Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis

Andrew S Bomback; Richard J Smith; Gaetano R Barile; Yuzhou Zhang; Eliot C Heher; Leal Herlitz; M. Barry Stokes; Glen S Markowitz; Vivette D D’Agati; Pietro A Canetta; Jai Radhakrishnan; Gerald B Appel

doi:10.2215/CJN.12901211

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Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis

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Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis

Andrew S Bomback, Richard J Smith, Gaetano R Barile, Yuzhou Zhang, Eliot C Heher, Leal Herlitz, M. Barry Stokes, Glen S Markowitz, Vivette D D’Agati, Pietro A Canetta, …

Clinical journal of the American Society of Nephrology, Vol.7(5), pp.748-756

05/2012

DOI: 10.2215/CJN.12901211

PMCID: PMC3338285

PMID: 22403278

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Abstract

Background and objectives: The principle defect in dense deposit disease and C3 glomerulonephritis is hyperactivity of the alternative complement pathway. Eculizumab, a monoclonal antibody that binds to C5 to prevent formation of the membrane attack complex, may prove beneficial. Design, setting, participants, & measurements: In this open-label, proof of concept efficacy and safety study, six subjects with dense deposit disease or C3 glomerulonephritis were treated with eculizumab every other week for 1 year. All had proteinuria >1 g/d and/or AKI at enrollment. Subjects underwent biopsy before enrollment and repeat biopsy at the 1-year mark. Results: The subjects included three patients with dense deposit disease (including one patient with recurrent dense deposit disease in allograft) and three patients with C3 glomerulonephritis (including two patients with recurrent C3 glomerulonephritis in allograft). Genetic and complement function testing revealed a mutation in CFH and MCP in one subject each, C3 nephritic factor in three subjects, and elevated levels of serum membrane attack complex in three subjects. After 12 months, two subjects showed significantly reduced serum creatinine, one subject achieved marked reduction in proteinuria, and one subject had stable laboratory parameters but histopathologic improvements. Elevated serum membrane attack complex levels normalized on therapy and paralleled improvements in creatinine and proteinuria. Conclusions: Clinical and histopathologic data suggest a response to eculizumab in some but not all subjects with dense deposit disease and C3 glomerulonephritis. Elevation of serum membrane attack complex before treatment may predict response. Additional research is needed to define the subgroup of dense deposit disease/C3 glomerulonephritis patients in whom eculizumab therapy can be considered.

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Title: Subtitle: Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis
Creators: Andrew S Bomback - Department of Medicine, Division of Nephrology, Columbia University Medical Center, New York, New York
Richard J Smith - Department of Medicine, Division of Nephrology and Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, Iowa
Gaetano R Barile - Department of Ophthalmology, Columbia University Medical Center, New York, New York
Yuzhou Zhang - Department of Medicine, Division of Nephrology and Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, Iowa
Eliot C Heher - Division of Nephrology and Transplantation Center, Massachusetts General Hospital, Boston, Massachusetts; and
Leal Herlitz - Department of Pathology, Columbia University Medical Center, New York, New York
M. Barry Stokes - Department of Pathology, Columbia University Medical Center, New York, New York
Glen S Markowitz - Department of Pathology, Columbia University Medical Center, New York, New York
Vivette D D’Agati - Department of Pathology, Columbia University Medical Center, New York, New York
Pietro A Canetta - Department of Medicine, Division of Nephrology, Columbia University Medical Center, New York, New York
Jai Radhakrishnan - Department of Medicine, Division of Nephrology, Columbia University Medical Center, New York, New York
Gerald B Appel - Department of Medicine, Division of Nephrology, Columbia University Medical Center, New York, New York
Resource Type: Journal article
Publication Details: Clinical journal of the American Society of Nephrology, Vol.7(5), pp.748-756
DOI: 10.2215/CJN.12901211
PMID: 22403278
PMCID: PMC3338285
NLM abbreviation: Clin J Am Soc Nephrol
ISSN: 1555-9041
eISSN: 1555-905X
Publisher: American Society of Nephrology
Language: English
Date published: 05/2012
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
Record Identifier: 9984006434002771

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