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To the Editor:

The letter to the editor by Fedrigo et al. (1) provides us with an opportunity to emphasize some important points covered in our recent paper (2). The authors raise the issue of relevance of the entity defined in our study by intravascular macrophages and circulating Anti-HLA donor-specific antibodies (DSA) without C3d/C4d deposition, and how this should be interpreted. We agree that this is a very timely point that is currently under discussion in the setting of kidney transplantation by the Banff classification group. Importantly, this new entity seems not to be restricted to kidney allografts (3,4), as suggested by a prospective study performed in 280 unselected heart endomyocardial biopsies (EMB), where intravascular macrophages without complement deposition was observed in 5.3% of EMB, but interestingly, 83.3% of which were associated with concomitant DSA (5). This suggests that the detection of C3d/C4d deposition in capillaries may not be sensitive enough to diagnose antibody-mediated rejection (ABMR) in some cases.

Several hypotheses may be put forward concerning the lack of complement deposition despite the evidence of MI and DSA in EMB. The low sensitivity of C3d/C4d can be related to technical issues including the type of fixative used and the different methods of C4d and C3d detection (IF-vs-IHC). Also, antibodies may have low affinity to fix complement, but are nonetheless able to activate the endothelial cells. Other authors have postulated the existence of a complement-independent pathway. Another explanation that may gain importance over the next few years is that the therapeutic agents used in high-risk patients (5) may modify the clinical and histological presentation of ABMR.

In their letter, the authors question the relevance of tracing intravascular macrophages as a marker for ABMR in the absence of tissue complement deposition (1). While we fully agree with this statement and the fact that MI without complement deposition may can be observed in cases of TCMR, it seems to us that there can be no question that MI in the presence of circulating DSA may represent at least in part an antibody participation in the rejection process (as underlined by the authors, we have cases that would qualify as mixed rejection).

The question that the authors raise about the absence of differences in terms of chronic allograft vasculopathy (CAV) progression between MI+ and MI– late rejections, which is likely due to the small sample size, has already been discussed and acknowledged in the manuscript.

Finally, our experience in heart recipients mirrors the kidney transplant literature and the growing evidence, that beyond the importance of complement deposition in the peritubular capillaries, C4d-negative kidneys can also manifest features of antibody-mediated injury that contribute ultimately to allograft loss (3,4). We believe that this concept will not only be confined to kidney transplantation but also expanded to the heart transplant population.

Further studies are needed to ascertain and refine the criteria of ABMR in heart recipients and particularly the clinical relevance of intravascular macrophages with circulating DSA in the absence of complement deposition. A better assessment and classification of rejection phenotypes is a mandatory step to understand the specific causes of late heart allograft loss and, particularly, ABMR.

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The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

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