Understanding the Correlation Between DSA, Complement Activation, and Antibody-Mediated Rejection in Heart Transplant Recipients

Abstract

Background: Donor-specific HLA antibodies (DSA) are associated with increased rates of rejection and of graft failure in cardiac transplantation. The goal of this study was to determine the association of preformed and posttransplant development of newly detected DSA (ndDSA) with antibody-mediated rejection (AMR) and characterize the clinical relevance of complement-activating DSA in heart allograft recipients.

Methods: The study included 128 adult and 48 pediatric heart transplant patients transplanted between 2010 and 2013. Routine posttransplant HLA antibody testing was performed by IgG single-antigen bead test. The C3d single-antigen bead assay was used to identify complement-activating antibodies. Rejection was diagnosed using International Society for Heart and Lung Transplantation criteria.

Results: In this study, 22 patients were transplanted with preexisting DSA, and 43 patients developed ndDSA posttransplant. Pretransplant (P < 0.05) and posttransplant (P < 0.001) ndDSA were associated with higher incidence of AMR. Patients with C3d + DSA had significantly higher incidence of AMR compared with patients with no DSA (P < 0.001) or patients with C3d-DSA (P = 0.02). Nine (36%) of 25 patients with AMR developed transplant coronary artery disease compared with 17 (15.9%) of 107 patients without AMR (P < 0.05). Among the 47 patients who received ventricular assistant device (VAD), 7 of 9 VAD+ patients with preformed DSA experienced AMR compared with 7 of 38 VAD+ patients without preformed DSA, indicating presensitization to donor HLA significantly increased the risk of AMR (P < 0.01).

Conclusions: Preformed and posttransplant ndDSA were associated with AMR. C3d + DSA correlates with complement deposition on the graft and higher risk of AMR which may permit the application of personalized immunotherapy targeting the complement pathway.

Figure 1. Incidence of ndDSA

1a) Cumulative incidence of ndDSA stratified in pediatric and adult patients. Solid line: pediatric patients; Dashed line: adult patients (log-rank: p = 0.72). 1b) Time to the first appearance of posttransplant ndDSA. The time to the first appearance of ndDSA was plotted on 56 patients. Patients that were transplanted with or without VAD were categorized into 3 groups. 1) Patients transplanted with preformed DSA that developed additional ndDSA (Preformed DSA+; n=13); 2) Sensitized patients with no HLA DSA (Sensitized DSA−; n=23); 3) Nonsensitized patients (n=20). y axis: Month to the development of first ndDSA. Whiskers indicate 95% confidence interval. Median values indicated by horizontal lines. Significance was calculated using 1-way Anova among the 3 groups or unpaired T test between 2 groups. 1c) Cumulative incidence of ndDSA stratified according to patient’s sensitization history. The cumulative incidence of ndDSA was plotted on 3 groups. 1) Nonsensitized patients; 2) Sensitized patients transplanted without preformed DSA; 3) Patients transplanted with preformed DSA (log-rank: p < 0.01). 1d) Cumulative incidence of ndDSA stratified according to induction therapy. Solid line: patient received induction therapy; Dashed line: patient without induction therapy (log-rank: p = 0.65). VAD: ventricular assistant device; DSA: donor specific antibody; ndDSA: newly developed DSA

Figure 2. Correlation of Immunodominant IgG DSA with C3d DSA positivity

The MFI of the Immunodominant IgG DSA was plotted according to C3d DSA positivity of 35 patients with concurrent biopsy results. Patients with C3d−DSA had median IgG−DSA MFI of 3474 ± 537. Patients C3d+DSA had had median IgG−DSA MFI of 10383 ± 1497 (p < 0.01). The statistical different of the IgG−DSA MFI values between C3d+DSA and C3d−DSA was performed using unpaired T test. DSA: donor specific antibody; MFI: median fluorescence intensity.

Figure 3

Kaplan-Meier curve comparing survival between heart transplant recipients with and without AMR in all patients. 3a). Solid line: AMR negative; dotted line: AMR positive. 3b). Kaplan-Meier curve comparing survival in heart transplant recipients with preformed DSA, ndDSA and no DSA. Solid line: no DSA; dotted line: ndDSA; dashed line: preformed DSA. Kaplan-Meier survival analysis was performed using multiple-record survival data showing freedom from TCAD 1 year after transplantation. AMR: antibody mediated rejection; DSA: donor specific antibody; ndDSA: newly developed donor specific antibody; TCAD: transplant coronary artery disease.