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

Young Ho Lee; Gwan Gyu Song

doi:10.4078/jrd.2017.24.2.85

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

Original Article

J Rheum Dis 2017;24(2):85-92.

Published online: 31 October 2017

DOI: https://doi.org/10.4078/jrd.2017.24.2.85

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

Young Ho Lee, Gwan Gyu Song

Division of Rheumatology, Department of Internal Medicine, Korea University Medical Center, Korea University College of Medicine, Seoul, Korea

Corresponding to: Young Ho Lee, Division of Rheumatology, Department of Internal Medicine, Korea University Medical Center, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea. E-mail: lyhcgh@korea.ac.kr

Received 3 March 2017 Accepted 10 April 2017

This is a Free Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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 co-efficient=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.

Keywords: Urinary TWEAK, Lupus nephritis, Biomarker

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Figure 1.

Meta-analysis of the relationship between serum TWEAK level and SLE compared with control (A), and between urinary TWEAK level and active LN compared with inactive LN (B). TWEAK: tumor necrosis factor-like weak inducer of apoptosis, SLE: systemic lupus erythematosus, LN: lupus nephritis, CI: confidence interval, Std diff: standardized difference.

Figure 2.

Meta-analysis of the correlation coefficient between urinary TWEAK and total SLEDAI (A) and renal SLEDAI (B). TWEAK: tumor necrosis factor-like weak inducer of apoptosis, SLEDAI: systemic lupus erythematosus disease activity index, CI: confidence interval.

Figure 3.

Summary receiver-operating characteristic curves for urinary TWEAK for the diagnosis of LN. Solid circles represent individual studies included in this meta-analysis. The curve shown is a regression line that summarizes the overall diagnostic accuracy. TWEAK: tumor necrosis factor-like weak inducer of apoptosis, LN: lupus nephritis, SROC: summary receiver operating characteristic, SE (AUC): standard error of the area under the curve, Q*: an index defined by the point on the SROC curve where the sensitivity and specificity are equal; and SE (Q*): Q* index standard error.

Table 1.

Characteristics of individual studies included in the meta-analysis

Author	Country	Number		Age, yr		Disease duration	Main findings
Author	Country	SLE	Control	SLE	Control	Disease duration	Main findings
Salem, 2016 [19]	Egypt	14^*	24^†	25.6±10.7^*	27.3±9.0^†	2.2±2.1^*	The uTWEAK levels were significantly higher in patients with SLE with active LN compared to those without or with inactive renal disease and normal healthy subjects.
Choe, 2016 [20]	Korea	70	61	40.4±11.2	4.6±9.1	6.4±4.4	sTWEAK might be a serologic biomarker candidate that reflects disease activity and renal involvement in patients with SLE.
Xuejing, 2012 [21]	China	34^*	12^†	14∼53^*	14∼53^†	12.7±3.4^*	uTWEAK levels were correlated with all active indexes of LN, suggesting its potential role as a novel biomarker of active lupus nephritis.
Wang, 2012 [22]	China	62	15	34.1±10.0	36.6±11.6	NA	Patients with SLE express low levels of TWEAK mRNA but high levels of sTWEAK. Additionally, sTWEAK level was associated with several clinical manifestations of SLE, indicating that TWEAK may play a complex role in SLE.
El-shehaby, 2011 [23]	Egypt	50^*	23^†	29.1±7.9^*	29.7±8.8^‡	6.1±4.2^*	Urinary levels of TWEAK positively correlate with renal involvement as assessed by rSLEDAI with reasonable sensitivity, specificity, and predictive values to detect LN.
Schwartz, 2009 [24]	USA	30^‡	61	40.4±11.2^‡	4.6±9.1	6.4±4.4	High uTWEAK levels are indicative of LN, as opposed to non-LN SLE and other healthy and disease control populations, and reflect renal disease activity in longitudinal follow-up.
ElGendi, 2009 [25]	Egypt	47	20	25.3±7.2	NA	25.7±3.1	sTWEAK may be used as a serum biomarker for the assessment of disease activity and development of LN.
Schwartz, 2006 [26]	USA	83	NA	35	NA	NA	Urinary TWEAK levels may be useful as a novel biomarker in LN.

Values are presented as number and mean±standard deviation. SLE: systemic lupus erythematosus, TWEAK: tumor necrosis factor-like weak inducer of apoptosis, uTWEAK: urinary TWEAK, LN: lupus nephritis, sTWEAK: serum TWEAK, NA: not available, rSLEDAI: renal SLE disease activity index. Definition of Active LN in this analysis: rSLEDAI score ≥4.

^* Active LN

^† non-LN SLE

^‡ LN.

Table 2.

Meta-analysis of serum and urinary TWEAK levels in lupus nephritis

Comparison	Population	^Number of study	Test of association			Test of heterogeneity			Publication bias p-value
Comparison	Population	^Number of study	SMD	95% CI	p-value	Model	p-value	I²	Publication bias p-value
Serum TWEAK
SLE vs. Control	Overall	4	0.850	−0.067∼1.767	0.069	R	0.000	92.5	0.823
LN vs. Control	Overall	3	1.326	−0.695∼3.347	0.198	R	0.000	95.9	0.244
LN vs. Non-LN	Overall	3	0.997	−0.513∼2.506	0.196	R	0.000	94.8	0.025
Urinary TWEAK
LN vs. Control	Overall	2	1.655	−0.289∼3.600	0.095	R	0.000	93.2	NA
Active LN vs.	Overall	3	2.865	0.831∼4.898	0.006	R	0.000	92.5	0.441
Inactive LN

TWEAK: tumor necrosis factor-like weak inducer of apoptosis, SMD: standard mean difference, CI: confidence interval, SLE: systemic lupus erythematosus, LN: lupus nephritis, R: random effects model, NA: not available.

Table 3.

Meta-analysis of the correlation coefficient between urinary TWEAK level and SLE and renal activity, and the diagnosis of LN

A. Correlation between uTWEAK and SLE or renal activity
Comparison	Number		Test of association			Test of heterogeneity			Publication bias p-value
Comparison	Study	Patient	Correlation coefficient	95% CI	p-value	Model	p-value	I²	Publication bias p-value
tSLEDAI	4	212	0.436	0.204∼0.622	4.3×10⁻⁴	R	0.002	79.7	0.949
rSLEDAI	4	289	0.483	0.108∼0.738	0.014	R	0.000	92.0	0.705
TWEAK: tumor necrosis factor-like weak inducer of apoptosis, SLE: systemic lupus erythematosus, LN: lupus nephritis, uTWEAK: urinary TWEAK, CI: confidence interval, tSLEDAI: total SLE disease activity index, rSLEDAI: renal SLE disease activity index, R: random effects model.

B. Diagnosis of LN
Population	Study No.	Number		Sensitivity (95% CI)	Specificity (95% CI)	PLR (95% CI)	NLR (95% CI)	DOR (95% CI)	AUC (SE)	Q^* (SE)
Population	Study No.	LN N	Non-LN	Sensitivity (95% CI)	Specificity (95% CI)	PLR (95% CI)	NLR (95% CI)	DOR (95% CI)	AUC (SE)	Q^* (SE)
Overall	3	123	96	0.813 (0.733∼0.878)	0.760 (0.663∼0.842)	2.723 (1.774∼4.180)	0.248 (0.073∼0.843)	11.28 (5.128∼24.82)	0.836 (0.038)	0.768 (0.035

LN: lupus nephritis, PLR: positive likelihood ratio, NLR: negative likelihood ratio, DOR: diagnostic odds ratio, AUC: area under the curve, CI: confidence interval, SE: standard error.

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