DOI QR코드

DOI QR Code

Pathology of C3 Glomerulopathy

  • Shin, Su-Jin (Department of Pathology, Yonsei University College of Medicine) ;
  • Seong, Yoonje (Department of Pathology, Yonsei University College of Medicine) ;
  • Lim, Beom Jin (Department of Pathology, Yonsei University College of Medicine)
  • Received : 2019.09.14
  • Accepted : 2019.10.10
  • Published : 2019.10.31

Abstract

C3 glomerulopathy is a renal disorder involving dysregulation of alternative pathway complement activation. In most instances, a membranoproliferative pattern of glomerular injury with a prevalence of C3 deposition is observed by immunofluorescence microscopy. Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are subclasses of C3 glomerulopathy that are distinguishable by electron microscopy. Highly electron-dense transformation of glomerular basement membrane is characteristic of DDD. C3GN should be differentiated from post-infectious glomerulonephritis and other immune complex-mediated glomerulonephritides showing C3 deposits.

Keywords

References

  1. Smith RJH, Appel GB, Blom AM, Cook HT, D'Agati VD, Fakhouri F, et al. C3 glomerulopathy - understanding a rare complementdriven renal disease. Nat Rev Nephrol 2019;15:129-43. https://doi.org/10.1038/s41581-018-0107-2
  2. Baines AC, Brodsky RA. Complementopathies. Blood Rev 2017;31:213-23. https://doi.org/10.1016/j.blre.2017.02.003
  3. Khalighi MA, Wang S, Henriksen KJ, Bock M, Keswani M, Meehan SM, et al. Revisiting post-infectious glomerulonephritis in the emerging era of C3 glomerulopathy. Clin Kidney J 2016;9:397-402. https://doi.org/10.1093/ckj/sfw032
  4. Ito N, Ohashi R, Nagata M. C3 glomerulopathy and current dilemmas. Clin Exp Nephrol 2017;21:541-51. https://doi.org/10.1007/s10157-016-1358-5
  5. 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. https://doi.org/10.1038/ki.2013.377
  6. Alchi B, Jayne D. Membranoproliferative glomerulonephritis. Pediatr Nephrol 2010;25:1409-18. https://doi.org/10.1007/s00467-009-1322-7
  7. Levy M, Gubler MC, Sich M, Beziau A, Habib R. Immunopathology of membranoproliferative glomerulonephritis with subendothelial deposits (Type I MPGN). Clin Immunol Immunopathol 1978;10:477-92. https://doi.org/10.1016/0090-1229(78)90160-5
  8. Habib R, Gubler MC, Loirat C, Maiz HB, Levy M. Dense deposit disease: a variant of membranoproliferative glomerulonephritis. Kidney Int 1975;7:204-15. https://doi.org/10.1038/ki.1975.32
  9. Burkholder PM, Marchand A, Krueger RP. Mixed membranous and proliferative glomerulonephritis. A correlative light, immunofluorescence, and electron microscopic study. Lab Invest 1970;23:459-79.
  10. Strife CF, McEnery PT, McAdams AJ, West CD. Membranoproliferative glomerulonephritis with disruption of the glomerular basement membrane. Clin Nephrol 1977;7:65-72.
  11. Anders D, Agricola B, Sippel M, Thoenes W. Basement membrane changes in membranoproliferative glomerulonephritis. II. Characterization of a third type by silver impregnation of ultra thin sections. Virchows Arch A Pathol Anat Histol 1977;376:1-19. https://doi.org/10.1007/BF00433081
  12. Nasr SH, Valeri AM, Appel GB, Sherwinter J, Stokes MB, Said SM, et al. Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Clin J Am Soc Nephrol 2009;4:22-32. https://doi.org/10.2215/CJN.03480708
  13. Walker PD, Ferrario F, Joh K, Bonsib SM. Dense deposit disease is not a membranoproliferative glomerulonephritis. Mod Pathol 2007;20:605-16. https://doi.org/10.1038/modpathol.3800773
  14. Belgiojoso GB, Tarantino A, Bazzi C, Colasanti G, Guerra L, Durante A. Immunofluorescence patterns in chronic membranoproliferative glomerulonephritis (MPGN). Clin Nephrol 1976;6:303-10.
  15. Pickering RJ, Herdman RC, Michael AF, Vernier RL, Gewurz H, Fish AJ, et al. Chronic glomerulonephritis associated with low serum complement activity (chronic hypocomplementemic glomerulonephritis). Medicine (Baltimore) 1970;49:207-26. https://doi.org/10.1097/00005792-197005000-00002
  16. Fakhouri F, Fremeaux-Bacchi V, Noel LH, Cook HT, Pickering MC. C3 glomerulopathy: a new classification. Nat Rev Nephrol 2010;6:494-9. https://doi.org/10.1038/nrneph.2010.85
  17. Noris M, Remuzzi G. Overview of complement activation and regulation. Semin Nephrol 2013;33:479-92. https://doi.org/10.1016/j.semnephrol.2013.08.001
  18. Bomback AS, Markowitz GS, Appel GB. Complement-Mediated Glomerular Diseases: A Tale of 3 Pathways. Kidney Int Rep 2016;1:148-55. https://doi.org/10.1016/j.ekir.2016.06.005
  19. Nilsson B, Nilsson Ekdahl K. The tick-over theory revisited: Is C3 a contact-activated protein? Immunobiology 2012;217:1106-10. https://doi.org/10.1016/j.imbio.2012.07.008
  20. Wong EKS, Kavanagh D. Diseases of complement dysregulationan overview. Semin Immunopathol 2018;40:49-64. https://doi.org/10.1007/s00281-017-0663-8
  21. Spitzer RE, Stitzel AE, Tsokos GC. Production of IgG and IgM autoantibody to the alternative pathway C3 convertase in normal individuals and patients with membranoproliferative glomerulonephritis. Clin Immunol Immunopathol 1990;57:10-8. https://doi.org/10.1016/0090-1229(90)90018-L
  22. Jozsi M, Reuter S, Nozal P, Lopez-Trascasa M, Sanchez-Corral P, Prohaszka Z, et al. Autoantibodies to complement components in C3 glomerulopathy and atypical hemolytic uremic syndrome. Immunol Lett 2014;160:163-71. https://doi.org/10.1016/j.imlet.2014.01.014
  23. Paixao-Cavalcante D, Lopez-Trascasa M, Skattum L, Giclas PC, Goodship TH, de Cordoba SR, et al. Sensitive and specific assays for C3 nephritic factors clarify mechanisms underlying complement dysregulation. Kidney Int 2012;82:1084-92. https://doi.org/10.1038/ki.2012.250
  24. Ito S, Tamura N, Fujita T. Effect of decay-accelerating factor on the assembly of the classical and alternative pathway C3 convertases in the presence of C4 or C3 nephritic factor. Immunology 1989;68:449-52.
  25. Zhang Y, Nester CM, Holanda DG, Marsh HC, Hammond RA, Thomas LJ, et al. Soluble CR1 therapy improves complement regulation in C3 glomerulopathy. J Am Soc Nephrol 2013;24:1820-9. https://doi.org/10.1681/ASN.2013010045
  26. Corvillo F, Okroj M, Nozal P, Melgosa M, Sanchez-Corral P, Lopez-Trascasa M. Nephritic Factors: An Overview of Classification, Diagnostic Tools and Clinical Associations. Front Immunol 2019;10:886. https://doi.org/10.3389/fimmu.2019.00886
  27. Marinozzi MC, Chauvet S, Le Quintrec M, Mignotet M, Petitprez F, Legendre C, et al. C5 nephritic factors drive the biological phenotype of C3 glomerulopathies. Kidney Int 2017;92:1232-41. https://doi.org/10.1016/j.kint.2017.04.017
  28. Zhang Y, Meyer NC, Fervenza FC, Lau W, Keenan A, Cara-Fuentes G, et al. C4 Nephritic Factors in C3 Glomerulopathy: A Case Series. Am J Kidney Dis 2017;70:834-43. https://doi.org/10.1053/j.ajkd.2017.07.004
  29. Ravindran A, Fervenza FC, Smith RJH, De Vriese AS, Sethi S. C3 Glomerulopathy: Ten Years' Experience at Mayo Clinic. Mayo Clin Proc 2018;93:991-1008. https://doi.org/10.1016/j.mayocp.2018.05.019
  30. Michels M, van de Kar N, van den Bos RM, van der Velden T, van Kraaij SAW, Sarlea SA, et al. Novel Assays to Distinguish Between Properdin-Dependent and Properdin-Independent C3 Nephritic Factors Provide Insight Into Properdin-Inhibiting Therapy. Front Immunol 2019;10:1350. https://doi.org/10.3389/fimmu.2019.01350
  31. Blanc C, Togarsimalemath SK, Chauvet S, Le Quintrec M, Moulin B, Buchler M, et al. Anti-factor H autoantibodies in C3 glomerulopathies and in atypical hemolytic uremic syndrome: one target, two diseases. J Immunol 2015;194:5129-38. https://doi.org/10.4049/jimmunol.1402770
  32. Marinozzi MC, Roumenina LT, Chauvet S, Hertig A, Bertrand D, Olagne J, et al. Anti-Factor B and Anti-C3b Autoantibodies in C3 Glomerulopathy and Ig-Associated Membranoproliferative GN. J Am Soc Nephrol 2017;28:1603-13. https://doi.org/10.1681/ASN.2016030343
  33. Goicoechea de Jorge E, Caesar JJ, Malik TH, Patel M, Colledge M, Johnson S, et al. Dimerization of complement factor H-related proteins modulates complement activation in vivo. Proc Natl Acad Sci U S A 2013;110:4685-90. https://doi.org/10.1073/pnas.1219260110
  34. Martinez-Barricarte R, Heurich M, Valdes-Canedo F, Vazquez- Martul E, Torreira E, Montes T, et al. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. J Clin Invest 2010;120:3702-12. https://doi.org/10.1172/JCI43343
  35. Pickering M, Cook HT. Complement and glomerular disease: new insights. Curr Opin Nephrol Hypertens 2011;20:271-7. https://doi.org/10.1097/MNH.0b013e328345848b
  36. Ravindran A, Fervenza FC, Smith RJH, Sethi S. C3 glomerulopathy associated with monoclonal Ig is a distinct subtype. Kidney Int. 2018;94:178-86. https://doi.org/10.1016/j.kint.2018.01.037
  37. Sethi S, Rajkumar SV, D'Agati VD. The Complexity and Heterogeneity of Monoclonal Immunoglobulin-Associated Renal Diseases. J Am Soc Nephrol. 2018;29:1810-23. https://doi.org/10.1681/ASN.2017121319
  38. Sethi S, Fervenza FC, Rajkumar SV. Spectrum of manifestations of monoclonal gammopathy-associated renal lesions. Curr Opin Nephrol Hypertens 2016;25:127-37. https://doi.org/10.1097/MNH.0000000000000201
  39. Hou J, Markowitz GS, Bomback AS, Appel GB, Herlitz LC, Barry Stokes M, et al. Toward a working definition of C3 glomerulopathy by immunofluorescence. Kidney Int 2014;85:450-6. https://doi.org/10.1038/ki.2013.340
  40. Yagi K, Yanagida H, Sugimoto K, Kuwajima H, Tabata N, Morita K, et al. Clinicopathologic features, outcome, and therapeutic interventions in four children with isolated C3 mesangial proliferative glomerulonephritis. Pediatr Nephrol 2005;20:1273-8. https://doi.org/10.1007/s00467-005-1919-4
  41. Cook HT. C3 glomerulopathy. F1000Res 2017;6:248. https://doi.org/10.12688/f1000research.10364.1
  42. Servais A, Noel LH, Roumenina LT, Le Quintrec M, Ngo S, Dragon- Durey MA, et al. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int 2012;82:454-64. https://doi.org/10.1038/ki.2012.63
  43. Viswanathan GK, Nada R, Kumar A, Ramachandran R, Rayat CS, Jha V, et al. Clinico-pathologic spectrum of C3 glomerulopathyan Indian experience. Diagn Pathol 2015;10:6. https://doi.org/10.1186/s13000-015-0233-0
  44. Ravindran A, Fervenza FC, Smith RJH, Sethi S. C3 glomerulonephritis with a severe crescentic phenotype. Pediatr Nephrol 2017;32:1625-33. https://doi.org/10.1007/s00467-017-3702-8
  45. Prema KSJ, Kurien AA, Gopalakrishnan N, Walker PD, Larsen CP. Dense deposit disease: a greatly increased biopsy incidence in India versus the USA. Clin Kidney J 2019;12:476-82. https://doi.org/10.1093/ckj/sfy125
  46. Park SJ, Kim YJ, Ha TS, Lim BJ, Jeong HJ, Park YH, et al. Dense deposit disease in Korean children: a multicenter clinicopathologic study. J Korean Med Sci 2012;27:1215-21. https://doi.org/10.3346/jkms.2012.27.10.1215
  47. Sethi S, Fervenza FC, Smith RJ, Haas M. Overlap of ultrastructural findings in C3 glomerulonephritis and dense deposit disease. Kidney Int 2015;88:1449-50.
  48. Cook HT, Pickering MC. Histopathology of MPGN and C3 glomerulopathies. Nat Rev Nephrol 2015;11:14-22. https://doi.org/10.1038/nrneph.2014.217
  49. Sethi S, Fervenza FC, Zhang Y, Nasr SH, Leung N, Vrana J, et al. Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement. Clin J Am Soc Nephrol 2011;6:1009-17. https://doi.org/10.2215/CJN.07110810
  50. Bridoux F, Desport E, Fremeaux-Bacchi V, Chong CF, Gombert JM, Lacombe C, et al. Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association? Clin J Am Soc Nephrol 2011;6:2165-74. https://doi.org/10.2215/CJN.06180710
  51. Hawf ield A, Iskandar SS, Smith RJ. Alternative pathway dysfunction in kidney disease: a case report and review of dense deposit disease and C3 glomerulopathy. Am J Kidney Dis 2013;61:828-31. https://doi.org/10.1053/j.ajkd.2012.11.045
  52. Strife CF, West CD, Witte DP. Crescentic glomerulonephritis in childhood: acute nonproliferative glomerulitis versus dense deposit disease. Am J Kidney Dis 2003;41:897; author reply 8. https://doi.org/10.1016/S0272-6386(03)00216-6
  53. Churg J, Duffy JL, Bernstein J. Identification of dense deposit disease: a report for the International Study of Kidney Diseases in Children. Arch Pathol Lab Med 1979;103:67-72.
  54. Medjeral-Thomas NR, O'Shaughnessy MM, O'Regan JA, Traynor C, Flanagan M, Wong L, et al. C3 glomerulopathy: clinicopathologic features and predictors of outcome. Clin J Am Soc Nephrol 2014;9:46-53. https://doi.org/10.2215/CJN.04700513
  55. Sethi S, Nasr SH, De Vriese AS, Fervenza FC. C4d as a Diagnostic Tool in Proliferative GN. J Am Soc Nephrol. 2015;26:2852-9. https://doi.org/10.1681/ASN.2014040406
  56. Goodship TH, Cook HT, Fakhouri F, Fervenza FC, Fremeaux-Bacchi V, Kavanagh D, et al. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int 2017;91:539-51. https://doi.org/10.1016/j.kint.2016.10.005
  57. Sethi S, Fervenza FC, Zhang Y, Zand L, Meyer NC, Borsa N, et al. Atypical postinfectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement. Kidney Int 2013;83:293-9. https://doi.org/10.1038/ki.2012.384
  58. Kanjanabuch T, Kittikowit W, Eiam-Ong S. An update on acute postinfectious glomerulonephritis worldwide. Nat Rev Nephrol 2009;5:259-69. https://doi.org/10.1038/nrneph.2009.44
  59. Fish AJ, Herdman RC, Michael AF, Pickering RJ, Good RA. Epidemic acute glomerulonephritis associated with type 49 streptococcal pyoderma. II. Correlative study of light, immunofluorescent and electron microscopic findings. Am J Med 1970;48:28-39. https://doi.org/10.1016/0002-9343(70)90095-1
  60. Sethi S, Fervenza FC, Zhang Y, Zand L, Vrana JA, Nasr SH, et al. C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up. Kidney Int 2012;82:465-73. https://doi.org/10.1038/ki.2012.212
  61. Sandhu G, Bansal A, Ranade A, Jones J, Cortell S, Markowitz GS. C3 glomerulopathy masquerading as acute postinfectious glomerulonephritis. Am J Kidney Dis 2012;60:1039-43. https://doi.org/10.1053/j.ajkd.2012.04.032
  62. Vernon KA, Goicoechea de Jorge E, Hall AE, Fremeaux-Bacchi V, Aitman TJ, Cook HT, et al. Acute presentation and persistent glomerulonephritis following streptococcal infection in a patient with heterozygous complement factor H-related protein 5 deficiency. Am J Kidney Dis 2012;60:121-5. https://doi.org/10.1053/j.ajkd.2012.02.329
  63. Suga K, Kondo S, Matsuura S, Kinoshita Y, Kitano E, Hatanaka M, et al. A case of dense deposit disease associated with a group A streptococcal infection without the involvement of C3NeF or complement factor H deficiency. Pediatr Nephrol 2010;25:1547-50. https://doi.org/10.1007/s00467-010-1479-0
  64. Prasto J, Kaplan BS, Russo P, Chan E, Smith RJ, Meyers KE. Streptococcal infection as possible trigger for dense deposit disease (C3 glomerulopathy). Eur J Pediatr 2014;173:767-72. https://doi.org/10.1007/s00431-013-2245-7
  65. Sawanobori E, Umino A, Kanai H, Matsushita K, Iwasa S, Kitamura H, et al. A prolonged course of Group A streptococcus-associated nephritis: a mild case of dense deposit disease (DDD)? Clin Nephrol 2009;71:703-7. https://doi.org/10.5414/CNP71703
  66. Okabe M, Tsuboi N, Yokoo T, Miyazaki Y, Utsunomiya Y, Hosoya T. A case of idiopathic membranoproliferative glomerulonephritis with a transient glomerular deposition of nephritis-associated plasmin receptor antigen. Clin Exp Nephrol 2012;16:337-41. https://doi.org/10.1007/s10157-011-0570-6