Abstract
There is a critical need to identify biomarkers for Systemic Lupus Erythematosus (SLE) which has a high prevalence of renal failure. When urine from patients with lupus nephritis was recently screened for the levels of ∼280 molecules using an exploratory array-based proteomic platform, elevated angiostatin levels were noted. Angiostatin is a bioactive fragment of plasminogen, and has been known to have modulatory function in angiogenesis and inflammation. The significant elevation in urinary angiostatin was next validated in an independent cohort of SLE patients (n = 100) using ELISA. Among patients with SLE, urine angiostatin was significantly increased in active SLE compared with inactive SLE, correlating well with the SLEDAI disease activity index and SLICC renal activity score (r = 0.66, p < 0.0001). ROC curve analysis further confirmed that urinary angiostatin had the capacity to discriminate patients with active SLE from those with inactive disease. Patients with Class IV lupus nephritis exhibited the highest levels of urinary angiostatin. Immunohistochemistry staining localized angiostatin expression to the renal tubular cells in these patients. Finally, when paired urine-kidney samples procured concurrently from patients with LN were next examined, urine angiostatin levels correlated strongly with the renal pathology chronicity index, but not with the activity index. Given that Class IV lupus nephritis and renal pathology chronicity changes forebode poor renal and patient survival, urinary angiostatin emerges as a novel noninvasive marker of renal disease in SLE. Longitudinal studies are in progress to further assess the disease-predictive potential of urinary angiostatin.
Highlights
From the ‡Division of Rheumatology, UT Southwestern Medical Center at Dallas, TX 75390; §Department of Pathology, Baylor University Medical Center at Dallas, TX 75246
The levels of angiostatin was increased by almost two orders of magnitude in lupus nephritis samples compared with healthy controls
The difference in overall urinary angiostatin levels did not reach significance between Systemic Lupus Erythematosus (SLE) and the CKD controls, indicating angiostatin might be involved in other types of chronic kidney diseases besides lupus nephritis
Summary
From the ‡Division of Rheumatology, UT Southwestern Medical Center at Dallas, TX 75390; §Department of Pathology, Baylor University Medical Center at Dallas, TX 75246. A number of potentially important urinary markers were identified by two-dimensional (2D)-gel electrophoresis followed by mass spectrometry [13]. Among these urine markers, a number of angiogenesis-related proteins emerged including angiotensinogen, renin, angiostatin, and plasminogen activator inhibitor 1 [13]. A number of angiogenesis-related proteins emerged including angiotensinogen, renin, angiostatin, and plasminogen activator inhibitor 1 [13] This is important because angiogenesis-related factors, including VEGF-A [14], VEGFR1 [15,16,17], VEGFR2 [16], angiopoietin-1, and angiopoietin-2, have been linked to the progression of chronic kidney diseases (CKD) [18]. This study is designed to assess whether elevated urinary angiostatin levels are indicative of renal disease in SLE, using a crosssectional study design
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