Complement is associated with several human kidney dieases and complement therapy is approved for atypical Hemolytic Uremic Syndrome. Sequence- and copy number variations in the human Factor H-CFHR (Complement Factor H Related) gene cluster are linked to the kidney diseases, atypical Hemolytic Uremic Syndrome, C3 Glomerulopathy, Membranous Nephropathy, IgA Nephropathy and lupus nephritis. Mutant CFHR-genes, FHR::FHR- and FHR::Factor H-hybrid-proteins and an altered FHR-plasma repertoire show that variant FHR proteins are associated with kidney pathology. FHRs are emerging immune and complement modulators: We have shown in the first funding period that FHR1 is an inflammatory mediator, FHR2 blocks C3 convertase action and inhibits FHR1 mediated inflammation. FHR5 is a complement activator binding to actin in damaged glomeruli. FHRs together with Factor H, the central C3 convertase regulator, adjust complement activity in glomeruli. In this project we aim to define how altered FHR variants cause pathology in the kidney, and evaluate whether FHR deposition in renal biopsies serve as diagnostic and predictive markers. To this end we plan to: 1) Define the physiological roles of FHR2 and FHR5 and evaluate how new FHR2 mutants (not listed in the exome aggregation consortium database) influence complement action, affect surface binding and complement regulation, 2) correlate FHR1-, FHR2- and FHR5 deposition with morphological changes, immunohistological staining or cellular modifications in glomeruli to define unique patterns for the various glomerular diseases, and 3) develop FHRs as diagnostic markers and coordinate with clinicians to extrapolate the altered FHR profiles for personalized, complement targeting therapies.