chronic graft rejection

**Timing:** Months to years post-transplant (contrast: hyperacute = minutes to hours; acute = weeks to months, typically within first 6 months).

**Pathophysiology:** - Combination of cell-mediated and antibody-mediated (humoral) immune responses against donor alloantigens (MHC/HLA class I and II), often with non-immune contributors (ischemia-reperfusion injury, hypertension, hyperlipidemia, CMV infection, calcineurin-inhibitor toxicity). - Indirect pathway of allorecognition predominates: recipient APCs process and present donor MHC peptides to recipient CD4+ T cells. These cells secrete cytokines (e.g., IFN-γ, TGF-β) and activate macrophages, causing chronic inflammation. Growth factors drive smooth muscle proliferation and fibrosis. - Donor-specific antibodies cause chronic endothelial injury (chronic antibody-mediated rejection, often with C4d deposition). - Net result: concentric intimal proliferation, vascular narrowing, ischemia, interstitial fibrosis, and parenchymal atrophy.

**Organ-specific manifestations (high-yield):** - **Kidney:** Chronic allograft nephropathy / interstitial fibrosis and tubular atrophy (IF/TA); transplant glomerulopathy (duplicated GBM); gradual rise in creatinine, proteinuria, hypertension. - **Heart:** Cardiac allograft vasculopathy (diffuse concentric coronary artery narrowing). Because the heart is denervated, patients often lack angina, so presentation may be heart failure, arrhythmia, or sudden death. - **Lung:** Bronchiolitis obliterans syndrome, with progressive obstructive airflow decline (falling FEV1), dyspnea, and cough. - **Liver:** Vanishing bile duct syndrome (ductopenia) with cholestasis, plus obliterative arteriopathy.

**Histology:** Obliterative intimal fibrosis/arteriosclerosis, interstitial fibrosis, atrophy, and mononuclear infiltrates.

**Clinical significance/management:** - A leading cause of late graft loss. - Largely irreversible and relatively resistant to standard immunosuppression; the damage is fibrotic rather than acutely inflammatory. - Management: optimize immunosuppression (e.g., minimize CNI toxicity, consider switching to mTOR inhibitors such as sirolimus/everolimus, which may reduce vasculopathy), control BP/lipids, treat CMV, and monitor for donor-specific antibodies. Retransplantation is the definitive therapy in advanced disease.

**Comparison of rejection types:** - *Hyperacute:* Preformed antibodies (type II hypersensitivity); ABO or HLA mismatch; complement activation, thrombosis, and necrosis. Graft must be removed. - *Acute cellular:* CD8+ and CD4+ T-cell-mediated (type IV); lymphocytic infiltrate, endothelialitis, tubulitis; reversible with immunosuppression. - *Acute humoral:* De novo antibodies; vasculitis with C4d deposition. - *Chronic:* Mixed immune and non-immune; fibrosis and vascular obliteration; irreversible.

**Boards pearls:** "Obliterative" is the keyword (bronchiolitis obliterans, vasculopathy, vanishing bile ducts). Chronic rejection is not prevented well by current immunosuppression, which mainly targets acute T-cell responses. Graft-versus-host disease is a separate process (donor immune cells attack the host) and is not chronic graft rejection.