Association between C4d staining in renal transplant biopsies, production of donor-specific HLA antibodies, and graft outcome

Background. We carried out a retrospective study of C4d staining in paraffin sections from renal transplant biopsies to determine the association between C4d staining, donor-specific antibodies (DSA), histological features, and graft outcome. Methods. We studied 92 patients who had been biopsied for graft dysfunction. Biopsies were classified using Banff 97 criteria and features suggestive of antibody-mediated rejection were noted. Paraffin sections were stained with a polyclonal antibody using an immunoperoxidase technique. The presence of DSA in concurrent sera was determined by enzyme-linked immunosorbent assay and clinical data were reviewed. Results. Of the 92 cases, 15% showed diffuse and 24% showed focal C4d positivity. The grafts failed in 36% of the diffuse (P < 0.025), 23% of the focal, and 7% of the negative group at between one month and 15 years posttransplantation. Only patients in the group with diffuse C4d positivity had concurrent DSA (five cases, P < 0.001). Of the five DSA-positive patients, three had type 11 acute rejection and two of these transplants subsequently failed. The remaining two had chronic allograft nephropathy with features of alloimmune injury. Only two of the nine DSA-negafive/C4d-positive transplants had failed at the time of writing, in one case due to recurrent disease. Conclusion. We demonstrated a significant association between diffuse C4d staining, production of DSA, and graft failure. Although the concurrent detection of DSA and C4d positivity is uncommon in our patients, these results indicate that outcome in this group is poor and they may benefit from therapies directed at the humoral response.