Complement Activation Is Involved in Renal Damage in Human Antineutrophil Cytoplasmic Autoantibody Associated Pauci-Immune Vasculitis

Xing, Guangqun; Chen, Min; Liu, Gang; Heeringa, Peter; Zhang, Junjun; Zheng, Xin; E, Jie; Kallenberg, Cees G. M.; Zhao, Ming‐Hui

doi:10.1007/s10875-008-9268-2

Cited by 183 publications

(156 citation statements)

References 27 publications

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“…Second, the complement system might be another potential contributor. Although AAV has traditionally been characterized as pauci-immune, and decreased levels of circulating C3 are uncommon in AAV, recent studies have demonstrated that activation of the alternative complement pathway plays a critical role in the pathogenesis of AAV (26)(27)(28)(29)(30). Patients with active AAV have elevated levels of circulating C3a, C5a, soluble C5b-9, and Bb, which suggests activation of the complement system via the alternative pathway (30).…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic Characteristics and Outcomes of Renal Thrombotic Microangiopathy in Anti-Neutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis

Chen

Wang

Huang

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Thrombotic microangiopathy (TMA) in ANCA-associated vasculitis (AAV) has been mainly reported in isolated case reports. The aim of this study was to analyze clinical and pathologic characteristics and prognosis of patients with renal TMA in ANCA-associated GN in a large cohort of Chinese patients.Design, setting, participants, & measurements Clinical and renal histopathologic data of 220 patients with biopsy-proven ANCA-associated GN from 1996 to 2013 were retrospectively analyzed. Patients were followed up for a median period of 32 (interquartile range [IQR], 12-65) months, and outcomes of patients were analyzed.Results Among the 220 patients with ANCA-associated GN, 30 were identified having concomitant renal TMA by pathologic evaluation. Compared with the non-TMA group, patients with renal TMA presented with more severe renal injury, as evidenced clinically by a higher level of serum creatinine at diagnosis (5.0 [IQR, 3.5-9.0] versus 3.2 [IQR, 1.7-6.8] mg/dl; P=0.02) and pathologically by a higher percentage of cellular crescents (15.0% [IQR, 6.9%-34.9%] versus 6.9% [IQR, 0%-21.1%]; P=0.04) and more severe interstitial infiltration (2 [IQR, 2-2] versus 2 [IQR, 1-2]; P=0.03) in renal biopsies. Furthermore, multivariate analysis showed that renal TMA was independently associated with mortality of patients with AAV after adjusting for age, sex, initial serum creatinine, tubular atrophy, and interstitial fibrosis (hazard ratio, 1.92; 95% confidence interval, 1.08 to 3.41; P=0.03) or for age, sex, the histopathologic classification scheme proposed by Berden et al. (J Am Soc Nephrol 21: 1628-1636, tubular atrophy, and interstitial fibrosis (hazard ratio, 1.95; 95% confidence interval, 1.07 to 3.55; P=0.03).Conclusions Renal TMA in ANCA-associated GN is not rare and presents with more severe renal injury. Renal TMA is independently associated with all-cause mortality in patients with AAV.

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Section: Discussionmentioning

confidence: 99%

Clinicopathologic Characteristics and Outcomes of Renal Thrombotic Microangiopathy in Anti-Neutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis

Chen

Wang

Huang

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…In the animal study by Xiao et al (7), it was found that activation of the alternative complement pathway, but not the classic or lectin pathway, was required for induction of GN with anti-MPO IgG. Our previous study in renal histopathology revealed that complement activation products of the alternative pathway could be detected in human ANCA-associated GN (14). Our additional investigation (15) found that circulating Bb level was associated with systemic disease activity of AAV measured by Birmingham Vasculitis Activity Score (BVAS).…”

Section: Introductionmentioning

confidence: 93%

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

Gou¹,

Yuan²,

Wang³

et al. 2013

Clinical Journal of the American Society of Nephrology

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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.

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“…ANCAs contribute to small vessel vasculitis, which is characterized by a paucity of Ig deposits (56) but with complement component deposition (Bb, C3d, C3c, and C5b-9) at sites of acute vascular and glomerular inflammation (57). Cytokine-primed neutrophils display ANCA-binding antigens (myeloperoxidase [MPO] and proteinase 3) on their surfaces and participate in vascular injury.…”

Section: Complement and Kidney Diseasementioning

confidence: 99%

Molecules Great and Small

Mathern

Heeger

2015

Clinical Journal of the American Society of Nephrology

236

192

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The complement cascade, traditionally considered an effector arm of innate immunity required for host defense against pathogens, is now recognized as a crucial pathogenic mediator of various kidney diseases. Complement components produced by the liver and circulating in the plasma undergo activation through the classical and/or mannose-binding lectin pathways to mediate anti-HLA antibody-initiated kidney transplant rejection and autoantibody-initiated GN, the latter including membranous glomerulopathy, antiglomerular basement membrane disease, and lupus nephritis. Inherited and/or acquired abnormalities of complement regulators, which requisitely limit restraint on alternative pathway complement activation, contribute to the pathogenesis of the C3 nephropathies and atypical hemolytic uremic syndrome. Increasing evidence links complement produced by endothelial cells and/or tubular cells to the pathogenesis of kidney ischemia-reperfusion injury and progressive kidney fibrosis. Data emerging since the mid-2000s additionally show that immune cells, including T cells and antigen-presenting cells, produce alternative pathway complement components during cognate interactions. The subsequent local complement activation yields production of the anaphylatoxins C3a and C5a, which bind to their respective receptors (C3aR and C5aR) on both partners to augment effector T-cell proliferation and survival, while simultaneously inhibiting regulatory T-cell induction and function. This immune cell-derived complement enhances pathogenic alloreactive T-cell immunity that results in transplant rejection and likely contributes to the pathogenesis of other T cell-mediated kidney diseases. C5a/C5aR ligations on neutrophils have additionally been shown to contribute to vascular inflammation in models of ANCA-mediated renal vasculitis. New translational immunology efforts along with the development of pharmacologic agents that block human complement components and receptors now permit testing of the intriguing concept that targeting complement in patients with an assortment of kidney diseases has the potential to abrogate disease progression and improve patient health.

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Complement Activation Is Involved in Renal Damage in Human Antineutrophil Cytoplasmic Autoantibody Associated Pauci-Immune Vasculitis

Abstract: The alternative pathway of the complement system is involved in renal damage of human pauci-immune AAV.

Cited by 183 publications

References 27 publications

Clinicopathologic Characteristics and Outcomes of Renal Thrombotic Microangiopathy in Anti-Neutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis

Clinicopathologic Characteristics and Outcomes of Renal Thrombotic Microangiopathy in Anti-Neutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis

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

Molecules Great and Small

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