Transplantation of kidneys into ABO-incompatible or HLA-sensitized individuals has historically been prohibited because of the risk of antibody-mediated rejection (ABMR). The most severe variant of ABMR is hyperacute rejection, representing fixation of preformed alloantibody to the microcirculation, but a burst of alloantibody from an anamnestic response can also create severe graft damage. ABMR is characterized by neutrophilic capillaritis, glomerular/arteriolar thrombi, and C4d deposition in peritubular capillaries (PTC), which occurs with both anti-HLA and anti-ABO antibodies.
With more than 6000 of the 45 676 people listed on OPTN/SRTR waiting list displaying panel-reactive antibody >80% (1), there is a growing will to transplant the sensitized patient. Recently, several new protocols have emerged to reduce preformed alloantibody and suppress alloantibody formation in such patients, utilizing a variety of combinations of plasmapheresis, immunoadsorption, IVIG, and anti-CD20 antibody together with splenectomy (in the case of ABO-incompatible transplants) (2). These protocols have permitted transplantation of some high-risk persons with good intermediate term results, but the incidence of early acute rejection in a positive crossmatch (+XM) or ABO-incompatible grafts is high: ABMR occurs in 19–58% of patients (3–5).
The paper of Haas et al. (6) in this issue of AJT reports that C4d deposition in biopsies from +XM renal allografts, including protocol biopsies, is usually associated with clinical or subclinical acute ABMR, but there is no such correlation between C4d staining and histologic changes in most ABO-incompatible grafts. In this report, 26% of all the protocol biopsies performed at 1–12 months and 60% of biopsies from dysfunctioning +XM grafts showed C4d staining, and 92% of C4d positive biopsies had histologic lesions of acute ABMR. In contrast, 80% of protocol biopsies and 59% of biopsies for graft dysfunction from ABO-incompatible grafts showed C4d positivity, and only 11% of C4d+ biopsies (4% of protocol biopsies and 29% of cause biopsies) had histologic changes suggestive of ABMR. The authors found C3d staining more predictive of neutrophilic capillaritis than C4d in ABO-incompatible grafts.
Thus some patients with ABO-incompatible grafts within 1 year of post-transplantation have positive C4d and detectable titers of antibody without evidence of graft injury. Resistance to antibody-mediated injury has been observed in a number of experimental and human ABO-incompatible or +XM allografts, a condition termed ‘accomodation,’ implying that the endothelium has developed resistance to antibody-mediated injury (7,8). However, Fidler et al. (4) reported C4d deposition with histologic abnormalities in 15 of 127 protocol biopsies from 32 ABO-incompatible allografts, suggesting that accommodation in the presence of anti-ABO antibodies is not often complete. Further studies are needed to determine whether true accomodation occurs, or whether the presence of such antibodies in the absence of classical histologic changes simply reflects subtle allograft injury over a long time frame.
The encouraging early outcomes in +XM grafts should not obscure the need to document the long-term risks of rejection and graft loss (9). Thus the study of Gloor et al. (10) in this issue sought evidence of the contribution of prior acute ABMR for the development of chronic graft injury, particularly transplant glomerulopathy (TG) in incompatible allografts. The authors report that the incidence of TG in protocol biopsies at 1-year post-transplant from +XM and ABO-incompatible alllografts is increased in comparison to conventional allografts (22% vs. 13% vs. 8%, respectively). Furthermore, they found prior acute ABMR is an independent predictor for TG: 44% of +XM patients with a history of ABMR subsequently developed TG. Similar to observations by Haas et al. (6), these investigators also observed a frequent C4d deposition and anti-HLA/anti-ABO antibody in both groups, but none of these were correlated with TG.
The paper by Smith et al. (11) on primates with long-surviving kidney allografts offers reassurance that long-standing alloantibody responses can produce TG. They also concluded that alloantibodies (probably against MHC antigens) are associated with C4d staining and graft damage, rather than “durable accommodation.”
While the messages of these papers are kidney-specific, the phenotype of alloantibody-mediated injury is being established in other organs. For example, the role of alloantibodies in the pathogenesis of heart transplant arterioscierosis is reviewed in the minireview by Soleimani et al. (12).
The effect of alloantibody against a transplant, in association with C4d staining, will ultimately have to be established by long-term follow-up. There is likely to be an influence of antibody specificity (anti-ABO being less aggressive than anti-HLA), titer and rate of binding, antigen expression, and above all time. The levels of antibody and complement deposition sufficient to evoke chronic endothelial injury in some individuals could be too low in some others. In any case the question of whether patients with C4d staining and circulating alloantibody, even against ABO antigens, are truly safe from late deterioration must remain open and the long-term consequences of ABMR and persistent antibody must be studied in greater detail. Recently, alternative strategies, i.e., live donor exchange and Acceptable Mismatch programs have emerged to expand the donor pool in case of incompatibility and though their infancy find compatible donors that obviate the need for immunotherapy (13,14). Therefore, while the immunotherapy declaration of victory awaits long-term reports, in the mean time these alternative strategies need to be promoted and optimized for patients.