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Transplant Pathology: Kidney and Liver Allograft Rejection
Introduction
Transplant pathology is a specialized field requiring expertise in the recognition and grading of allograft rejection, drug toxicity, recurrent disease, and other complications. Standardized classification systems (Banff for kidney, Banff for liver) provide a common framework for diagnosis and guide therapeutic decisions.
Kidney Allograft Pathology
Banff Classification Overview
The Banff classification is an international consensus classification updated biennially at the Banff Conference on Allograft Pathology. Categories include normal, antibody-mediated rejection (AMR), T-cell-mediated rejection (TCMR), borderline changes, interstitial fibrosis/tubular atrophy (IFTA), and other findings (drug toxicity, BK nephropathy, recurrent disease). Diagnosis requires integration of histology, serology (DSA), and C4d staining.
T-Cell-Mediated Rejection (TCMR)
Acute TCMR manifests as tubulointerstitial inflammation and tubulitis. The Banff criteria score tubulitis (t), interstitial inflammation (i), and intimal arteritis (v). Grade IA shows significant interstitial inflammation (i2 or i3) with moderate tubulitis (t2). Grade IB shows significant interstitial inflammation with severe tubulitis (t3). Grade IIA demonstrates mild-to-moderate intimal arteritis (v1). Grade IIB shows severe intimal arteritis (v2, with more than 25% luminal occlusion). Grade III features transmural arteritis and/or arterial fibrinoid necrosis (v3).
| Banff Grade | Key Histologic Findings | |
|---|---|---|
| IA | Interstitial inflammation (i2/i3) + moderate tubulitis (t2) | |
| IB | Interstitial inflammation (i2/i3) + severe tubulitis (t3) | |
| IIA | Mild-to-moderate intimal arteritis (v1) | |
| IIB | Severe intimal arteritis (v2, >25% luminal occlusion) | |
| III | Transmural arteritis and/or fibrinoid necrosis (v3) | Chronic active TCMR is characterized by transplant arteriopathy with mononuclear cell infiltration of the fibrotic intima. |
Antibody-Mediated Rejection (AMR)
AMR is mediated by donor-specific antibodies (DSA) against HLA or non-HLA antigens. Three diagnostic criteria must all be present for diagnosis. First, histologic evidence includes microvascular inflammation (glomerulitis [g] plus peritubular capillaritis [ptc]), intimal arteritis, TMA, or acute tubular injury. Second, evidence of antibody interaction with endothelium is demonstrated by C4d staining of peritubular capillaries, molecular markers (gene expression classifiers), or microvascular inflammation (g plus ptc score of 2 or greater). Third, serologic evidence of circulating DSA is required. C4d staining detects complement split product deposited on endothelium, scored as diffuse, focal, or negative, with IF on frozen tissue being more sensitive than IHC on paraffin. Chronic active AMR features transplant glomerulopathy (double contours on silver stain), peritubular capillary basement membrane multilayering on EM, and IFTA with inflammation.
Other Important Findings
BK polyomavirus nephropathy shows viral cytopathic effect in tubular epithelium, confirmed by IHC with SV40 large T antigen, and scored using the Banff pvl system for viral load categories. Calcineurin inhibitor (CNI) toxicity presents acutely with arteriolar vasoconstriction and isometric tubular vacuolization, and chronically with arteriolar hyalinosis and striped fibrosis. Recurrent disease includes IgA nephropathy, FSGS, membranous nephropathy, diabetic nephropathy, and MPGN/C3 glomerulopathy. Distinguishing polyomavirus from rejection is critical because immunosuppression should be reduced in BK nephropathy but increased in rejection.
Protocol (Surveillance) Biopsies
Protocol biopsies are performed at 3, 6, 12, and 24 months post-transplant at many centers, though timing varies. They detect subclinical rejection and early chronic changes before clinical deterioration. Subclinical inflammation and IFTA on protocol biopsies predict long-term graft survival.
Liver Allograft Pathology
Acute (Cellular) Rejection
The Banff criteria for liver rejection use the Rejection Activity Index (RAI) scored from 0 to 9. Three components are each scored 0-3: portal inflammation (density of inflammatory infiltrate), bile duct damage (lymphocytic cholangitis, degenerative changes in bile duct epithelium), and venous endothelial inflammation (endotheliitis) (subendothelial lymphocyte infiltration of portal and/or central veins). An RAI of 0-2 is indeterminate, 3-4 is mild, 5-6 is moderate, and 7-9 is severe rejection.
| RAI Component | Score 0 | Score 1 | Score 2 | Score 3 |
|---|---|---|---|---|
| Portal inflammation | None | Mild (minority of triads) | Moderate (most triads) | Severe (all triads, spillover) |
| Bile duct damage | None | Mild (minority of ducts) | Moderate (most ducts) | Severe (degeneration/necrosis) |
| Venous endotheliitis | None | Mild (minority of veins) | Moderate (most veins) | Severe (perivenular necrosis) |
| Total RAI Score | Interpretation | |
|---|---|---|
| 0–2 | Indeterminate | |
| 3–4 | Mild rejection | |
| 5–6 | Moderate rejection | |
| 7–9 | Severe rejection | The typical triad consists of portal inflammation, bile duct damage, and endotheliitis. |
Chronic (Ductopenic) Rejection
Chronic rejection features progressive loss of interlobular bile ducts, with ductopenia defined as fewer than 50% of portal tracts containing bile ducts. Vanishing bile duct syndrome represents end-stage chronic rejection. Obliterative arteriopathy with foam cell arteriopathy of medium and large arteries is characteristic. The condition is often irreversible and may require retransplantation. Foam cells in the intima of hepatic artery branches are a hallmark finding.
Antibody-Mediated Rejection in Liver
AMR in liver transplants is less well characterized than in kidney transplantation. Features include portal and periportal edema, ductular reaction, cholestasis, and C4d positivity in portal capillaries and veins. DSA against HLA antigens is present. This entity is increasingly recognized as a cause of late graft dysfunction, and the Banff criteria for liver AMR are still evolving with consensus definitions published.
Other Liver Allograft Complications
Preservation-reperfusion injury features hepatocyte ballooning, centrilobular necrosis, and neutrophilic infiltrate, occurring in the first 1-2 weeks. Biliary complications include strictures, bile leaks, and ischemic cholangiopathy, with histology showing ductular reaction, periductal fibrosis, and bile infarcts. Recurrent disease includes hepatitis C (historically the most common, now curable with DAAs), hepatitis B, primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis, and NAFLD/NASH. Post-transplant lymphoproliferative disorder (PTLD) is EBV-associated in most cases, spanning a spectrum from reactive hyperplasia to monomorphic lymphoma. Drug hepatotoxicity from calcineurin inhibitors, azathioprine, and antibiotics may also be encountered.
Donor-Specific Antibodies and Crossmatch
HLA Testing in Transplantation
Panel reactive antibody (PRA/cPRA) represents the percentage of the donor pool against which the recipient has antibodies, with higher cPRA indicating greater sensitization. The virtual crossmatch is a computational assessment of compatibility using the recipient antibody profile and donor HLA typing. The flow cytometric crossmatch is the most sensitive crossmatch method, detecting low-level DSA. The single-antigen bead (SAB) assay identifies antibodies to individual HLA antigens, reported as mean fluorescence intensity (MFI). De novo DSA developing after transplant is a risk factor for AMR and chronic rejection.
Monitoring Post-Transplant
Serial DSA monitoring is performed, and de novo DSA development triggers clinical vigilance and consideration of biopsy. Correlation between DSA level, C4d, and histologic findings guides treatment. Molecular diagnostics using gene expression profiling on biopsy tissue, such as classifications from the Banff Molecular Diagnostics Working Group, are increasingly used to complement histology.
Clinical Pearls
The Banff classification of kidney allograft rejection requires integration of histology, C4d staining, and donor-specific antibody status for the diagnosis of antibody-mediated rejection; histology alone is insufficient. BK polyomavirus nephropathy must be distinguished from rejection because the treatments are opposite: reduction of immunosuppression for BK versus intensification for rejection. Acute cellular rejection of the liver is characterized by the triad of portal inflammation, bile duct damage, and endotheliitis, graded using the Rejection Activity Index. Protocol (surveillance) biopsies in kidney transplant recipients detect subclinical rejection and early chronic changes that predict long-term graft outcomes before clinical deterioration.
References
- Loupy A, et al. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant. 2020;20(9):2318-2331.
- Demetris AJ, et al. 2016 Comprehensive update of the Banff Working Group on liver allograft pathology. Am J Transplant. 2016;16(5):1318-1366.
- Haas M, et al. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant. 2018;18(2):293-307.
- Mengel M, et al. Banff 2019 Meeting Report: Molecular diagnostics in solid organ transplantation. Am J Transplant. 2020;20(4):944-950.