title: Glomerular C4d deposits can mark structural capillary wall remodelling in thrombotic microangiopathy and transplant glomerulopathy: C4d beyond active antibody-mediated injury: a retrospective study.
abstract: Peritubular capillary C4d (ptc-C4d) usually marks active antibody-mediated rejection, while pseudolinear glomerular capillary C4d (GBM-C4d) is of undetermined diagnostic significance, especially when seen in isolation without concurrent ptc-C4d. We correlated GBM-C4d with structural GBM abnormalities and active antibody-mediated rejection in 319 renal transplant and 35 control native kidney biopsies. In kidney transplants, ptc-C4d was associated with GBM-C4d in 97% by immunofluorescence microscopy (IF) and 61% by immunohistochemistry (IHC; P < 0.001). Transplant glomerulopathy correlated with GBM-C4d (P < 0.001) and presented with isolated GBM-C4d lacking ptc-C4d in 69% by IF and 40% by IHC. Strong isolated GBM-C4d was found post year-1 in repeat biopsies with transplant glomerulopathy. GBM-C4d staining intensity correlated with Banff cg scores (rs = 0.45, P < 0.001). Stepwise exclusion and multivariate logistic regression corrected for active antibody-mediated rejection showed significant correlations between GBM duplication and GBM-C4d (P = 0.001). Native control biopsies with thrombotic microangiopathies demonstrated GBM-C4d in 92% (IF, P < 0.001) and 35% (IHC). In conclusion, pseudolinear GBM-C4d staining can reflect two phenomena: (i) structural GBM changes with duplication in native and transplant kidneys or (ii) active antibody-mediated rejection typically accompanied by ptc-C4d. While ptc-C4d is a dynamic 'etiologic' marker for active antibody-mediated rejection, isolated strong GBM-C4d can highlight architectural glomerular remodelling.
authors.affiliation: Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Adil H
authors.initials: AH
authors.lastname: Gasim
authors.affiliation: Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina School of Medicine, Chapel Hill, NC, USA.|Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jamie S
authors.initials: JS
authors.lastname: Chua
authors.affiliation: Department of Medical Statistics and Bio-Informatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ron
authors.initials: R
authors.lastname: Wolterbeek
authors.affiliation: Department of Pathology and Laboratory Medicine, McLendon Clinical Laboratories, The University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: John
authors.initials: J
authors.lastname: Schmitz
authors.affiliation: Department of Pathology and Laboratory Medicine, McLendon Clinical Laboratories, The University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Weimer
authors.affiliation: Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Harsharan K
authors.initials: HK
authors.lastname: Singh
authors.affiliation: Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Volker
authors.initials: V
authors.lastname: Nickeleit
mesh_terms: D015935:Complement C4b / Q000378:metabolism*; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007678:Kidney Glomerulus / Q000276:immunology* / Q000648:ultrastructure; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism*; D012189:Retrospective Studies; D057049:Thrombotic Microangiopathies / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D066253:Vascular Remodeling
chemical_list: D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d
keywords: complement factor C4d; electron microscopy; glomerular basement membrane duplication; immunofluorescence microscopy; thrombotic microangiopathy; transplant glomerulopathy