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

BackgroundAnti-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. MethodsWe 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. ResultsThe 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). ConclusionsAssessment 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. This study showed that assessment of the complement-binding capacity of donor-specific anti-HLA antibodies may help identify patients at high risk for kidney-allograft loss and may improve risk stratification to guide treatment. Despite considerable advances in transplantation, the induced alloimmune response remains a major determinant of late kidney-allograft loss.(1)-(3) In the United States and Europe, thousands of kidney transplants fail each year, and kidney-allograft failure is a major cause of end-stage renal disease, leading to increased morbidity, mortality, and costs.(4),(5) One of the most important advances in transplantation medicine has been the recognition that anti-HLA antibodies are destructive.(6)-(10) Various studies over the past decade have indicated that the alloimmune response, mediated by anti-HLA antibodies, plays a key role in the failure of kidney allografts; this concept has been extended ...