Acute cellular rejection results from an interaction between recipient antigen-presenting cells (APCs), recipient T cells, and MHC antigens on donor cells. The T cells become activated, resulting in the transcription of genes for cytokines and cytokine receptors, leading to inflammation in the allograft. Histopathologic findings include interstitial inflammation, predominantly by T lymphocytes, accompanied by tubulitis, which occurs when T cells cross tubular basement membranes and infiltrate tubular epithelium. Inflammation of arteries (endarteritis) may also be noted. It usually begins as endotheliitis, characterized by swelling and detachment of endothelial cells, as well as lymphocyte infiltration of the endothelial layer. In severe cases, transmural vasculitis may occur, in which lymphocytes infiltrate and inflame the entire thickness of the vessel wall. Acute cellular rejection can usually be treated with a pulse of high-dose corticosteroids or, in cases of steroid resistance, antilymphocyte antibodies.

Acute antibody-mediated rejection is less common than acute cellular rejection, and it may result from a previous exposure to a specific antigen, or from de novo reactivity and clonal expansion of reactive B cells. It typically occurs within 2 weeks of transplantation, and the presentation is similar to acute cellular rejection. Patients are found to have antibodies that target donor HLA or ABO-group antigens. Histopathologic findings can range from a subtle form of tubular injury, similar to what is seen in ATN, to dramatic occlusion of glomerular capillaries by neutrophils and fibrin-rich thrombi. One of the most common histologic manifestations of acute antibody-mediated rejection is peritubular capillaritis, characterized by dilation of the interstitial capillaries and margination of leukocytes, most often a combination of neutrophils and lymphocytes. A helpful marker of acute antibody-mediated rejection is the presence of C4d within peritubular capillaries. C4d is a degradation product of complement factor C4 and can be detected using either immunofluorescence or immunohistochemistry. Acute antibody-mediated rejection can be treated with plasmapheresis to remove the antibodies and infusion of intravenous immunoglobulin.