Biomarker Commons

Plasma soluble urokinase plasminogen activator receptor (suPAR) levels in systemic lupus erythematosus.

Biomarkers. 2012 Dec;17(8):758-63

Authors: Toldi G, Szalay B, Bekő G, Bocskai M, Deák M, Kovács L, Vásárhelyi B, Balog A

Abstract
OBJECTIVE: Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of systemic inflammation. We aimed to characterize plasma suPAR levels in SLE patients.
METHODS: We measured plasma suPAR, C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in 89 SLE patients and 29 healthy controls.
RESULTS: suPAR and ESR values were higher in SLE than in controls, while CRP levels were comparable. ROC analysis of suPAR levels indicated a cut-off value of 5.70 ng/mL to distinguish patients with high disease activity (SLEDAI >8).
CONCLUSION: suPAR might be an objective marker for identifying SLE patients with active disease.

PMID: 23033975 [PubMed - indexed for MEDLINE]

Differential proteomic analysis of renal tissue in lupus nephritis using iTRAQ reagent technology.

Rheumatol Int. 2012 Nov;32(11):3537-43

Authors: Sui W, Tang D, Zou G, Chen J, Ou M, Zhang Y, Dai Y

Abstract
In clinical practice, it is difficult to monitor the repeating relapse in patients suffering from systemic lupus erythematosus (SLE), who usually associated with some potential complications, for example, lupus nephritis (LN), repetition renal biopsy is necessary to determine LN flares. To identify and quantify the total proteins in renal tissue of LN patients, isobaric tags for relative and absolute quantification (iTRAQ) technology was performed. Eight-plex iTRAQ coupled with multiple chromatographic fractionation and tandem mass spectrometry were used to analyze total proteins in renal tissue of LN patients and healthy controls. Proteins were identified by mascot, which expressed differentially were noted. A total of 490 distinct proteins were identified, 113 proteins were up-regulation or down-regulation at one fold or more alteration in levels. Among of them, there was significant deviation of four proteins between our present iTRAQ study, which are up-regulated heterogeneous nuclear ribonucleoprotein (hnRNP-), Annexins and down-regulated Argininosuccinate synthetase (ASS), aldolase. iTRAQ-based quantitative proteomic technology is efficiently applicable for identification and relative quantitation of proteome of renal tissue. Differentially expressed proteome profiles of LN patients are determined. And further investigation is necessary using large cohorts of patient samples with long-term clinical follow-up data, to assess the usefulness of the pathogenesis and novel biomarker candidates of LN, which may develop a new way for diagnosis of LN.

PMID: 22083613 [PubMed - indexed for MEDLINE]

Autoantibodies against galectins are associated with antiphospholipid syndrome in patients with systemic lupus erythematosus.

Glycobiology. 2013 Jan;23(1):12-22

Authors: Sarter K, Janko C, André S, Muñoz LE, Schorn C, Winkler S, Rech J, Kaltner H, Lorenz HM, Schiller M, Andreoli L, Manfredi AA, Isenberg DA, Schett G, Herrmann M, Gabius HJ

Abstract
The presence of autoantibodies against immunoregulatory effectors can be relevant for onset and/or the progression of autoimmune disease. Emerging insights into an immunological activity profile including a role as opsonins give reason to systematically monitor sera of patients for immunoglobulin G (IgG) autoantibodies, preferably for several galectins at the same time. Here, we report on a study of chronic inflammatory rheumatic diseases, i.e. systemic lupus erythematosus (SLE; pilot cohort p, n = 40; confirmation cohort c, n = 109), rheumatoid arthritis (RA; p, n = 32; c, n = 25) and primary antiphospholipid syndrome (APS; c, n = 64). Enzyme-linked immunosorbent assay-based series using galectin-1, -2, -3, -4, -7, -8 and -9 and natural processing products, i.e. the truncated version of galectin-3 and the N-terminal domains of galectin-4, -8 and -9, were performed. Normal healthy donors (p, n = 20; c, n = 21) and patients with paraproteins (c, n = 19) served as controls. Highly significant optical density-value readings for IgG autoantibodies were consistently detected for the proto-type galectin-7 (SLE) and the tandem repeat-type galectin-8 and -9 (SLE and RA). Their presence was independent from the autoantibody status against double-stranded DNA (for patients with SLE) or a rheumatoid factor (for patients with RA), respectively. Importantly, anti-galectin-2 autoantibodies highly significantly correlated with the appearance of a secondary APS in patients with SLE so that this parameter may serve as an additional biomarker for APS. Equally of note, the presence of IgG autoantibodies against galectins capable to act as an opsonin may contribute to a sustained immune dysregulation in patients with chronic inflammatory rheumatic diseases.

PMID: 22887862 [PubMed - indexed for MEDLINE]

Physicochemical and immunological studies on 4-hydroxynonenal modified HSA: implications of protein damage by lipid peroxidation products in the etiopathogenesis of SLE.

Hum Immunol. 2012 Nov;73(11):1132-9

Authors: Khatoon F, Moinuddin, Alam K, Ali A

Abstract
4-Hydroxynonenal (HNE) is the most abundant and toxic aldehyde generated by the oxidation of plasma membrane polyunsaturated fatty acids. Systemic lupus erythematosus (SLE), a chronic autoimmune disease, is primarily characterized by increased levels of autoantibodies, predominantly against ds-DNA. However, the initial antigenic stimulus for the disease etiopathogenesis has remained elusive. HNE has been extensively used as a biomarker of oxidative stress. It can form adduct with proteins, making them highly immunogenic. Increased levels of such aldehyde-protein adducts have been reported in various pathological states, including autoimmune disorders like SLE and arthritis. In the present study, HNE-mediated structural changes in human serum albumin (HSA) were characterized by UV, fluorescence, CD and FT-IR spectroscopy as well as by polyacrylamide gel electrophoresis. Furthermore, immunogenicity of native and HNE-modified HSA was probed in female rabbits. The HNE-modified HSA was highly immunogenic eliciting high titre immunogen specific antibodies. Binding of SLE anti-DNA antibodies was analyzed by direct binding and competition ELISA. The data show preferential binding of SLE autoantibodies to HNE-modified HSA as compared to native HSA or native DNA. Our results suggest that HNE modification generates neoepitopes on HSA causing enhanced autoantibodies production. The results point towards the possible role of HNE-modified HSA in SLE etiopathogenesis.

PMID: 22917540 [PubMed - indexed for MEDLINE]

Serum growth arrest-specific protein 6 levels are a reliable biomarker of disease activity in systemic lupus erythematosus.

J Clin Immunol. 2013 Jan;33(1):143-50

Authors: Kim HA, Nam JY, Jeon JY, An JM, Jung JY, Bae CB, Suh CH

Abstract
PURPOSE: Growth arrest-specific protein 6 (Gas6) has been suggested to be a biomarker of disease activity in patients with systemic lupus erthematosus (SLE). We investigated the clinical significance of this protein in Korean SLE.
METHODS: Blood samples were collected from 150 SLE patients and 50 normal controls (NC). In addition, follow-up samples were collected from 50 SLE patients.
RESULTS: Serum Gas6 levels of SLE patients (43.01 ± 28.02 ng/mL) were higher than those of NC (20.15 ± 9.23 ng/mL, p<0.001). When evaluated sensitivity and specificity of the Gas6 for diagnosing SLE using ROC curves, the sensitivity and specificity were 72.7 % and 84 % with a cut-off value of 25.3 ng/mL. In the ROC analysis of Gas6, anti-dsDNA antibody, ESR, complement 3 and complement 4 to identify patients with active lupus, area under the curve (AUC) of Gas6 was highest with 0.763. Serum Gas6 levels were significantly higher in the patients with serositis (70.04 ± 30.85 ng/mL) and renal disorder (65.66 ± 32.28 ng/mL) compared to those without (41.88 ± 27.44 ng/mL, p=0.033, 40.3 ± 26.33 ng/mL, p=0.001, respectively). Gas6 levels were correlated positively with anti-dsDNA antibody (r=0.199, p=0.015), ESR (r=0.204, p=0.013) and SLEDAI (r=0.512, p<0.001). In addition, serum Gas6 levels were correlated negatively with hemoglobin (r= -0.165, p=0.043), lymphocyte count (r= -0.165, p=0.043), complement 3 (r= -0.343, p<0.001) and complement 4 (r= -0.316, p<0.001). Furthermore, change in serum Gas6 levels was correlated with change in SLEDAI levels in the SLE patients that were followed up (r=0.524, p<0.001).
CONCLUSION: These results suggest that serum Gas6 can be a reliable clinical marker for monitoring disease activity and treatment response in SLE.

PMID: 22914895 [PubMed - indexed for MEDLINE]

A composite urine biomarker reflects interstitial inflammation in lupus nephritis kidney biopsies.

Kidney Int. 2012 Feb;81(4):401-6

Authors: Zhang X, Nagaraja HN, Nadasdy T, Song H, McKinley A, Prosek J, Kamadana S, Rovin BH

Abstract
The initial treatment of lupus nephritis is usually based on a renal biopsy. Subsequent disease flares, however, are often treated without the benefit of kidney pathology because repeat biopsies are infrequent. A noninvasive, real-time method to assess renal pathology would be useful to adjust treatment and improve outcome. To develop such a method we collected urine samples at or close to the time of 64 biopsies from 61 patients with lupus nephritis to identify potential biomarkers of tubulointerstitial inflammation and correlated these to biopsy parameters scored by a renal pathologist using a semiquantitative scale. Linear discriminant analysis was used to weight variables and derive composite biomarkers that identified the level of tubulointerstitial inflammation based on urine concentrations of monocyte chemotactic protein-1, hepcidin (a marker of active lupus), and liver fatty acid-binding protein. The discriminant function that described the most accurate composite biomarkers included urine monocyte chemotactic protein-1 and serum creatinine as the independent variables. This composite had sensitivity, specificity, positive predictive value, and negative predictive value of 100, 81, 67, and 100%, respectively. Only 14% of the biopsies were misclassified. Thus, specific renal pathologic lesions can be modeled by composite biomarkers to noninvasively follow and adjust the treatment of lupus nephritis reflecting renal injury.

PMID: 21993584 [PubMed - indexed for MEDLINE]

Monocyte chemoattractant-1 as a urinary biomarker for the diagnosis of activity of lupus nephritis in Brazilian patients.

J Rheumatol. 2012 Oct;39(10):1948-54

Authors: Rosa RF, Takei K, Araújo NC, Loduca SM, Szajubok JC, Chahade WH

Abstract
OBJECTIVE: Monocyte chemotactic protein (MCP-1), involved in the pathogenesis of lupus nephritis (LN), has recently been indicated as a new biomarker of kidney activity in systemic lupus erythematosus (SLE). Our aim was to assess urinary MCP-1 (uMCP-1) as a biomarker of renal activity in patients with SLE and to compare it to other disease activity markers, using the ELISA.
METHODS: Seventy-five female Brazilian patients with SLE and a control group participated in our study. Patients with SLE were distributed among 3 groups according to kidney involvement and classified according to disease activity based on clinical and laboratory measures such as urinary sediment, proteinuria, kidney function, C3, C4, anti-dsDNA, disease activity index, and renal SLE disease activity index. The serum and uMCP-1 concentrations were measured by sandwich ELISA.
RESULTS: In the A-LN group (active lupus nephritis: SLE with kidney involvement), the concentration of uMCP-1 was significantly higher than in other groups. A cutoff point was established using the results of the control group to apply this test in the detection of LN. A-LN had a higher frequency of positive results for uMCP-1 in comparison to the other groups (p < 0.001). To detect disease activity in patients with LN, a new cutoff was determined based on the results of patients with SLE with kidney involvement. Setting specificity at 90%, the sensitivity of the test was 50%.
CONCLUSION: The high specificity makes uMCP-1 a useful test as a predictor of kidney activity in SLE, especially when associated to other measures used in clinical practice.

PMID: 22942263 [PubMed - indexed for MEDLINE]

Circulating anti-double-stranded DNA antibody-secreting cells in patients with systemic lupus erythematosus: a novel biomarker for disease activity.

Lupus. 2012 Oct;21(12):1284-93

Authors: Hanaoka H, Okazaki Y, Satoh T, Kaneko Y, Yasuoka H, Seta N, Kuwana M

Abstract
Antibodies against double-stranded DNA (dsDNA) are widely used to diagnose systemic lupus erythematosus (SLE) and evaluate its activity in patients. This study was undertaken to examine the clinical utility of circulating anti-dsDNA antibody-secreting cells for evaluating SLE patients. Anti-dsDNA antibody-secreting cells quantified using an enzyme-linked immunospot assay were detected in the spleen, bone marrow and peripheral blood from MRL/lpr but not in control BALB/c mice. Circulating anti-dsDNA antibody-secreting cells were detected in 29 (22%) of 130 patients with SLE, but in none of 49 with non-SLE connective-tissue disease or 18 healthy controls. The presence of circulating anti-dsDNA antibody-secreting cells was associated with persistent proteinuria, high SLE disease activity index and systemic lupus activity measures, and a high serum anti-dsDNA antibody titre measured with an enzyme-linked immunosorbent assay. The positive predictive value for active disease was 48% for circulating anti-dsDNA antibody-secreting cells versus 17% for serum anti-dsDNA antibodies. A prospective cohort of patients with circulating anti-dsDNA antibodies and inactive SLE showed that the cumulative disease flare-free rate was significantly lower in patients with than without circulating anti-dsDNA antibody-secreting cells (p < 0.001). Circulating anti-dsDNA antibody-secreting cells are a useful biomarker for assessing disease activity in SLE patients.

PMID: 22740429 [PubMed - indexed for MEDLINE]

MCP-1 in urine as biomarker of disease activity in Systemic Lupus Erythematosus.

Cytokine. 2012 Nov;60(2):583-6

Authors: Barbado J, Martin D, Vega L, Almansa R, Gonçalves L, Nocito M, Jimeno A, Ortiz de Lejarazu R, Bermejo-Martin JF

Abstract
Conventional clinical parameters are not sensitive or specific enough for detecting ongoing disease activity in the Systemic Lupus Erythematosus (SLE). Measurement of cytokines in urine is an encouraging approach to detection of early flares in this disease. Here we have profiled 27 different cytokines, chemokines and celular growth factors in the urine of 48 patients previously diagnosed of SLE as potential biomarkers of disease activity. Correlation analysis with Bonferroni correction showed that MCP-1 was the only immune mediator which levels in urine correlated directly with the SLE Disease Activity Index 2000 (SLEDAI-2K) score (correlation coefficient, p): MCP-1 (0.45,0.003). MCP-1 correlated inversely with levels of C3 complement protein in serum (-0.50,0.001). MCP-1 showed significant higher levels in patients with severe disease activity in comparison with those exhibiting mild activity. Levels of this chemokine were also higher in patients with severe disease activity in comparison with patients with inactive disease and healthy controls. Areas under receiver operating characteristic curves (AUROC) for detection of severe disease (SLEDAI⩾8) was as follows for MCP-1: [AUROC, (IC95%), p]: [0.81 (0.65-0.96) 0.003]. In addition, MCP-1 showed a good result in the AUROC analysis for detecting renal involvement [0.70 (0.52-0.87) 0.050]. When correlation analysis were repeated excluding those patients with active renal disease (n=14), levels of MCP-1 in urine kept on showing a significant positive association with SLEDAI-2K score. In conclusion, multiplex-based cytokine profiling in urine demonstrated the superiority of MCP-1 over a wide range of cytokines as biomarker of disease activity in SLE.

PMID: 22857869 [PubMed - indexed for MEDLINE]

Urinary sediment ICAM-1 level in lupus nephritis.

Lupus. 2012 Oct;21(11):1190-5

Authors: Guan J, Wang G, Tam LS, Kwan BC, Li EK, Chow KM, Li PK, Szeto CC

Abstract
BACKGROUND: Urinary intercellular adhesion molecule-1 (ICAM-1) level is potentially a valuable biomarker of lupus nephritis (LN), but because ICAM-1 is a cell-surface molecule, soluble ICAM-1 level in urinary supernatant measured by ELISA may not be biologically relevant.
METHODS: The ICAM-1 level in urine sediment of 12 LN patients, 10 patients with pauci-immune necrotizing glomerulonephritis (NecGN), and six healthy controls were determined with a polymerase chain reaction (PCR)-based assay. The urinary sediment levels of miR-221, miR-222, miR-339-3P and miR-339-5P, which are involved in the regulation of ICAM-1 production, were also quantified.
RESULTS: LN patients had lower urinary sediment ICAM-1 levels than the other two groups (overall p = 0.034). In addition, urinary sediment ICAM-1 level inversely correlated with the estimated glomerular filtration rate (GFR) (r = -0.474, p = 0.026) but not other markers of lupus activity, or urinary sediment levels of miR-221, miR-222, miR-339-3P, or miR-339-5P. However, serum anti-dsDNA level inversely correlated with urinary sediment levels of miR-221 (r = -0.591, p = 0.043) and miR-222 (r = -0.689, p = 0.013), while urinary sediment miR-221 level also correlated with serum C3 level (r = 0.658, p = 0.02).
CONCLUSIONS: We conclude that urinary sediment ICAM-1 level was significantly reduced in LN, and the level inversely correlated with renal function. Urinary sediment miR-221 and miR-222 levels correlate with lupus disease activity and may serve as biomarkers of LN.

PMID: 22685016 [PubMed - indexed for MEDLINE]

Urinary TWEAK level as a marker of lupus nephritis activity in 46 cases.

J Biomed Biotechnol. 2012;2012:359647

Authors: Xuejing Z, Jiazhen T, Jun L, Xiangqing X, Shuguang Y, Fuyou L

Abstract
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.

PMID: 22719208 [PubMed - indexed for MEDLINE]