Background:Lupus nephritis (LN) represents a serious manifestation of systemic lupus erythematosus (SLE) which requires timely diagnosis, treatment and monitoring. Kidney biopsy is the gold standard of diagnosis and is instrumental to treatment decisions, however it is not generally performed for monitoring and evaluation of response to treatment. To such purposes, accessible biomarkers, for instance urinary, might be highly advantageous.Objectives:To evaluate urine-Galectin 3 binding protein (uGAL3BP) as a novel biomarker in biopsy-proven active lupus nephritis (A-LN) in comparison to active non-renal SLE (ANR-SLE), inactive SLE (I-SLE), and in population-based controls (HC). Furthermore, we compared uGAL3BP with known markers of renal pathology including neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), kidney injury molecule 1 (KIM-1), and galectin 3 (GAL3).Methods:Urine samples from A-LN (n=86), ANR-SLE (n=63), I-SLE (n=73) and HC (n=48) were included. uGAL3BP was measured using a commercial ELISA kit and values, adjusted for u-creatinine levels, were expressed as ng/mmol. Other markers analyzed according to clinical routine at the Department of Clinical Chemistry at Uppsala University Hospital were also adjusted for u-creatinine levels. Renal biopsies were graded according to the ISN/RPS classification(1) and evaluated for activity and chronicity index. Ten A-LN patients were evaluated before and after induction treatment.Results:In the A-LN group, median (IQR) levels of u-GAL3BP were 15.8 (6.8-24.6) ng/mmol, while in ANR-SLE, I-SLE, HC were significantly lower 4.4 (2.0-9.0), 2.8 (1.7-4.7), 2.0 (0.9-4.8) respectively (Kruskal-Wallis p<0.0001). Similarly, u-NGAL was found at higher levels in A-LN patients, 3.3 (2.0-5.7) μg/mmol, with respect to the ANR-SLE 2.0 (0.9-4.5), I-SLE 1.6 (0.8-3.2), and HC 2.4 (1.2-5.3), (p=0.008). The highest levels of OPN were found in the group of I-SLE (190.6 (85.1-299.9) μg/mmol, compared to A-LN 72.98 (37.6-118.1), ANR-SLE 92.3 (58.5-129.7) and HC 76.5 (58.2-120.3), (p<0.0001). KIM-1 levels differed among groups with higher levels in the A-LN group (188.9 (113.7-309.7) ng/mmol), in comparison to ANR-SLE 131.4 (92.2-186.1), I-SLE 123.8 (70.3-200.2), and HC 78.2 (68.8-115.1), (p<0.0001). GAL3 showed comparable levels across groups.When exploring the biomarkers across histologic subgroups of LN, u-GAL3BP could discriminate between proliferative and mesangial forms (17.7(9.6-32.5) vs 6.7(5.1-16.1) ng/mmol, p=0.027), while it did not discriminate against membranous LN. U-NGAL was higher in proliferative LN 3.7(2.4-5.8) µg/mmol with respect to membranous 2.4 (1.1-3.8) (p=0.01), while mesangial LN showed comparable levels. OPN, KIM-1 and GAL3 were comparable across groups.In the ten patients with available samples after induction therapy (mycophenolate mofetil (MMF) in 4, rituximab (RTX) in one, cyclophosphamide in 5 (one combined with MMF and one with RTX), u-GAL3BP showed a significant decrease of median levels from 218.8 to 41.5 ng/mmol (Wilcoxon p=0.03). u-GAL3BP associated with renal activity in class III/IV LN (R=0.42, p=0.004).Conclusion:Among the tested markers, high uGal3BP adjusted for creatinine was found to be a promising marker of renal involvement in SLE patients and associated with renal activity in patients with proliferative forms (class III/IV) of LN. A decrease was further seen following therapy, suggesting that u GAL3-BP could be used to monitor renal activity.References:[1]Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15(2):241-50.[2]Houssiau FA, Vasconcelos C, D’Cruz D, Sebastiani GD, Garrido Ed Ede R, Danieli MG, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002;46(8):2121-31.Disclosure of Interests:Francesca Faustini Speakers bureau: I have received speaking fees, last time more than two years ago, Helena Idborg: None declared, Elisabet Svenungsson: None declared, Sven Poetzsch Employee of: Merck Serono, Shinji Okitsu Employee of: Merck Serono, Anders Larsson: None declared, Iva Gunnarsson: None declared
A review of studies of the proteomes of circulating microparticles: key roles for galectin-3-binding protein-expressing microparticles in vascular diseases and systemic lupus erythematosus
