A comprehensive review of rejection mechanisms, timing, pathophysiology, and the Banff Classification grading system used by transplant pathologists worldwide.
Allograft rejection remains one of the central challenges in transplant medicine. Rejection episodes are classified by their timing, underlying immune mechanism, and histological appearance. Understanding these distinctions is essential for selecting appropriate treatment and predicting graft outcomes.
Hyperacute rejection (HAR) is the most dramatic and historically devastating form of graft rejection. It occurs within minutes to hours of reperfusion and is characterized by immediate graft dysfunction that is not reversible. In the era before reliable cross-matching, hyperacute rejection was a catastrophic outcome that necessitated emergency graft removal.
HAR is mediated by pre-formed, circulating donor-specific antibodies (DSAs) that the recipient already possesses at the time of transplantation. These antibodies arise from prior sensitization events including:
Upon reperfusion of the graft, pre-formed antibodies immediately bind to donor endothelial antigens (primarily HLA class I antigens and ABO antigens). This triggers rapid complement activation via the classical pathway, producing C3a, C4a, and C5a (anaphylatoxins) and the membrane attack complex (MAC, C5b-9).
The cascade results in:
In kidney transplantation, the graft becomes swollen, mottled, and cyanotic within minutes of reperfusion — visibly in the operating room. Urine output ceases immediately. The graft is non-salvageable and must be removed.
In heart transplantation, the organ may fail to resume effective contractile function after reperfusion.
HAR is effectively prevented by:
Due to modern crossmatching protocols, true hyperacute rejection is now exceedingly rare in clinical practice.
Acute cellular rejection is the most common form of rejection in the early post-transplant period, typically occurring within the first days to months after transplantation. Unlike hyperacute rejection, ACR is generally reversible with prompt intensification of immunosuppression.
ACR is primarily mediated by T lymphocytes — both CD4+ helper T cells and CD8+ cytotoxic T cells. The immune response proceeds through two pathways:
Activated CD4+ T cells release pro-inflammatory cytokines (IL-2, IFN-gamma, TNF-alpha) that recruit and activate macrophages, natural killer cells, and CD8+ cytotoxic T cells. CD8+ cells directly kill donor parenchymal cells via perforin/granzyme and Fas/FasL pathways.
In kidney transplants, ACR shows:
Clinical signs include rising serum creatinine, decreased urine output, graft tenderness, fever, and hypertension. However, these signs overlap considerably with other causes of graft dysfunction (infection, drug toxicity, obstruction), making biopsy essential for diagnosis.
First-line treatment is high-dose corticosteroids (pulse methylprednisolone). Steroid-resistant rejection is treated with anti-thymocyte globulin (ATG). Most ACR episodes (70–90%) respond to treatment when diagnosed early.
Antibody-mediated rejection (AMR) occurs when the recipient generates or possesses donor-specific antibodies (DSAs) targeting HLA antigens or other donor endothelial antigens. AMR can be acute or chronic and is increasingly recognized as a major cause of late graft loss. It carries a worse prognosis than pure ACR.
DSAs bind to donor endothelial cells expressing the target HLA antigens, leading to:
AMR diagnosis requires all three criteria:
AMR treatment targets antibody removal and B cell/plasma cell suppression: plasmapheresis, IVIG, rituximab, bortezomib, and complement inhibition (eculizumab). See the Treatments page for detailed protocols.
Chronic rejection is the leading cause of late graft loss, responsible for the gradual deterioration of transplanted organs over months to years. Unlike acute rejection, chronic rejection is largely irreversible once established, as fibrosis replaces functional graft parenchyma.
Chronic rejection results from a combination of immune and non-immune injury:
Immune mechanisms:
Non-immune mechanisms (also contribute to interstitial fibrosis):
In kidney transplants, chronic rejection manifests as interstitial fibrosis and tubular atrophy (IF/TA). Additional features include:
In heart transplants: cardiac allograft vasculopathy (CAV) — diffuse concentric intimal proliferation affecting the entire coronary tree, distinct from native atherosclerosis.
In lung transplants: bronchiolitis obliterans syndrome (BOS) — progressive airflow obstruction from obliterative fibrosis of small airways.
The Banff Classification is an internationally standardized schema for grading allograft pathology. First established in Banff, Canada in 1991, the classification is updated regularly through international consensus conferences. It provides pathologists and clinicians with a common language for reporting and comparing biopsy findings.
Each histological lesion is scored 0–3:
| Lesion | Banff Code | 0 | 1 (Mild) | 2 (Moderate) | 3 (Severe) |
|---|---|---|---|---|---|
| Interstitial infiltrate | i | <10% inflamed cortex | 10–25% | 26–50% | >50% |
| Tubulitis | t | No mononuclear cells in tubules | 1–4 cells/tubule cross-section | 5–10 cells | >10 cells or destruction |
| Intimal arteritis | v | Absent | <25% luminal area | ≥25% luminal area | Transmural arteritis |
| Glomerulitis | g | No glomerulitis | ≤25% glomeruli | 26–75% glomeruli | >75% glomeruli |
| Peritubular capillaritis | ptc | Absent | ≤3 cells/ptc lumen | ≥4 cells, <10% | ≥4 cells, ≥10% ptc |
| Interstitial fibrosis | ci | <6% cortical area | 6–25% | 26–50% | >50% |
| Tubular atrophy | ct | <6% of tubules | 6–25% | 26–50% | >50% |
| Category | Diagnosis | Key Criteria |
|---|---|---|
| 1 | Normal or non-specific changes | No rejection features |
| 2 | Antibody-mediated changes | C4d+, DSA+, microvascular inflammation |
| 3 | Borderline / suspicious ACR | t1–t2 + i1–i2 but insufficient for ACR |
| 4 | T cell-mediated rejection (TCMR) | i2–3 + t2–3 ± v1–3 |
| 5 | Interstitial fibrosis and tubular atrophy | IF/TA with/without inflammation |
| 6 | Other changes | Not due to rejection (drug toxicity, pyelonephritis, recurrence) |
| Feature | Hyperacute | Acute Cellular | Acute AMR | Chronic |
|---|---|---|---|---|
| Timing | Minutes–hours | Days–months | Days–years | Months–years |
| Mediator | Pre-formed DSAs + complement | T cells (CD4+ / CD8+) | De novo DSAs + complement | T cells + DSAs + non-immune |
| Reversibility | No — graft loss | Yes (70–90% with treatment) | Partial (30–60%) | No (fibrosis permanent) |
| Key histology | Thrombosis, infarction | Tubulitis, interstitial infiltrate | Microvascular inflammation, C4d | IF/TA, transplant glomerulopathy |
| Prevention | Crossmatch, ABO typing | Maintenance IS, monitoring | DSA surveillance, adherence | Optimal IS, risk factor management |
| Treatment | Graft removal | Pulse steroids, ATG | PLEX, IVIG, rituximab | No cure; slow progression |
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