Urinary angiostatin: a novel biomarker of kidney disease associated with disease severity and progression.

BACKGROUND: This study aimed to evaluate the value of urinary angiostatin levels for assessing disease severity and progression of IgA nephropathy (IgAN). METHODS: Urinary angiostatin was identified as one of the distinct proteins in samples of patients with IgAN analyzed by Raybiotech protein array, and further confirmed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Urinary angiostatin levels were significantly higher in IgAN patients than that in healthy controls (HC) subjects and lower than in disease controls (DC) patients. The concentrations of angiostatin in urine normalized to urinary creatinine (angiostatin/Cr) were positively associated with proteinuria level. With advancing chronic kidney disease (CKD) stage, urinary angiostatin/Cr levels were gradually increased. Urinary angiostatin/Cr levels in patients with Lee's grade IV-V were significantly higher than those in Lee's grade I-II and III. We further compared urinary angiostatin/Cr levels by using Oxford classification and found the expression in patients with mesangial proliferative score 1(M1) was significantly higher than that in M0 (P < 0.001). In addition, the levels of urinary angiostatin/Cr in patients with tubular atrophy/interstitial fibrosis score 1(T1) and T2 were significantly higher than those in T0 (P < 0.01, P < 0.001, respectively). After follow-up, renal survival was significantly worse in patients with higher levels of urinary angiostatin (P < 0.05). CONCLUSIONS: Urinary angiostatin may be a useful novel noninvasive biomarker to evaluate disease severity and progression of IgAN.

Urinary angiostatin, CXCL4 and VCAM-1 as biomarkers of lupus nephritis.

BACKGROUND: The aim was to study urinary angiostatin, CXC chemokine ligand 4 (CXCL4) and vascular cell adhesion molecule-1 (VCAM-1) as biomarkers of renal disease in systemic lupus erythematosus (SLE). METHOD: Patients who fulfilled ≥ 4 American College of Rheumatology (ACR) criteria for SLE with active renal, active non-renal or inactive disease, and a group of healthy controls were studied. Urine samples were assayed for angiostatin, CXCL4 and VCAM-1 by ELISA, and normalized by creatinine. Receiver operating characteristic analysis was performed to obtain the best cutoff values to calculate the performance of these markers in differentiating the different groups of patients as compared to anti-double-stranded DNA (anti-dsDNA) and complement C3. Correlation between these urinary biomarkers and various renal parameters was also tested. RESULTS: Patients with SLE (n = 227; 80 with inactive SLE, 67 with active non-renal disease and 80 with active renal disease; 94% women; age 39.2 ± 13.8 years) and 53 controls (96% women) were studied. All were ethnic Chinese. Urinary angiostatin, CXCL4 and VCAM-1 (normalized for creatinine) were significantly higher in patients with active renal disease than in patients with active non-renal disease, patients with inactive SLE and controls. These markers correlated significantly with total SLE disease activity index (SLEDAI) and renal SLEDAI scores, and with the urinary protein-to-creatinine ratio. Urine angiostatin exhibited higher specificity and sensitivity in differentiating active renal from active non-renal SLE (area under the curve (AUC) 0.87) than serum anti-dsDNA/C3. Urine CXCL4 (AUC 0.64) and VCAM-1 (AUC 0.73), on the other hand, performed similarly to anti-dsDNA/C3. All three markers performed comparably to anti-dsDNA/C3 in distinguishing active from inactive SLE. In a subgroup of 68 patients with paired renal biopsy, the urinary levels of these proteins did not differ significantly between the proliferative and non-proliferative types of lupus nephritis. Urinary CXCL4 and VCAM-1 correlated significantly with the histologic activity score, and urinary angiostatin correlated significantly with proteinuria in this subgroup. CONCLUSIONS: Urinary angiostatin, CXCL4 and VCAM-1 are potential biomarkers for SLE, in particular lupus nephritis. Further longitudinal studies are necessary to delineate the performance of these markers in predicting renal flares and prognosis in SLE patients.

Urine angiostatin and VCAM-1 surpass conventional metrics in predicting elevated renal pathology activity indices in lupus nephritis.

AIM: The goal of this study is to investigate how urinary angiostatin, vascular cell adhesion molecule 1 (VCAM-1) and established measures of renal function relate to specific histologic findings in paired kidney biopsy samples from patients with lupus nephritis (LN). METHOD: Urine samples were collected from 54 LN patients together with paired kidney biopsy samples and examined for urinary angiostatin and VCAM-1 protein levels. Nonparametric tests were used to examine the association of both urinary biomarkers and established traditional laboratory markers of renal function with nine specific renal histologic features seen in LN, including glomerular leukocyte infiltration, endocapillary proliferation, cellular crescents, fibrinoid necrosis, wire loops, interstitial inflammation, glomerulosclerosis, fibrous crescents, tubular atrophy and interstitial fibrosis. RESULTS: Compared to traditional renal disease metrics, both urinary angiostatin and VCAM-1 exhibited outstanding potential (area under the curve 0.97, 0.98, respectively) to predict renal biopsy activity index score ≥ 7, which is associated with poor long-term prognosis. Whereas urine VCAM-1 was most significantly associated with fibrous crescents, urine angiostatin was most significantly associated with endocapillary proliferation, cellular crescents, fibrinoid necrosis and fibrous crescents in concurrent renal biopsies. CONCLUSION: Urinary angiostatin and VCAM-1 are predictive of specific histological changes in concurrent LN renal biopsies. Both urinary biomarkers are good candidates for use as noninvasive measures of renal pathology activity changes in LN.

Systemic lupus erythematosus biomarkers: the challenging quest.

SLE, a multisystem heterogeneous disease, is characterized by production of antibodies to cellular components, with activation of both the innate and the adaptive immune system. Decades of investigation of blood biomarkers has resulted in incremental improvements in the understanding of SLE. Owing to the heterogeneity of immune dysregulation, no single biomarker has emerged as a surrogate for disease activity or prediction of disease. Beyond identification of surrogate biomarkers, a multitude of clinical trials have sought to inhibit elevated SLE biomarkers for therapeutic benefit. Armed with new -omics technologies, the necessary yet daunting quest to identify better surrogate biomarkers and successful therapeutics for SLE continues with tenacity.

Urine is a better biomarker source than blood especially for kidney diseases.

Change is the soul of biomarker definition. Changes are more likely to be removed from blood because of homeostasis mechanisms of the body. Therefore, urine is probably a better biomarker source than blood. The road map to the urinary biomarker era is proposed. Researchers are reminded the potential opportunities and risks in their study design. Kidney diseases are emphasized as they produce most significant changes in urine.

Urinary angiostatin levels are elevated in patients with epithelial ovarian cancer.

OBJECTIVE: The poor prognosis associated with epithelial ovarian cancer (EOC) is due to the lack of overt early symptoms and the absence of reliable diagnostic screening methods. Since many tumors over express angiogenic regulators, the purpose of this study was to determine whether elevated levels of the angiogenic or angiostatic molecules vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), endostatin (ES), and angiostatin (AS) were elevated in plasma and urine from patients with EOC. METHODS: VEGF, HGF, ES and AS were assayed by ELISA in samples from pilot cohort consisting of healthy women (N=48; pre-menopausal N=23, post-menopausal N=25), women with benign gynecological disease (N=54), patients with primary peritoneal cancer (PP) (N=2) and EOC (N=35). Wherever possible, parallel serum samples were measured for CA125 levels by ELISA. RESULTS: AS was the angioregulator that independently discriminated EOC patients from healthy individuals. Levels of urinary AS (uAS) from healthy individuals or women with benign gynecological disease averaged 21.4 ng/mL+/-3.7 and 41.5 ng/mL+/-8.8, respectively. In contrast, uAS averaged 115 ng/mL+/-39.2 and 276 ng/mL+/-45.8 from women with Stage I (N=6) and late stage (N=31) EOC, respectively. Furthermore, uAS was elevated in EOC patients regardless of tumor grade, stage, size, histological subtype, creatinine levels, menopausal status, or patient age, but appeared to complement CA125 measurements. CONCLUSIONS: Levels of AS are elevated in the urine of patients with EOC and may be of diagnostic and/or prognostic clinical importance. Further studies of uAS as a biomarker for EOC alone or in combination with other markers are warranted.

Decrease in circulating anti-angiogenic factors (angiostatin and endostatin) after surgical removal of primary colorectal carcinoma coincides with increased metabolic activity of liver metastases.

Removal of a primary colorectal tumor resulted in an increase in metabolic activity in its liver metastasis. Concomitantly, levels of angiostatin and endostatin in urine and plasma, respectively, dropped. This finding indicates that the primary tumor suppressed angiogenesis in its distant metastasis, and that removal of the primary lesion caused a flare-up in vessel neoformation and, thus, enhanced metabolic activity in its liver metastasis.