Urinary TWEAK Levels Research Articles

Monitoring of Serum TWEAK Level Guides Glucocorticoid Dosages in the Treatment of Systemic Lupus Erythematosus

Objective: Accurate assessment of systemic lupus erythematosus (SLE) disease activity is critical. This study explored the relationship between the serum level of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score as well as the role of TWEAK in guiding the glucocorticoid dosage in SLE treatment. Methods: This study involved 131 patients with SLE, 34 with subacute cutaneous lupus erythematosus (SCLE), 22 with discoid lupus erythematosus (DLE), and 32 healthy volunteers. The serum and urinary TWEAK levels were determined. Monomeric C-reactive protein (mCRP), anti-dsDNA IgG, antinuclear antibody (ANA), complements in serum and urinary albumin level were measured. The SLEDAI 2000 (SLEDAI-2K) was used to evaluate disease activity. The correlation of the SLEDAI-2K score with all biomarkers was determined. Methylprednisolone was orally administered to patients with SLE depending on the serum level of TWEAK. Results: TWEAK levels were higher in patients with SLE or SCLE than in patients with DLE or healthy controls. The serum TWEAK level was positively correlated with the SLEDAI-2K score in patients with SLE (P < 0.001), and was more strongly correlated with the SLEDAI-2K score than other parameters (P < 0.001). Moreover, TWEAK-based glucocorticoid therapy was associated with lower SLEDAI-2K scores, better tapering of glucocorticoid doses, and fewer lupus flares in patients with SLE. Conclusions: Serum TWEAK is a useful biomarker reflecting SLE disease activity. Monitoring of the serum TWEAK level can improve the outcomes of glucocorticoid therapy in patients with SLE.

Urinary TWEAK; Diagnostic and Prognostic Biomarker in Evaluating Lupus Nephritis Case Control Study

Background: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine that belongs to the TNF-ligand superfamily. Objective: To evaluate the ability of urinary TWEAK (uTWEAK) to diagnose lupus nephritis (LN) and its correlation with activity and chronicity index. Patients and Methods: This study was carried out on 75 individuals, 50 SLE patients, fulfilling the SLICC revision of the ACR classification criteria for SLEand25 age and sex matched apparently healthy control subjects. Patients were assessed by SLE disease activity index (SLEDAI-2K) score. Renal biopsy were done for SLE patients who have confirmed proteinuria >0.5 g in 24-hour urine samples or active urinary sediment or inexplicable decrease in renal function. UrinaryTWEAK levels were measured by ELISA. Results: uTWEAK level showed a highly statistical significant difference among groups (P<0.001). There was direct highly significant correlations between uTWEAK and total (t)SLEDAI (r=0.58, P< 0.001) and renal (r)SLEDAI (r=0.73, P<0.001). uTWEAK hadsignificant association with the presence of proliferative GN (Class III, IV) (p= 0.003). At cutoff point ≥ 9.9 pg/mg Cr, uTWEAK had sensitivity of 76% and a specificity of 60 % to diagnose SLE patients with nephritis. At cutoff point of ≤ 14.9 pg/mg Cr, the uTWEAK level had a sensitivity of 88% and a specificity of 76% to predict good response to treatment in LN patients. Conclusion: We concluded that uTWEAK is a candidate biomarker for evaluating LN. It possesses numerous properties that make it suitable for assessment of LN activity and prognosis.

Urinary TWEAK; Diagnostic and Prognostic Biomarker in Evaluating Lupus Nephritis Case Control Study

Background: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine that belongs to the TNF-ligand superfamily. Objective: To evaluate the ability of urinary TWEAK (uTWEAK) to diagnose lupus nephritis (LN) and its correlation with activity and chronicity index. Patients and Methods: This study was carried out on 75 individuals, 50 SLE patients, fulfilling the SLICC revision of the ACR classification criteria for SLEand25 age and sex matched apparently healthy control subjects. Patients were assessed by SLE disease activity index (SLEDAI-2K) score. Renal biopsy were done for SLE patients who have confirmed proteinuria >0.5 g in 24-hour urine samples or active urinary sediment or inexplicable decrease in renal function. UrinaryTWEAK levels were measured by ELISA. Results: uTWEAK level showed a highly statistical significant difference among groups (P<0.001). There was direct highly significant correlations between uTWEAK and total (t)SLEDAI (r=0.58, P< 0.001) and renal (r)SLEDAI (r=0.73, P<0.001). uTWEAK hadsignificant association with the presence of proliferative GN (Class III, IV) (p= 0.003). At cutoff point ≥ 9.9 pg/mg Cr, uTWEAK had sensitivity of 76% and a specificity of 60 % to diagnose SLE patients with nephritis. At cutoff point of ≤ 14.9 pg/mg Cr, the uTWEAK level had a sensitivity of 88% and a specificity of 76% to predict good response to treatment in LN patients. Conclusion: We concluded that uTWEAK is a candidate biomarker for evaluating LN. It possesses numerous properties that make it suitable for assessment of LN activity and prognosis.

Assessment of urinary TWEAK levels in Mexican patients with untreated lupus nephritis: An exploratory study

ObjectivesUrinary levels of TWEAK (uTWEAK) may be correlated with the degree of lupus nephritis (LN) activity. Our objective was to determine the sensitivity and specificity of uTWEAK in Mexican patients with untreated active lupus nephritis. MethodsAn exploratory study was performed; four groups of patients were analyzed as follows: 1) patients with systemic lupus erythematosus (SLE) without renal activity (SLE-LN), 2) patients with SLE with renal activity (SLE+LN), 3) patients with other types of glomerulopathy (glomerulonephritis, GMN), 4) and healthy patients (controls). ResultsIn all, 44 patients, with an average age of 35.9±11.5 years, were evaluated. uTWEAK levels were higher in patients with SLE+LN compared with patients in the other groups: SLE+LN 12.88±8.33, SLE-LN 3.12±2.31, GMN 4.36±2.31 and controls 2.41±1.94pg/mg Cr (p=0.007). A total of 72.7% of the cases had renal activity index scores above 12, and 90.9% of the cases had scores of chronicity below 6 points. Receiver Operating Characteristic (ROC) curve analysis revealed that uTWEAK levels above 4.91pg/mg Cr had a sensitivity of 81% and a specificity of 75% for the diagnosis of renal activity due to lupus, with an area under the curve of 0.876 (95% CI: 0.75–0.99). However, no significant correlation was observed between the levels of uTWEAK and the histological findings specific to the activity and chronicity associated with SLE. ConclusionsOur study revealed that uTWEAK can adequately distinguish renal activity due to lupus, but cannot predict the degree of histological activity in Mexican patients with active lupus nephropathy.

Assessment of urinary TWEAK levels in Mexican patients with untreated lupus nephritis: An exploratory study

ObjectivesUrinary levels of TWEAK (uTWEAK) may be correlated with the degree of lupus nephritis (LN) activity. Our objective was to determine the sensitivity and specificity of uTWEAK in Mexican patients with untreated active lupus nephritis. MethodsAn exploratory study was performed; four groups of patients were analyzed as follows: 1) patients with systemic lupus erythematosus (SLE) without renal activity (SLE-LN), 2) patients with SLE with renal activity (SLE+LN), 3) patients with other types of glomerulopathy (glomerulonephritis, GMN), 4) and healthy patients (controls). ResultsIn all, 44 patients, with an average age of 35.9±11.5 years, were evaluated. uTWEAK levels were higher in patients with SLE+LN compared with patients in the other groups: SLE+LN 12.88±8.33, SLE-LN 3.12±2.31, GMN 4.36±2.31 and controls 2.41±1.94pg/mg Cr (p=0.007). A total of 72.7% of the cases had renal activity index scores above 12, and 90.9% of the cases had scores of chronicity below 6 points. Receiver Operating Characteristic (ROC) curve analysis revealed that uTWEAK levels above 4.91pg/mg Cr had a sensitivity of 81% and a specificity of 75% for the diagnosis of renal activity due to lupus, with an area under the curve of 0.876 (95% CI: 0.75–0.99). However, no significant correlation was observed between the levels of uTWEAK and the histological findings specific to the activity and chronicity associated with SLE. ConclusionsOur study revealed that uTWEAK can adequately distinguish renal activity due to lupus, but cannot predict the degree of histological activity in Mexican patients with active lupus nephropathy.

Urinary Tumor Necrosis Factor-like Weak Inducer of Apoptosis as a Biomarker for Lupus Nephritis: A Meta-analysis

Objective. This study evaluates serum or urinary tumor necrosis factor-like weak inducer of apoptosis (TWEAK) as a biomarker for lupus nephritis (LN). Methods. We conducted a meta-analysis examining serum or urinary TWEAK levels in patients with systemic lupus erythematosus (SLE), patients with LN (active or inactive), and healthy controls. We tabulated correlation coefficients between urinary TWEAK level and total or renal SLE Disease Activity Index (tSLEDAI or rSLEDAI). Results. Eight studies were included in this meta-analysis. The meta-analysis revealed that serum TWEAK levels tended to be higher in patients with SLE than in controls (standard mean difference [SMD]=0.850, 95% confidence interval [CI]=-0.067∼1.767, p=0.069). Urinary TWEAK was significantly higher in patients with active LN than in those with inactive LN (SMD=2.865, 95% CI= -0.831∼4.898, p=0.006). In addition, urinary TWEAK was positively associated with tSLEDAI and rSLEDAI (correlation coefficient= 0.436, 95% CI=0.204∼0.622, p=4.3×10-4; correlation coefficient=0.483, 95% CI=0.108∼0.738, p=0.014). Pooled sensitivity and specificity of urinary TWEAK for diagnosis of LN were 81.3% (95% CI, 73.3∼87.8) and 76.0% (95% CI, 66.3∼84.2), indicating good diagnostic accuracy. Conclusion. The meta-analysis demonstrated that urinary TWEAK was significantly higher in patients with active LN than in those with inactive LN, and that urinary TWEAK levels were positively correlated with renal disease activity. (J Rheum Dis 2017;24:85-92)

TWEAK/Fn14 and Non-Canonical NF-kappaB Signaling in Kidney Disease

The incidence of acute kidney injury (AKI) and chronic kidney disease (CKD) is increasing. However, there is no effective therapy for AKI and current approaches only slow down, but do not prevent progression of CKD. TWEAK is a TNF superfamily cytokine. A solid base of preclinical data suggests a role of therapies targeting the TWEAK or its receptor Fn14 in AKI and CKD. In particular TWEAK/Fn14 targeting may preserve renal function and decrease cell death, inflammation, proteinuria, and fibrosis in mouse animal models. Furthermore there is clinical evidence for a role of TWEAK in human kidney injury including increased tissue and/or urinary levels of TWEAK and parenchymal renal cell expression of the receptor Fn14. In this regard, clinical trials of TWEAK targeting are ongoing in lupus nephritis. Nuclear factor-kappa B (NF-κB) activation plays a key role in TWEAK-elicited inflammatory responses. Activation of the non-canonical NF-κB pathway is a critical difference between TWEAK and TNF. TWEAK activation of the non-canonical NF-κB pathways promotes inflammatory responses in tubular cells. However, there is an incomplete understanding of the role of non-canonical NF-κB activation in kidney disease and on its contribution to TWEAK actions in vivo.

Urinary TWEAK Level as a Marker of Lupus Nephritis Activity in 46 Cases

Objective. This study is designed to observe the urinary tumor necrosis factor-like weak inducer of apoptosis (TWEAK) levels in patients with lupus nephritis (LN) and to identify new biomarker of lupus nephritis activity. Methods. Study subjects were 46 cases of patients with LN (including 34 of active cases) who underwent routine renal biopsy. Activity and chronicity indexes of LN were assessed using pathological criteria proposed by Hill et al. in 2000. Urinary TWEAK (uTWEAK) level and Monocyte chemoattractant protein-1 (MCP-1) level were detected by ELISA. Results. Urinary TWEAK level was significantly higher in active LN group than in non-active LN group. Correlation analysis showed that urinary TWEAK levels were significantly correlated with activity index (r = 0.825, P < 0.01), glomerular activity index (r = 0.754, P < 0.01), and tubulointerstitial qualitative activity index (r = 0.751, P < 0.01), while not significant correlated with chronicity Index (P > 0.05). The association between urinary TWEAK levels and urinary MCP-1 levels were significant in active LN group (r = 0.809, P < 0.01) but not significant in non-active LN group (P > 0.05). Conclusions. uWEAK levels were correlated with all active indexes of LN, suggesting its potential role as novel biomarker of active lupus nephritis.

Correlations of Urinary Biomarkers, TNF-Like Weak Inducer of Apoptosis (TWEAK), Osteoprotegerin (OPG), Monocyte Chemoattractant Protein-1 (MCP-1), and IL-8 with Lupus Nephritis

This case-controlled study was designed to correlate urinary biomarkers, TNF-like weak inducer of apoptosis (TWEAK), osteoprotegerin (OPG), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8) levels, with renal involvement in a cohort of systemic lupus erythematosus (SLE) patients to examine their diagnostic performance. In 73 SLE patients, and in 23 healthy volunteers, urinary levels of TWEAK, OPG, MCP-1, and IL-8 levels were measured. Disease activity was assessed by total SLE disease activity index, and renal activity by renal activity index (rSLEDAI), and both were correlated with urinary biomarkers. Sensitivity, specificity, and predictive values of individual biomarkers to predict lupus nephritis were also calculated. Significantly higher levels of urinary biomarkers were observed in SLE patients with lupus nephritis (LN) compared with those without LN (TWEAK, p < 0.001; MCP-1, p < 0.001; OPG, p < 0.001; IL-8, p < 0.032). Other significantly higher levels were observed in SLE patients with LN compared with control subjects (TWEAK, MCP-1, OPG, and IL-8 p < 0.001). Positive correlations were observed between rSLEDAI and TWEAK (r = 0.612 and p < 0.001), MCP-1 (r = 0.635 and p < 0.001), and OPG (r = 0.505 and p < 0.001). Urinary levels of TWEAK, OPG, and MCP-1 positively correlate with renal involvement as assessed by rSLEDAI with reasonable sensitivity, specificity, and predictive values to detect lupus nephritis while IL-8 was not significantly associated with global or rSLEDAI.

TNF-like weak inducer of apoptosis (TWEAK) induces inflammatory and proliferative effects in human kidney cells

Members of the TNF-ligand and receptor superfamilies are important in the pathogenesis of lupus nephritis, a major cause of mortality and morbidity in SLE. TWEAK, a member of the TNF-ligand superfamily, is markedly increased in urine from patients with active lupus nephritis, and urinary TWEAK levels significantly correlate with renal disease activity. To support a possible role of TWEAK in the pathogenesis of lupus nephritis and other inflammatory nephritides, we examined the effects of TWEAK in human kidney mesangial cells, podocytes and tubular cells, following our demonstration of the presence of the TWEAK receptor Fn14 on these cells. We found that TWEAK induces human kidney cells to express multiple inflammatory mediators, including RANTES, MCP-1, IP-10, MIP-1α, ICAM-1, and VCAM-1. Cytokine production is mediated through NF-κB activation, and is inhibited by anti-TWEAK monoclonal antibodies. TWEAK stimulated chemokines induced migration of human PBMC, particularly monocytes/macrophages. Furthermore, we found that TWEAK promotes kidney infiltration of inflammatory cells, and stimulates proliferation of kidney cells in vitro and in vivo. Thus, TWEAK may play an important pathogenic role in the development of glomerulonephritis by promoting a local inflammatory environment and inducing kidney cell proliferation. Blocking TWEAK/Fn14 interactions may be a promising therapeutic target in immune-mediated renal diseases.

TWEAKing renal injury

TWEAK is a recently identified cytokine of the TNF superfamiliy. Through activation of the Fn14 receptor, TWEAK regulates cell proliferation, cell death and inflammation. Recent studies show increased TWEAK and Fn14 expression in tubular cells during acute kidney injury as well as elevated urinary TWEAK levels in patients with active lupus nephritis. Furthermore, glomerular mesangial cells and renal tubular epithelial cells express the Fn14 receptor under the regulation of proinflammatory cytokines. TWEAK weakly increases cell death and promotes secretion of inflammatory mediators in non-stimulated mesangial cells. In addition, in a proinflammatory milieu, TWEAK induces apoptosis of mesangial and tubular cells. The available data suggest that TWEAK is a new player in kidney injury both at the glomerular and tubulointerstitial levels and might be a target for therapeutic intervention.

Urinary TWEAK and the activity of lupus nephritis

The TNF superfamily cytokine TWEAK induces mesangial cells, podocytes, and endothelial cells to secrete pro-inflammatory chemokines including MCP-1, IP-10 and RANTES, which are crucial in the pathogenesis of lupus nephritis (LN). As TWEAK regulates the secretion of these inflammatory mediators, we studied whether urinary TWEAK (uTWEAK) levels might be predictive and/or diagnostic in LN. In a cross-sectional study of a large, multi-center cohort of systemic lupus erythematosus (SLE) patients, uTWEAK levels were higher in patients with active as compared to never or non-active nephritis (median (IQR): 16.3 (9.9–23.0) versus 5.5 (2.3–16.8) pg/mg creatinine, p = 0.001), and levels of uTWEAK correlated with the renal SLE disease activity index (rSLEDAI) score ( r = 0.405, p < 0.001). uTWEAK levels were higher in patients undergoing a flare as compared to patients with chronic stable disease (11.1 (8.1–18.2) and 5.2 (2.3–15.3) pg/mg creatinine, respectively; p = 0.036). Moreover, uTWEAK levels were significantly higher in patients undergoing a renal flare, as opposed to a non-renal flare (12.4 (9.1–18.2) and 5.2 (3.0–11.9) pg/mg creatinine, respectively; p = 0.029). An accurate, non-invasive method to repeatedly assess kidney disease in lupus would be very helpful in managing these often challenging patients. Our study indicates that urinary TWEAK levels may be useful as a novel biomarker in LN.