C4d revisited

C4d is a byproduct of complement activation in classic and lectin pathway. It is non-functional but served as a robust evidence of antibody-mediated injury. It has been used as a tissue marker for antibody-mediated rejection (AMR) in kidney transplants for more than a decade. Its use has been extended to other transplant organs including heart, lung and pancreas though the liver grafts do not benefit from C4d yet.


A review by Cohen et al. puts the role of C4d as a biologic marker into a perspective. Its pros and cons have been described. Although staining with C4d is considered to be standard in evaluating kidney allograft biopsies, some limitation should be kept in mind. These include:

• C4d negative AMR in which antibody-mediated injury to endothelium occurs by mechanism other than complement activation
•  C4d positivity in ABO-incompatible allograft represent accommodation rather than antibody-mediated rejection
• Uncertainty about significance of focally positive C4d staining by immunofluorescence method

The interest of using C4d as biologic marker has been expanded to non-transplant-related diseases in which the role of complement activation is crucial in their pathogenesis. More intense C4d staining of lupus nephritis could indicates a concurrent thrombotic microangiopathy. C4d positivity in placenta can be used as evidence of antibody-mediated pregnancy loss from autoimmune diseases such as SLE, antiphospholipid syndrome.

The role of C4d could be increased due to the advent of anti-complement therapy or diminished due to the new development of other diagnostic modalities such as genomics, molecular method and endothelial transcript.