Urinary matrix metalloproteinases reflect renal damage in anti-neutrophil cytoplasm autoantibody-associated vasculitis

Abstract

Sanders J-S, Huitema MG, Hanemaaijer R, van Goor H, Kallenberg CG, Stegeman CA. Urinary matrix metalloproteinases reflect renal damage in anti-neutrophil cytoplasm autoantibody-associated vasculitis. Am J Physiol Renal Physiol 293: F1927-F1934, 2007. First published September 26, 2007; doi:10.1152/ajprenal.00310.2007.-Renal expression of MMP-2, -9, and tissue inhibitor of MMP-1 (TIMP-1) correlates with histological disease activity in anti-neutrophil cytoplasm autoantibody (ANCA)-associated vasculitis (AAV). We studied whether urinary and plasma levels of MMP-2, -9, and TIMP-1 reflect renal expression of these proteins and renal disease-activity in AAV. Urine and plasma samples of patients with AAV who underwent a renal biopsy were collected (n ϭ 32). Urinary activity of MMP-2 and -9 was measured by activity assays. Urinary and plasma levels of MMP-2, MMP-9, and TIMP-1 proteins were measured by ELISA. Healthy controls provided plasma and urine for comparison (n ϭ 31). In patients, the relationship of urinary and plasma levels with renal expression of MMP-2 and MMP-9 and clinical and histological disease activity was studied. Renal MMP expression was compared between patients and controls (n ϭ 8). Urinary MMP-2 and MMP-9 activity and urinary and plasma TIMP-1 levels were significantly higher in patients than in controls. In glomeruli of patients, both MMP-2 and MMP-9 expression reflected active glomerular inflammation. Urinary activity of MMP-2 and MMP-9 did not correlate with renal MMP expression or plasma levels. Urinary MMP activity correlated negatively with glomerular inflammation, but positively with fibrous crescents. Urinary MMP-2 and TIMP-1 levels showed a positive correlation with tubulointerstitial damage and a negative correlation with creatinine clearance. Urinary MMP-2, MMP-9, and TIMP-1 are elevated in AAV but do not reflect renal MMP expression and glomerular inflammation. However, urinary MMP-2 activity and TIMP-1 levels reflect tubulointerstitial damage and correlate negatively with creatinine clearance at biopsy.ANCA-associated vasculitis; crescentic glomerulonephritis; MMP-2; MMP-9; TIMP-1; immunohistochemistry; urinary levels; plasma levels MANY PATIENTS WITH VASCULITIS associated with anti-neutrophil cytoplasmic autoantibodies (ANCA) develop pauci-immune necrotizing crescentic glomerulonephritis, which is frequently associated with rapidly progressive deterioration of renal function (5). Although the pathogenesis of this glomerulonephritis is not precisely known, leukocyte infiltration, matrix degradation, and necrosis are essential steps in disease development. Following institution of immunosuppressive treatment, some glomeruli with active crescentic lesions resolve with improvement of glomerular function, whereas others become acellular and fibrotic leading to permanent loss of glomerular function (8).The role of matrix metalloproteinases (MMPs) in glomerular disease is increasingly appreciated. MMPs mediate both degradation of extracellular matrix components and cell proliferation and fa...

Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS

“…Serum, ethylenediaminetetraacetic acid plasma, and urine samples (N 5 26-38, depending on sample matrix) were obtained from patients with aHUS at baseline, before eculizumab treatment, and at visits 3 (weeks 1-3), 6 (weeks 4-6), 12 (weeks 12-17), 17 (weeks 26-33), 18 (weeks [38][39][40][41][42], and 19 (weeks 49-54) during eculizumab treatment. For simplicity, visit 17 is referred to as week 26 and visit 19 as week 52 of treatment.…”

“…Baseline plasma F112 and D-dimer levels were also 6-and 10-fold higher than levels observed in HV in more than 94% of patients, indicating thrombin generation and fibrinolysis (Table 2). At baseline, 69% to 83% of patients with aHUS also showed significantly elevated levels of candidate renal injury biomarkers associated with acute kidney injury, ischemic injury, and nephrotoxicity in rodent models and human disease, including those associated with proximal tubular injury (U-cystatin-C, 38,[53][54][55] clusterin, 38,58,59 and b2-M 38,60 ), interstitial injury (TIMP-1 40,56 ), and deteriorating renal function (U-L-FABP-1 39,57 ); levels of these markers were 9-to 48-fold higher than levels measured in HV (Table 2).…”

“…24,25 The effect of terminal complement blockade with eculizumab on upstream AP activation or other markers of disease activity is unclear. We conducted a prespecified exploratory analysis as part of the C10-004 trial to investigate the effect of terminal complement blockade on biological markers associated with proximal and terminal complement activation, 22,23,26 inflammation, 27,28 endothelial cell activation and damage, [28][29][30][31][32][33][34][35] coagulation, 5,33,36,37 and renal injury [38][39][40] in patients with aHUS.…”

Urinary FSP1 Is a Biomarker of Crescentic GN

“…Kanno and colleagues 12 showed that levels of urinary sediment podocalyxin are elevated in children with cellular crescents. Levels of urinary macrophage migration inhibitory factor and matrix metalloproteinase activity are reportedly higher in patients with crescentic GN and ANCA-associated GN than in healthy controls, 13,14 but the levels are not significantly higher than in patients with other glomerular diseases. By contrast, urinary FSP1 levels strongly correlated with the percentage of glomeruli showing cellular or fibrocellular crescent formation in patients with crescent formation, irrespective of the specific glomerular disease (Supplemental Figure 3).…”

Matrix Metalloproteinases in Renal Diseases: A Critical Appraisal

“…Patients with various forms of glomerulonephritis including focal segmental glomerulosclerosis, minimal change disease, human immunodeficiency-associated nephropathy and antineutrophil cytoplasmatic antibody-associated vasculitis each had distinct expression of gelatinases [169-174]. Plasma concentrations of MMP-2, MMP-9, and TIMP-1 are remarkably changed in patients with primary glomerulonephritis including IgA nephropathy, membranous glomerulonephritis, minimal change nephrotic disease, and segmental glomerular sclerosis [169, 171].…”