Complement-Binding Anti-HLA Antibodies and Kidney-Allograft Survival

TLDR

Anti‑HLA antibodies impair transplantation success, partly through complement activation that drives antibody‑mediated rejection. The study examined whether complement‑binding anti‑HLA antibodies contribute to kidney‑allograft failure. The authors screened 1,016 kidney‑transplant recipients for circulating donor‑specific anti‑HLA antibodies and their complement‑binding capacity, and evaluated graft injury phenotype and time to loss. Complement‑binding donor‑specific anti‑HLA antibodies were associated with a markedly higher risk of graft loss (5‑year survival 54 % vs 93–94 %, HR 4.78), increased rejection and microvascular injury, and improved risk stratification when added to traditional models.

Abstract

Anti-HLA antibodies hamper successful transplantation, and activation of the complement cascade is involved in antibody-mediated rejection. We investigated whether the complement-binding capacity of anti-HLA antibodies plays a role in kidney-allograft failure.We enrolled patients who received kidney allografts at two transplantation centers in Paris between January 1, 2005, and January 1, 2011, in a population-based study. Patients were screened for the presence of circulating donor-specific anti-HLA antibodies and their complement-binding capacity. Graft injury phenotype and the time to kidney-allograft loss were assessed.The primary analysis included 1016 patients. Patients with complement-binding donor-specific anti-HLA antibodies after transplantation had the lowest 5-year rate of graft survival (54%), as compared with patients with non-complement-binding donor-specific anti-HLA antibodies (93%) and patients without donor-specific anti-HLA antibodies (94%) (P<0.001 for both comparisons). The presence of complement-binding donor-specific anti-HLA antibodies after transplantation was associated with a risk of graft loss that was more than quadrupled (hazard ratio, 4.78; 95% confidence interval [CI], 2.69 to 8.49) when adjusted for clinical, functional, histologic, and immunologic factors. These antibodies were also associated with an increased rate of antibody-mediated rejection, a more severe graft injury phenotype with more extensive microvascular inflammation, and increased deposition of complement fraction C4d within graft capillaries. Adding complement-binding donor-specific anti-HLA antibodies to a traditional risk model improved the stratification of patients at risk for graft failure (continuous net reclassification improvement, 0.75; 95% CI, 0.54 to 0.97).Assessment of the complement-binding capacity of donor-specific anti-HLA antibodies appears to be useful in identifying patients at high risk for kidney-allograft loss.