Urinary Angiostatin - A Novel Putative Marker of Renal Pathology Chronicity in Lupus Nephritis

Systemic lupus erythematosus (SLE)1 is a chronic autoimmune disease capable of causing devastating clinical manifestations such as kidney failure. Approximately 60% of SLE patients present with lupus nephritis (1); of these, about 10–15% of patients will eventually progress to end-stage renal disease (ESRD) (1). It has been known that early diagnosis of lupus nephritis can offer a better opportunity to control disease progression. Therefore, an early biomarker for diagnosing lupus nephritis is highly desirable in the renal clinic. Currently, renal biopsy is still the gold standard for diagnosing kidney disease because despite its invasive nature, this method allows accurate detection of the severity of renal pathology. Besides the risk of infection and other clinical complications associated with needle biopsy, this method of retrieving renal tissue might also have limitations in acquiring representative kidney specimens reflective of real pathological changes. Serum biomarkers are relatively less invasive; however, serological measurement of anti-dsDNA, C3, C4, and other protein markers does not necessarily correlate well with renal disease. Urine biomarkers have emerged in recent years and have proven effective in reflecting disease activity in lupus nephritis. Potential biomarkers include IL-6 (2), IL-18 (3), MCP-1 (4), VCAM-1 (5, 6), NGAL (7, 8), and TWEAK (9, 10). Indeed urine may be by far the best source for screening biomarkers for kidney diseases for several reasons. First, urine samples are easily obtained and are noninvasive. Second, because urine is a direct product of the kidney, urine biomarkers may be a direct reflection of renal function. Nevertheless, the ideal urine biomarker for monitoring lupus nephritis (LN) remains elusive. A limited number of urinary proteomic studies in lupus nephritis have been reported to date. Initial indications are that this approach will open up new avenues for discovery of novel urinary biomarkers of this disease. Mosley et al. (2006) identified unique mass spectral patterns utilizing SELDI-TOF mass spectrometry which could discriminate urine samples from patients with inactive and active lupus nephritis (11). However, the proteins represented by these spectra have not yet been identified. By using a similar technology, Zhang et al. (2008) identified hepcidin as a potential urinary biomarker of lupus nephritis (12). Our previous proteomic study of urine markers in murine immune nephritis included a more comprehensive interrogation of the urinary proteome (13). In that study, 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). This is particularly important because angiogenesis-related factors, including VEGF-A (14), VEGFR1 (15–17), VEGFR2 (16), angiopoietin-1, and angiopoietin-2, have been linked to the progression of chronic kidney diseases (CKD) (18). Angiostatin is a proteolytic fragment of plasminogen, and has been found to be protective in cancer growth through the blockade of angiogenesis via inhibition of migration and proliferation of endothelial cells (19, 20). In addition to the murine studies (13), a second array based study in human lupus nephritis also indicated that urine angiostatin may be elevated in lupus nephritis, as described below. Thus, this study is designed to assess whether elevated urinary angiostatin levels are indicative of renal disease in SLE, using a cross-sectional study design.