Early and late antibody mediated rejection: Which game is the complement playing?

The role of the complement system in antibody mediated rejection (AMR) emerged in the last decades, and the demonstration of the presence of complement fragments in renal allograft biopsies is a consolidated diagnostic sign of AMR. However, antibodies against donor antigens may lead to microvascular inflammation and endothelial injury even in the absence of complement activation, and growing evidence suggests that complement-independent mechanisms may be prominent in late (i.e., occurring >6 months after transplantation) vs early AMR. Different donor specific antibodies (DSA) with different biological features and complement activation ability may be involved in late or early AMR. Downregulation of tissue complement inhibitors may happen early after transplantation, partially due to ischemia reperfusion injury, and could facilitate complement activation in early vs late AMR. Clinical and histological features of late AMR and C4d negative AMR seem to converge, and this narrative review analyzes the evidence that supports lower complement activation in late vs early AMR, including differential C4d staining prevalence based on the time after transplantation, differential response to anti-complement therapy and other direct and indirect signs of the complement system activation. The therapeutic approach in early vs late AMR should take into account possible differences in the pathophysiological mechanisms of microvascular inflammation and endothelial injury in early vs late AMR.