Complement-mediated kidney diseases are ultra-rare conditions associated with genetic variants or circulating auto-antibodies, allowing uncontrolled complement activation, and resulting in complement deposition in the kidneys. This leads to renal inflammation and ultimately end-stage renal failure that can recur after renal transplantation. Here we will investigate two rare kidney diseases, atypical hemolytic uremic syndrome and C3 glomerulopathy. In both there is an unmet need for accurate testing of genetic and acquired complement abnormalities. Interlaboratory complement assays vary considerably, and their standardization is a great necessity. Solving of these challenges is needed for the understanding of disease pathophysiology and for correct diagnosis and treatment. We aim to determine appropriate biomarkers in the circulation and tissue for diagnosis using patient blood samples, DNA, blood cell-derived endothelial cells, extracellular vesicles, and kidney biopsies. With the advantage of a large patient cohort, we will standardize immunological detection assays. Furthermore, we will use advanced state-of-the-art methodology for the development of diagnostic assays for complement activation based on proteomics, flow cytometry, cell-free glycocalyx-based assays, transcriptomics and histological immunostaining. The phenotype of genetic variants found in patients will be assessed using these novel assays both on cells and intracellularly. We also aim to explore novel pathways of complement activation by renin, the kallikrein-kinin system and heme using both in vitro and in vivo models. The scientific consortium, from 6 European countries, including an early career scientist, combines expertise in adult and pediatric nephrology, immunology, genetics, basic and translational research with extensive experience in the research, diagnosis and cure of these rare kidney diseases. The consortium is associated with a specialized SME in the field of complement and several European patient organizations. The findings generated here we will provide better diagnostics, novel disease biomarkers, stratified genetic variants and offer a better understanding of disease pathophysiology. This will allow better improvement patient diagnosis and follow-up and define which patients will benefit from novel therapies.