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.

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.

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.

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

B. ISHLT Working Formulation for Heart and Lung Allografts

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.

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)

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.