Peter F. Zipfel ^1* Karin Heidenreich ² Deepti Goel ³ PS Priyamvada ⁴ Sagar Kulkarni ⁵ Vipul Chakurkar ⁶ Dinesh Khullar ⁷ Ravi Singh ⁸ Charan Bale ⁹

• ¹ Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany
• ² Eleva GmbH, Freiburg, Germany
• ³ Independent researcher, Mumbai, India
• ⁴ Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, Puducherry, India
• ⁵ Department of Nephrology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Pune, Maharashtra, India
• ⁶ King Edward Memorial Hospital Research Centre, Pune, Maharashtra, India
• ⁷ Max Super Speciality Hospital, Delhi, India
• ⁸ Jaypee Hospital, Noida, Uttar Pradesh, India
• ⁹ Department of Nephrology, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pune, Maharashtra, India

C3 glomerulopathy (C3G) is an ultra-rare complement-mediated kidney disease due to deregulation of the Alternative Pathway (AP) of proximal complement. Consequently, all effector loops of complement are active and can cause pathologies: such as C3a-and C5amediated inflammation, C3b opsonization, surface C3b-mediated AP C3-convertase assembly, C3 cleavage product deposition in the glomerulus, and lytic C5b-9/MAC cell damage.The most common pathologic mechanisms are defective chronic alternative pathway deregulation, mostly occurring in plasma, often causing C3 consumption, and chronic complement-mediated glomerular damage and pathology. C3G develops over several years, and loss of renal function occurs in more than 50% of patients. C3G is triggered by both genetic and autoimmune alterations. Genetic causes include mutations in individual complement genes, chromosomal variations in the form of deletions and duplications affecting genes encoding complement modulators. Many genetic aberrations result in increased AP C3 convertase activity, either through decreased activity of regulators, increased activity of modulators, or gain-of-function mutations in genes encoding components of the convertase. Autoimmune forms of C3G do also exist. Autoantibodies target individual complement components, regulators, or bind to neoepitopes exposed in the central alternative pathway C3 convertase, thereby increasing enzyme activity. Overactive AP C3 convertase is common in C3G patients. Given that C3G is a complement disease mediated by defective alternative pathway action, complement blockade is an emerging concept for therapy. Here we summarize both the causes of C3G, the rationale for complement inhibition and list the inhibitors that are being used in the most advanced clinical trials for C3G. With several inhibitors in phase II and III trials, it is expected that treatment for C3G will be possible in the near future.