**4.1 Acute humoral rejection**

Humoral rejection is a form of allograft injury and subsequent dysfunction that is primarily mediated by antibodies and complement. The antibodies involved are either preformed antibodies or anti-donor antibodies that develop following transplantation. Proteinuria is associated with donor-specific antibody detection; it is likely an important factor in the rapid decline in glomerular filtration rates and early graft failure in patients that develop de novo anti-HLA antibodies. The presence of even low levels of donor-specific antibodies, which may not be detected by complement-dependent cytotoxic and flow cytometry crossmatches, have been shown to be associated with inferior allograft outcomes. These patients may require augmented immunosuppression.

Following transplantation, the inactive product C4d from the classical complement activation pathway is deposited in peritubular capillaries (PTC); immune detection of this product in allograft biopsies is used for the diagnosis of antibody-mediated rejection. However, one study reported substantial fluctuations in C4d Banff scores in the first year following transplantation[8]; these authors suggested that these results may reflect the dynamic and unpredictable nature of the humoral process. Thus, C4d by itself may not be a sufficiently sensitive indicator, and detection of microvascular inflammation utilizing donor-specific antibodies may be more useful for diagnosing antibody-mediated rejection.
