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A clinical approach to children with C3 glomerulopathy

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Abstract

C3 glomerulopathy is a relatively new clinical entity that represents a challenge both to diagnose and to treat. As new therapeutic agents that act as complement inhibitors become available, many with an oral formulation, a better understanding of this disease and of the underlying complement dysregulation driving it has become increasingly useful to optimize patient care. Moreover, recent advances in research have clarified the role of complement in other glomerular diseases in which its role was less established, namely in immune-complex membranoproliferative glomerulonephritis (IC-MPGN), ANCA-vasculitis, IgA nephropathy, and idiopathic membranous nephropathy. Complement inhibitors are being studied in adult and adolescent clinical trials for these indications. This review summarizes current knowledge and future perspectives on every aspect of the diagnosis and management of C3 glomerulopathy and elucidates current understanding of the role of complement in this condition and in other glomerular diseases in children. An overview of ongoing trials involving therapeutic agents targeting complement in glomerular diseases is also provided.

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References

  1. Bao L, Cunningham PN, Quigg RJ (2015) Complement in lupus nephritis: new perspectives. Kidney Dis (Basel) 1:91–99

  2. Chen M, Jayne DRW, Zhao M-H (2017) Complement in ANCA-associated vasculitis: mechanisms and implications for management. Nat Rev Nephrol 13:359–367

    Article  CAS  PubMed  Google Scholar 

  3. Brglez V, Boyer-Suavet S, Seitz-Polski B (2020) Complement pathways in membranous nephropathy: complex and multifactorial. Kidney Int Rep 5:572–574

    Article  PubMed  PubMed Central  Google Scholar 

  4. Maillard N, Wyatt RJ, Julian BA, Kiryluk K, Gharavi A, Fremeaux-Bacchi V, Novak J (2015) Current understanding of the role of complement in IgA nephropathy. J Am Soc Nephrol 26:1503–1512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chauvet S, Berthaud R, Devriese M, Mignotet M, Vieira Martins P, Robe-Rybkine T, Miteva MA, Gyulkhandanyan A, Ryckewaert A, Louillet F, Merieau E, Mestrallet G, Rousset-Rouviere C, Thervet E, Hogan J, Ulinski T, Villoutreix BO, Roumenina L, Boyer O, Fremeaux-Bacchi V (2020) Anti-factor B antibodies and acute postinfectious GN in children. J Am Soc Nephrol 31:829–840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zipfel PF, Wiech T, Rudnick R, Afonso S, Person F, Skerka C (2019) Complement inhibitors in clinical trials for glomerular diseases. Front Immunol 10:2166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT (2015) Complement system part I — molecular mechanisms of activation and regulation. Front Immunol 6:262

    Article  PubMed  PubMed Central  Google Scholar 

  8. Garred P, Genster N, Pilely K, Bayarri-Olmos R, Rosbjerg A, Ma YJ, Skjoedt MO (2016) A journey through the lectin pathway of complement-MBL and beyond. Immunol Rev 274:74–97

    Article  CAS  PubMed  Google Scholar 

  9. Endo M, Ohi H, Ohsawa I, Fujita T, Matsushita M, Fujita T (1998) Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy. Nephrol Dial Transplant 13:1984–1990

    Article  CAS  PubMed  Google Scholar 

  10. Roos A, Rastaldi MP, Calvaresi N, Oortwijn BD, Schlagwein N, van Gijlswijk-Janssen DJ, Stahl GL, Matsushita M, Fujita T, van Kooten C, Daha MR (2006) 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

    Article  CAS  PubMed  Google Scholar 

  11. Ma H, Sandor DG, Beck LH Jr (2013) The role of complement in membranous nephropathy. Semin Nephrol 33:531–542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ozaki M, Kang Y, Tan YS, Pavlov VI, Liu B, Boyle DC, Kushak RI, Skjoedt MO, Grabowski EF, Taira Y, Stahl GL (2016) Human mannose-binding lectin inhibitor prevents Shiga toxin-induced renal injury. Kidney Int 90:774–782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Smith RJH, Appel GB, Blom AM, Cook HT, D'Agati VD, Fakhouri F, Fremeaux-Bacchi V, Jozsi M, Kavanagh D, Lambris JD, Noris M, Pickering MC, Remuzzi G, de Cordoba SR, Sethi S, Van der Vlag J, Zipfel PF, Nester CM (2019) C3 glomerulopathy - understanding a rare complement-driven renal disease. Nat Rev Nephrol 15:129–143

    Article  PubMed  PubMed Central  Google Scholar 

  14. Goodship TH, Cook HT, Fakhouri F, Fervenza FC, Fremeaux-Bacchi V, Kavanagh D, Nester CM, Noris M, Pickering MC, Rodriguez de Cordoba S, Roumenina LT, Sethi S, Smith RJ, Conference P (2017) Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int 91:539–551

    Article  CAS  PubMed  Google Scholar 

  15. Bally S, Debiec H, Ponard D, Dijoud F, Rendu J, Faure J, Ronco P, Dumestre-Perard C (2016) Phospholipase A2 receptor-related membranous nephropathy and mannan-binding lectin deficiency. J Am Soc Nephrol 27:3539–3544

    Article  PubMed  PubMed Central  Google Scholar 

  16. Gou SJ, Yuan J, Wang C, Zhao MH, Chen M (2013) Alternative complement pathway activation products in urine and kidneys of patients with ANCA-associated GN. Clin J Am Soc Nephrol 8:1884–1891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Xiao H, Schreiber A, Heeringa P, Falk RJ, Jennette JC (2007) Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies. Am J Pathol 170:52–64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Thurman JM, Ljubanovic D, Edelstein CL, Gilkeson GS, Holers VM (2003) Lack of a functional alternative complement pathway ameliorates ischemic acute renal failure in mice. J Immunol 170:1517–1523

    Article  CAS  PubMed  Google Scholar 

  19. Strainic MG, Shevach EM, An F, Lin F, Medof ME (2013) Absence of signaling into CD4(+) cells via C3aR and C5aR enables autoinductive TGF-beta1 signaling and induction of Foxp3(+) regulatory T cells. Nat Immunol 14:162–171

    Article  CAS  PubMed  Google Scholar 

  20. Jayne DRW, Bruchfeld AN, Harper L, Schaier M, Venning MC, Hamilton P, Burst V, Grundmann F, Jadoul M, Szombati I, Tesar V, Segelmark M, Potarca A, Schall TJ, Bekker P, CLEAR Study Group (2017) Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J Am Soc Nephrol 28:2756–2767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jayne DRW, Merkel PA, Schall TJ, Bekker P, ADVOCATE Study (2021) Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med 384:599–609

    Article  CAS  PubMed  Google Scholar 

  22. Baker PJ, Ochi RF, Schulze M, Johnson RJ, Campbell C, Couser WG (1989) Depletion of C6 prevents development of proteinuria in experimental membranous nephropathy in rats. Am J Pathol 135:185–194

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Takano T, Cybulsky AV, Yang X, Aoudjit L (2001) Complement C5b-9 induces cyclooxygenase-2 gene transcription in glomerular epithelial cells. Am J Physiol Ren Physiol 281:F841–F850

    Article  CAS  Google Scholar 

  24. Pickering MC, Cook HT, Warren J, Bygrave AE, Moss J, Walport MJ, Botto M (2002) Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat Genet 31:424–428

    Article  CAS  PubMed  Google Scholar 

  25. Athanasiou Y, Voskarides K, Gale DP, Damianou L, Patsias C, Zavros M, Maxwell PH, Cook HT, Demosthenous P, Hadjisavvas A, Kyriacou K, Zouvani I, Pierides A, Deltas C (2011) Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees. Clin J Am Soc Nephrol 6:1436–1446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bu F, Borsa NG, Jones MB, Takanami E, Nishimura C, Hauer JJ, Azaiez H, Black-Ziegelbein EA, Meyer NC, Kolbe DL, Li Y, Frees K, Schnieders MJ, Thomas C, Nester C, Smith RJH (2015) High-Throughput genetic testing for thrombotic microangiopathies and C3 glomerulopathies. J Am Soc Nephrol 27:1245–1253

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chen Q, Wiesener M, Eberhardt HU, Hartmann A, Uzonyi B, Kirschfink M, Amann K, Buettner M, Goodship T, Hugo C, Skerka C, Zipfel PF (2014) Complement factor H-related hybrid protein deregulates complement in dense deposit disease. J Clin Invest 124:145–155

    Article  CAS  PubMed  Google Scholar 

  28. Gale DP, de Jorge EG, Cook HT, Martinez-Barricarte R, Hadjisavvas A, McLean AG, Pusey CD, Pierides A, Kyriacou K, Athanasiou Y, Voskarides K, Deltas C, Palmer A, Fremeaux-Bacchi V, de Cordoba SR, Maxwell PH, Pickering MC (2010) Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. Lancet 376:794–801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Malik TH, Lavin PJ, Goicoechea de Jorge E, Vernon KA, Rose KL, Patel MP, de Leeuw M, Neary JJ, Conlon PJ, Winn MP, Pickering MC (2012) A hybrid CFHR3-1 gene causes familial C3 glomerulopathy. J Am Soc Nephrol 23:1155–1160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Medjeral-Thomas N, Malik TH, Patel MP, Toth T, Cook HT, Tomson C, Pickering MC (2014) A novel CFHR5 fusion protein causes C3 glomerulopathy in a family without Cypriot ancestry. Kidney Int 85:933–937

    Article  CAS  PubMed  Google Scholar 

  31. Tortajada A, Yebenes H, Abarrategui-Garrido C, Anter J, Garcia-Fernandez JM, Martinez-Barricarte R, Alba-Dominguez M, Malik TH, Bedoya R, Cabrera Perez R, Lopez Trascasa M, Pickering MC, Harris CL, Sanchez-Corral P, Llorca O, Rodriguez de Cordoba S (2013) C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation. J Clin Invest 123:2434–2446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Corvillo F, Okroj M, Nozal P, Melgosa M, Sanchez-Corral P, Lopez-Trascasa M (2019) Nephritic factors: an overview of classification, diagnostic tools and clinical associations. Front Immunol 10:886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Daha MR, Fearon DT, Austen KF (1976) C3 nephritic factor (C3NeF): stabilization of fluid phase and cell-bound alternative pathway convertase. J Immunol 116:1–7

    Article  CAS  PubMed  Google Scholar 

  34. Licht C, Schlotzer-Schrehardt U, Kirschfink M, Zipfel PF, Hoppe B (2007) MPGN II--genetically determined by defective complement regulation? Pediatr Nephrol 22:2–9

    Article  PubMed  Google Scholar 

  35. Walker PD, Ferrario F, Joh K, Bonsib SM (2007) Dense deposit disease is not a membranoproliferative glomerulonephritis. Mod Pathol 20:605–616

    Article  PubMed  Google Scholar 

  36. Servais A, Fremeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J, Knebelmann B, Grunfeld JP, Lesavre P, Noel LH, Fakhouri F (2007) 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

    Article  CAS  PubMed  Google Scholar 

  37. Sethi S, Gamez JD, Vrana JA, Theis JD, Bergen HR 3rd, Zipfel PF, Dogan A, Smith RJ (2009) Glomeruli of Dense Deposit Disease contain components of the alternative and terminal complement pathway. Kidney Int 75:952–960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Pickering MC, D'Agati VD, Nester CM, Smith RJ, Haas M, Appel GB, Alpers CE, Bajema IM, Bedrosian C, Braun M, Doyle M, Fakhouri F, Fervenza FC, Fogo AB, Fremeaux-Bacchi V, Gale DP, Goicoechea de Jorge E, Griffin G, Harris CL, Holers VM, Johnson S, Lavin PJ, Medjeral-Thomas N, Paul Morgan B, Nast CC, Noel LH, Peters DK, Rodriguez de Cordoba S, Servais A, Sethi S, Song WC, Tamburini P, Thurman JM, Zavros M, Cook HT (2013) C3 glomerulopathy: consensus report. Kidney Int 84:1079–1089

    Article  PubMed  PubMed Central  Google Scholar 

  39. Martin B, Smith RJH (2007) C3 glomerulopathy. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A (eds) GeneReviews((R)), Seattle (WA), pp 1993-2020

  40. Pınarbaşı AS, Dursun I, Gokce I, Çomak E, Saygılı S, Bayram MT, Donmez O, Melek E, Tekcan D, Çiçek N, Yılmaz D, Tabel Y, Yıldırım ZY, Bahat E, Koyun M, Soylu A, Canpolat N, Aksu B, Çelakıl ME, Taşdemir M, Benzer M, Özçelik G, Bakkaloğlu SA, Düşünsel R (2020) Predictors of poor kidney outcome in children with C3 glomerulopathy. Pediatr Nephrol 36:1195–1205

    Article  PubMed  Google Scholar 

  41. Khandelwal P, Bhardwaj S, Singh G, Sinha A, Hari P, Bagga A (2021) Therapy and outcomes of C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis. Pediatr Nephrol 36:591–600

    Article  PubMed  Google Scholar 

  42. Iatropoulos P, Noris M, Mele C, Piras R, Valoti E, Bresin E, Curreri M, Mondo E, Zito A, Gamba S, Bettoni S, Murer L, Fremeaux-Bacchi V, Vivarelli M, Emma F, Daina E, Remuzzi G (2016) Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome. Mol Immunol 71:131–142

    Article  CAS  PubMed  Google Scholar 

  43. Regunathan-Shenk R, Avasare RS, Ahn W, Canetta PA, Cohen DJ, Appel GB, Bomback AS (2019) Kidney transplantation in C3 glomerulopathy: a case series. Am J Kidney Dis 73:316–323

    Article  PubMed  Google Scholar 

  44. Iatropoulos P, Daina E, Curreri M, Piras R, Valoti E, Mele C, Bresin E, Gamba S, Alberti M, Breno M, Perna A, Bettoni S, Sabadini E, Murer L, Vivarelli M, Noris M, Remuzzi G, Registry of Membranoproliferative Glomerulonephritis /C3 Glomerulopathy, Nastasi (2018) Cluster analysis identifies distinct pathogenetic patterns in C3 glomerulopathies/immune complex-mediated membranoproliferative GN. J Am Soc Nephrol 29:283–294

    Article  CAS  PubMed  Google Scholar 

  45. Servais A, Noel LH, Roumenina LT, Le Quintrec M, Ngo S, Dragon-Durey MA, Macher MA, Zuber J, Karras A, Provot F, Moulin B, Grunfeld JP, Niaudet P, Lesavre P, Fremeaux-Bacchi V (2012) Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int 82:454–464

    Article  CAS  PubMed  Google Scholar 

  46. Sethi S, Nasr SH, De Vriese AS, Fervenza FC (2015) C4d as a diagnostic tool in proliferative GN. J Am Soc Nephrol 26:2852–2859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bouatou Y, Kers J, Chevalier-Florquin MSN, Claessen N, Nguyen TQ, Damman J, Proenca H, Roelofs J, Florquin S (2018) Diagnostic accuracy of immunofluorescence versus immunoperoxidase staining to distinguish immune complex-mediated glomerulonephritis and C3 dominant glomerulopathy. Histopathology 72:601–608

    Article  PubMed  Google Scholar 

  48. Gupta N, Wakefield DN, Clapp WL, Garin EH (2017) Use of C4d as a diagnostic tool to classify membranoproliferative glomerulonephritis. Nefrologia 37:78–86

    Article  PubMed  Google Scholar 

  49. Singh G, Singh SK, Nalwa A, Singh L, Pradeep I, Barwad A, Sinha A, Hari P, Bagga A, Bagchi S, Agarwal SK, Dinda AK (2019) Glomerular C4d staining does not exclude a C3 glomerulopathy. Kidney Int Rep 4:698–709

    Article  PubMed  PubMed Central  Google Scholar 

  50. Medjeral-Thomas NR, O'Shaughnessy MM, O'Regan JA, Traynor C, Flanagan M, Wong L, Teoh CW, Awan A, Waldron M, Cairns T, O'Kelly P, Dorman AM, Pickering MC, Conlon PJ, Cook HT (2014) C3 glomerulopathy: clinicopathologic features and predictors of outcome. Clin J Am Soc Nephrol 9:46–53

    Article  CAS  PubMed  Google Scholar 

  51. Zhang Y, Nester CM, Martin B, Skjoedt MO, Meyer NC, Shao D, Borsa N, Palarasah Y, Smith RJ (2014) Defining the complement biomarker profile of c3 glomerulopathy. Clin J Am Soc Nephrol 9:1876–1882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Noris M, Donadelli R, Remuzzi G (2019) Autoimmune abnormalities of the alternative complement pathway in membranoproliferative glomerulonephritis and C3 glomerulopathy. Pediatr Nephrol 34:1311–1323

    Article  PubMed  Google Scholar 

  53. Garam N, Prohaszka Z, Szilagyi A, Aigner C, Schmidt A, Gaggl M, Sunder-Plassmann G, Bajcsi D, Brunner J, Dumfarth A, Cejka D, Flaschberger S, Flogelova H, Haris A, Hartmann A, Heilos A, Mueller T, Rusai K, Arbeiter K, Hofer J, Jakab D, Sinko M, Szigeti E, Bereczki C, Janko V, Kelen K, Reusz GS, Szabo AJ, Klenk N, Kobor K, Kojc N, Knechtelsdorfer M, Laganovic M, Lungu AC, Meglic A, Rus R, Kersnik-Levart T, Macioniene E, Miglinas M, Pawlowska A, Stompor T, Podracka L, Rudnicki M, Mayer G, Romana R, Reiterova J, Saraga M, Tomas S, Zieg J, Sladkova E, Szabo T, Capitanescu A, Stancu S, Tisljar M, Galesic K, Tisler A, Vainumae I, Windpessl M, Zaoral T, Zlatanova G, Csuka D (2019) C4 nephritic factor in patients with immune-complex-mediated membranoproliferative glomerulonephritis and C3-glomerulopathy. Orphanet J Rare Dis 14:247

    Article  PubMed  PubMed Central  Google Scholar 

  54. Marinozzi MC, Chauvet S, Le Quintrec M, Mignotet M, Petitprez F, Legendre C, Cailliez M, Deschenes G, Fischbach M, Karras A, Nobili F, Pietrement C, Dragon-Durey MA, Fakhouri F, Roumenina LT, Fremeaux-Bacchi V (2017) C5 nephritic factors drive the biological phenotype of C3 glomerulopathies. Kidney Int 92:1232–1241

    Article  CAS  PubMed  Google Scholar 

  55. Blanc C, Togarsimalemath SK, Chauvet S, Le Quintrec M, Moulin B, Buchler M, Jokiranta TS, Roumenina LT, Fremeaux-Bacchi V, Dragon-Durey MA (2015) Anti-factor H autoantibodies in C3 glomerulopathies and in atypical hemolytic uremic syndrome: one target, two diseases. J Immunol 194:5129–5138

    Article  CAS  PubMed  Google Scholar 

  56. Goodship TH, Pappworth IY, Toth T, Denton M, Houlberg K, McCormick F, Warland D, Moore I, Hunze EM, Staniforth SJ, Hayes C, Cavalcante DP, Kavanagh D, Strain L, Herbert AP, Schmidt CQ, Barlow PN, Harris CL, Marchbank KJ (2012) Factor H autoantibodies in membranoproliferative glomerulonephritis. Mol Immunol 52:200–206

    Article  CAS  PubMed  Google Scholar 

  57. Chen Q, Muller D, Rudolph B, Hartmann A, Kuwertz-Broking E, Wu K, Kirschfink M, Skerka C, Zipfel PF (2011) Combined C3b and factor B autoantibodies and MPGN type II. N Engl J Med 365:2340–2342

    Article  CAS  PubMed  Google Scholar 

  58. Prohaszka Z, Nilsson B, Frazer-Abel A, Kirschfink M (2016) Complement analysis 2016: Clinical indications, laboratory diagnostics and quality control. Immunobiology 221:1247–1258

    Article  CAS  PubMed  Google Scholar 

  59. Licht C, Heinen S, Jozsi M, Loschmann I, Saunders RE, Perkins SJ, Waldherr R, Skerka C, Kirschfink M, Hoppe B, Zipfel PF (2006) Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II). Kidney Int 70:42–50

    Article  CAS  PubMed  Google Scholar 

  60. Imamura H, Konomoto T, Tanaka E, Hisano S, Yoshida Y, Fujimura Y, Miyata T, Nunoi H (2015) Familial C3 glomerulonephritis associated with mutations in the gene for complement factor B. Nephrol Dial Transplant 30:862–864

    Article  CAS  PubMed  Google Scholar 

  61. Martinez-Barricarte R, Heurich M, Valdes-Canedo F, Vazquez-Martul E, Torreira E, Montes T, Tortajada A, Pinto S, Lopez-Trascasa M, Morgan BP, Llorca O, Harris CL, Rodriguez de Cordoba S (2010) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Rabasco C, Cavero T, Roman E, Rojas-Rivera J, Olea T, Espinosa M, Cabello V, Fernandez-Juarez G, Gonzalez F, Avila A, Baltar JM, Diaz M, Alegre R, Elias S, Anton M, Frutos MA, Pobes A, Blasco M, Martin F, Bernis C, Macias M, Barroso S, de Lorenzo A, Ariceta G, Lopez-Mendoza M, Rivas B, Lopez-Revuelta K, Campistol JM, Mendizabal S, de Cordoba SR, Praga M, Spanish Group for the Study of Glomerular Disease (2015) Effectiveness of mycophenolate mofetil in C3 glomerulonephritis. Kidney Int 88:1153–1160

    Article  CAS  PubMed  Google Scholar 

  63. Levine AP, Chan MMY, Sadeghi-Alavijeh O, Wong EKS, Cook HT, Ashford S, Carss K, Christian MT, Hall M, Harris CL, McAlinden P, Marchbank KJ, Marks SD, Maxwell H, Megy K, Penkett CJ, Mozere M, Stirrups KE, Tuna S, Wessels J, Whitehorn D, MPGN/DDD/C3 Glomerulopathy Rare Disease Group; NIHR BioResource; Johnson SA, Gale DP (2020) Large-scale whole-genome sequencing reveals the genetic architecture of primary membranoproliferative GN and C3 glomerulopathy. J Am Soc Nephrol 31:365–373

  64. Caravaca-Fontan F, Diaz-Encarnacion MM, Lucientes L, Cavero T, Cabello V, Ariceta G, Quintana LF, Marco H, Barros X, Ramos N, Rodriguez-Mendiola N, Cruz S, Fernandez-Juarez G, Rodriguez A, Perez de Jose A, Rabasco C, Rodado R, Fernandez L, Perez Gomez V, Avila AI, Bravo L, Lumbreras J, Allende N, Sanchez de la Nieta MD, Rodriguez E, Olea T, Melgosa M, Huerta A, Miquel R, Mon C, Fraga G, de Lorenzo A, Draibe J, Cano-Megias M, Gonzalez F, Shabaka A, Lopez-Rubio ME, Fenollosa MA, Martin-Penagos L, Da Silva I, Alonso Titos J, Rodriguez de Cordoba S, Goicoechea de Jorge E, Praga M, Spanish Group for the Study of Glomerular Diseases GLOSEN (2020) Mycophenolate mofetil in C3 glomerulopathy and pathogenic drivers of the disease. Clin J Am Soc Nephrol 15:1287–1298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bomback AS, Smith RJ, Barile GR, Zhang Y, Heher EC, Herlitz L, Stokes MB, Markowitz GS, D'Agati VD, Canetta PA, Radhakrishnan J, Appel GB (2012) Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin J Am Soc Nephrol 7:748–756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gurkan S, Fyfe B, Weiss L, Xiao X, Zhang Y, Smith RJ (2013) Eculizumab and recurrent C3 glomerulonephritis. Pediatr Nephrol 28:1975–1981

    Article  PubMed  PubMed Central  Google Scholar 

  67. Le Quintrec M, Lionet A, Kandel C, Bourdon F, Gnemmi V, Colombat M, Goujon JM, Fremeaux-Bacchi V, Fakhouri F (2015) Eculizumab for treatment of rapidly progressive C3 glomerulopathy. Am J Kidney Dis 65:484–489

    Article  PubMed  Google Scholar 

  68. Le Quintrec M, Lapeyraque AL, Lionet A, Sellier-Leclerc AL, Delmas Y, Baudouin V, Daugas E, Decramer S, Tricot L, Cailliez M, Dubot P, Servais A, Mourey-Epron C, Pourcine F, Loirat C, Fremeaux-Bacchi V, Fakhouri F (2018) Patterns of clinical response to eculizumab in patients with C3 glomerulopathy. Am J Kidney Dis 72:84–92

    Article  PubMed  Google Scholar 

  69. Oosterveld MJS, Garrelfs MR, Hoppe B, Florquin S, Roelofs JJTH, van den Heuvel LP, Amann K, Davin J-C, Bouts AHM, Schriemer PJ, Groothoff JW (2015) Eculizumab in pediatric dense deposit disease. Clin J Am Soc Nephrol 10:1773–1782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ruggenenti P, Daina E, Gennarini A, Carrara C, Gamba S, Noris M, Rubis N, Peraro F, Gaspari F, Pasini A, Rigotti A, Lerchner RM, Santoro D, Pisani A, Pasi A, Remuzzi G, EAGLE Study Group (2019) C5 convertase blockade in membranoproliferative glomerulonephritis: a single-arm clinical trial. Am J Kidney Dis 74:224–238

    Article  CAS  PubMed  Google Scholar 

  71. Welte T, Arnold F, Kappes J, Seidl M, Haffner K, Bergmann C, Walz G, Neumann-Haefelin E (2018) Treating C3 glomerulopathy with eculizumab. BMC Nephrol 19:7

    Article  PubMed  PubMed Central  Google Scholar 

  72. Konar M, Granoff DM (2017) Eculizumab treatment and impaired opsonophagocytic killing of meningococci by whole blood from immunized adults. Blood 130:891–899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Thurman JM, Lucia MS, Ljubanovic D, Holers VM (2005) Acute tubular necrosis is characterized by activation of the alternative pathway of complement. Kidney Int 67:524–530

    Article  CAS  PubMed  Google Scholar 

  74. Trouw LA, Seelen MA, Daha MR (2003) Complement and renal disease. Mol Immunol 40:125–134

    Article  CAS  PubMed  Google Scholar 

  75. Clynes R, Dumitru C, Ravetch JV (1998) Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science 279:1052–1054

    Article  CAS  PubMed  Google Scholar 

  76. Hawlisch H, Belkaid Y, Baelder R, Hildeman D, Gerard C, Kohl J (2005) C5a negatively regulates toll-like receptor 4-induced immune responses. Immunity 22:415–426

    Article  CAS  PubMed  Google Scholar 

  77. Zhang X, Kimura Y, Fang C, Zhou L, Sfyroera G, Lambris JD, Wetsel RA, Miwa T, Song WC (2007) Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo. Blood 110:228–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Carter RH, Fearon DT (1989) Polymeric C3dg primes human B lymphocytes for proliferation induced by anti-IgM. J Immunol 143:1755–1760

    Article  CAS  PubMed  Google Scholar 

  79. Clarke EV, Tenner AJ (2014) Complement modulation of T cell immune responses during homeostasis and disease. J Leukoc Biol 96:745–756

    Article  PubMed  PubMed Central  Google Scholar 

  80. Rizk DV, Maillard N, Julian BA, Knoppova B, Green TJ, Novak J, Wyatt RJ (2019) The Emerging role of complement proteins as a target for therapy of IgA nephropathy. Front Immunol 10:504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Corvillo F, Bravo Garcia-Morato M, Nozal P, Garrido S, Tortajada A, Rodriguez de Cordoba S, Lopez-Trascasa M (2016) Serum properdin consumption as a biomarker of C5 convertase dysregulation in C3 glomerulopathy. Clin Exp Immunol 184:118–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Prof Christoph Licht for conceptual help in designing Fig. 3.

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Authors and Affiliations

  1. Division of Nephrology and Dialysis, Department of Pediatric Subspecialties, Bambino Gesù Pediatric Hospital IRCCS, Piazza S Onofrio 4, 00165, Rome, Italy

    Marina Vivarelli & Raffaella Labbadia

  2. Department of Pediatric Nephrology, Amalia Children’s Hospital, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands

    Nicole van de Kar

  3. Pathology Unit, Department of Laboratories, Bambino Gesù Pediatric Hospital IRCCS, Rome, Italy

    Francesca Diomedi-Camassei

  4. Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA

    Joshua M. Thurman

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  1. Marina Vivarelli
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  2. Nicole van de Kar
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  3. Raffaella Labbadia
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  4. Francesca Diomedi-Camassei
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  5. Joshua M. Thurman
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All authors participated in the preparation of the manuscript and concur with submission.

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Correspondence to Marina Vivarelli.

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Competing interests

MV received funding from the Associazione per la cura del Bambino Nefropatico ONLUS and has served on advisory boards for Novartis, Apellis, Roche, Achillion, Retrophin and participated in the C3G clinical trials by Chemocentrix and Achillion. NK is member of the advisory board of Roche and participant in the clinical trials in C3G by Chemocentryx and Achillion. RL and FD: no funding or conflict of interest to report. JMT receives royalties from Alexion Pharmaceuticals, Inc. and is a consultant for Q32 Bio, Inc., a company developing complement inhibitors. He also holds stock and will receive royalty income from Q32 Bio, Inc. This does not influence the content of this manuscript.

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1. d; 2. b; 3. c; 4. a; 5. c

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Vivarelli, M., van de Kar, N., Labbadia, R. et al. A clinical approach to children with C3 glomerulopathy. Pediatr Nephrol 37, 521–535 (2022). https://doi.org/10.1007/s00467-021-05088-7

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