Journal List > J Korean Soc Transplant > v.27(3) > 1034420

J Korean Soc Transplant. 2013 Sep;27(3):87-91. Korean.
Published online September 26, 2013.  https://doi.org/10.4285/jkstn.2013.27.3.87
Copyright © 2013 The Korean Society for Transplantation
The Significance and Limitation of C4d as a Biomarker in the Transplanted Kidney
Jee-Young Han, M.D.
Department of Pathology, Inha University Hospital, Inha University College of Medicine, Incheon, Korea.

Corresponding author (Email: jeeyhan@inha.ac.kr )
Received August 31, 2013; Accepted September 03, 2013.

Abstract

C4d is produced from the direct interaction between antibodies and tissue injury at an antibody binding site in a graft. C4d deposition along peritubular capillaries (PTCs) in a renal allograft is a characteristic finding of antibody-mediated rejection (AMR), and is a useful diagnostic tool of AMR. The C4d along PTCs is associated with poor graft survival. Therefore C4d is regarded as a biomarker of AMR and was included in the diagnosis criteria of AMR at 2007 Banff conference. However, although C4d assay is widely used, it has several limitations. ABO-incompatible transplantations develop C4d along the PTCs in the majority of grafts but this seems to be graft accommodation rather than AMR. Recent studies reported that more than half of renal allograft biopsies with chronic AMR were C4d-negative. Without treatment, the C4d-negative AMR can cause scarring within the graft, transplant glomerulopathy (TG) or even graft loss. C4d is not a certain indicator of antibody-mediated rejection and C4d staining is not always highly sensitive for detecting AMR. Measuring endothelial gene expression in kidney graft biopsies with alloantibody can be another sensitive and specific method to diagnose AMR and predict graft outcomes. Because of these complexities, at the 2011 Banff meeting, criteria for diagnosis of chronic AMR in the kidney were refined, and the need for inclusion of C4d-negative AMR in the Banff classification was investigated.

Keywords: C4d; Antibody; Rejection; Limitation

References
1. Feucht HE, Felber E, Gokel MJ, Hillebrand G, Nattermann U, Brockmeyer C, et al. Vascular deposition of complement-split products in kidney allografts with cell-mediated rejection. Clin Exp Immunol 1991;86:464–470.
2. Feucht HE, Schneeberger H, Hillerbrand G, Burkhardt K, Weiss M, Riethmüller G, et al. Capillary deposition of C4d complement fragment and early renal graft loss. Kidney Int 1993;43:1333–1338.
3. Collins AB, Schneeberger EE, Pascula MA, Saidman SL, Williams WW, Tolkoff-Rubin N, et al. Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d deposits in peitubular capillaries. J Am Soc Nephrol 1999;10:2208–2214.
4. Nickeleit V, Mihastsch MJ. Kidney transplants, antibodies and rejection: is C4d a magic marker? Nephrol Dial Transplant 2003;18:2232–2239.
5. 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;81:628–639.
6. Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant 2008;8:753–760.
7. Mengel M, Husain S, Hidalgo L, Sis B. Phenotypes of antibody mediated rejection in organ transplants. Transpl Int 2012;25:611–622.
8. Haas M, Mirocha J. Early ultrastructural changes in renal allografts correlation with antibody-mediated rejection and transplant glomerulopathy. Am J Transplant 2011;11:2123–2131.
9. Loupy A, Suberbielle-Boissel C, Hill GS, Lefaucheur C, Anglicheau D, Zuber J, et al. Outcome of subclinical antibody-mediated rejection in kidney transplant recipients with preformed donor-specific antibodies. Am J Transplant 2009;9:2561–2570.
10. Mengel M, Sis B, Haas M, Colvin RB, Halloran PF, Racusen LC, et al. Banff 2011 Meeting report: new concepts in antibody-mediated rejection. Am J Transplant 2012;12:563–570.
11. Racusen LC, Halloran PF, Solez K. Banff 2003 meeting report: new diagnostic insights and standards. Am J Transplant 2004;4:1562–1566.
12. Regele H, Böhmig GA, Habicht A, Gollowitzer D, Schillinger M, Rockenschaub S, et al. Capillary deposition of complement split product C4d in renal allografts is associated with basement membrane injury in peritubular and glomerular capillaries: a contribution of humoral immunity to chronic allograft rejection. J Am Soc Nephrol 2002;13:2371–2380.
13. Herzenberg AM, Gill JS, Djurdjev O, Magil AB. C4d deposition in acute rejection: an independent long-term prognostic factor. J Am Soc Nephrol 2002;13:234–241.
14. Mauiyyedi S, Pelle PD, Saidman S, Collins AB, Pascual M, Tolkoff-Rubin NE, et al. Chronic humoral rejection: identification of antibody-mediated chronic renal allograft rejection by C4d deposits in peritubular capillaries. J Am Soc Nephrol 2001;12:574–582.
15. Sis B, Jhangri GS, Bunnag S, Allanach K, Kaplan B, Halloran PF. Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining. Am J Transplant 2009;9:2312–2323.
16. Sis B, Halloran PF. Endothelial transcripts uncover a previously unknown phenotype: C4d-negative antibody-mediated rejection. Curr Opin Organ Transplant 2010;15:42–48.
17. Haas M. Pathology of C4d-negative antibody-mediated rejection in renal allografts. Curr Opin Organ Transplant 2013;18:319–326.
18. Zhang X, Reed EF. Effect of antibodies on endothelium. Am J Transplant 2009;9:2459–2465.
19. Hirohashi T, Chase CM, Della Pelle P, Sebastian D, Alessandrini A, Madsen JC, et al. A novel pathway of chronic allograft rejection mediated by NK cells and alloantibody. Am J Transplant 2012;12:313–321.
20. Hidalgo LG, Sis B, Sellares J, Campbell PM, Mengel M, Einecke G, et al. NK cell transcripts and NK cells in kidney biopsies from patients with donor-specific antibodies: evidence for NK cell involvement in antibody-mediated rejection. Am J Transplant 2010;10:1812–1822.
21. Haas M, Segev DL, Racusen LC, Bagnasco SM, Locke JE, Warren DS, et al. C4d deposition without rejection correlates with reduced early scarring in ABO-incompatible renal allografts. J Am Soc Nephrol 2009;20:197–204.
22. Setoguchi K, Ishida H, Shimmura H, Shimizu T, Shirakawa H, Omoto K, et al. Analysis of renal transplant protocol biopsies in ABO-incompatible kidney transplantation. Am J Transplant 2008;8:86–94.
23. Park WD, Grande JP, Ninova D, Nath KA, Platt JL, Gloor JM, et al. Accommodation in ABO-incompatible kidney allografts, a novel mechanism of self-protection against antibody-mediated injury. Am J Transplant 2003;3:952–960.
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