Urinary TWEAK as a biomarker of lupus nephritis: a multicenter cohort study

Schwartz, Noa; Rubinstein, Tamar; Burkly, Linda C.; Collins, Christopher; Blanco, Irene; Su, Lihe; Hojaili, Bernard; Mackay, Meggan; Aranow, Cynthia; Stohl, William; Rovin, Brad H.; Michaelson, Jennifer S.; Putterman, Chaim

doi:10.1186/ar2816

Cited by 159 publications

(146 citation statements)

References 31 publications

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“…20,21 In a cross-sectional single-cohort study using a modest sampling of patients with LN, we previously reported that serum or urine CSF-1 was elevated in patients with LN compared with those who had other noninflammatory kidney diseases and healthy controls; in that study we also found that amplified CSF-1 levels correlated with more severe clinical disease activity. 8 Another study indicated that flares were more likely in patients with persistently increased regulated upon activation normal T cell expressed and presumably secreted or M-CSF (also known as CSF-1) levels in urine after induction therapy using group survival curve analysis.…”

Section: Discussionmentioning

confidence: 59%

Colony-Stimulating Factor-1

Menke¹,

Amann

Cavagna

et al. 2015

Journal of the American Society of Nephrology

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A noninvasive means to predict the onset and recurrence of lupus nephritis (LN) before overt renal injury is needed to optimize and individualize treatment. Colony-stimulating factor-1 (CSF-1) is expressed by kidney tubules at the onset of LN, increases with disease progression, and spills into the circulation in lupus-prone mice. We tested the hypothesis that amplified expression of CSF-1 detected in the serum or urine correlates with intrarenal CSF-1 expression and histopathology (increased macrophage accumulation, activity indices) and clinical kidney disease activity and predicts the onset and recurrence of nephritis in patients with systemic lupus erythematosus (SLE). We found increased serum or urine CSF-1 levels in patients with cutaneous, serositis, and musculoskeletal disease; however, the increase in CSF-1 levels was far greater in LN. Moreover, an elevation in serum or urine CSF-1 levels correlated with increasing intrarenal CSF-1 expression and histopathology. By longitudinally tracking patients, we found that elevated serum CSF-1 heralded the initial onset of disease, and a rise in serum or urine CSF-1 predicted recurrences of LN before clinical evidence of glomerular dysfunction and conventional serologic measures, even in patients with other manifestations of SLE. These findings indicate that serial monitoring for a rise in serum or urine CSF-1 levels in patients with SLE reflects kidney histopathology and may predict renal disease activity and the onset and recurrence of LN more accurately than conventional laboratory measures. 26: 379-389, 201526: 379-389, . doi: 10.1681 Lupus nephritis (LN) is the main cause of morbidity and mortality for patients with systemic lupus erythematosus (SLE). 1 Despite current treatment, ESRD is frequent in patients with LN (up to 26%). 2 Moreover, relapses or flares of LN are common (27%-66%) and contribute to mortality. 3,4 Current methods for diagnosing LN in patients with SLE include proteinuria, active sediment, and a decrease in GFR with confirmation by a renal biopsy. 5 Clearly, identification of a biomarker that heralds LN before structural renal damage and the loss of renal function would provide a window to treat early and obviate renal tissue injury. J Am Soc NephrolColony-stimulating factor-1 (CSF-1) is largely responsible for Mø development, survival, proliferation, and activation. 6 We hypothesize that amplified expression of CSF-1 in serum or urine reflects the magnitude of intrarenal CSF-1 and histopathology, correlates with LN clinical disease activity, and heralds the onset and recurrence of LN.

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Section: Discussionmentioning

confidence: 59%

Colony-Stimulating Factor-1

Menke¹,

Amann

Cavagna

et al. 2015

Journal of the American Society of Nephrology

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“…In addition, a variety of studies have demonstrated the value of TWEAK in assessing renal damage severity (10)(11)(12). Notably, it has been reported that urine TWEAK content in patients with active LN was significantly higher than in those with inactive LN (13), and that urine TWEAK level was correlated with the degree of renal damage (14). Previous results also indicated that TWEAK was highly expressed in the renal tissue of an LN animal model (15).…”

Section: Introductionmentioning

confidence: 97%

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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“…16 In clinical studies, significantly higher urinary TWEAK levels were present in human LN, which increased with renal flares. [17][18][19][20] Interestingly, intrarenal TWEAK and Fn14 expression varied with the histologic class of LN and correlated with the activity index. 21,22 Finally, elevated production of TWEAK in lupus PBMCs correlated with disease activity and proteinuria.…”

mentioning

confidence: 95%

Deficiency of Fibroblast Growth Factor-Inducible 14 (Fn14) Preserves the Filtration Barrier and Ameliorates Lupus Nephritis

Xia

Herlitz

Gindea

et al. 2015

Journal of the American Society of Nephrology

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115

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TNF ligand superfamily member 12, also known as TNF-related weak inducer of apoptosis (TWEAK), acts through its receptor, fibroblast growth factor-inducible 14 (Fn14), to mediate several key pathologic processes involved in tissue injury relating to lupus nephritis. To explore the potential for renal protection in lupus nephritis by targeting this pathway, we introduced the Fn14 null allele into the MRL-lpr/lpr lupus mouse strain. At 26-38 weeks of age, female Fn14-knockout MRL-lpr/lpr mice had significantly lower levels of proteinuria compared with female wild-type MRL-lpr/lpr mice. Furthermore, Fn14-knockout mice had significantly improved renal histopathology accompanied by attenuated glomerular and tubulointerstitial inflammation. There was a significant reduction in glomerular Ig deposition in Fn14-knockout mice, despite no detectable differences in either serum levels of antibodies or splenic immune cell subsets. Notably, we found that the Fn14-knockout mice displayed substantial preservation of podocytes in glomeruli and that TWEAK signaling directly damaged barrier function and increased filtration through podocyte and glomerular endothelial cell monolayers. Our results show that deficiency of the Fn14 receptor significantly improves renal disease in a spontaneous lupus nephritis model through prevention of the direct injurious effects of TWEAK on the filtration barrier and/or modulation of cytokine production by resident kidney cells. Thus, blocking the TWEAK/Fn14 axis may be a novel therapeutic intervention in immune-mediated proliferative GN.

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Urinary TWEAK as a biomarker of lupus nephritis: a multicenter cohort study

Cited by 159 publications

References 31 publications

Colony-Stimulating Factor-1

Colony-Stimulating Factor-1

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

Deficiency of Fibroblast Growth Factor-Inducible 14 (Fn14) Preserves the Filtration Barrier and Ameliorates Lupus Nephritis

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