Alternative Complement Pathway Activation Products in Urine and Kidneys of Patients with ANCA-Associated GN

Abstract

SummaryBackground and objectives Previous study revealed that complement activation products of the alternative pathway could be detected in renal specimens of human ANCA-associated vasculitis. The current study aimed to investigate the clinical and pathologic significance of complement activation products in the urine and kidneys of patients with ANCA-associated vasculitis.Design, setting, participants, & measurements Renal biopsy specimens from 29 patients with ANCA-associated vasculitis diagnosed at Peking University First Hospital from January of 2008 to December of 2010 were randomly collected. Urine samples from 27 of 29 patients in active stage and 22 ANCA-associated vasculitis patients in complete remission who were independent of the above-mentioned 29 patients were collected. Urine samples from 28 patients with lupus nephritis and 25 healthy individuals were also collected. The renal deposition of Bb, C3d, and C5b-9 were detected by immunohistochemistry. The urinary levels of Bb, C3a, C5a, and soluble C5b-9 were determined by ELISA.Results The deposition, measured by the mean optical density of Bb, which is an alternative complement pathway marker, in glomeruli correlated with the proportion of total crescents (r=0.50, P=0.006), the extent of interstitial infiltrate (r=0.59, P=0.001), interstitial fibrosis (r=0.45, P=0.01), and tubular atrophy (r=0.55, P=0.002), whereas it correlated inversely with the proportion of normal glomeruli (r=20.49, P=0.008). The urinary levels of Bb, C3a, C5a, and soluble C5b-9 were all significantly higher in active compared with remission stage. The urinary levels of Bb in patients with active ANCA-associated vasculitis correlated with the serum creatinine (r=0.56, P=0.002) and correlated inversely with the proportion of normal glomeruli in renal specimens (r=20.49, P=0.009). ConclusionsThe present study provides additional evidence that complement activation through the alternative pathway occurred in the development of ANCA-associated vasculitis. The renal deposition of Bb and urinary Bb levels were associated with the severity of renal injury.

Complement regulatory proteins in kidneys of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis

“…The complement activation products were detected in kidneys of patients with AAV, even in ANCAnegative AAV patients [4][5][6][7]22]. The complement system was regulated strictly in the normal state.…”

“…Considerable evidence has confirmed that activation of the complement system is involved in the pathogenesis of AAV [7,20,21]. The complement activation products were detected in kidneys of patients with AAV, even in ANCAnegative AAV patients [4][5][6][7]22].…”

“…Our previous study found that systemic activation of complement occurred in human AAV [6]. Complement activation products -Bb, C3d and C5b-9 -were detected along the glomerular capillary wall and mesangial area of glomeruli of patients with AAV in a granular pattern [7]. However, there was no correlation between the level of complement activation products deposited in renal specimens and of corresponding complement activation products in circulation, which suggested that the circulating complement activation products were not the only sources for complement activation products in kidney.…”

“…Increasing evidence has confirmed that complement activation plays a key role in the pathogenesis of AAV [4][5][6][7]. Xiao et al [4] first reported that complement activation was involved in an animal study of experimental vasculitis.…”

Overview of the Pathogenesis of ANCA-Associated Vasculitis

“…The mouse model of anti-MPO IgG-induced NCGN identified an unsuspected role of complement activation [53] that has subsequently been supported by observations in patients [54,55,56,57,58,59]. The NCGN induced by transfer of anti-MPO IgG into wild-type mice or anti-MPO splenocytes into immunodeficient (Rag2-/-) mice could be completely blocked by complement depletion using cobra venom factor [53].…”