Future Directions / Areas of Research

Prognostic significance of C3d staining

As noted above, C3d staining by immunohistochemistry is not included in the 2013 ISHLT-WF. However, it is included in the recommended immunofluorescent panel. The experience at some centers, including Cleveland Clinic and Utah, has been that C3d immunohistochemical positivity identifies patients at increased risk for allograft dysfunction and death. Centers performing and reporting C3d staining have treatment algorithms incorporating this information. Certainly whenever C3d staining is performed it should be reported, if only to allow collection of data on the clinical import of C3d status.

Weak C4d staining

Additionally, inclusion of information on weak C4d staining or on incomplete C4d staining (fewer than 50% of capillaries are stained) is advisable in order to collect data to correlate with DSA and graft dysfunction. If weak or focal C4d staining is only very rarely accompanied by DSA or graft dysfunction it will provide additional rationale for considering this weak or focal staining to be 'negative' for pAMR.


In the ISHLT WF, pAMR2 is considered definite with all features present. pAMR1 is more controversial and the appropriate clinical response to pAMR1 depends mostly on graft function and DSA. Various centers' responses to pAMR1(I+) and pAMR1(H+) have yet to be catalogued. The inclusion of both pAMR 1(H+) and pAMR1(I+) in the "Suspicious for AMR" category suggests they are pathologically and clinically equivalent; this has not yet been confirmed by systematic study and it should be the focus of additional study. It is possible that the release of various cytokines, associated with infection or other non-rejection inflammatory responses, will result in endothelial cell activation and prominence and even leaking of plasma into interstitial spaces as edema, without the binding of C4d. If true, this would suggest that pAMR1(I+) is more likely associated with DSA than pAMR1(H+). It will be interesting to see if the incidence of graft dysfunction differs in pAMR1(H+) and pAMR1(I+). It is also worth collecting data on pAMR1(I+) and pAMR2,3 indicating if the positive immunologic diagnosis is based on C4d, C3d, and/or CD68 positivity. Again, eventual correlation with DSA and graft function will be very useful in defining the appropriate clinical response to various manifestations of pAMR.

Correlating pAMR with DSA

Studies in both renal and cardiac allograft recipients have shown a positive correlation between C4d staining and circulating donor specific antibodies, making C4d perhaps the best single marker of AMR. However, it should be noted that recent studies in renal allograft recipients have demonstrated C4d negative antibody-mediated rejection in renal allografts (Haas review and 2014 Banff 2013 Meeting Report) so it should be noted that C4d is not an absolute marker of AMR.

Mixed rejection

Although at present there are not sufficient data in the literature, one of the goals for the future is to work on understanding and defining mixed rejection, the relationship between ACR and AMR and the pathways involved when coexisting.

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