Project Summary/Abstract C3 glomerulopathy (C3G) is an aggressive ultra-rare kidney disease that occurs at any age and carries the highest risk for irreversible renal failure of the known glomerular diseases. It is defined by underlying complement dysregulation and characterized by predominant complement C3 deposition on kidney biopsy. Two major disease subgroups are recognized–dense deposit disease (DDD) and C3 glomerulonephritis (C3GN)–although overlapping clinical and pathological features suggest that C3G is more appropriately considered a disease continuum. Dysregulation of the alternative pathway (AP) of complement is fundamental to disease manifestation although terminal pathway dysregulation is also common. The estimated renal half-life in C3G patients is 10 years and in patients who progress to end-stage renal disease (ESRD), transplant decisions, including timing and post-transplant medical therapy, are overshadowed by the fact that disease recurrence remains a major medical issue. The challenges faced by clinicians in caring for C3G patients reflect our incomplete understanding of both the underlying pathophysiology and natural history of this disease. These knowledge gaps impact treatment decisions and the development of disease-specific therapies. In this grant, we propose to: • Specific Aim 1. To study the role of genetic variation in C3G • Specific Aim 2. To define the characteristics of autoantibodies in C3G by epitope mapping • Specific Aim 3. To develop and clinically validate predictive models of disease outcome in C3G Completing these specific aims will significantly refine our insight into the pathogenesis of C3G, improve clinical care of these patients, and lay the foundation for effective and personalized treatments for this disease.