Original contributionGlomerular C3d as a novel prognostic marker for renal vasculitis☆
Introduction
Pauci-immune crescentic glomerulonephritis (PCGN) is one of the most common causes of rapidly progressive glomerulonephritis and usually associated with circulating antineutrophil cytoplasmic antibodies (ANCAs) [1]. ANCAs not only serve as diagnostic markers but also are pathogenically linked to vasculitis process [2]. ANCA-associated vasculitis (AAV) has been reproduced in experimental models demonstrating that complement activation is crucial in the pathogenesis of ANCA-associated disease [3], [4], [5]. In AAV, primed neutrophils by inflammatory mediators express cell surface myeloperoxidase (MPO) and proteinase 3, and the subsequent interaction with ANCA leads to enhanced neutrophil activation and degranulation. ANCA-activated neutrophils release factors, including factor B and properdin, which engage the alternative complement pathway amplification loop, including production of C5a, which has chemotactic as well as priming effects on neutrophils [6], [7]. In patients with AAV, evidence of systemic activation of the alternative complement pathway has been observed, as demonstrated by increased levels of factor Bb, C3a, and C5a found [8]. Studies of plasma levels of complement components in patients with AAV are also consistent with systemic activation of the alternative pathway of complement, as demonstrated by increased levels of factor Bb, C3a, and C5a found in patients with active vasculitis disease. However, also increased serum levels of C4d in patients with AAV were observed in this study [8].
Only a limited number of studies have analyzed the presence of different complement components in renal specimens of patients with AAV [8], [9], [10], [11], [12]. Some of these studies observed positive immunohistochemical staining for the alternative pathway and final loop of complement components (C3d, Bb, and C5b-9), but the in-depth long-term prognostic implications of these deposits have not been evaluated. Chen et al [9] observed C3c deposition in 33% of patients with PCGN. C3c deposition was associated with more severe renal insufficiency and higher proteinuria at the onset of PCGN. Xing et al [11] detected C3d in glomeruli and small blood vessels with active vasculitis of patients with crescentic glomerulonephritis. More recently, Hilhorst et al [12] analyzed the presence of C3d and C4d renal deposits in a larger cohort of individuals with PCGN and reported C3d- and C4d-positive staining in 58.1% and 70.8% of the biopsies, respectively. C3d, mainly a marker for alternative pathway of complement activation, can be detected not only at active lesions at the time of ongoing complement activation but also at lesions after complement activation [13], [14]. C4d is a marker for classical and lectin pathways activation and has been demonstrated to have prognostic value for other glomerulonephritis such as IgA nephropathy [15], [16]. Our study aimed to assess the clinical and prognostic implications of C3d and C4d deposition in a large cohort of patients with PCGN. The identification of new prognostic markers based on complement factors deposition could provide insights into the pathogenesis of PCGN and unveil new therapeutic approaches in these patients.
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Patients
Eighty-five patients with biopsy-proven pauci-immune extracapillary glomerulonephritis diagnosed between 1995 and 2014 at the Nephrology Division of the Fundacion Hospital Alcorcon (Alcorcon) and Hospital Virgen de la Salud (Toledo) were enrolled in the study. The study was approved by the medical ethics committee at the 2 participating centers. Informed consent was obtained from each patient. Renal biopsy was performed at the time of diagnosis. Patients with secondary vasculitis or with
Complement staining
Glomerular staining for C3d and C4d was observed in 42 (49.4%) of 85 biopsies and 38 (44.7%) of 85 biopsies, respectively. In 20 patients (23.5%), both C3d- and C4d- positive glomerular staining were observed, whereas only positive staining for either C3d or C4d was found in 25.9% and 20% of the cases, respectively. No significant differences were found in C3d and C4d staining according to ANCA status. Table 3 shows the distribution of the different complement staining in ANCA-positive and
Discussion
Pauci-immune necrotizing crescentic glomerulonephritis is a histologic manifestation of small vessel renal vasculitis. In recent years, several studies have shown the prognostic relevance of renal biopsy in AAV, so that classifications implying prognostic value have been developed [22], [23], [24]. Histologic factors such as the percentage of normal glomeruli, the percentage of sclerosed glomeruli, and a greater degree of tubular atrophy in the initial renal biopsy have been proven to be
Acknowledgments
The authors thank the Hospital Virgen de la Salud BioBank staff for their assistance with biopsies collection and processing and Elia Pérez from the Statistical Unit of Hospital Fundacion Alcorcon for her help with data analysis.
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