De Novo Donor HLA-Specific Antibodies after Heart Transplantation Are an Independent Predictor of Poor Patient Survival

Abstract

Preformed donor HLA-specific antibodies are a known indicator for poor patient survival after cardiac transplantation. The role of de novo donor-specific antibodies (DSA) formed after cardiac transplantation is less clear. Here we have retrospectively analyzed 243 cardiac transplant recipients, measuring HLA antibody production every year after transplantation up to 13 years post-transplant. Production of de novo DSA was analyzed in patients who had been negative for DSA prior to their transplant. DSA including transient antibodies were associated with poor patient survival (p = 0.0018, HR = 3.198). However, de novo and persistent DSA was strongly associated with poor patient survival (p = 0.0001 HR = 4.351). Although complement fixing persistent DSA correlated with poor patient survival, this was not increased compared to noncomplement fixing persistent DSA. Multivariable analysis indicated de novo persistent DSA to be an independent predictor of poor patient survival along with HLA-DR mismatch and donor age. Only increasing donor age was found to be an independent risk factor for earlier development of CAV. In conclusion, patients who are transplanted in the absence of preexisting DSA make de novo DSA after transplantation which are associated with poor survival. Early and regular monitoring of post-transplant DSA is required to identify patients at risk of allograft failure.

De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation

“…In multivariable analyses, de novo DSA was found to be an independent predictor for development of BOS1, BOS2 and BOS3, as well as being an independent predictor for poor patient survival. These findings are similar to those seen in both renal 10,16 and cardiac 12,17 transplant studies. In a large study of renal allografts, Lachmann et al showed that DSA detected post-transplant using Luminex single-antigen bead assays were associated with significantly reduced graft survival, 10 whereas we previously found de novo DSA after cardiac transplantation to be an independent predictor of poor patient survival.…”

“…In both renal and cardiac transplantation there is evidence that development of HLA-specific antibodies, particularly if donorspecific, are associated with poor graft survival. [10][11][12] The development of BOS is the major cause of death beyond the first year after lung transplantation. 1,13 BOS is defined according to loss of lung function (forced expiratory volume in 1 second [FEV 1 ]) in proportion to maximal baseline value obtained post-transplantation in the absence of known acute causes of declining FEV 1 , such as acute rejection and infection.…”

Current Concepts in Histocompatibility During Heart Transplant

“…33 Several recent reports have emphasized the clinical effect not only of preformed, but also especially of de novo anti-HLA alloantibodies on graft outcomes in heart transplant recipients. [33][34][35] In particular, de novo anti-HLA donor-specific antibody development was associated with increased rejection, CAV, and poor survival. 30,31,36 Indeed, antibodies against class I or class II antigens seem to have negative effects.…”

“…39 Recent studies have demonstrated that most de novo donor-specific antibodies were directed against class II antigens, while an analysis of all de novo antibodies produced after transplant, showed an equal proportion of class I and II antibodies. 35,40 Furthermore, inflammatory events, caused by class II HLA up-regulation on endothelial cells, make graft endothelium vulnerable to donor-specific anti-HLA antibodies. 41 It has been shown that class I anti-HLA antibodies, binding to endothelial cells, induce tyrosine kinase phosphorylation, playing a pivotal role in regulating cell survival through activation of PI3K and protein kinase B (PKB) pathways and expression of anti-apoptotic proteins such as Bcl-2.…”

“…Antibody-mediated rejection is complemented by cell-mediated immune responses, which involve direct and indirect recognition pathways. 31,35 Furthermore, a better understanding of the interaction between cellular and antibodymediated responses against the graft could allow early modification and customization of the immunosuppressive therapy in transplant.…”