C4d is the degradation product of the activated complement factor C4. Following activation and degradation of the C4 molecule, thioester groups are exposed which allow transient, covalent binding of the degradation product C4d to endothelial cell surfaces and extracellular matrix components of vascular basement membranes near the sites of C4 activation. C4d is also found in intracytoplasmic vacuoles of endothelial cells. Covalent binding renders C4d a stable molecule that can easily be detected by immunohistochemistry.

Feucht et al. were the first to demonstrate the occurrence of capillary C4d staining in kidney allografts and its association with inferior graft outcomes, and later confirmed by other studies. It was demonstrated that patients with suspected antibody-mediated injury in the renal graft had a linear C4d staining pattern in peritubular capillaries and that the presence of C4d was associated with impaired graft function. Except kidney allografts, little is known currently about C4d accumulation in other solid organ allografts. Preliminary data suggest that heart allografts are comparable with kidney transplants. C4d was found in early posttransplant endomyocardial biopsies and was associated with poor graft survival. In dysfunctioning lung transplants, C4d could be detected in septal capillaries. C4d has also been found in liver allografts carrying a diagnosis of antibody-mediated rejection.

In 2003, C4d was incorporated in the Banff classification, the accumulation of C4d along peritubular capillaries is generally regarded as a marker for an antibody-mediated alloresponse and is associated with poor graft survival.