Clinical significance of C4d positivity within the first month after heart transplantation in detecting antibody-mediated rejection on endomyocardial biopsies

Background

The pathologic definition for antibody-mediated rejection (AMR) includes both histopathological and immunopathological components. C4d is the most validated diagnostic marker for immunopathologic AMR; however, the clinical significance of early C4d positivity (≤1 month post-transplant) on endomyocardial biopsies (EMBs) is unknown.

Methods

Patients who had ≥1 episode of C4d-positive EMB within the first month after heart transplantation were selected, the coexistence with acute cellular rejection (ACR) and the correlations of C4d positivity with histopathologic features of AMR, clinical graft dysfunction, presence of donor specific antibodies (DSAs), and clinical outcomes were examined.

Results

112 EMBs from 46 patients were qualified and included in the study. 19 patients had single C4d-positive EMB whereas 27 patients developed multiple (2-4) episodes of C4d positivity within the first month. 40 % of C4d-positive EMBs showed concurrent ACR (26 with G1R, 6 with G2R). The C4d positivity correlated well with the histopathologic AMR, with 73 % of C4d-positive EMBs showing all or partial histologic features of AMR. Only 29 % of the C4d-positive EMBs were associated with clinical graft dysfunction, indicating that most early C4d-positive EMBs were clinically asymptomatic. DSAs were found positive in 28 patients (61 %), with preformed DSAs being more common than de novo DSAs. Although no cardiac allograft vasculopathy was observed in any patient, two pediatric patients died of AMR shortly after transplantation whereas three adult patients passed away mostly because of infection.

Conclusion

Heart transplant recipients with C4d-positive EMBs within the first month post-transplant were mainly asymptomatic; combined evaluation including clinical, pathological, and serological testing should be conducted for the best management of AMR.