2025 PACUPrep BCCCP Preparatory Course Transplant Immunology & Acute Rejection Diagnostic Criteria and Classification Systems for Acute Transplant Rejection
Diagnostic Criteria and Classification Systems for Acute Transplant Rejection

Diagnostic Criteria and Classification Systems for Acute Transplant Rejection

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Lesson Objective

Apply integrated clinical, laboratory, imaging, and histopathologic criteria to diagnose acute rejection in solid-organ transplant recipients and guide urgency stratification.

1. Clinical Assessment

Early recognition of graft dysfunction—ranging from subtle lab changes to overt organ failure—is critical. Clinical signs overlap with infection and drug toxicity, necessitating systematic evaluation.

Organ-Specific Presentations

  • Kidney: Rising serum creatinine, decreased urine output, graft tenderness, hypertension.
  • Heart: New arrhythmias, reduced ejection fraction on echo, elevated troponin or BNP, hypotension.
  • Lung: A decline of 10% or more in FEV₁ for over 48 hours, dyspnea, nonproductive cough, low-grade fever, new crackles or wheezes.

Differential Diagnosis (“Infection vs. Rejection vs. Toxicity”)

  • Infections: Fever, leukocytosis, microbiology/histology, radiographic focal consolidations.
  • Drug toxicity: Calcineurin inhibitors can cause nephrotoxicity or neurotoxicity; mTOR inhibitors may lead to pneumonitis or mucositis.
  • Hemodynamic factors: Volume overload/depletion, graft vessel thrombosis.
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  • Any unexplained graft function decline in the ICU should trigger a rejection workup even without overt symptoms.
  • Concurrent infection does not exclude rejection; always consider the possibility of mixed pathology.

2. Laboratory and Immunologic Evaluation

Graft-specific function tests and immunologic assays are used to quantify injury and detect humoral activation.

Graft Function Markers

  • Kidney: Rising serum creatinine (greater than 20% from baseline), oliguria/anuria.
  • Heart: Troponin I/T elevations, rising BNP, decreased cardiac index, new wall-motion abnormalities.
  • Lung: Spirometry (FEV₁ decline ≥10%), arterial blood gases.

Donor-Specific Antibodies (DSA)

  • Solid-phase assays (e.g., Luminex single-antigen beads) measure class I and class II HLA antibodies.
  • A mean fluorescence intensity (MFI) of 1,500–2,000 or higher is often considered clinically significant; a rising MFI trend is predictive of antibody-mediated rejection (AMR).
  • The absence of DSA does not rule out AMR—histology remains the key diagnostic tool.
  • Complement-binding assays (C1q/C3d) may help refine risk stratification.

Complement Split Products (C4d)

  • Tissue C4d deposition indicates classical complement activation in AMR and is graded as focal (<50%) or diffuse (>50%).
  • Low-level or focal C4d can represent subclinical complement fixation and must be interpreted in the full clinical context.

Emerging Biomarkers

  • Donor-specific T cell ELISPOT (IFN-γ) assays, where pre- or post-transplant positivity correlates with early cellular rejection risk.
  • Gene-expression profiles (e.g., allograft rejection index) and cell-free donor DNA are currently under investigation.
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  • Serial DSA monitoring allows for preemptive interventions before significant histologic damage occurs.
  • Always correlate C4d staining with clinical and serologic data to avoid overcalling AMR.

3. Imaging and Functional Studies

Noninvasive imaging supports—but does not replace—biopsy. Clinicians must be aware of the moderate sensitivity and specificity of these studies.

Echocardiography (Heart)

Used to assess systolic/diastolic dysfunction, new wall-motion abnormalities, and pericardial effusion. There are no pathognomonic signs of rejection on echocardiogram.

High-Resolution CT (Lung)

Findings may include ground-glass opacities, peri-bronchial thickening, septal lines, and mosaic attenuation. Sensitivity is approximately 60–70% and specificity is 50–60%; biopsy is required for confirmation.

CT/MRI (Kidney)

May show cortical enhancement defects and edema, but these modalities have a limited role in the diagnosis of acute rejection.

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  • Radiographic findings of rejection significantly overlap with infection, pulmonary edema, and drug-induced injury.
  • Functional tests like spirometry and echocardiography can detect graft dysfunction but lack specificity for rejection.

4. Histopathologic Classification

Biopsy-based grading remains the gold standard for diagnosing acute rejection. Two main systems are utilized: the Banff criteria for renal allografts and the International Society for Heart and Lung Transplantation (ISHLT) criteria for thoracic organs.

A. Banff Criteria for Renal Allografts

Editor’s Note: A full review of the Banff classification is beyond the scope of this summary but includes detailed scoring of tubulitis (t-score), intimal arteritis (v-score), interstitial inflammation (i-score), C4d staining patterns, and specific lesions associated with antibody-mediated rejection.

B. ISHLT Working Formulation for Heart and Lung Allografts

ISHLT Grading for Acute Cellular Rejection (ACR) and Lymphocytic Bronchiolitis
Grade Description Key Histologic Feature
A0 Acute Cellular Rejection (Heart) No perivascular mononuclear infiltrates.
A1 (Minimal) Acute Cellular Rejection (Heart) Focal perivascular infiltrates without myocyte damage.
A2 (Mild) Acute Cellular Rejection (Heart) One to several foci of infiltrates with associated myocyte damage.
A3 (Moderate) Acute Cellular Rejection (Heart) Multifocal infiltrates with myocyte damage and edema.
A4 (Severe) Acute Cellular Rejection (Heart) Diffuse infiltrates with myocyte necrosis and hemorrhage.
B0 Lymphocytic Bronchiolitis (Lung) None.
B1R Lymphocytic Bronchiolitis (Lung) Low-grade lymphocytic infiltration of small airways.
B2R Lymphocytic Bronchiolitis (Lung) High-grade, dense lymphocytic infiltration of the airways.

C. Distinguishing ACR vs. AMR (Lung & Kidney)

  • ACR Features: Mononuclear perivascular infiltrates, tubulitis (renal), myocyte damage (heart), airway inflammation (lung).
  • AMR Features: Capillaritis with neutrophils, endothelial swelling, C4d deposition, microvascular injury, presence of DSA.
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  • Mixed rejection phenotypes are common; treatment must address both cellular and humoral pathways concurrently.
  • Transbronchial biopsy is subject to sampling error and may underdiagnose AMR. Consider a repeat or surgical biopsy if clinical suspicion remains high despite a negative result.

5. Risk Stratification and Urgency Scoring

A comprehensive approach that integrates clinical status, biomarkers, and histology is necessary to determine biopsy timing and the potential need for empiric therapy in critically ill patients.

Integrated Risk Factors

  • Clinical: Rapid decline in graft function, hemodynamic instability.
  • Serologic: Rising DSA MFI, positive complement-binding assays.
  • Histology: History of high-grade rejection on a prior biopsy.

Biopsy Timing Algorithm (ICU Setting)

Biopsy Timing Algorithm Flowchart A flowchart for deciding when to biopsy a transplant patient in the ICU. It starts with graft dysfunction, moves to non-invasive tests, then to a decision point based on suspicion level, leading to either biopsy, empiric therapy, or continued observation. 1. Trigger Graft Dysfunction + No Obvious Cause 2. Non-Invasive Tests Echo/CT, Labs, DSA, C4d 3. Assess Suspicion for Rejection (Based on clinical, lab, and imaging data) Low Suspicion High Suspicion Proceed to Biopsy Within 24-48 hours Empiric Therapy (If biopsy delayed)
Figure 1: Biopsy Timing Algorithm in the ICU. This pathway guides clinicians from the initial trigger of graft dysfunction through non-invasive testing to a decision point for proceeding with biopsy or considering empiric therapy based on the level of clinical suspicion.

Empiric Therapy Decision Points

  • ACR Suspicion Alone: Methylprednisolone 500–1,000 mg IV daily for 3 days.
  • AMR Features (DSA positive, C4d positive, histology pending): Consider plasmapheresis (5 sessions), IVIG (1–2 g/kg), and/or rituximab 375 mg/m².
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  • Early empiric therapy may prevent progression but increases infection risk; the benefits must be balanced against the risks.
  • Reassess the patient’s response to therapy at 72 hours with repeat labs and imaging, and modify the treatment plan accordingly.

References

  1. Stewart S, Fishbein MC, Snell GI, et al. Revision of the 1996 working formulation for standardization of nomenclature in the diagnosis of lung rejection. J Heart Lung Transplant. 2007;26(12):1229–1242.
  2. Levine DJ, Glanville AR, Aboyoun C, et al. Antibody-mediated rejection of the lung: consensus report of the ISHLT. J Heart Lung Transplant. 2016;35(4):397–406.
  3. Subramani MV, Pandit S, Gadre SK. Acute rejection and post–lung transplant surveillance. Indian J Thorac Cardiovasc Surg. 2022;38(Suppl 2):S271–S279.
  4. Udomkarnjananun S, Kerr SJ, Townamchai N, et al. Donor-specific ELISPOT assay for predicting acute rejection and allograft function after kidney transplantation: meta-analysis. Clin Biochem. 2021;94:1–11.
  5. Chambers DC, Cherikh WS, Harhay MO, et al. ISHLT 36th adult lung and heart–lung transplantation report—2019; donor and recipient size match. J Heart Lung Transplant. 2019;38:1042–1055.
  6. Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: update of diagnostic criteria. J Heart Lung Transplant. 2002;21(3):297–310.
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