acute graft rejection

**Timing:** Days to weeks after transplant (classically <6 months, but can occur later if immunosuppression is reduced or nonadherence occurs). Distinguish from hyperacute (minutes–hours), chronic (months–years).

**Pathophysiology:** - *Cellular (T-cell–mediated) rejection – most common type:* Recipient CD4+ and CD8+ T cells recognize donor MHC class I/II on graft cells (direct allorecognition: donor APCs present donor MHC; indirect: recipient APCs present processed donor peptides). CD8+ cytotoxic T cells kill graft cells; CD4+ Th1 cells drive delayed-type hypersensitivity (type IV) and macrophage activation. Costimulation (CD28–B7) and IL-2 signaling are key (basis for calcineurin inhibitor, belatacept, and anti-CD25 therapy). - *Humoral (antibody-mediated) rejection:* Newly formed (de novo) anti-donor HLA or anti-ABO antibodies → complement activation (C4d deposition), endothelial injury, vasculitis, thrombosis (type II hypersensitivity). Often more severe and less responsive to steroids. - Often both mechanisms coexist.

**Histology:** - Cellular: lymphocytic interstitial infiltrate, tubulitis (kidney), endothelialitis/intimal arteritis (Banff classification); in the heart, lymphocytic infiltrate with myocyte damage; liver – portal inflammation, bile duct damage, endothelialitis; lung – perivascular lymphocytic infiltrates. - Humoral: vasculitis/neutrophilic capillaritis, C4d positivity on peritubular capillaries, fibrinoid necrosis.

**Clinical features (organ-specific):** - Kidney: ↑ creatinine, oliguria, graft tenderness/swelling, HTN, fever (often asymptomatic on immunosuppression). - Liver: ↑ LFTs/bilirubin, jaundice. - Heart: heart failure, arrhythmias; surveillance by endomyocardial biopsy. - Lung: dyspnea, decreased FEV1, infiltrates.

**Diagnosis:** Biopsy of the graft is the gold standard (rule out other causes of dysfunction such as CNI toxicity, infection—e.g., BK virus, CMV—and obstruction/vascular problems). Donor-specific antibody (DSA) testing and C4d staining for antibody-mediated rejection.

**Treatment:** - Cellular: pulse high-dose IV corticosteroids; steroid-resistant → anti-thymocyte globulin (polyclonal) or OKT3 (historical). - Antibody-mediated: plasmapheresis, IVIG, rituximab, ± eculizumab/bortezomib. - Optimize maintenance immunosuppression (tacrolimus, mycophenolate, prednisone).

**Prevention/Prophylaxis:** HLA/ABO matching, crossmatching (prevents hyperacute rejection), induction therapy (basiliximab = anti-CD25, ATG), maintenance triple therapy.

**Key immunosuppressant mechanisms (high-yield):** - Tacrolimus/cyclosporine: calcineurin inhibitors → ↓ IL-2 transcription (nephrotoxicity, neurotoxicity, HTN, hyperglycemia/tremor for tacrolimus). - Mycophenolate: inhibits IMP dehydrogenase → ↓ guanine synthesis (marrow suppression, GI upset). - Azathioprine: purine antimetabolite (6-MP; toxicity ↑ with allopurinol; TPMT). - Sirolimus: mTOR inhibitor (↓ IL-2 response; hyperlipidemia, impaired wound healing). - Belatacept: CTLA-4-Ig blocks CD28–B7 costimulation.

**Comparison of rejection types:** - Hyperacute: minutes–hours; preformed antibodies (type II); thrombotic occlusion, graft cyanosis/necrosis; irreversible → graft removal. - Acute: weeks–months; T-cell (and/or antibody); reversible with immunosuppression. - Chronic: months–years; CD4+ T cell/antibody-mediated, with cytokine-driven fibrosis; vascular intimal thickening/obliterative changes (atherosclerosis in heart, bronchiolitis obliterans in lung, vanishing bile duct in liver, interstitial fibrosis/tubular atrophy in kidney); poorly responsive to treatment. - Graft-versus-host disease: donor T cells attack host tissue (bone marrow/liver transplant; skin, gut, liver involvement).

**Board pearl:** A kidney transplant recipient 2–8 weeks post-op with rising creatinine and a biopsy showing lymphocytic infiltrate with tubulitis → acute cellular rejection → treat with high-dose steroids.