated factors interleukin (IL)-6, monocyte chemotactic protein 1 (MCP-1), chemokine ligand 5 (CCL5), IL-8 and IL-10 were also detected by reverse transcription-quantitative polymerase chain reaction. It was observed that the urine levels of TWEAK in patients with LN were significantly elevated compared with those in the other groups (P<0.05). LN kidneys exhibited markedly increased cell proliferative ability, macrophage infiltration, TWEAK expression and NF-κB transcriptional activity compared with normal kidneys. Furthermore, the results indicated that treatment with recombinant TWEAK notably enhanced NF-κB transcriptional activity and significantly promoted cell proliferation and cell cycle activity (P<0.05), induced macrophage chemotaxis (P<0.05), significantly increased the expression of the chemotactic factors IL-6, IL-8, MCP-1 and CCL5 (P<0.05), and significantly reduced anti-inflammatory cytokine IL-10 mRNA expression in HMCs (P<0.05), relative to normal controls. Accordingly, blocking TWEAK function or inhibiting NF-κB activity reversed these effects. Collectively these data indicate that urine TWEAK may be considered as a novel biomarker of LN activity, and that blocking TWEAK function or NF-κB activity may effectively alleviate glomerular mesangial cell proliferation and macrophage chemotaxis.

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Section: Discussionmentioning

confidence: 99%

Involvement of TWEAK and the NF-κB signaling pathway in lupus nephritis

Sun

Teng

et al. 2018

Exp Ther Med

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“…Given that all of the UBMs are proteins, standardization by urine albumin, the predominant protein excreted with proteinuria, has been proposed. As such, Torres-Salido et al reported that urine NGAL was a predictor of LN flare, but only if corrected for urine albumin and not when corrected for urine creatinine or when expressed as a concentration (19). Of note, we were unable to replicate this observation in our study cohort.…”

Section: Discussionmentioning

confidence: 99%

Prospective validation of a novel renal activity index of lupus nephritis

Gulati

Bennett

Abulaban

et al. 2016

Lupus

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Objectives The Renal Activity Index for Lupus (RAIL) score was developed in children with lupus nephritis (LN) as a weighted sum of six urine biomarkers (RAIL-UBMs) [neutrophil gelatinase associated lipocalin, monocyte chemotactic protein 1, ceruloplasmin, adiponectin, hemopexin and kidney injury molecule 1] measured in a random urine sample. We aimed at prospectively validating the RAIL in adults with LN. Methods Urine from 79 adults was collected at the time of kidney biopsy to assay the RAIL-UBMs. Using Receiver Operating Characteristic curve (ROC) analysis, we evaluated the accuracy of the RAIL to discriminate high LN-activity status [National Institutes of Health Activity Index (NIH-AI) score > 10], from low/moderate LN-activity status [NIH-AI score ≤ 10]. Results In this mixed racial cohort, high LN-activity was present in 15 patients (19%), and 71% had proliferative LN. Use of the identical RAIL algorithm developed in children (P-RAIL) resulted only in fair prediction of LN-activity status of adults [area-under the ROC-curve (AUC) 0.62]. Alternative weightings of the six RAIL-UBMs as suggested by logistic regression yielded excellent accuracy to predict LN-activity status (A-RAIL; AUC = 0.88). Accuracy of the model did not improve with adjustment of the UBMs for urine creatinine or albumin, and was little influenced by concurrent kidney damage. Conclusions The RAIL-UBMs provide excellent prediction of LN-activity in adults. Age-adaption of the RAIL is warranted to optimize its discriminative validity to non-invasively predict high LN-activity status.

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“…4C). Urine NGAL has been used as a biomarker of kidney damage in lupus nephritis patients (21). Doses of BMS-986126 as low as 1 mg/kg/d demonstrated significant protection of all end points.…”

Section: In Vivo Efficacy Of Bms-986126mentioning

confidence: 99%

Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity

Dudhgaonkar

Ranade

Nagar

et al. 2017

The Journal of Immunology

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The serine/threonine kinase IL-1R–associated kinase (IRAK)4 is a critical regulator of innate immunity. We have identified BMS-986126, a potent, highly selective inhibitor of IRAK4 kinase activity that demonstrates equipotent activity against multiple MyD88-dependent responses both in vitro and in vivo. BMS-986126 failed to inhibit assays downstream of MyD88-independent receptors, including the TNF receptor and TLR3. Very little activity was seen downstream of TLR4, which can also activate an MyD88-independent pathway. In mice, the compound inhibited cytokine production induced by injection of several different TLR agonists, including those for TLR2, TLR7, and TLR9. The compound also significantly suppressed skin inflammation induced by topical administration of the TLR7 agonist imiquimod. BMS-986126 demonstrated robust activity in the MRL/lpr and NZB/NZW models of lupus, inhibiting multiple pathogenic responses. In the MRL/lpr model, robust activity was observed with the combination of suboptimal doses of BMS-986126 and prednisolone, suggesting the potential for steroid sparing activity. BMS-986126 also demonstrated synergy with prednisolone in assays of TLR7- and TLR9-induced IFN target gene expression using human PBMCs. Lastly, BMS-986126 inhibited TLR7- and TLR9-dependent responses using cells derived from lupus patients, suggesting that inhibition of IRAK4 has the potential for therapeutic benefit in treating lupus.

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Neutrophil gelatinase-associated lipocalin as a biomarker for lupus nephritis

Abstract: The FE NGAL/FE protein ratio is a reliable marker of disease activity in patients with SLE and could be used as an indicator of response to therapy, although further studies are required to confirm these results.

Cited by 37 publications

References 32 publications

Involvement of TWEAK and the NF-κB signaling pathway in lupus nephritis

Involvement of TWEAK and the NF-κB signaling pathway in lupus nephritis

Prospective validation of a novel renal activity index of lupus nephritis

Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity

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