Acute antibody-mediated rejection after lung transplantation

Abstract

Background: Antibody-mediated rejection (AMR) after lung transplantation remains enigmatic, and there is no consensus on the characteristic clinical, immunologic and histologic features.

Methods: We performed a retrospective, single-center cohort study and identified cases of acute AMR based on the presence of circulating donor-specific human leukocyte antigen (HLA) antibodies (DSA), histologic evidence of acute lung injury, C4d deposition and clinical allograft dysfunction.

Results: We identified 21 recipients with acute AMR based on the aforementioned criteria. AMR occurred a median 258 days after transplantation; 7 recipients developed AMR within 45 days of transplantation. All patients had clinical allograft dysfunction, DSA, histology of acute lung injury and capillary endothelial C4d deposition. Fifteen recipients improved clinically and survived to hospital discharge, but 6 died of refractory AMR. One survivor had bronchiolitis obliterans syndrome at the time of AMR diagnosis; 13 of the 14 remaining survivors developed chronic lung allograft dysfunction (CLAD) during follow-up. Overall, 15 recipients died during the study period, and the median survival after the diagnosis of AMR was 593 days.

Conclusions: Acute AMR can be a fulminant form of lung rejection, and survivors are at increased risk of developing CLAD. The constellation of acute lung injury, DSA and capillary endothelial C4d deposition is compelling for acute AMR in recipients with allograft dysfunction. This clinicopathologic definition requires validation in a multicenter cohort, but may serve as a foundation for future studies to further characterize AMR.

Keywords: C4d deposition; acute antibody-mediated rejection; chronic lung allograft dysfunction; donor specific antibodies; human leukocyte antigen antibodies; lung transplantation.

Figure 1. Study design and case selection. AMR, antibody-mediated rejection; DSA, donor-specific anti-human leukocyte antigen antibody

Figure 2

Histopathological findings in AMR. (A) Diffuse alveolar damage with hyaline membrane (arrows) formation (original magnification 400×) (B) Capillary injury with capillaritis (arrows) and hyaline membrane (star) formation (original magnification 400×) (C) Neutrophilic infiltrate (arrows) of the alveolar septa (original magnification 400×) (D) Circumferential C4d staining (arrows) of the capillary endothelium (original magnification 400×)

Figure 3

Kaplan-Meier curves of freedom from chronic lung allograft dysfunction (CLAD) after diagnosis of antibody mediated rejection (AMR): (A) All patients (B) Comparing those who cleared donor specific antibodies (DSA) versus those with persistent DSA.

Figure 4

Kaplan-Meier curves of survival after diagnosis of antibody-mediated rejection (AMR): (A) All patients (B) Comparing those who cleared donor specific antibodies (DSA) versus those with persistent DSA.

Figure 5

Kaplan-Meier curves of survival comparing those with antibody mediated rejection (AMR) by all four criteria versus those with allograft dysfunction and donor specific antibodies (DSA) without C4d deposition. Note that it is not clear that the 26 patients without C4 deposition all had the same syndrome, but likely represents a heterogeneous group with different causes of allograft dysfunction.