Causes of alternative pathway dysregulation in dense deposit disease

Yuzhou Zhang; Nicole C Meyer; Kai Wang; Carla Nishimura; Kathy Frees; Michael Jones; Louis M Katz; Sanjeev Sethi; Richard J H Smith

doi:10.2215/CJN.07900811

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Causes of alternative pathway dysregulation in dense deposit disease

Journal article

Open access

Causes of alternative pathway dysregulation in dense deposit disease

Yuzhou Zhang, Nicole C Meyer, Kai Wang, Carla Nishimura, Kathy Frees, Michael Jones, Louis M Katz, Sanjeev Sethi and Richard J H Smith

Clinical journal of the American Society of Nephrology, Vol.7(2), pp.265-274

02/2012

DOI: 10.2215/CJN.07900811

PMCID: PMC3280037

PMID: 22223606

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Abstract

This study was designed to investigate the causes of alternative pathway dysregulation in a cohort of patients with dense deposit disease (DDD). Thirty-two patients with biopsy-proven DDD underwent screening for C3 nephritic factors (C3Nefs), factor H autoantibodies (FHAAs), factor B autoantibodies (FBAAs), and genetic variants in CFH. C3Nefs were detected by: ELISA, C3 convertase surface assay (C3CSA), C3CSA with properdin (C3CSAP), two-dimensional immunoelectrophoresis (2DIEP), and immunofixation electrophoresis (IFE). FHAAs and FBAAs were detected by ELISA, and CFH variants were identified by Sanger sequencing. Twenty-five patients (78%) were positive for C3Nefs. Three C3Nef-positive patients were also positive for FBAAs and one of these patients additionally carried two novel missense variants in CFH. Of the seven C3Nef-negative patients, one patient was positive for FHAAs and two patients carried CFH variants that may be causally related to their DDD phenotype. C3CASP was the most sensitive C3Nef-detection assay. C3CASP and IFE are complementary because C3CSAP measures the stabilizing properties of C3Nefs, whereas IFE measures their expected consequence-breakdown of C3b. A test panel that includes C3CSAP, IFE, FHAAs, FBAAs, and genetic testing for CFH variants will identify a probable cause for alternative pathway dysregulation in approximately 90% of DDD patients. Dysregulation is most frequently due to C3Nefs, although some patients test positive for FHAAs, FBAAs, and CFH mutations. Defining the pathophysiology of DDD should facilitate the development of mechanism-directed therapies.

Prognosis

Kidney - pathology

Autoantibodies - blood

Humans

Middle Aged

Kidney - immunology

Male

Glomerulonephritis, Membranoproliferative - blood

Mutation, Missense

Young Adult

Properdin - immunology

Time Factors

DNA Mutational Analysis

Adult

Female

Child

Erythrocytes - immunology

Complement Factor H - immunology

Enzyme-Linked Immunosorbent Assay

Kaplan-Meier Estimate

Genotype

Complement C3 Nephritic Factor - analysis

Biomarkers - blood

Complement C3-C5 Convertases - immunology

Glomerulonephritis, Membranoproliferative - genetics

Glomerulonephritis, Membranoproliferative - immunology

Iowa

Phenotype

Animals

Biopsy

Adolescent

Complement Factor B - immunology

Sheep

Glomerulonephritis, Membranoproliferative - diagnosis

Complement Factor H - genetics

Complement Pathway, Alternative

Immunoelectrophoresis, Two-Dimensional

Details

Title: Subtitle: Causes of alternative pathway dysregulation in dense deposit disease
Creators: Yuzhou Zhang - Department of Otolaryngology-Head & Neck Surgery, Caver College of Medicine, University of Iowa, 5270 CBRB Building, Iowa City, IA 52242, USA
Nicole C Meyer
Kai Wang
Carla Nishimura
Kathy Frees
Michael Jones
Louis M Katz
Sanjeev Sethi
Richard J H Smith
Resource Type: Journal article
Publication Details: Clinical journal of the American Society of Nephrology, Vol.7(2), pp.265-274
DOI: 10.2215/CJN.07900811
PMID: 22223606
PMCID: PMC3280037
NLM abbreviation: Clin J Am Soc Nephrol
ISSN: 1555-9041
eISSN: 1555-905X
Publisher: United States
Grant note: R01 DK074409 / NIDDK NIH HHS DK074409 / NIDDK NIH HHS
Language: English
Date published: 02/2012
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; Biostatistics; Otolaryngology; Internal Medicine
Record Identifier: 9983997347802771

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