Impact of IgG3 subclass and C1q-fixing donor-specific hla alloantibodies on rejection and survival in liver transplantation

Recent literature confirms donor-specific HLA alloantibodies (DSA) impair 5-year survival in some but not all liver transplant recipients. In an effort to improve DSA testing's association with rejection and death, we retrospectively evaluated 1270 liver transplant recipients for the presence of IgG3 and C1q-fixing DSA. In patients with preformed DSA, 29 and 51% had IgG3 and C1q-fixing DSA, respectively. In patients with de novo DSA, 62% and 67% had IgG3 and C1q-fixing DSA, respectively. When different types of DSA positive patients were compared to DSA negative patients, multivariable analysis showed that IgG3 DSA positivity had the highest numerical hazard ratio for death (IgG3: HR=2.4, p<0.001; C1q: HR=1.9, p<0.001; standard DSA: HR=1.6, p<0.001). Similarly, multivariable analysis demonstrated de novo IgG3 DSA positivity compared to no DSA had the highest hazard ratio for death (IgG3: HR=2.1, p=0.004; C1q: HR=1.9, p=0.02; standard DSA: HR=1.8, p=0.007). Preformed C1q-fixing class II DSA showed the strongest correlation with early rejection. In conclusion, preformed and de novo IgG3 subclass DSA positive patients had the highest absolute HR for death in side-by-side comparison with C1q and standard DSA positive versus DSA negative patients; however, IgG3 negative DSA positive patients still had inferior outcomes compared to DSA negative patients. Although all liver transplant recipients with donor-specific alloantibodies (DSA) in serum are at risk for adverse outcomes, preformed and de novo IgG3 subclass DSA-positive patients have the highest absolute hazard ratio for death in side-by-side comparison with C1q and standard DSA-positive versus DSA-negative patients. See editorial by Amico and Schaub on page 861.