Diagnostic value of TWEAK for predicting active lupus nephritis in patients with systemic lupus erythematosus: a systematic review and meta-analysis

Figures & data

Figure 1. Flowchart of paper selection. TWEAK: tumor necrosis factor (TNF)-like weak inducer of apoptosis; LN: lupus nephritis; SLE: systemic lupus erythematosus.

Table 1. Characteristics of the included studies.

Author, year	Country	Study design	Participants, female (%)	Baseline Scr (mg/dl)	Definition of active LN	Key findings
Noa Schwartz, et al. 2009	USA	Multicenter cohort study. Cross-sectional and longitudinal studies.	SLE + LN: n = 30. F: 93%. SLE-LN: n = 49. F: 88%.	SLE + LN: 0.85 (0.60–1.20)^b. SLE–LN: 0.70 (0.60–0.80)^b.	rSLEDAI score > 0.	High uTWEAK indicated the presence of LN and reflected renal disease activity in the follow-up. TWEAK signaling pathway might be involved in the pathogenesis of LN.
Jiazhen Tan, et al. 2009	China	Cross-sectional study.	SLE + LN: n = 34. F: 97.1%. SLE-LN: n = 12. F: 75%.	SLE + LN: 1.28 ± 0.11. SLE–LN: 1.04 ± 0.22.	rSLEDAI score > 4.	The level of uTWEAK reflected renal disease activity and could be a novel biomarker of LN.
S. Marzouk, et al. 2011	Egypt	Cross-sectional study.	SLE + LN: n = 50. SLE-LN: n = 23. F (total): 96%.	SLE + LN: 0.80 ± 0.30. SLE–LN: 0.56 ± 0.20.	rSLEDAI score > 4.	uTWEAK along with other urinary biomarkers (OPG, MCP-1, and IL-8) correlated with renal involvement in patients with SLE.
Jung-Yoon Choe, et al. 2016	Republic of Korea	Cross-sectional study.	SLE + LN: n = 32. F: 100%. SLE-LN: n = 38. F: 100%.	Not reported separately. SLE + LN and SLE–LN: 0.8 ± 0.8.	rSLEDAI score > 0.	sTWEAK might be a biomarker candidate that reflected renal involvement in patients with SLE.
Fabiola Reyes Martínez, et al. 2017	Mexico	Cross-sectional study.	SLE + LN: n = 11. F: 81.8%. SLE-LN: n = 11. F: 90.9%.	SLE + LN: 1.60 ± 1.53. SLE–LN: 0.72 ± 0.16.	Renal activity was proven by kidney biopsy.	uTWEAK could distinguish renal activity with higher sensitivity and specificity compared with the commonly used biomarkers.
XW Dong, et al. 2018	China	Cross-sectional study.	SLE + LN: n = 48. F: 85.4%. SLE-LN: n = 22. F: 90.9%.	SLE + LN: 1.04 ± 0.48. SLE–LN: 0.86 ± 0.22.	rSLEDAI score > 0.	uTWEAK combined with uMCP-1 could discriminate severe LN patients and predict LN renal prognosis.
XW Dong, et al. 2018^a	China	Cross-sectional study.	SLE + LN: n = 39. F: 89.7%. SLE-LN: n = 20. F: 90%.	NR.	24-hour urine proteinuria > 300 mg/day, further confirmed by kidney biopsy.	uTWEAK was elevated in patients with active LN and correlated with 24-hour urine proteinuria.
M. N. Salem, et al. 2018	Egypt	Cross-sectional study.	SLE + LN: n = 14. F: 96.7%. SLE-LN: n = 30. F: 78.6%.	SLE + LN: 2.10 ± 1.90. SLE–LN: 0.84 ± 0.68.	rSLEDAI score > 4.	uTWEAK was a sensitive biomarker for early detection of active LN.
S Mirioglu, et al. 2020	Turkey	Cross-sectional study.	SLE + LN: n = 15. F: 73.3%. SLE-LN: n = 15. F: 93.3%.	SLE + LN: 0.7 (0.6–1.63)^b. SLE–LN: NR.	rSLEDAI score > 0.	sTWEAK was helpful in distinguishing patients with active LN. uTWEAK was not able to discriminate active LN.

^aThis study compared the level of uTWEAK with urine albumin/creatinine ratio in proteinuria detection in patients with LN. Since proteinuria is a component of rSLEDAI scoring system, the study was also included.

^bData were presented as the median (interquartile range). Scr: serum creatinine; SLE: systemic lupus erythematosus; LN: lupus nephritis; SLE + LN: SLE patients with active LN; SLE-LN: SLE patients without active LN; rSLEDAI: renal systemic lupus erythematosus disease activity index; uTWEAK: urinary TNF-like weak inducer of apoptosis; sTWEAK: serum TNF-like weak inducer of apoptosis; OPG: osteoprotegerin; MCP-1: monocyte chemoattractant protein-1; IL-8: interleukin-8; NR: not reported.

Figure 2. Methodological quality graph.

Figure 3. Methodological quality summary. *This study compared the level of uTWEAK with urine albumin/creatinine ratio in proteinuria detection in patients with LN. Since proteinuria is a component of rSLEDAI scoring system, the study was also included. (The asterisk* in the following figures indicates the same.)

Figure 4. Deeks’funnel plot for detecting publication bias of the included studies.

Figure 6. SROC curve for quantitative analysis of TWEAK in the diagnosis of active LN. SROC: summary receiver operating characteristic; AUC, area under the receiver operating characteristic curve; SE, standard error.

Table 2. Diagnostic accuracies of the included studies for TWEAK to predict active LN from lupus patients.

Author, year	Sample type	Measurement method	TP	FN	FP	TN	TWEAK cutoff	Sensitivity	Specificity	AUC (95% CI)
Schwartz, et al. 2009	Urine	ELISA	15	15	5	44	13 pg/mg Cr	50%	90%	0.724 (NR)
Tan, et al. 2009	Urine	ELISA	24	10	1	11	4.34 pg/mg Cr	69.70%	92.31%	0.790 (NR)
El-shehaby, et al. 2011	Urine	ELISA	45	5	10	13	9.1 pg/mg Cr	89%	56%	0.816 (NR)
Choe, et al. 2016^b	Serum	ELISA	26	6	20	18	395.0 pg/mL	81.3%	47.5%	0.648 (0.52–0.78)
Martínez, et al. 2017	Urine	ELISA	9	2	3	8	4.91 pg/mg Cr	81%	75%	0.876 (0.75–0.99)
Dong, et al. 2018	Urine	ELISA	30	18	1	21	12.53 pg/mg Cr	62.22%	93.33%	0.815 (0.699–0.930)
Dong, et al. 2018^a	Urine	ELISA	14	25	2	18	26.95 pg/mg Cr	36.7%	88.9%	0.626 (0.427–0.825)
Salem, et al. 2018	Urine	ELISA	14	0	6	24	8.22 pg/mg Cr	100%	80%	0.96 (NR)
Mirioglu, et al. 2020^b	Serum	ELISA	12	3	3	12	1542.2 ng/mL	80%	80%	0.796 (0.622–0.969)

^aThis study compared the level of uTWEAK with urine albumin/creatinine ratio in proteinuria detection in patients with LN. Since proteinuria is a component of rSLEDAI scoring system, the study was also included.

^buTWEAK levels were also measured in the indicated studies. However, there was lack of mandatory indexes regarding uTWEAK in distinguishing patients with active LN in the studies. TWEAK: TNF-like weak inducer of apoptosis; LN: lupus nephritis; TP: true positive; FN: false negative; FP: false positive; TN: true negative; AUC: area under the receiver operating characteristic curve; CI: confidence interval; ELISA: enzyme-linked immunosorbent assay; Cr: creatinine; NR: not reported.

Table 3. Subgroup analysis of the included studies.

	N	Sensitivity (95% CI)	I^2 (%)	Specificity (95% CI)	I^2 (%)	PLR (95% CI)	I^2 (%)	NLR (95% CI)	I^2 (%)	DOR (95% CI)	I^2 (%)	AUC
rSLEDAI score
> 0	4	0.66 (0.57–0.75)	65.1	0.77 (0.68–0.84)	88.8	3.80 (1.29–11.22)	82.8	0.44 (0.35–0.57)	4.1	8.90 (3.79–20.98)	29.6	0.79
> 4	3	0.85 (0.76–0.91)	80.4	0.74 (0.61–0.84)	68.3	3.39 (1.59–7.22)	61.2	0.20 (0.08–0.55)	62.6	19.00 (6.38–56.55)	7.7	0.90
Sample type
Urine	7	0.67 (0.60–0.73)	87.3	0.83 (0.77–0.89)	63.2	3.71 (2.33–5.91)	38.0	0.38 (0.25–0.60)	77.3	12.40 (6.65–23.13)	0	0.86
Serum	2	0.81 (0.67–0.91)	0	0.57 (0.42–0.70)	79.8	2.21 (0.84–5.84)	69.8	0.33 (0.18–0.63)	0	6.56 (1.73–24.94)	42.6	NA

rSLEDAI: renal systemic lupus erythematosus disease activity index; N: number of studies; CI: confidence interval; PLR: positive likelihood ratio; NLR: negative likelihood ratio; DOR: diagnostic odds ratio; AUC: area under the receiver operating characteristic curve; NA: not available.

Table 4. Correlations between TWEAK and laboratory/pathological/clinical parameters in the included studies.

Author, year	Sample type	Scr	BUN	24h UP	UP/Cr	C3	C4	Anti-dsDNA	CRP	ESR	BAI	BCI	rSLEDAI	Hematuria	Pyuria
Schwartz, et al. 2009	Urine	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	+	NR	NR
Tan, et al. 2009	Urine	NR	NR	NR	NR	NR	NR	NR	NR	NR	+	NS	NR	NR	NR
El-shehaby, et al. 2011	Urine	NR	NR	+	NR	–	–	NR	NR	NR	NR	NR	+	+	+
Choe, et al. 2016	Serum Urine	NS NS	NS NS	NR NR	+ NS	NS NS	NS NS	NS NS	NS NS	+ NS	NR NR	NR NR	+ NS	NR NR	NR NR
Martínez, et al. 2017	Urine	NS	NS	+	NR	–	–	NR	NR	NR	NR	NR	NR	NR	NR
Dong, et al. 2018	Urine	NR	NR	NR	NR	NR	NR	NR	NR	NR	+	NS	+	NR	NR
Dong, et al. 2018^a	Urine	NS	NS	+	NR	NR	NR	+	NR	NR	NR	NR	+	NR	NR
Salem, et al. 2018	Urine	NS	NS	NS	NR	NS	NS	NS	NS	NS	NR	NR	+	+	+
Mirioglu, et al. 2020	Serum Urine (ng/ml) Urine (ng/mgCr)	NR NR NR	NR NR NR	+ NS NS	NR NR NR	– NS NS	NS NS NS	NR NR NR	NR NR NR	NR NR NR	NR NR NR	NR NR NR	+ + NS	NR NR NR	NR NR NR

^aThis study compared the level of uTWEAK with urine albumin/creatinine ratio in proteinuria detection in patients with LN. Since proteinuria is a component of rSLEDAI scoring system, the study was also included. Scr: serum creatinine; BUN: blood urea nitrogen; 24 h UP: 24 h urine protein; UP/Cr: urine protein/creatinine ratio; C3, C4: serum complement components C3 and C4; Anti-dsDNA: anti-double stranded DNA; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; BAI: biopsy activity index; BCI: biopsy chronicity index; rSLEDAI: renal systemic lupus erythematosus disease activity index; +: positive correlation; -: negative correlation; NS: no significance; NR: not reported.