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Published on: January 29, 2014
Defining the complement biomarker profile of C3 glomerulopathy
Yuzhou Zhang1, Carla M Nester2, Bertha Martin3
1Molecular Otolaryngology and Renal Research Laboratories.
Insights
C3 glomerulopathy (C3G) involves abnormal complement alternative pathway control. Biomarker analysis revealed significant differences between C3G subtypes and controls, confirming complement dysregulation in C3G.
Area of Science:
- Nephrology
- Immunology
- Complement System
Background:
- C3 glomerulopathy (C3G) is defined by C3 fragment deposition on kidney biopsy.
- Its primary cause is abnormal alternative complement pathway regulation.
- The full disease spectrum and specific complement abnormalities require further definition.
Purpose of the Study:
- To validate and define the association between complement dysregulation and C3G.
- To determine if specific complement pathway abnormalities can inform C3G disease definition.
Main Methods:
- 34 C3G patients (17 C3GN, 17 DDD) and 100 controls were analyzed.
- Nineteen complement biomarkers were measured in all samples.
- Results were compared between C3G subtypes and controls.
Main Results:
- C3G patients showed lower serum C3 and factor B, and higher C3d and Bb levels than controls.
- Terminal complement pathway analysis revealed suppressed C5 and elevated C5a in C3GN.
- C3 nephritic factor activity was higher in DDD than C3GN.
Conclusions:
- Complement biomarkers are significantly altered in C3G patients.
- These findings confirm the link between complement dysregulation and C3G.
- Specific complement biomarker patterns differentiate C3G subtypes.
Background And Objectives:
C3 glomerulopathy (C3G) applies to a group of renal diseases defined by a specific renal biopsy finding: a dominant pattern of C3 fragment deposition on immunofluorescence. The primary pathogenic mechanism involves abnormal control of the alternative complement pathway, although a full description of the disease spectrum remains to be determined. This study sought to validate and define the association of complement dysregulation with C3G and to determine whether specific complement pathway abnormalities could inform disease definition.
Design, Setting, Participants, & Measurements:
This study included 34 patients with C3G (17 with C3 glomerulonephritis [C3GN] and 17 with dense deposit disease [DDD]) diagnosed between 2008 and 2013 selected from the C3G Registry. Control samples (n=100) were recruited from regional blood drives. Nineteen complement biomarkers were assayed on all samples. Results were compared between C3G disease categories and with normal controls.
Results:
Assessment of the alternative complement pathway showed that compared with controls, patients with C3G had lower levels of serum C3 (P<0.001 for both DDD and C3GN) and factor B (P<0.001 for both DDD and C3GN) as well as higher levels of complement breakdown products including C3d (P<0.001 for both DDD and C3GN) and Bb (P<0.001 for both DDD and C3GN). A comparison of terminal complement pathway proteins showed that although C5 levels were significantly suppressed (P<0.001 for both DDD and C3GN) its breakdown product C5a was significantly higher only in patients with C3GN (P<0.05). Of the other terminal pathway components (C6-C9), the only significant difference was in C7 levels between patients with C3GN and controls (P<0.01). Soluble C5b-9 was elevated in both diseases but only the difference between patients with C3GN and controls reached statistical significance (P<0.001). Levels of C3 nephritic factor activity were qualitatively higher in patients with DDD compared with patients with C3GN.
Conclusions:
Complement biomarkers are significantly abnormal in patients with C3G compared with controls. These data substantiate the link between complement dysregulation and C3G and identify C3G interdisease differences.
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