C3 glomerulopathy (C3G) is an aggressive form of glomerular disease that occurs at any age and carries the highest risk for irreversible renal failure of the known glomerular diseases. Recurrence post-renal transplant remains a major medical issue for the most patients. This dismal outlook reflects an incomplete understanding of the underlying pathophysiology of C3G, a knowledge gap that has not only led to our inability to explain the limited success of currently available anti-complement agents, but has also hindered the development of new therapies for C3G. Familial cases support the hypothesis that C3G results from primary complement dysregulation however our understanding of the genetics of C3G is incomplete. An adequate accounting for the role of autoantibodies in C3G is also lacking. Finally, in the majority of patients, C3G follows a chronic, indolent course. Activation of the alternative complement pathway can be documented, with kidney biopsies confirming the deposition of complement proteins and their cleavage products in the renal glomerulus. However, the association between complement activity and clinical outcome is poorly understood, a reflection of the absence of longitudinal studies of C3G focused on genetics, autoantibodies, and complement activity in relationship to long-term renal outcome. In this grant, we propose to: ? Specific Aim 1. Define genetic drivers of C3G ? Specific Aim 2. Identify and characterize autoantibodies to complement proteins and convertases ? Specific Aim 3. Develop and validate clinically useful predictive models of disease progression in a longitudinal data-driven analysis of complement factors in C3G Completing these aims will meet our short-term goals, which are to provide a better understanding of C3G and to improve care for C3G patients, and provide a foundation for our long-term goal, which is to identify an effective treatment for this disease.

Public Health Relevance

The over-arching goals of this study focused on C3 glomerulopathy are to define genetic drivers of disease, to identify and characterize autoantibodies to complement proteins and convertases, and to develop and validate clinically useful predictive models of disease progression in a longitudinal data-driven analysis of complement factors in C3G. Completing these goals will provide a better understanding of C3G and improve care for C3G patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK110023-02
Application #
9447169
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Mendley, Susan Ruth
Project Start
2017-04-01
Project End
2022-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Iowa
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Mastellos, Dimitrios C; Reis, Edimara S; Ricklin, Daniel et al. (2017) Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery. Trends Immunol 38:383-394
Zhang, Yuzhou; Meyer, Nicole C; Fervenza, Fernando C et al. (2017) C4 Nephritic Factors in C3 Glomerulopathy: A Case Series. Am J Kidney Dis 70:834-843