Abstract
Membranous glomerulonephritis (MGN) is the most common cause of adulthood nephrotic syndrome. Diagnosis of membranous nephritis is based on light electron immunofluorescence microscopy and clinical signs. Immune complex deposition against podocyte antigens such as phospholipase A2 receptor (PLA2R) activates the complement system. Of this, complement Component C4d (C4d) is involved in the classical and lectin pathways. This marker may be used by immunohistochemistry to diagnose MGN when other methods are not available. In this work, C4d expression was monitored by immunohistochemical analysis in the glomerular capillaries of patients with primary MGN (study group, N=33) versus patients with minimal change disease (MCD, control group, N=20) in a cross-sectional evaluation performed based on the diagnosis confirmed by light microscopy and immunofluorescence. There was no significant demographic difference between the two groups except for age (P=0.002). C4d immune-expression was positive in glomerular capillary (2+ to 4+) in most of the MGN patients, while it was negative in the MCD group. The sensitivity and specificity of C4d immunostaining were 95% and 100%, respectively. The Pearson correlation coefficient was 0.74 between C4d (immunohistochemistry) and immunoglobulins (IgG; immunofluorescence) and 0.65 between C4d (immunohistochemistry) and the C3 complement product (immunofluorescence). Immunohistochemical evaluation of C4d is, therefore, a sensitive and specific method that has a high correlation with IgG immunofluorescence.
References
1. Dahan K. Membranous nephropathy: diagnosis, new insights in pathophysiology, and therapeutic approach. Rev Med Interne. 2016;37(10):674.
2. Ponticelli C, Passerini P. Can prognostic factors assist therapeutic decisions in idiopathic membranous nephropathy. J Nephrol. 2010;23(2):156-63.
3. Ronco P, Debiec H. Pathophysiology of extramembranous glomerulopathies. Fifty years of progress, from laboratory to patient. Biologie aujourd’hui. 2013;207(4):249-59.
4. Debiec H, Hanoy M, Francois A, Guerrot D, Ferlicot S, Johanet C, et al. Recurrent membranous nephropathy in an allograft caused by IgG3κ targeting the PLA2 receptor. J Am Soc Nephrol. 2012;23(12):1949-54.
5. Filinte D, Arıkan H, Koç M, Kaya H, Özener IC, Akbaş G. The intensity of PLA2R and C4d immunoexpression in primary membranous nephropathy. South Clin Ist Euras. 2020;31(2).
6. Debiec H, Ronco P. Immunopathogenesis of membranous nephropathy: an update. Sem Immunopathol. 2014;36(4):381-97.
7. Torbati PM, Haleh Tavakolian H. Diagostic Accuracy of C4d-IHC in Diagnosis of Membranous Glomerulonephritis. Iran J Kidney Dis. 2020;14(1):20.
8. Kościelska-Kasprzak K, Bartoszek D, Myszka M, Żabińska M, Klinger M. The complement cascade and renal disease. Arch Immunol Ther Exp. 2014;62(1):47-57.
9. Ma H, Sandor DG, Beck LH. The role of complement in membranous nephropathy. Sem Nephrol. 2013;33(6):531-42.
10. Beck LH, Salant DJ. Membranous nephropathy: recent travels and new roads ahead. Kidney Int. 2010;77(9):765-70.
11. Cohen D, Colvin RB., Daha MR, Drachenberg CB. Haas M, Nickeleit V, et al. Pros and cons for C4d as a biomarker. Kidney Int. 2012;81(7):628-39.
12. 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(5):897-904.
13. Larsen C P, Messias NC, Silva FG, Messias E, Walker PD. Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies. Mod Pathol. 2013;26(5):709-15.
14. Stangou MJ, Marinaki S, Papachristou E, Liapis G, Pateinakis P, Gakiopoulou H, et al. Histological grading in primary membranous nephropathy is essential for clinical management and predicts outcome of patients. Histopathology. 2019;75(5):660-71.
15. McClish DK. Analyzing a portion of the ROC curve. Med Decis Making. 1989;9(3):190-5.
16. Glassock RJ. The pathogenesis of idiopathic membranous nephropathy: a 50-year odyssey. Am J Kidney Dis. 2010;56(1):157-67.
17. Noris M, Remuzzi G. Overview of complement activation and regulation. Semin Nephrol. 2013;33(6):479-92.
18. Sheerm 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(4):1065-72.
19. Colvin RB. Pathology of chronic humoral rejection. Contrib Nephrol. 2009;162:75-86.
20. Einecke GB, Sis J, Reeve M, Mengel PM, Campbell LG, Hidalgo B, et al. Halloran antibody‐mediated microcirculation injury is the major cause of late kidney transplant failure. Am J Transplant. 2009;9(11):2520-31.
21. Murata K, Baldwin WM. Mechanisms of complement activation, C4d deposition, and their contribution to the pathogenesis of antibody-mediated rejection. Transpl Rev. 2009;23(3):139-50.
22. Zwirner J, Felber E, Herzog V, Riethmüller G, Feucht HE. Classical pathway of complement activation in normal and diseased human glomeruli. Kidney Int. 1989;36(6):1069-77.
23. Zwirner J, Felber E, Burger R, Bitter-Suermann D, Riethmüller G, Feucht HE. Classical pathway of complement activation in mammalian kidneys. Immunology. 1993;80(2):162.
24. Beck Jr LH, Bonegio RGB, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. Salant M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. New Engl J Med. 2009;361(1):11-21.
25. Couser WG. Primary membranous nephropathy. CJASN. 2017;12(6):983-97.
26. Ranjan P, Nada R, Jha V, Sakhuja V, Joshi K. The role of C4d immunostaining in the evaluation of the causes of renal allograft dysfunction. Nephrol Dial Transplant. 2008;23(5):1735-41.
27. Val-Bernal J, Fernando M, Garijo 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. 2011;26(11):1391-7.
28. Espinosa-Hernández M, Ortega-Salas R, López-Andreu M, Gómez-Carrasco JM, Pérez-Sáez MJ, Pérez-Seoane C, et al. C4d as a diagnostic tool in membranous nephropathy. Nefrología (English Edition). 2012;32(4):536.
29. Bichuette CF, Aparecida da Silva C, Rodrigues Helmo F, Reis Machado J, Antônia dos Reis M. Complement System and C4d expression in cases of Membranous nephropathy. Braz J Nephrology. 2017;39(4):370-5.
30. Song YS, Min KW, Kim JH, Kim GH, Park MH. Differential diagnosis of lupus and primary membranous nephropathies by IgG subclass analysis. Clin J Am Soc Nephrol. 2012;7(12):1947-55.
31. Obana M, Nakanishi K, Sako M, Yata N, Nozu K, Tanaka R, et al. Segmental membranous glomerulonephritis in children: comparison with global membranous glomerulonephritis. Clin J Am Soc Nephrol. 2006;1(4):723-9.
32. Segawa Y, Hisano S, Matsushita M, Fujita T, Hirose S, Takeshita M, et al. IgG subclasses and complement pathway in segmental and global membranous nephropathy. Pediat Nephrol. 2010;25(6):1091-9.
33. Bally S, Debiec H, Ponard D, Dijoud F, Rendu J, Fauré J, et al. Phospholipase A2 receptor–related membranous nephropathy and mannan-binding lectin deficiency. J Am Soc Nephrol. 2016;27(12):3539-44.
34. Cunningham PN, Quigg RJ. Contrasting roles of complement activation and its regulation in membranous nephropathy. J Am Soc Nephrol. 2005;16(5):1214-22.
35. Ponticelli C, Glassock RJ. Glomerular diseases: membranous nephropathy –a modern view. Clin J Am Soc Nephrol. 2014;9(3):609-16.
36. Murtas C, Bruschi M, Candiano G, Moroni G, Magistroni R, Magnano A, et al. Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy. Clin J Am Soc Nephrol. 2012;7(9):1394-400.
37. mmunohistochemistry in membranous nephropathy. J Lab Physicians. 2014;6(2):76.
38. Espinosa-Hernández M, Ortega-Salas R, López-Andreu M, Gómez-Carrasco JM, Pérez-Sáez MJ, Pérez-Seoane C, Aljama-García P. C4d as a diagnostic tool in membranous nephropathy. Nefrología (English Edition). 2012;32(3):295-9.
39. Lim BJ, Kim MS, Kim YS, Kim SI, Jeong HI. C4d deposition and multilayering of peritubular capillary basement membrane in posttransplantation membranous nephropathy indicate its association with antibody-mediated injury. Transplant Proc. 2012;44(3):619-20.
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