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Am J Kidney Dis. 2017 Dec;70(6):834-843. doi: 10.1053/j.ajkd.2017.07.004. Epub 2017 Aug 24.

C4 Nephritic Factors in C3 Glomerulopathy: A Case Series.

Author information

1
Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA.
2
Department of Internal Medicine, Mayo Clinic, Rochester, MN.
3
Internal Medicine, Nephrology, Indian River Medical Center, Vero Beach, FL.
4
Department of Pediatrics, University of Florida, Gainesville, FL.
5
Department of Nephrology, Kaiser Permanente, Oakland, CA.
6
Department of Immunology, Hospital European Georges Pompidou, AP-HP, Paris, France.
7
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
8
Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA.
9
Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA. Electronic address: richard-smith@uiowa.edu.

Abstract

BACKGROUND:

C3 glomerulopathy (C3G) defines a group of rare complement-mediated kidney diseases with a shared underlying pathophysiology: dysregulation of complement in the fluid phase and glomerular microenvironment. Dysregulation can be driven by autoantibodies to C3 and C5 convertases.

STUDY DESIGN:

Case series.

SETTING & PARTICIPANTS:

168 patients with C3G (dense deposit disease, 68; C3 glumerulonephritis, 100) selected from our C3G biobank.

OUTCOMES:

Patient-purified immunoglobulin Gs were tested for C4 nephritic factors (C4NeFs). These autoantibodies recognize C4b2a, the C3 convertase of the classical pathway of complement.

MEASUREMENTS:

C4NeFs were detected using a modified hemolytic assay.

RESULTS:

C4NeFs were identified in 5 patients, 4 of whom had C3 glomerulonephritis. C4NeFs were associated with dysregulation of C3 and C5 convertases, and they appear to stabilize these convertases in a dose-dependent manner. C4NeFs also appear to protect C4b2a from decay mediated by soluble CR1 and C4 binding protein. The stabilizing activity of the autoantibodies was further demonstrated by using heat treatment to inactivate complement. C4NeFs were not detected in 150 patients with another complement-mediated kidney disease, atypical hemolytic uremic syndrome. They were also absent in 300 apparently healthy controls.

LIMITATIONS:

In addition to C4NeFs, 2 patients had positive findings for other autoantibodies: one patient also had autoantibodies to factor H; the other patient also had autoantibodies to C3bBb (C3NeFs).

CONCLUSIONS:

The finding of C4NeFs in a small percentage of patients with C3G highlights the challenge in identifying autoantibodies that drive complement dysregulation and underscores the complexity of the autoantibody repertoire that can be identified in these patients.

KEYWORDS:

C3 glomerulonephritis; C3 glomerulopathy (C3G); C3 nephritic factors (C3NeFs); C4 nephritic factors (C4NeFs); autoantibodies; case series; complement dysregulation; complement-mediated renal disease; dense deposit disease (DDD); immune deposits; kidney biopsy

PMID:
28838767
PMCID:
PMC5701858
[Available on 2018-12-01]
DOI:
10.1053/j.ajkd.2017.07.004
[Indexed for MEDLINE]
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