hyperacute graft rejection

**Timing:** Minutes to hours after reperfusion (occasionally up to 24-48 h). The earliest of the rejection types (hyperacute < acute < chronic).

**Mechanism (Type II hypersensitivity, antibody-mediated):** - Preformed recipient IgG (or IgM) antibodies bind donor antigens on graft vascular endothelium: ABO blood group antigens or HLA (MHC class I) antigens. - Sensitization sources: prior transfusion, prior transplant, pregnancy (exposure to paternal HLA), or naturally occurring anti-A/anti-B isohemagglutinins. - Antibody binding activates the classical complement pathway, leading to membrane attack complex formation, endothelial injury and loss of anticoagulant properties, platelet aggregation, and neutrophil recruitment. - Result: widespread intravascular thrombosis, fibrinoid necrosis of vessel walls, and ischemic necrosis of the graft. - It does not require T-cell activation, so the process is not sensitization-dependent in the recipient at the time of transplant (the memory/antibodies already exist).

**Clinical findings:** - Kidney: the graft turns cyanotic, mottled, flaccid, and anuric on the operating table shortly after anastomosis. - Histology: neutrophilic infiltration in glomeruli and capillaries, fibrin-platelet thrombi, arteriolar fibrinoid necrosis, cortical necrosis. Immunofluorescence may show C4d deposition along peritubular capillaries.

**Management/prevention:** - No effective treatment. Immunosuppression does not reverse it. The graft must be removed (graftectomy). - Prevention: ABO compatibility testing, pretransplant crossmatch (recipient serum vs. donor lymphocytes), and panel reactive antibody (PRA) screening. Desensitization protocols (plasmapheresis, IVIG, rituximab) can be used in selected sensitized patients, and ABO-incompatible transplants are sometimes done with such protocols.

**Comparison of rejection types (high-yield):** - **Hyperacute:** minutes to hours; preformed antibodies; type II hypersensitivity; complement-mediated vascular thrombosis/necrosis. - **Acute cellular:** days to weeks (up to months); CD8+ and CD4+ T cells against donor MHC (type IV); lymphocytic infiltrate of the interstitium/tubules (tubulitis); reversible with immunosuppression (steroids, tacrolimus, etc.). - **Acute humoral:** newly formed (de novo) antibodies; vasculitis; C4d positive. - **Chronic:** months to years; both T-cell and antibody-mediated; fibrosis, vascular intimal thickening/obliterative arteriopathy (e.g., chronic allograft nephropathy, bronchiolitis obliterans in lung, accelerated atherosclerosis in heart). - **Graft-versus-host disease:** donor T cells attack the recipient (bone marrow/liver transplant); rash, diarrhea, jaundice.

**Board pearls:** - "Graft turns blue/mottled in the OR" = hyperacute rejection. - Mechanism = preformed antibodies, type II hypersensitivity. - Avoided by cross-matching; unresponsive to immunosuppression.