Complement Activation

  • Isao OhsawaEmail author


The complement system has devastating effects on several forms of glomerulonephritis. Although the pathogenesis of IgA nephropathy (IgAN) has heterogeneity, ample studies have clearly demonstrated that the alternative and lectin pathways act as an enhancer of glomerular damage. However, certain ligands of starter molecules in these two pathways are not yet identified. On the other hand, the clinical progress of IgAN is often more than a decade, with the patients’ nutritional status fluctuating. An excess of nutrition might exacerbate the natural course of IgAN. Actually, serum levels of C3 fluctuate with not only disease activity but also metabolic parameters. Concomitant with recent genetic analysis, we can deduce that the gene mutations of complement components and regulatory proteins affect disease progression. Mannose-binding lectin (MBL) deficiency is very common in a normal population, but conversely, patients with sufficient MBL have a risk for a worse prognosis of IgAN. This review documents contemporary information concerning the possible role of the complement system in the pathogenesis of IgAN.


Alternative pathway Factor H Complement factor H-related (CFHR) proteins Lectin pathway Mannose-binding lectin (MBL) 


Conflict of Interest

The author declares that he has no conflict of interest.


  1. 1.
    Haas M. Histologic subclassification of IgA nephropathy: a clinicopathologic study of 244 cases. Am J Kidney Dis. 1997;29:829–42.CrossRefPubMedGoogle Scholar
  2. 2.
    Wyatt RJ, Julian BA. Activation of complement in IgA nephropathy. Am J Kidney Dis. 1988;12:437–42.CrossRefPubMedGoogle Scholar
  3. 3.
    Ermini L, Wilson I, Goodship T, Sheerin N. Complement polymorphisms: geographical distribution and relevance to disease. Immunobiology. 2012;217:265–71.CrossRefPubMedGoogle Scholar
  4. 4.
    Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11:785–97.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kemper C, Atkinson JP, Hourcade DE. Properdin: emerging roles of a pattern-recognition molecule. Annu Rev Immunol. 2009;28:131–55.CrossRefGoogle Scholar
  6. 6.
    Chen M, Daha MR, Kallenberg CG. The complement system in systemic autoimmune disease. J Autoimmun. 2010;34:J276–86.CrossRefPubMedGoogle Scholar
  7. 7.
    Zipfel PF, Skerka C. Complement regulators and inhibitory proteins. Nat Rev Immunol. 2009;9:729–40.PubMedGoogle Scholar
  8. 8.
    Noris M, Remuzzi G. Overview of complement activation and regulation. Semin Nephrol. 2013;33:479–92.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Nilsson B, Ekdahl KN. Complement diagnostics: concepts, indications, and practical guidelines. Clin Dev Immunol. 2012. doi: 10.1155/2012/962702.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Hauptmann G, Goetz J, Uring-Lambert B, Grosshans E. Component deficiencies: 2. Fourth Component. 1986;39:232–49.Google Scholar
  11. 11.
    Pettigrew HD, Teuber SS, Gershwin ME. Clinical significance of complement deficiencies. Ann N Y Acad Sci. 2009;1173:108–23.CrossRefPubMedGoogle Scholar
  12. 12.
    Dean M, Minchinton R, Heatley S, Eisen D. Mannose binding lectin acute phase activity in patients with severe infection. J Clin Immunol. 2005;25:346–52.CrossRefPubMedGoogle Scholar
  13. 13.
    Ohsawa I, Ohi H, Endo M, Fujita T, Kanmatsuse K, Nonaka M. Novel estimation of histologic activity in human glomerulonephritis by detection of complement component C3 messenger RNA. Clin Exp Nephrol. 1998;2:50–7.CrossRefGoogle Scholar
  14. 14.
    Sheerin NS, Risley P, Abe K, Tang Z, Wong W, Lin T, et al. Synthesis of complement protein C3 in the kidney is an important mediator of local tissue injury. FASEB J. 2008;22:1065–72.CrossRefPubMedGoogle Scholar
  15. 15.
    Tang S, Zhou W, Sheerin NS, Vaughan RW, Sacks SH. Contribution of renal secreted complement C3 to the circulating pool in humans. J Immunol. 1999;162:4336–41.PubMedGoogle Scholar
  16. 16.
    Cianflone K, Xia Z, Chen LY. Critical review of acylation-stimulating protein physiology in humans and rodents. Biochim Biophys Acta (BBA) Biomembr. 2003;1609:127–43.CrossRefGoogle Scholar
  17. 17.
    Ohsawa I, Inoshita H, Ishii M, Kusaba G, Sato N, Mano S, et al. Metabolic impact on serum levels of complement component 3 in Japanese patients. J Clin Lab Anal. 2010;24:113–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Sargur R, White P, Egner W. Cryoglobulin evaluation: best practice? Ann Clin Biochem. 2010;47(Pt 1):8–16.CrossRefPubMedGoogle Scholar
  19. 19.
    Nagamachi S, Ohsawa I, Sato N, Ishii M, Kusaba G, Kobayashi T, et al. Immune complex-mediated complement activation in a patient with IgG4-related tubulointerstitial nephritis. Case Rep Nephrol Urol. 2011;1:7–14.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Pickering MC, D’Agati VD, Nester CM, Smith RJ, Haas M, Appel GB, et al. C3 glomerulopathy: consensus report. Kidney Int. 2013;84:1079–89.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Tomino Y, Suzuki S, Imai H, Saito T, Kawamura T, Yorioka N, et al. Measurement of serum IgA and C3 may predict the diagnosis of patients with IgA nephropathy prior to renal biopsy. J Clin Lab Anal. 2000;14:220–3.CrossRefPubMedGoogle Scholar
  22. 22.
    Nakayama K, Ohsawa I, Maeda-Ohtani A, Murakoshi M, Horikoshi S, Tomino Y. Prediction of diagnosis of immunoglobulin A nephropathy prior to renal biopsy and correlation with urinary sediment findings and prognostic grading. J Clin Lab Anal. 2008;22:114–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Onda K, Ohi H, Tamano M, Ohsawa I, Wakabayashi M, Horikoshi S, et al. Hypercomplementemia in adult patients with IgA nephropathy. J Clin Lab Anal. 2007;21:77–84.CrossRefPubMedGoogle Scholar
  24. 24.
    Hiemstra PS, Gorter A, Stuurman ME, Van Es LA, Daha MR. Activation of the alternative pathway of complement by human serum IgA. Eur J Immunol. 1987;17:321–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Nikolova EB, Tomana M, Russell MW. The role of the carbohydrate chains in complement (C3) fixation by solid-phase-bound human IgA. Immunology. 1994;82:321–7.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Roos A, Rastaldi MP, Calvaresi N, Oortwijn BD, Schlagwein N, van Gijlswijk-Janssen DJ, et al. Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease. J Am Soc Nephrol. 2006;17:1724–34.CrossRefPubMedGoogle Scholar
  27. 27.
    Kokubo T, Hiki Y, Iwase H, Tanaka A, Toma K, Hotta K, et al. Protective role of IgA1 glycans against IgA1 self-aggregation and adhesion to extracellular matrix proteins. J Am Soc Nephrol. 1998;9:2048–54.PubMedGoogle Scholar
  28. 28.
    Roos A, Bouwman LH, van Gijlswijk-Janssen DJ, Faber-Krol MC, Stahl GL, Daha MR. Human IgA activates the complement system via the mannan-binding lectin pathway. J Immunol. 2001;167:2861–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Coppo R, Amore A. Aberrant glycosylation in IgA nephropathy (IgAN). Kidney Int. 2004;65:1544–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Oortwijn BD, Rastaldi MP, Roos A, Mattinzoli D, Daha MR, van Kooten C. Demonstration of secretory IgA in kidneys of patients with IgA nephropathy. Nephrol Dial Transplant. 2007;22:3191–5.CrossRefPubMedGoogle Scholar
  31. 31.
    Suzuki H, Ohsawa I, Kodama F, Nakayama K, Ohtani A, Onda K, et al. Fluctuation of serum C3 levels reflects disease activity and metabolic background in patients with IgA nephropathy. J Nephrol. 2013;26:708–15.CrossRefPubMedGoogle Scholar
  32. 32.
    Shimamoto M, Ohsawa I, Suzuki H, Hisada A, Nagamachi S, Honda D, et al. Impact of body mass index on progression of IgA nephropathy among Japanese patients. J Clin Lab Anal. 2014. doi: 10.1002/jcla.21778.PubMedGoogle Scholar
  33. 33.
    Garred P, Larsen F, Seyfarth J, Fujita R, Madsen H. Mannose-binding lectin and its genetic variants. Genes Immun. 2006;7:85–94.CrossRefPubMedGoogle Scholar
  34. 34.
    Ishii M, Ohsawa I, Inoshita H, Kusaba G, Onda K, Wakabayashi M, et al. Serum concentration of complement components of the lectin pathway in maintenance hemodialysis patients, and relatively higher levels of L-ficolin and MASP-2 in mannose-binding lectin deficiency. Ther Apher Dial. 2011;15:441–7.CrossRefPubMedGoogle Scholar
  35. 35.
    Ohsawa I, Ishii M, Ohi H, Tomino Y. Pathological scenario with the mannose-binding lectin in patients with IgA nephropathy. J Biomed Biotechnol. 2012. doi: 10.1155/2012/476739.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Pirulli D, Boniotto M, Vatta L, Crovella S, Spano A, Morgutti M, et al. Polymorphisms in the promoter region and at codon 54 of the MBL2 gene are not associated with IgA nephropathy. Nephrol Dial Transplant. 2001;16:759–64.CrossRefPubMedGoogle Scholar
  37. 37.
    Barbour TD, Pickering MC, Cook HT. Dense deposit disease and C3 glomerulopathy. Semin Nephrol. 2013;33:493–507.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Kavanagh D, Goodship TH, Richards A. Atypical hemolytic uremic syndrome. Semin Nephrol. 2013;33:508–30.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Díaz-Guillén MA, Rodríguez de Córdoba S, Heine-Suñer D. A radiation hybrid map of complement factor H and factor H-related genes. Immunogenetics. 1999;49:549–52.CrossRefPubMedGoogle Scholar
  40. 40.
    Gharavi AG, Kiryluk K, Choi M, Li Y, Hou P, Xie J, et al. Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet. 2011;43:321–7.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Malik TH, Lavin PJ, de Goicoechea JE, Vernon KA, Rose KL, Patel MP, et al. A hybrid CFHR3-1 gene causes familial C3 glomerulopathy. J Am Soc Nephrol. 2012;23:1155–60.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Raychaudhuri S, Ripke S, Li M, Neale BM, Fagerness J, Reynolds R, et al. Associations of CFHR1-CFHR3 deletion and a CFH SNP to age-related macular degeneration are not independent. Nat Genet. 2010;42:553–5.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Zhu L, Zhai YL, Wang FM, Hou P, Lv JC, Xu DM, et al. Variants in complement factor H and complement factor H-related protein genes, CFHR3 and CFHR1, affect complement activation in IgA nephropathy. J Am Soc Nephrol 2014; pii: ASN.2014010096Google Scholar
  44. 44.
    Tomino Y, Endoh M, Nomoto Y, Sakai H. Immunoglobulin A1 and IgA nephropathy. N Engl J Med. 1981;305:1159–60.CrossRefPubMedGoogle Scholar
  45. 45.
    Conley ME, Cooper MD, Michael AF. Selective deposition of immunoglobulin A1 in immunoglobulin A nephropathy, anaphylactoid purpura nephritis, and systemic lupus erythematosus. J Clin Invest. 1980;66:1432–6.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Tomino Y, Sakai H, Miura M, Endoh M, Nomoto Y. Detection of polymeric IgA in glomeruli from patients with IgA nephropathy. Clin Exp Immunol. 1982;49:419–25.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Hisano S, Matsushita M, Fujita T, Endo Y, Takebayashi S. Mesangial IgA2 deposits and lectin pathway-mediated complement activation in IgA glomerulonephritis. Am J Kidney Dis. 2001;38:1082–8.CrossRefPubMedGoogle Scholar
  48. 48.
    Endo M, Ohi H, Ohsawa I, Fujita T, Matsushita M, Fujita T. Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy. Nephrol Dial Transplant. 1998;13:1984–90.CrossRefPubMedGoogle Scholar
  49. 49.
    Liu L, Liu N, Chen Y, Wang L, Jiang Y, Wang J, et al. Glomerular mannose‐binding lectin deposition is a useful prognostic predictor in immunoglobulin A nephropathy. Clin Exp Immunol. 2013;174:152–60.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Hashimoto A, Suzuki Y, Suzuki H, Ohsawa I, Brown R, Hall S, et al. Determination of severity of murine IgA nephropathy by glomerular complement activation by aberrantly glycosylated IgA and immune complexes. Am J Pathol. 2012;181:1338–47.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Sato N, Ohsawa I, Nagamachi S, Ishii M, Kusaba G, Inoshita H, et al. Significance of glomerular activation of the alternative pathway and lectin pathway in lupus nephritis. Lupus. 2011;20:1378–86.CrossRefPubMedGoogle Scholar
  52. 52.
    Espinosa M, Ortega R, Sanchez M, Segarra A, Salcedo MT, Gonzalez F, et al. Association of C4d deposition with clinical outcomes in IgA nephropathy. Clin J Am Soc Nephrol. 2014;9:897–904.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Sahin OZ, Yavas H, Taslı F, Gibyeli DG, Ersoy R, Uzum A, et al. Prognostic value of glomerular C4d staining in patients with IgA nephritis. Int J Clin Exp Pathol. 2014;7:3299–304.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Vangelista A, Frasca GM, Mondini S, Bonomini V. Idiopathic IgA mesangial nephropathy: immunohistological features. Contrib Nephrol. 1984;40:167–73.CrossRefPubMedGoogle Scholar
  55. 55.
    Ohsawa I, Kusaba G, Ishii M, Sato N, Inoshita H, Onda K, et al. Extraglomerular C3 deposition and metabolic impacts in patients with IgA nephropathy. Nephrol Dial Transplant. 2012;28:1856–64.CrossRefPubMedGoogle Scholar
  56. 56.
    Valenzuela R, Gogate PA, Deodhar SD, Gifford RW. Hyaline arteriolar nephrosclerosis. Immunofluorescence findings in the vascular lesions. Lab Invest. 1980;43:530–4.PubMedGoogle Scholar
  57. 57.
    Makino H, Hironaka K, Shikata K, Nagake Y, Kumagai I, Kashihara N, et al. Mesangial matrices act as mesangial channels to the juxtaglomerular zone. Nephron. 1994;66:181–8.CrossRefPubMedGoogle Scholar
  58. 58.
    Sterzel RB, Perfetto M, Biemesderfer D, Kashgarian M. Disposal of ferritin in the glomerular mesangium of rats. Kidney Int. 1983;23:480–8.CrossRefPubMedGoogle Scholar
  59. 59.
    Van Es LA. Pathogenesis of IgA nephropathy. Kidney Int. 1992;41:1720–9.CrossRefPubMedGoogle Scholar
  60. 60.
    Suzuki S, Sato H, Tsukada H, Arakawa M, Nakatomi Y. Haemophilus parainfluenzae antigen and antibody in renal biopsy samples and serum of patients with IgA nephropathy. Lancet. 1994;343:12–6.CrossRefPubMedGoogle Scholar
  61. 61.
    Gong R, Liu Z, Li L. Mannose-binding lectin gene polymorphism associated with the patterns of glomerular immune deposition in IgA nephropathy. Scand J Urol Nephrol. 2001;35:228–32.CrossRefPubMedGoogle Scholar
  62. 62.
    Tamano M, Fuke Y, Endo M, Ohsawa I, Fujita T, Ohi H. Urinary complement factor H in renal disease. Nephron. 2002;92:705–7.CrossRefPubMedGoogle Scholar
  63. 63.
    Ogrodowski JL, Hebert LA, Sedmak D, Cosio FG, Tamerius J, Kolb W. Measurement of SC5b-9 in urine in patients with the nephrotic syndrome. Kidney Int. 1991;40:1141–7.CrossRefPubMedGoogle Scholar
  64. 64.
    Endo M, Fuke Y, Tamano M, Hidaka M, Ohsawa I, Fujita T, et al. Glomerular deposition and urinary excretion of complement factor H in idiopathic membranous nephropathy. Nephron Clin Pract. 2004;97:c147–53.CrossRefPubMedGoogle Scholar
  65. 65.
    Onda K, Ohsawa I, Ohi H, Tamano M, Mano S, Wakabayashi M, et al. Excretion of complement proteins and its activation marker C5b-9 in IgA nephropathy in relation to renal function. BMC Nephrol. 2011;12:64. doi: 10.1186/1471-2369-12-64.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Liu L, Jiang Y, Wang L, Liu N. Urinary mannose‐binding lectin is a biomarker for predicting the progression of immunoglobulin (Ig) A nephropathy. Clin Exp Immunol. 2012;169:148–55.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Nagamachi S, Ohsawa I, Suzuki H, Sato N, Inoshita H, Hisada A, et al. Properdin has an ascendancy over factor H regulation in complement-mediated renal tubular damage. BMC Nephrol. 2014;15:82. doi: 10.1186/1471-2369-15-82.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Zuber J, Fakhouri F, Roumenina LT, Loirat C, Fremeaux-Bacchi V, French Study Group for aHUS/C3G. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol. 2012;8:643–57.CrossRefPubMedGoogle Scholar
  69. 69.
    Rosenblad T, Rebetz J, Johansson M, Békássy Z, Sartz L, Karpman D. Eculizumab treatment for rescue of renal function in IgA nephropathy. Pediatr Nephrol. 2014;29:2225–8.CrossRefPubMedGoogle Scholar

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© Springer Japan 2016

Authors and Affiliations

  1. 1.Nephrology unit, Saiyu Soka HospitalSoka CityJapan

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