title: Complement Factor C4d Is a Common Denominator in Thrombotic Microangiopathy.
abstract: Complement activation has a major role in thrombotic microangiopathy (TMA), a disorder that can occur in a variety of clinical conditions. Promising results of recent trials with terminal complement-inhibiting drugs call for biomarkers identifying patients who might benefit from this treatment. The primary aim of this study was to determine the prevalence and localization of complement factor C4d in kidneys of patients with TMA. The secondary aims were to determine which complement pathways lead to C4d deposition and to determine whether complement activation results in deposition of the terminal complement complex. We examined 42 renal sections with histologically confirmed TMA obtained from a heterogeneous patient group. Deposits of C4d, mannose-binding lectin, C1q, IgM, and C5b-9 were scored in the glomeruli, peritubular capillaries, and arterioles. Notably, C4d deposits were present in 88.1% of TMA cases, and the various clinical conditions had distinct staining patterns within the various compartments of the renal vasculature. Classical pathway activation was observed in 90.5% of TMA cases. C5b-9 deposits were present in 78.6% of TMA cases and in 39.6% of controls (n=53), but the staining pattern differed between cases and controls. In conclusion, C4d is a common finding in TMA, regardless of the underlying clinical condition. Moreover, C5b-9 was present in >75% of the TMA samples, suggesting that terminal complement inhibitors may have a beneficial effect in these patients. C4d and C5b-9 should be investigated as possible diagnostic biomarkers in the clinical work-up of patients suspected of having complement-mediated TMA.
authors.affiliation: Department of Pathology and j.s.chua@lumc.nl.
authors.forename: Jamie S
authors.initials: JS
authors.lastname: Chua
authors.affiliation: Department of Pathology and.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Baelde
authors.affiliation: Department of Pathology and.
authors.forename: Malu
authors.initials: M
authors.lastname: Zandbergen
authors.affiliation: Department of Pathology and.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Wilhelmus
authors.affiliation: Department of Pathology and.
authors.forename: Leendert A
authors.initials: LA
authors.lastname: van Es
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Johan W
authors.initials: JW
authors.lastname: de Fijter
authors.affiliation: Department of Pathology and.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Bruijn
authors.affiliation: Department of Pathology and.
authors.forename: Ingeborg M
authors.initials: IM
authors.lastname: Bajema
authors.affiliation: Department of Pathology and.
authors.forename: Danielle
authors.initials: D
authors.lastname: Cohen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000378:metabolism; D016736:Antiphospholipid Syndrome / Q000378:metabolism; D001160:Arterioles / Q000737:chemistry; D015415:Biomarkers / Q000032:analysis; D002196:Capillaries / Q000737:chemistry; D002648:Child; D015922:Complement C1q / Q000032:analysis; D015935:Complement C4b / Q000032:analysis*; D015938:Complement Membrane Attack Complex / Q000032:analysis; D003171:Complement Pathway, Classical; D005260:Female; D006801:Humans; D007075:Immunoglobulin M / Q000032:analysis; D007674:Kidney Diseases / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000098:blood supply* / Q000737:chemistry* / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism; D008297:Male; D037601:Mannose-Binding Lectin / Q000032:analysis; D008875:Middle Aged; D010446:Peptide Fragments / Q000032:analysis*; D057049:Thrombotic Microangiopathies / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
chemical_list: D015415:Biomarkers; D015938:Complement Membrane Attack Complex; D007075:Immunoglobulin M; D037601:Mannose-Binding Lectin; D010446:Peptide Fragments; D015922:Complement C1q; D015935:Complement C4b; C032261:complement C4d
keywords: complement; hemolytic uremic syndrome; renal biopsy; renal pathology; renal transplantation; thrombosis