title: C4 Glomerulopathy: A Disease Entity Associated With C4d Deposition.
abstract: Complement-mediated glomerulonephritis, which includes C3 glomerulopathy, is characterized by dominant staining of C3 with minimal or no immunoglobulin deposits on immunofluorescence studies. We describe a new entity of complement-mediated glomerulonephritis that is characterized by bright C4d staining but with no or minimal C3 or immunoglobulin deposits on immunofluorescence studies. We label this entity as C4 glomerulopathy. C4 glomerulopathy includes C4 dense deposit disease and C4 glomerulonephritis. C4 dense deposit disease is characterized by bright C4d staining and dense deposits along glomerular basement membranes. C4 glomerulonephritis is characterized by bright C4d staining and many mesangial electron-dense deposits, with or without rare intramembranous electron-dense deposits. We describe clinical features and kidney biopsy results in a short series of 3 patients to highlight these findings. All 3 patients presented with proteinuria, and 2 patients also had hematuria. Kidney function was preserved in 2 patients, whereas 1 patient presented with declining kidney function. Evaluation for autoimmune disease, infection, and paraprotein yielded negative results in all patients. Complement levels were normal, although 1 patient had borderline low C4 levels. Kidney biopsy showed mesangial proliferative or membranoproliferative glomerulonephritis with bright C4d staining and absent or minimal C1q, C3, and immunoglobulin. Laser microdissection and mass spectrometry of glomeruli in all 3 patients showed large to moderate numbers of spectra matching C4. Furthermore, analysis of amino acid sequences showed that they were localized to the C4d portion of C4, consistent with immunofluorescence findings. Further studies are required to determine the underlying cause. In summary, we describe a novel complement-mediated glomerulonephritis that is characterized by bright glomerular C4d staining with minimal or absent staining for C1q, C3, and immunoglobulin.
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. Electronic address: sethi.sanjeev@mayo.edu.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Sethi
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Quint
authors.affiliation: Department of Nephrology, Beaumont Hospital, Dublin, Ireland.
authors.forename: Conall M
authors.initials: CM
authors.lastname: O'Seaghdha
authors.affiliation: Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.
authors.forename: Fernando C
authors.initials: FC
authors.lastname: Fervenza
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Bijol
authors.affiliation: Department of Pathology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Anthony
authors.initials: A
authors.lastname: Dorman
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN.
authors.forename: Surendra
authors.initials: S
authors.lastname: Dasari
authors.affiliation: Otolaryngology and Renal Research Laboratories, Departments of Internal Medicine and Pediatrics, Division of Nephrology, Carver College of Medicine, Iowa City, IA.
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kurtin
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA.
authors.forename: Helmut G
authors.initials: HG
authors.lastname: Rennke
mesh_terms: D000293:Adolescent; D000328:Adult; D015935:Complement C4b / Q000276:immunology*; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative / Q000175:diagnosis / Q000276:immunology*; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000276:immunology*
chemical_list: D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d
keywords: C4 dense deposit disease; C4 glomerulonephritis; C4 glomerulopathy; C4d deposition; complement; kidney biopsy; membranoproliferative glomerulonephritis (MPGN); proteinuria; renal pathology