C4 Nephritic Factors in C3 Glomerulopathy: A Case Series

Yuzhou Zhang, Nicole C. Meyer, Fernando Custodio Fervenza, Winnie Lau, Adam Keenan, Gabriel Cara-Fuentes, Dingwu Shao, Aalia Akber, Veronique Fremeaux-Bacchi, Sanjeev M Sethi, Carla M. Nester, Richard J.H. Smith

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAmerican Journal of Kidney Diseases
DOIs
StateAccepted/In press - 2017

Fingerprint

Autoantibodies
Complement C3-C5 Convertases
Kidney Diseases
Classical Pathway Complement C3 Convertase
Membranoproliferative Glomerulonephritis
Complement Factor H
complement 4 nephritic factor
Glomerulonephritis
Immunoglobulins
Carrier Proteins
Hot Temperature

Keywords

  • Autoantibodies
  • C3 glomerulonephritis
  • C3 glomerulopathy (C3G)
  • C3 nephritic factors (C3NeFs)
  • C4 nephritic factors (C4NeFs)
  • Case series
  • Complement dysregulation
  • Complement-mediated renal disease
  • Dense deposit disease (DDD)
  • Immune deposits
  • Kidney biopsy

ASJC Scopus subject areas

  • Nephrology

Cite this

Zhang, Y., Meyer, N. C., Fervenza, F. C., Lau, W., Keenan, A., Cara-Fuentes, G., ... Smith, R. J. H. (Accepted/In press). C4 Nephritic Factors in C3 Glomerulopathy: A Case Series. American Journal of Kidney Diseases. https://doi.org/10.1053/j.ajkd.2017.07.004

C4 Nephritic Factors in C3 Glomerulopathy : A Case Series. / Zhang, Yuzhou; Meyer, Nicole C.; Fervenza, Fernando Custodio; Lau, Winnie; Keenan, Adam; Cara-Fuentes, Gabriel; Shao, Dingwu; Akber, Aalia; Fremeaux-Bacchi, Veronique; Sethi, Sanjeev M; Nester, Carla M.; Smith, Richard J.H.

In: American Journal of Kidney Diseases, 2017.

Research output: Contribution to journalArticle

Zhang, Y, Meyer, NC, Fervenza, FC, Lau, W, Keenan, A, Cara-Fuentes, G, Shao, D, Akber, A, Fremeaux-Bacchi, V, Sethi, SM, Nester, CM & Smith, RJH 2017, 'C4 Nephritic Factors in C3 Glomerulopathy: A Case Series', American Journal of Kidney Diseases. https://doi.org/10.1053/j.ajkd.2017.07.004
Zhang, Yuzhou ; Meyer, Nicole C. ; Fervenza, Fernando Custodio ; Lau, Winnie ; Keenan, Adam ; Cara-Fuentes, Gabriel ; Shao, Dingwu ; Akber, Aalia ; Fremeaux-Bacchi, Veronique ; Sethi, Sanjeev M ; Nester, Carla M. ; Smith, Richard J.H. / C4 Nephritic Factors in C3 Glomerulopathy : A Case Series. In: American Journal of Kidney Diseases. 2017.
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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.",
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author = "Yuzhou Zhang and Meyer, {Nicole C.} and Fervenza, {Fernando Custodio} and Winnie Lau and Adam Keenan and Gabriel Cara-Fuentes and Dingwu Shao and Aalia Akber and Veronique Fremeaux-Bacchi and Sethi, {Sanjeev M} and Nester, {Carla M.} and Smith, {Richard J.H.}",
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T1 - C4 Nephritic Factors in C3 Glomerulopathy

T2 - A Case Series

AU - Zhang, Yuzhou

AU - Meyer, Nicole C.

AU - Fervenza, Fernando Custodio

AU - Lau, Winnie

AU - Keenan, Adam

AU - Cara-Fuentes, Gabriel

AU - Shao, Dingwu

AU - Akber, Aalia

AU - Fremeaux-Bacchi, Veronique

AU - Sethi, Sanjeev M

AU - Nester, Carla M.

AU - Smith, Richard J.H.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

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KW - C3 nephritic factors (C3NeFs)

KW - C4 nephritic factors (C4NeFs)

KW - Case series

KW - Complement dysregulation

KW - Complement-mediated renal disease

KW - Dense deposit disease (DDD)

KW - Immune deposits

KW - Kidney biopsy

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