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

Abstract

Introduction: TNF-like weak inducer of apoptosis (TWEAK) has been implicated as a mediator of chronic inflammatory processes via prolonged activation of the NF-kappaB pathway in several tissues, including the kidney. Evidence for the importance of TWEAK in the pathogenesis of lupus nephritis (LN) has been recently introduced. Thus, TWEAK levels may serve as an indication of LN presence and activity.

Methods: Multicenter cohorts of systemic lupus erythematosus (SLE) patients and controls were recruited for cross-sectional and longitudinal analysis of urinary TWEAK (uTWEAK) and/or serum TWEAK (sTWEAK) levels as potential biomarkers of LN. The performance of TWEAK as a biomarker for nephritis was compared with routinely used laboratory tests in lupus patients, including anti-double stranded DNA antibodies and levels of C3 and C4.

Results: uTWEAK levels were significantly higher in LN patients than in non-LN SLE patients and other disease control groups (P = 0.039). Furthermore, uTWEAK was better at distinguishing between LN and non-LN SLE patients than anti-DNA antibodies and complement levels, while high uTWEAK levels predicted LN in SLE patients with an odds ratio of 7.36 (95% confidence interval = 2.25 to 24.07; P = 0.001). uTWEAK levels peaked during LN flares, and were significantly higher during the flare than at 4 and 6 months prior to or following the flare event. A linear mixed-effects model showed a significant association between uTWEAK levels in SLE patients and their disease activity over time (P = 0.008). sTWEAK levels, however, were not found to correlate with the presence of LN or the degree of nephritis activity.

Conclusions: 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. Thus, our study further supports a role for TWEAK in the pathogenesis of LN, and provides strong evidence for uTWEAK as a candidate clinical biomarker for LN.

Figure 1

Systemic lupus erythematosus patients with lupus nephritis have high urinary TWEAK. A multigroup comparison between urinary TNF-like weak inducer of apoptosis (uTWEAK) levels of 30 patients with biopsy-proven lupus nephritis (LN), 49 systemic lupus erythematosus (SLE) patients without LN, 28 healthy individuals, 79 rheumatoid arthritis (RA) patients, 25 osteoarthritis (OA) patients and 31 renal controls (P = 0.039). *P < 0.05 in two-group post-hoc comparisons with LN. Graphs represent median levels with the interquartile range.

Figure 2

High urinary TWEAK is characteristic of lupus nephritis in systemic lupus erythematosus patients. (a) Thirty lupus nephritis (LN) patients have significantly higher urinary TNF-like weak inducer of apoptosis (uTWEAK) levels (corrected to creatinine) than 49 systemic lupus erythematosus (SLE) patients without LN (P < 0.001). (b) uTWEAK levels of 78 SLE patients (both LN patients and non-LN patients) correlate significantly with renal Systemic Lupus Erythematosus Disease Activity Index (rSLEDAI) scores (r = 0.388, P = 0.047). (c) Nonparametric receiver operating characteristic (ROC) curve for uTWEAK and the presence of LN in SLE patients; area under the curve = 0.724. (d) uTWEAK levels in 30 patients with biopsy-proven LN versus 11 SLE patients with a clinical diagnosis of LN not confirmed by renal biopsy (P = 0.941). Graphs represent median levels with the interquartile range. **P < 0.01.

Figure 3

Urinary TWEAK levels at different timepoints relative to a lupus nephritis flare. Urinary TNF-like weak inducer of apoptosis (uTWEAK) levels of 13 lupus nephritis (LN) patients followed in the Ohio SLE Study cohort, taken 6, 4 and 2 months before and after a LN flare, including at the time of the flare itself (timepoint 0). Graph represents least-squares (LS) means with standard error. *P < 0.05 compared with uTWEAK level at flare.