Endothelial Injury in Renal Antibody-Mediated Allograft Rejection: A Schematic View Based on Pathogenesis

Circulating donor-specific antibodies (DSA) cause profound changes in endothelial cells (EC) of the allograft microvasculature. EC injury ranges from rapid cellular necrosis to adaptive changes allowing for EC survival, but with modifications of morphology and function resulting in obliteration of the microvasculature. Lytic EC injury: Lethal exposure to DSA/complement predominates in early-acute antibody-mediated rejection (AMR) and presents with EC swelling, cell necrosis, denudation of the underlying matrix and platelet aggregation, thrombotic microangiopathy, and neutrophilic infiltration. Sublytic EC injury: Sublethal exposure to DSA with EC activation predominates in late-chronic AMR. Sublytic injury presents with (a) EC shape and proliferative-reparative alterations: ongoing cycles of cellular injury and repair manifested with EC swelling/loss of fenestrations and expression of growth and mitogenic factors, leading to proliferative changes and matrix remodeling (transplant glomerulopathy and capillaropathy); (b) EC procoagulant changes: EC activation and disruption of the endothelium integrity is associated with production of procoagulant factors, platelet aggregation, and facilitation of thrombotic events manifested with acute and chronic thrombotic microangiopathy; and (c) EC proinflammatory changes: increased EC expression of adhesion molecules including monocyte chemotactic protein-1 and complement and platelet-derived mediators attract inflammatory cells, predominantly macrophages manifested as glomerulitis and capillaritis. Throughout the course of AMR, lytic and sublytic EC injury coexist, providing the basis for the overwhelming morphologic and clinical heterogeneity of AMR. This can be satisfactorily explained by correlating the ultrastructural EC changes and pathophysiology. The vast array of EC responses provides great opportunities for intervention but also represents a colossal challenge for the development of universally successful therapies.