The complement cascade comprises soluble and cell surface proteins and is an important arm of the innate immune system. Once activated, the complement system rapidly generates large quantities of protein fragments that are potent mediators of inflammatory, vasoactive and metabolic responses. Although complement is crucial to host defence and homeostasis, its inappropriate or uncontrolled activation can also drive tissue injury. For example, the complement system has been known for more than 50 years to be activated by glomerular immune complexes and to contribute to autoimmune kidney disease. Notably, the latest research shows that complement is also activated in kidney diseases that are not traditionally thought of as immune-mediated, including haemolytic-uraemic syndrome, diabetic kidney disease and focal segmental glomerulosclerosis. Several complement-targeted drugs have been approved for the treatment of kidney disease, and additional anti-complement agents are being investigated in clinical trials. These drugs are categorically different from other immunosuppressive agents and target pathological processes that are not effectively inhibited by other classes of immunosuppressants. The development of these new drugs might therefore have considerable benefits in the treatment of kidney disease.

Institute for Clinical and Experimental Medicine Prague Czech Republic

University of Colorado Anschutz Medical Campus Aurora Colorado USA

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Ehrlich, P. Collected Studies on Immunity (John Wiley & Sons, 1906).

Thurman, J. M., Lucia, M. S., Ljubanovic, D. & Holers, V. M. Acute tubular necrosis is characterized by activation of the alternative pathway of complement. Kidney Int. 67, 524–530 (2005). PubMed DOI

Noris, M. et al. Hypocomplementemia discloses genetic predisposition to hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: role of factor H abnormalities. Italian Registry of Familial and Recurrent Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura. J. Am. Soc. Nephrol. 10, 281–293 (1999). PubMed DOI

Loupy, A. et al. The Banff 2019 Kidney Meeting Report (I): updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am. J. Transplant. 20, 2318–2331 (2020). PubMed DOI PMC

Reis, E. S., Mastellos, D. C., Hajishengallis, G. & Lambris, J. D. New insights into the immune functions of complement. Nat. Rev. Immunol. 19, 503–516 (2019). PubMed DOI PMC

Stephan, A. H., Barres, B. A. & Stevens, B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu. Rev. Neurosci. 35, 369–389 (2012). PubMed DOI

Arbore, G. et al. T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4 PubMed DOI PMC

Zhang, X. et al. Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo. Blood 110, 228–236 (2007). PubMed DOI PMC

Huber-Lang, M. et al. Generation of C5a in the absence of C3: a new complement activation pathway. Nat. Med. 12, 682–687 (2006). PubMed DOI

Holers, V. M. Contributions of animal models to mechanistic understandings of antibody-dependent disease and roles of the amplification loop. Immunol. Rev. 313, 181–193 (2023). PubMed DOI

Pouw, R. B., Vredevoogd, D. W., Kuijpers, T. W. & Wouters, D. Of mice and men: the factor H protein family and complement regulation. Mol. Immunol. 67, 12–20 (2015). PubMed DOI

Ebanks, R. O. & Isenman, D. E. Mouse complement component C4 is devoid of classical pathway C5 convertase subunit activity. Mol. Immunol. 33, 297–309 (1996). PubMed DOI

Brooimans, R. A. et al. Interleukin 2 mediates stimulation of complement C3 biosynthesis in human proximal tubular epithelial cells. J. Clin. Invest. 88, 379–384 (1991). PubMed DOI PMC

Welch, T. R., Beischel, L. S., Frenzke, M. & Witte, D. Regulated expression of complement factor B in the human kidney. Kidney Int. 50, 521–525 (1996). PubMed DOI

Zwirner, J., Felber, E., Herzog, V., Riethmuller, G. & Feucht, H. E. Classical pathway of complement activation in normal and diseased human glomeruli. Kidney Int. 36, 1069–1077 (1989). PubMed DOI

Dodds, A. W. & Matsushita, M. The phylogeny of the complement system and the origins of the classical pathway. Immunobiology 212, 233–243 (2007). PubMed DOI

Matsushita, M. et al. Origin of the classical complement pathway: Lamprey orthologue of mammalian C1q acts as a lectin. Proc. Natl Acad. Sci. USA 101, 10127–10131 (2004). PubMed DOI PMC

Garred, P. et al. A journey through the lectin pathway of complement-MBL and beyond. Immunol. Rev. 274, 74–97 (2016). PubMed DOI

Roos, A. et al. Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease. J. Am. Soc. Nephrol. 17, 1724–1734 (2006). PubMed DOI

Seifert, L. et al. The classical pathway triggers pathogenic complement activation in membranous nephropathy. Nat. Commun. 14, 473 (2023). PubMed DOI PMC

Harboe, M., Ulvund, G., Vien, L., Fung, M. & Mollnes, T. E. The quantitative role of alternative pathway amplification in classical pathway induced terminal complement activation. Clin. Exp. Immunol. 138, 439–446 (2004). PubMed DOI PMC

de Boer, E. C. et al. The contribution of the alternative pathway in complement activation on cell surfaces depends on the strength of classical pathway initiation. Clin. Transl. Immunol. 12, e1436 (2023). DOI

Lachmann, P. J., Lay, E. & Seilly, D. J. Experimental confirmation of the C3 tickover hypothesis by studies with an Ab (S77) that inhibits tickover in whole serum. FASEB J. 32, 123–129 (2018). PubMed DOI

Jean, D. et al. A cysteine proteinase, which cleaves human C3, the third component of complement, is involved in tumorigenicity and metastasis of human melanoma. Cancer Res. 56, 254–258 (1996). PubMed

Volanakis, J. E., Barnum, S. R., Giddens, M. & Galla, J. H. Renal filtration and catabolism of complement protein D. N. Engl. J. Med. 312, 395–399 (1985). PubMed DOI

Zhang, Y. et al. C3(H PubMed DOI PMC

Jalal, D. et al. Endothelial microparticles and systemic complement activation in patients with chronic kidney disease. J. Am. Heart Assoc. https://doi.org/10.1161/JAHA.117.007818 (2018). PubMed DOI PMC

Merle, N. S., Church, S. E., Fremeaux-Bacchi, V. & Roumenina, L. T. Complement system part I — molecular mechanisms of activation and regulation. Front. Immunol. 6, 262 (2015). PubMed DOI PMC

Brown, K. M. et al. Influence of donor C3 allotype on late renal-transplantation outcome. N. Engl. J. Med. 354, 2014–2023 (2006). PubMed DOI

Pratt, J. R., Basheer, S. A. & Sacks, S. H. Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat. Med. 8, 582–587 (2002). PubMed DOI

Lake, B. B. et al. A single-nucleus RNA-sequencing pipeline to decipher the molecular anatomy and pathophysiology of human kidneys. Nat. Commun. 10, 2832 (2019). PubMed DOI PMC

Sircar, M. et al. Complement 7 is up-regulated in human early diabetic kidney disease. Am. J. Pathol. 188, 2147–2154 (2018). PubMed DOI PMC

Tang, S., Zhou, W., Sheerin, N. S., Vaughan, R. W. & Sacks, S. H. Contribution of renal secreted complement C3 to the circulating pool in humans. J. Immunol. 162, 4336–4341 (1999). PubMed DOI

West, E. E. & Kemper, C. Complosome — the intracellular complement system. Nat. Rev. Nephrol. 19, 426–439 (2023). PubMed DOI

Vandendriessche, S., Cambier, S., Proost, P. & Marques, P. E. Complement receptors and their role in leukocyte recruitment and phagocytosis. Front. Cell. Dev. Biol. 9, 624025 (2021). PubMed DOI PMC

Stokowska, A. et al. Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity. J. Clin. Invest. https://doi.org/10.1172/JCI162253 (2023). PubMed DOI PMC

Strey, C. W. et al. The proinflammatory mediators C3a and C5a are essential for liver regeneration. J. Exp. Med. 198, 913–923 (2003). PubMed DOI PMC

Serna, M., Giles, J. L., Morgan, B. P. & Bubeck, D. Structural basis of complement membrane attack complex formation. Nat. Commun. 7, 10587 (2016). PubMed DOI PMC

Zipfel, P. F. & Skerka, C. Complement regulators and inhibitory proteins. Nat. Rev. Immunol. 9, 729–740 (2009). PubMed DOI

Blom, A. M., Webb, J., Villoutreix, B. O. & Dahlback, B. A cluster of positively charged amino acids in the C4BP α-chain is crucial for C4b binding and factor I cofactor function. J. Biol. Chem. 274, 19237–19245 (1999). PubMed DOI

Degn, S. E. et al. MAp44, a human protein associated with pattern recognition molecules of the complement system and regulating the lectin pathway of complement activation. J. Immunol. 183, 7371–7378 (2009). PubMed DOI

Mueller-Ortiz, S. L. et al. Targeted disruption of the gene encoding the murine small subunit of carboxypeptidase N (CPN1) causes susceptibility to C5a anaphylatoxin-mediated shock. J. Immunol. 182, 6533–6539 (2009). PubMed DOI

Lucientes-Continente, L., Marquez-Tirado, B. & Goicoechea de Jorge, E. The factor H protein family: the switchers of the complement alternative pathway. Immunol. Rev. 313, 25–45 (2023). PubMed DOI

Martin Merinero, H. et al. Functional characterization of 105 factor H variants associated with aHUS: lessons for variant classification. Blood 138, 2185–2201 (2021). PubMed DOI PMC

Servais, A. et al. Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome. J. Med. Genet. 44, 193–199 (2007). PubMed DOI

Medjeral-Thomas, N. R. et al. Glomerular complement factor H-related protein 5 (FHR5) is highly prevalent in C3 glomerulopathy and associated with renal impairment. Kidney Int. Rep. 4, 1387–1400 (2019). PubMed DOI PMC

Medjeral-Thomas, N. R. et al. Circulating complement factor H-related proteins 1 and 5 correlate with disease activity in IgA nephropathy. Kidney Int. 92, 942–952 (2017). PubMed DOI PMC

Goodship, T. H. et al. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int. 91, 539–551 (2017). PubMed DOI

Noris, M. & Remuzzi, G. Atypical hemolytic-uremic syndrome. N. Engl. J. Med. 361, 1676–1687 (2009). PubMed DOI

Savige, J. et al. Retinal disease in the C3 glomerulopathies and the risk of impaired vision. Ophthalmic Genet. 37, 369–376 (2016). PubMed DOI

Durey, M. A., Sinha, A., Togarsimalemath, S. K. & Bagga, A. Anti-complement-factor H-associated glomerulopathies. Nat. Rev. Nephrol. 12, 563–578 (2016). PubMed DOI

Donadelli, R. et al. Unraveling the molecular mechanisms underlying complement dysregulation by nephritic factors in C3G and IC-MPGN. Front. Immunol. 9, 2329 (2018). PubMed DOI PMC

Sethi, S. et al. Dense deposit disease associated with monoclonal gammopathy of undetermined significance. Am. J. Kidney Dis. 56, 977–982 (2010). PubMed DOI PMC

Schaefer, F. et al. Clinical and genetic predictors of atypical hemolytic uremic syndrome phenotype and outcome. Kidney Int. 94, 408–418 (2018). PubMed DOI

Blanc, C. et al. Overall neutralization of complement factor H by autoantibodies in the acute phase of the autoimmune form of atypical hemolytic uremic syndrome. J. Immunol. 189, 3528–3537 (2012). PubMed DOI

Martinez-Barricarte, R. et al. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. J. Clin. Invest. 120, 3702–3712 (2010). PubMed DOI PMC

Osborne, A. J. et al. Statistical validation of rare complement variants provides insights into the molecular basis of atypical hemolytic uremic syndrome and C3 glomerulopathy. J. Immunol. 200, 2464–2478 (2018). PubMed DOI

Thurman, J. M. & Harrison, R. A. The susceptibility of the kidney to alternative pathway activation — a hypothesis. Immunol. Rev. https://doi.org/10.1111/imr.13168 (2022). PubMed DOI

Rondeau, E. et al. The long-acting C5 inhibitor, ravulizumab, is effective and safe in adult patients with atypical hemolytic uremic syndrome naive to complement inhibitor treatment. Kidney Int. 97, 1287–1296 (2020). PubMed DOI

Legendre, C. M. et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N. Engl. J. Med. 368, 2169–2181 (2013). PubMed DOI

Ruggenenti, P. et al. C5 Convertase blockade in membranoproliferative glomerulonephritis: a single-arm clinical trial. Am. J. Kidney Dis. 74, 224–238 (2019). PubMed DOI

Nasr, S. H. et al. Proliferative glomerulonephritis with monoclonal IgG deposits: a distinct entity mimicking immune-complex glomerulonephritis. Kidney Int. 65, 85–96 (2004). PubMed DOI

Nasr, S. H. et al. Proliferative glomerulonephritis with monoclonal IgG deposits. J. Am. Soc. Nephrol. 20, 2055–2064 (2009). PubMed DOI PMC

Nasr, S. H. et al. Dysproteinemia, proteinuria, and glomerulonephritis. Kidney Int. 69, 772–775 (2006). PubMed DOI

Ravindran, A., Fervenza, F. C., Smith, R. J. H. & Sethi, S. C3 glomerulopathy associated with monoclonal Ig is a distinct subtype. Kidney Int. 94, 178–186 (2018). PubMed DOI PMC

Meri, S., Koistinen, V., Miettinen, A., Tornroth, T. & Seppala, I. J. Activation of the alternative pathway of complement by monoclonal lambda light chains in membranoproliferative glomerulonephritis. J. Exp. Med. 175, 939–950 (1992). PubMed DOI

Servais, A. et al. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int. 82, 454–464 (2012). PubMed DOI

Sethi, S., Nasr, S. H., De Vriese, A. S. & Fervenza, F. C. C4d as a diagnostic tool in proliferative GN. J. Am. Soc. Nephrol. 26, 2852–2859 (2015). PubMed DOI PMC

Hou, J. et al. Toward a working definition of C3 glomerulopathy by immunofluorescence. Kidney Int. 85, 450–456 (2014). PubMed DOI

Iatropoulos, P. et al. Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome. Mol. Immunol. 71, 131–142 (2016). PubMed DOI

Diebolder, C. A. et al. Complement is activated by IgG hexamers assembled at the cell surface. Science 343, 1260–1263 (2014). PubMed DOI PMC

Ding, Y. et al. The spectrum of C4d deposition in renal biopsies of lupus nephritis patients. Front. Immunol. 12, 654652 (2021). PubMed DOI PMC

Verroust, P. J., Wilson, C. B., Cooper, N. R., Edgington, T. S. & Dixon, F. J. Glomerular complement components in human glomerulonephritis. J. Clin. Invest. 53, 77–84 (1974). PubMed DOI PMC

Ma, H., Sandor, D. G. & Beck, L. H. Jr The role of complement in membranous nephropathy. Semin. Nephrol. 33, 531–542 (2013). PubMed DOI PMC

Tomas, N. M. et al. Autoantibodies against thrombospondin type 1 domain-containing 7A induce membranous nephropathy. J. Clin. Invest. 126, 2519–2532 (2016). PubMed DOI PMC

Murtas, C. et al. Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy. Clin. J. Am. Soc. Nephrol. 7, 1394–1400 (2012). PubMed DOI PMC

van der Zee, J. S., van Swieten, P. & Aalberse, R. C. Inhibition of complement activation by IgG4 antibodies. Clin. Exp. Immunol. 64, 415–422 (1986). PubMed PMC

Val-Bernal, J. F., Garijo, M. F., Val, D., Rodrigo, E. & Arias, M. C4d immunohistochemical staining is a sensitive method to confirm immunoreactant deposition in formalin-fixed paraffin-embedded tissue in membranous glomerulonephritis. Histol. Histopathol. 26, 1391–1397 (2011). PubMed

Haddad, G. et al. Altered glycosylation of IgG4 promotes lectin complement pathway activation in anti-PLA2R1-associated membranous nephropathy. J. Clin. Invest. 131, https://doi.org/10.1172/JCI140453 (2021).

Bally, S. et al. Phospholipase A2 receptor-related membranous nephropathy and mannan-binding lectin deficiency. J. Am. Soc. Nephrol. 27, 3539–3544 (2016). PubMed DOI PMC

Lhotta, K., Wurzner, R., Rumpelt, H. J., Eder, P. & Mayer, G. Membranous nephropathy in a patient with hereditary complete complement C4 deficiency. Nephrol. Dial. Transpl. 19, 990–993 (2004). DOI

Baker, P. J. et al. Depletion of C6 prevents development of proteinuria in experimental membranous nephropathy in rats. Am. J. Pathol. 135, 185–194 (1989). PubMed PMC

Cunningham, P. N. & Quigg, R. J. Contrasting roles of complement activation and its regulation in membranous nephropathy. J. Am. Soc. Nephrol. 16, 1214–1222 (2005). PubMed DOI

Gao, S., Cui, Z. & Zhao, M. H. Complement C3a and C3a receptor activation mediates podocyte injuries in the mechanism of primary membranous nephropathy. J. Am. Soc. Nephrol. 33, 1742–1756 (2022). PubMed DOI PMC

Pickering, M. C., Botto, M., Taylor, P. R., Lachmann, P. J. & Walport, M. J. Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv. Immunol. 76, 227–324 (2000). PubMed DOI

Taylor, P. R. et al. A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J. Exp. Med. 192, 359–366 (2000). PubMed DOI PMC

Birmingham, D. J. et al. The complex nature of serum C3 and C4 as biomarkers of lupus renal flare. Lupus 19, 1272–1280 (2010). PubMed DOI PMC

Kim, A. H. J. et al. Association of blood concentrations of complement split product iC3b and serum C3 with systemic lupus erythematosus disease activity. Arthritis Rheumatol. 71, 420–430 (2019). PubMed DOI PMC

Martin, M. et al. Plasma C4d correlates with C4d deposition in kidneys and with treatment response in lupus nephritis patients. Front. Immunol. 11, 582737 (2020). PubMed DOI PMC

Jennette, J. C. & Hipp, C. G. Immunohistopathologic evaluation of C1q in 800 renal biopsy specimens. Am. J. Clin. Pathol. 83, 415–420 (1985). PubMed DOI

Turley, A. J. et al. Spectrum and management of complement immunodeficiencies (excluding hereditary angioedema) across Europe. J. Clin. Immunol. 35, 199–205 (2015). PubMed DOI

Elliott, M. K. et al. Effects of complement factor D deficiency on the renal disease of MRL/lpr mice. Kidney Int. 65, 129–138 (2004). PubMed DOI

Watanabe, H. et al. Modulation of renal disease in MRL/lpr mice genetically deficient in the alternative complement pathway factor B. J. Immunol. 164, 786–794 (2000). PubMed DOI

Pedchenko, V. et al. Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis. N. Engl. J. Med. 363, 343–354 (2010). PubMed DOI PMC

Bowman, C., Ambrus, K. & Lockwood, C. M. Restriction of human IgG subclass expression in the population of auto-antibodies to glomerular basement membrane. Clin. Exp. Immunol. 69, 341–349 (1987). PubMed PMC

Ma, R. et al. The alternative pathway of complement activation may be involved in the renal damage of human anti-glomerular basement membrane disease. PLoS One 9, e91250 (2014). PubMed DOI PMC

Quigg, R. J. et al. Blockade of antibody-induced glomerulonephritis with Crry-Ig, a soluble murine complement inhibitor. J. Immunol. 160, 4553–4560 (1998). PubMed DOI

van Daalen, E. E. et al. Predicting outcome in patients with anti-GBM glomerulonephritis. Clin. J. Am. Soc. Nephrol. 13, 63–72 (2018). PubMed DOI

Nithagon, P. et al. Eculizumab and complement activation in anti-glomerular basement membrane disease. Kidney Int. Rep. 6, 2713–2717 (2021). PubMed DOI PMC

Haas, M. Histology and immunohistology of IgA nephropathy. J. Nephrol. 18, 676–680 (2005). PubMed

Kim, S. J. et al. Decreased circulating C3 levels and mesangial C3 deposition predict renal outcome in patients with IgA nephropathy. PLoS One 7, e40495 (2012). PubMed DOI PMC

Hiemstra, P. S., Gorter, A., Stuurman, M. E., Van Es, L. A. & Daha, M. R. Activation of the alternative pathway of complement by human serum IgA. Eur. J. Immunol. 17, 321–326 (1987). PubMed DOI

Suzuki, H. et al. IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1. J. Clin. Invest. 118, 629–639 (2008). PubMed PMC

Suzuki, H. et al. Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J. Clin. Invest. 119, 1668–1677 (2009). PubMed PMC

Rizk, D. V. et al. Glomerular immunodeposits of patients with IgA nephropathy are enriched for IgG autoantibodies specific for galactose-deficient IgA1. J. Am. Soc. Nephrol. 30, 2017–2026 (2019). PubMed DOI PMC

Espinosa, M. et al. Association of C4d deposition with clinical outcomes in IgA nephropathy. Clin. J. Am. Soc. Nephrol. 9, 897–904 (2014). PubMed DOI PMC

Tan, L. et al. A multicenter, prospective, observational study to determine association of mesangial C1q deposition with renal outcomes in IgA nephropathy. Sci. Rep. 11, 5467 (2021). PubMed DOI PMC

Jiang, Y. et al. Glomerular C4d deposition and kidney disease progression in IgA nephropathy: a systematic review and meta-analysis. Kidney Med. 3, 1014–1021 (2021). PubMed DOI PMC

Wu, L. et al. Immunofluorescence deposits in the mesangial area and glomerular capillary loops did not affect the prognosis of immunoglobulin a nephropathy except C1q:a single-center retrospective study. BMC Nephrol. 22, 43 (2021). PubMed DOI PMC

Evans, D. J. et al. Glomerular deposition of properdin in Henoch-Schonlein syndrome and idiopathic focal nephritis. Br. Med. J. 3, 326–328 (1973). PubMed DOI PMC

Chiu, Y. L. et al. Alternative complement pathway is activated and associated with galactose-deficient IgA PubMed DOI PMC

Holmes, L. V. et al. Determining the population frequency of the CFHR3/CFHR1 deletion at 1q32. PLoS One 8, e60352 (2013). PubMed DOI PMC

Xie, J. et al. Fine mapping implicates a deletion of CFHR1 and CFHR3 in protection from IgA nephropathy in Han Chinese. J. Am. Soc. Nephrol. 27, 3187–3194 (2016). PubMed DOI PMC

Kiryluk, K. et al. Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. Nat. Genet. 46, 1187–1196 (2014). PubMed DOI PMC

Murphy, B., Georgiou, T., Machet, D., Hill, P. & McRae, J. Factor H-related protein-5: a novel component of human glomerular immune deposits. Am. J. Kidney Dis. 39, 24–27 (2002). PubMed DOI

Medjeral-Thomas, N. R. et al. Progressive IgA nephropathy is associated with low circulating mannan-binding lectin-associated serine protease-3 (MASP-3) and increased glomerular factor H-related protein-5 (FHR5) deposition. Kidney Int. Rep. 3, 426–438 (2018). PubMed DOI

Tortajada, A. et al. Elevated factor H-related protein 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy. Kidney Int. 92, 953–963 (2017). PubMed DOI

Zhai, Y. L. et al. Rare variants in the complement factor H-related protein 5 gene contribute to genetic susceptibility to IgA nephropathy. J. Am. Soc. Nephrol. 27, 2894–2905 (2016). PubMed DOI PMC

Harris, A. A., Falk, R. J. & Jennette, J. C. Crescentic glomerulonephritis with a paucity of glomerular immunoglobulin localization. Am. J. Kidney Dis. 32, 179–184 (1998). PubMed DOI

Xiao, H., Schreiber, A., Heeringa, P., Falk, R. J. & Jennette, J. C. Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies. Am. J. Pathol. 170, 52–64 (2007). PubMed DOI PMC

Xiao, H. et al. C5a receptor (CD88) blockade protects against MPO-ANCA GN. J. Am. Soc. Nephrol. 25, 225–231 (2014). PubMed DOI

Haas, M. & Eustace, J. A. Immune complex deposits in ANCA-associated crescentic glomerulonephritis: a study of 126 cases. Kidney Int. 65, 2145–2152 (2004). PubMed DOI

Yuan, J. et al. C5a and its receptors in human anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Arthritis Res. Ther. 14, R140 (2012). PubMed DOI PMC

Gou, S. J., Yuan, J., Wang, C., Zhao, M. H. & Chen, M. Alternative complement pathway activation products in urine and kidneys of patients with ANCA-associated GN. Clin. J. Am. Soc. Nephrol. 8, 1884–1891 (2013). PubMed DOI PMC

Gou, S. J., Yuan, J., Chen, M., Yu, F. & Zhao, M. H. Circulating complement activation in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Kidney Int. 83, 129–137 (2013). PubMed DOI

Jayne, D. R. W., Merkel, P. A., Schall, T. J., Bekker, P. & Group, A. S. Avacopan for the treatment of ANCA-associated vasculitis. N. Engl. J. Med. 384, 599–609 (2021). PubMed DOI

Jayne, D. R. W. et al. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J. Am. Soc. Nephrol. 28, 2756–2767 (2017). PubMed DOI PMC

Stone, J. H. et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N. Engl. J. Med. 363, 221–232 (2010). PubMed DOI PMC

Jones, R. B. et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N. Engl. J. Med. 363, 211–220 (2010). PubMed DOI

Jiao, Y. et al. Activation of complement C1q and C3 in glomeruli might accelerate the progression of diabetic nephropathy: evidence from transcriptomic data and renal histopathology. J. Diabetes Investig. 13, 839–849 (2022). PubMed DOI PMC

Duan, S. et al. Association of glomerular complement C4c deposition with the progression of diabetic kidney disease in patients with type 2 diabetes. Front. Immunol. 11, 2073 (2020). PubMed DOI PMC

Fortpied, J., Vertommen, D. & Van Schaftingen, E. Binding of mannose-binding lectin to fructosamines: a potential link between hyperglycaemia and complement activation in diabetes. Diabetes Metab. Res. Rev. 26, 254–260 (2010). PubMed DOI

Ostergaard, J. et al. Mannose-binding lectin deficiency attenuates renal changes in a streptozotocin-induced model of type 1 diabetes in mice. Diabetologia 50, 1541–1549 (2007). PubMed DOI

Ostergaard, J. A. et al. Mannan-binding lectin in diabetic kidney disease: the impact of mouse genetics in a type 1 diabetes model. Exp. Diabetes Res. 2012, 678381 (2012). PubMed DOI PMC

Ostergaard, J. A. et al. Diabetes-induced changes in mannan-binding lectin levels and complement activation in a mouse model of type 1 diabetes. Scand. J. Immunol. 77, 187–194 (2013). PubMed DOI

Saraheimo, M. et al. Increased levels of mannan-binding lectin in type 1 diabetic patients with incipient and overt nephropathy. Diabetologia 48, 198–202 (2005). PubMed DOI

Hansen, T. K. et al. Association between mannose-binding lectin, high-sensitivity C-reactive protein and the progression of diabetic nephropathy in type 1 diabetes. Diabetologia 53, 1517–1524 (2010). PubMed DOI

Lu, H., Deng, S., Zheng, M. & Hu, K. iTRAQ plasma proteomics analysis for candidate biomarkers of type 2 incipient diabetic nephropathy. Clin. Proteom. 16, 33 (2019). DOI

Qin, X. et al. Glycation inactivation of the complement regulatory protein CD59: a possible role in the pathogenesis of the vascular complications of human diabetes. Diabetes 53, 2653–2661 (2004). PubMed DOI

Acosta, J. et al. Molecular basis for a link between complement and the vascular complications of diabetes. Proc. Natl Acad. Sci. USA 97, 5450–5455 (2000). PubMed DOI PMC

Ghosh, P. et al. Plasma glycated CD59, a novel biomarker for detection of pregnancy-induced glucose intolerance. Diabetes Care 40, 981–984 (2017). PubMed DOI PMC

Angeletti, A. et al. Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis. J. Exp. Med. https://doi.org/10.1084/jem.20191699 (2020). PubMed DOI PMC

Valoti, E. et al. Impact of a complement factor H gene variant on renal dysfunction, cardiovascular events, and response to ACE inhibitor therapy in type 2 diabetes. Front. Genet. 10, 681 (2019). PubMed DOI PMC

Kopp, J. B. et al. Podocytopathies. Nat. Rev. Dis. Prim. 6, 68 (2020). PubMed DOI

Zhang, Y. M. et al. Clinical significance of IgM and C3 glomerular deposition in primary focal segmental glomerulosclerosis. Clin. J. Am. Soc. Nephrol. 11, 1582–1589 (2016). PubMed DOI PMC

Trachtman, H. et al. Natural antibody and complement activation characterize patients with idiopathic nephrotic syndrome. Am. J. Physiol. Renal Physiol. 321, F505–F516 (2021). PubMed DOI PMC

Strassheim, D. et al. IgM contributes to glomerular injury in FSGS. J. Am. Soc. Nephrol. 24, 393–406 (2013). PubMed DOI PMC

van de Lest, N. A. et al. Glomerular C4d deposition can precede the development of focal segmental glomerulosclerosis. Kidney Int. 96, 738–749 (2019). PubMed DOI

Thurman, J. M. et al. Complement activation in patients with focal segmental glomerulosclerosis. PLoS One 10, e0136558 (2015). PubMed DOI PMC

Huang, J. et al. Complement activation profile of patients with primary focal segmental glomerulosclerosis. PLoS One 15, e0234934 (2020). PubMed DOI PMC

Lenderink, A. M. et al. The alternative pathway of complement is activated in the glomeruli and tubulointerstitium of mice with adriamycin nephropathy. Am. J. Physiol. Renal Physiol. 293, F555–F564 (2007). PubMed DOI

Turnberg, D. et al. Complement activation contributes to both glomerular and tubulointerstitial damage in adriamycin nephropathy in mice. J. Immunol. 177, 4094–4102 (2006). PubMed DOI

Hisano, S. et al. Clinicopathologic correlation and outcome of C1q nephropathy. Clin. J. Am. Soc. Nephrol. 3, 1637–1643 (2008). PubMed DOI PMC

Vizjak, A. et al. Pathology, clinical presentations, and outcomes of C1q nephropathy. J. Am. Soc. Nephrol. 19, 2237–2244 (2008). PubMed DOI PMC

Gunasekara, V. N., Sebire, N. J. & Tullus, K. C1q nephropathy in children: clinical characteristics and outcome. Pediatr. Nephrol. 29, 407–413 (2014). PubMed DOI

Thurman, J. M., Ljubanovic, D., Edelstein, C. L., Gilkeson, G. S. & Holers, V. M. Lack of a functional alternative complement pathway ameliorates ischemic acute renal failure in mice. J. Immunol. 170, 1517–1523 (2003). PubMed DOI

Thurman, J. M. et al. Altered renal tubular expression of the complement inhibitor Crry permits complement activation after ischemia/reperfusion. J. Clin. Invest. 116, 357–368 (2006). PubMed DOI PMC

Farrar, C. A. et al. Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury. J. Clin. Invest. 126, 1911–1925 (2016). PubMed DOI PMC

Boudhabhay, I. et al. Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis. Kidney Int. 99, 581–597 (2021). PubMed DOI

Merchant, M. L., Brier, M. E., Slaughter, M. S., Klein, J. B. & McLeish, K. R. Biomarker enhanced risk prediction for development of AKI after cardiac surgery. BMC Nephrol. 19, 102 (2018). PubMed DOI PMC

Laskowski, J., Philbrook, H. T., Parikh, C. R. & Thurman, J. M. Urine complement activation fragments are increased in patients with kidney injury after cardiac surgery. Am. J. Physiol. Renal Physiol. 317, F650–F657 (2019). PubMed DOI PMC

Mrug, M. et al. Overexpression of innate immune response genes in a model of recessive polycystic kidney disease. Kidney Int. 73, 63–76 (2008). PubMed DOI

Zhou, J. et al. Kidney injury accelerates cystogenesis via pathways modulated by heme oxygenase and complement. J. Am. Soc. Nephrol. 23, 1161–1171 (2012). PubMed DOI PMC

Mrug, M. et al. Complement C3 activation in cyst fluid and urine from autosomal dominant polycystic kidney disease patients. J. Intern. Med. 276, 539–540 (2014). PubMed DOI

Ichida, S., Yuzawa, Y., Okada, H., Yoshioka, K. & Matsuo, S. Localization of the complement regulatory proteins in the normal human kidney. Kidney Int. 46, 89–96 (1994). PubMed DOI

Cosio, F. G., Sedmak, D. D., Mahan, J. D. & Nahman, N. S. Jr. Localization of decay accelerating factor in normal and diseased kidneys. Kidney Int. 36, 100–107 (1989). PubMed DOI

Endoh, M. et al. Immunohistochemical demonstration of membrane cofactor protein (MCP) of complement in normal and diseased kidney tissues. Clin. Exp. Immunol. 94, 182–188 (1993). PubMed DOI PMC

Baker, P. J., Adler, S., Yang, Y. & Couser, W. G. Complement activation by heat-killed human kidney cells: formation, activity, and stabilization of cell-bound C3 convertases. J. Immunol. 133, 877–881 (1984). PubMed DOI

Tang, S., Sheerin, N. S., Zhou, W., Brown, Z. & Sacks, S. H. Apical proteins stimulate complement synthesis by cultured human proximal tubular epithelial cells. J. Am. Soc. Nephrol. 10, 69–76 (1999). PubMed DOI

Farrar, C. A., Zhou, W., Lin, T. & Sacks, S. H. Local extravascular pool of C3 is a determinant of postischemic acute renal failure. FASEB J. 20, 217–226 (2006). PubMed DOI

Roth, A. et al. Sutimlimab in cold agglutinin disease. N. Engl. J. Med. 384, 1323–1334 (2021). PubMed DOI

Hillmen, P. et al. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 384, 1028–1037 (2021). PubMed DOI

Harris, C. L. Expanding horizons in complement drug discovery: challenges and emerging strategies. Semin. Immunopathol. 40, 125–140 (2018). PubMed DOI

Stites, E., Le Quintrec, M. & Thurman, J. M. The complement system and antibody-mediated transplant rejection. J. Immunol. 195, 5525–5531 (2015). PubMed DOI

Khaled, S. K. et al. Narsoplimab, a Mannan-binding lectin-associated serine protease-2 inhibitor, for the treatment of adult hematopoietic stem-cell transplantation-associated thrombotic microangiopathy. J. Clin. Oncol. 40, 2447–2457 (2022). PubMed DOI PMC

Bomback, A. S. et al. Alternative complement pathway inhibition with iptacopan for the treatment of C3 glomerulopathy-study design of the APPEAR-C3G trial. Kidney Int. Rep. 7, 2150–2159 (2022). PubMed DOI PMC

Hasturk, H. et al. Phase IIa clinical trial of complement C3 inhibitor AMY-101 in adults with periodontal inflammation. J. Clin. Invest. https://doi.org/10.1172/JCI152973 (2021). PubMed DOI PMC

Li, C., Li, H., Wen, Y. B., Li, X. M. & Li, X. W. Analysis of predictive factors for immunosuppressive response in anti-phospholipase A2 receptor antibody positive membranous nephropathy. BMC Nephrol. 19, 354 (2018). PubMed DOI PMC

Bech, A. P., Hofstra, J. M., Brenchley, P. E. & Wetzels, J. F. Association of anti-PLA PubMed DOI PMC

Robson, J. et al. Glucocorticoid treatment and damage in the anti-neutrophil cytoplasm antibody-associated vasculitides: long-term data from the European Vasculitis Study Group trials. Rheumatology 54, 471–481 (2015). PubMed DOI

Stojan, G. & Petri, M. The risk benefit ratio of glucocorticoids in SLE: have things changed over the past 40 years? Curr. Treatm. Opt. Rheumatol. 3, 164–172 (2017). PubMed DOI PMC

Morigi, M. et al. C3a receptor blockade protects podocytes from injury in diabetic nephropathy. JCI Insight https://doi.org/10.1172/jci.insight.131849 (2020). PubMed DOI PMC

Carter, R. H., Spycher, M. O., Ng, Y. C., Hoffman, R. & Fearon, D. T. Synergistic interaction between complement receptor type 2 and membrane IgM on B lymphocytes. J. Immunol. 141, 457–463 (1988). PubMed DOI

Strainic, M. G., Shevach, E. M., An, F., Lin, F. & Medof, M. E. Absence of signaling into CD4 PubMed DOI

Heeger, P. S. et al. Decay-accelerating factor modulates induction of T cell immunity. J. Exp. Med. 201, 1523–1530 (2005). PubMed DOI PMC

Bomback, A. S. et al. Improving clinical trials for anticomplement therapies in complement-mediated glomerulopathies: report of a scientific workshop sponsored by the National Kidney Foundation. Am. J. Kidney Dis. 79, 570–581 (2022). PubMed DOI

Skattum, L., Martensson, U. & Sjoholm, A. G. Hypocomplementaemia caused by C3 nephritic factors (C3 NeF): clinical findings and the coincidence of C3 NeF type II with anti-C1q autoantibodies. J. Intern. Med. 242, 455–464 (1997). PubMed DOI

Thurman, J. M. & Fremeaux-Bacchi, V. Alternative pathway diagnostics. Immunol. Rev. 313, 225–238 (2023). PubMed DOI

Wyatt, R. J., Forristal, J., West, C. D., Sugimoto, S. & Curd, J. G. Complement profiles in acute post-streptococcal glomerulonephritis. Pediatr. Nephrol. 2, 219–223 (1988). PubMed DOI

Brenchley, P. E. et al. Urinary C3dg and C5b-9 indicate active immune disease in human membranous nephropathy. Kidney Int. 41, 933–937 (1992). PubMed DOI

Coupes, B. M., Kon, S. P., Brenchley, P. E., Short, C. D. & Mallick, N. P. The temporal relationship between urinary C5b-9 and C3dg and clinical parameters in human membranous nephropathy. Nephrol. Dial. Transplant. 8, 397–401 (1993). PubMed

Fakhouri, F. et al. Eculizumab discontinuation in children and adults with atypical hemolytic-uremic syndrome: a prospective multicenter study. Blood 137, 2438–2449 (2021). PubMed DOI

Hill, G. S., Hinglais, N., Tron, F. & Bach, J. F. Systemic lupus erythematosus. Morphologic correlations with immunologic and clinical data at the time of biopsy. Am. J. Med. 64, 61–79 (1978). PubMed DOI

Drachenberg, C. B. et al. Epidemiology and pathophysiology of glomerular C4d staining in native kidney biopsies. Kidney Int. Rep. 4, 1555–1567 (2019). PubMed DOI PMC

Fremeaux-Bacchi, V. et al. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin. J. Am. Soc. Nephrol. 8, 554–562 (2013). PubMed DOI PMC

Caprioli, J. et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108, 1267–1279 (2006). PubMed DOI PMC

Le Quintrec, M. et al. Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome. Am. J. Transplant. 13, 663–675 (2013). PubMed DOI

Renner, B. et al. Annexin A2 enhances complement activation by inhibiting factor H. J. Immunol. 196, 1355–1365 (2016). PubMed DOI

Noris, M. et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin. J. Am. Soc. Nephrol. 5, 1844–1859 (2010). PubMed DOI PMC

Karasu, E., Eisenhardt, S. U., Harant, J. & Huber-Lang, M. Extracellular vesicles: packages sent with complement. Front. Immunol. 9, 721 (2018). PubMed DOI PMC

Sethi, S. K. et al. Eculizumab for atypical hemolytic-uremic syndrome in India: first report from India and the challenges faced. Indian J. Nephrol. 27, 58–61 (2017). PubMed DOI PMC

Sridharan, M., Go, R. S. & Willrich, M. A. V. Clinical utility and potential cost savings of pharmacologic monitoring of eculizumab for complement-mediated thrombotic microangiopathy. Mayo Clin. Proc. Innov. Qual. Outcomes 6, 458–464 (2022). PubMed DOI PMC

Fakhouri, F., Zuber, J., Fremeaux-Bacchi, V. & Loirat, C. Haemolytic uraemic syndrome. Lancet 390, 681–696 (2017). PubMed DOI

Smith, R. J. H. et al. C3 glomerulopathy — understanding a rare complement-driven renal disease. Nat. Rev. Nephrol. 15, 129–143 (2019). PubMed DOI PMC

Yan, K., Desai, K., Gullapalli, L., Druyts, E. & Balijepalli, C. Epidemiology of atypical hemolytic uremic syndrome: a systematic literature review. Clin. Epidemiol. 12, 295–305 (2020). PubMed DOI PMC

Smith, R. J. et al. New approaches to the treatment of dense deposit disease. J. Am. Soc. Nephrol. 18, 2447–2456 (2007). PubMed DOI

Kavanagh, D., Goodship, T. H. & Richards, A. Atypical hemolytic uremic syndrome. Semin. Nephrol. 33, 508–530 (2013). PubMed DOI PMC

Nasr, S. H. et al. Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Clin. J. Am. Soc. Nephrol. 4, 22–32 (2009). PubMed DOI PMC

Fakhouri, F. et al. Insights from the use in clinical practice of eculizumab in adult patients with atypical hemolytic uremic syndrome affecting the native kidneys: an analysis of 19 cases. Am. J. Kidney Dis. 63, 40–48 (2014). PubMed DOI

Zuber, J. et al. New insights into postrenal transplant hemolytic uremic syndrome. Nat. Rev. Nephrol. 7, 23–35 (2011). PubMed DOI

Misra, A., Peethambaram, A. & Garg, A. Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature. Medicine 83, 18–34 (2004). PubMed DOI

Dalvin, L. A., Fervenza, F. C., Sethi, S. & Pulido, J. S. Shedding light on Fundus Drusen Associated with Membranoproliferative Glomerulonephritis: breaking stereotypes of types I, II, and III. Retin. Cases Brief. Rep. https://doi.org/10.1097/ICB.0000000000000164 (2015). DOI

Noris, M. et al. Dynamics of complement activation in aHUS and how to monitor eculizumab therapy. Blood 124, 1715–1726 (2014). PubMed DOI PMC

Chauvet, S. et al. Results from a national-wide retrospective cohort measure the impact of C3 and soluble C5b-9 levels on kidney outcomes in C3 glomerulopathy. Kidney Int. https://doi.org/10.1016/j.kint.2022.05.027 (2022). PubMed DOI PMC

Zhang, Y. et al. Factor H autoantibodies and complement-mediated diseases. Front. Immunol. 11, 607211 (2020). PubMed DOI PMC

Corvillo, F. et al. Nephritic factors: an overview of classification, diagnostic tools and clinical associations. Front. Immunol. 10, 886 (2019). PubMed DOI PMC

Chauvet, S. et al. Both monoclonal and polyclonal immunoglobulin contingents mediate complement activation in monoclonal gammopathy associated-C3 glomerulopathy. Front. Immunol. 9, 2260 (2018). PubMed DOI PMC

Schubart, A. et al. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc. Natl Acad. Sci. USA 116, 7926–7931 (2019). PubMed DOI PMC

Zelek, W. M., Xie, L., Morgan, B. P. & Harris, C. L. Compendium of current complement therapeutics. Mol. Immunol. 114, 341–352 (2019). PubMed DOI