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Case 016: Post-Transplant Rejection Surveillance

Clinical Presentation

Setting: Cardiac transplant clinic

Patient: 8-year-old female, 14 months post-orthotopic heart transplant for dilated cardiomyopathy

History: - Transplant at age 7 for end-stage DCM (idiopathic) - Uncomplicated post-operative course - One treated rejection episode at 3 months (Grade 2R, treated with pulse steroids) - Current immunosuppression: tacrolimus, mycophenolate, prednisone - Last biopsy (3 months ago): Grade 0R

Current Visit: Routine surveillance visit. Mom reports she's "been doing great" but seems "a little more tired" the last few days. Attributed to starting a new school year.

Medications: - Tacrolimus 2mg BID (recent level 8.2 ng/mL) - Mycophenolate 500mg BID - Prednisone 5mg daily - TMP-SMX prophylaxis - Valganciclovir prophylaxis

Surveillance Workup

Vital Signs: - HR 110 (baseline 85-90) - BP 108/72 - SpO2 99% on RA - Temp 37.2°C - Weight: stable

Physical Exam: - Alert, comfortable - Cardiac: Tachycardic, regular, no murmur, no gallop - Lungs: Clear - Abdomen: Soft, no hepatomegaly - Extremities: No edema

Routine Labs: - BNP: 425 pg/mL (was 85 three months ago) - Tacrolimus level: 8.2 ng/mL (therapeutic) - Creatinine: 0.8 mg/dL (stable) - CMV PCR: Not detected - EBV PCR: Not detected - DSA (donor-specific antibodies): Negative

ECG: - Sinus tachycardia, HR 108 - Low QRS voltage (decreased from baseline) - Nonspecific ST-T changes

Echocardiogram: - LV EF 50% (was 65% three months ago) - Mild RV dysfunction (new) - Mild tricuspid regurgitation (new) - Small pericardial effusion (new) - No significant MR

Clinical Reasoning Questions

Question 1

What is the most likely diagnosis, and what are the concerning findings?

Answer **Most Likely Diagnosis: Acute Cellular Rejection (ACR)** **Concerning Findings:** | Finding | Significance | |---------|--------------| | **New fatigue** | Often subtle early symptom | | **Resting tachycardia** | Denervated heart compensates with HR for decreased function | | **BNP rise** (85 → 425) | Sensitive marker of ventricular strain/rejection | | **EF decline** (65% → 50%) | 15% drop is significant | | **New RV dysfunction** | RV often affected before LV in rejection | | **New pericardial effusion** | Can accompany rejection | | **Low ECG voltage** | May indicate edema/inflammation | **Why ACR Over AMR (Antibody-Mediated Rejection)?** - DSA negative (would expect positive in AMR) - Clinical pattern more consistent with ACR - However, can have overlap; biopsy will clarify **Key Point:** Subtle symptoms + objective changes = rejection until proven otherwise. The denervated transplanted heart doesn't feel chest pain, so symptoms are often nonspecific.

Question 2

What is the gold standard for diagnosing rejection, and what findings would you expect?

Answer **Gold Standard: Endomyocardial Biopsy** **Technique:** - Right heart catheterization - Bioptome samples from RV septum - Typically 4-6 samples obtained - Examined by pathology for rejection **ISHLT Grading System for Cellular Rejection:** | Grade | Description | Action | |-------|-------------|--------| | **Grade 0R** | No rejection | Routine surveillance | | **Grade 1R** | Mild (focal perivascular/interstitial infiltrate) | Usually observe; treat if hemodynamic compromise | | **Grade 2R** | Moderate (multifocal infiltrate ± myocyte damage) | **Treat** | | **Grade 3R** | Severe (diffuse infiltrate with myocyte necrosis) | **Aggressive treatment** | **Expected Finding in This Patient:** - Likely **Grade 2R or 3R** given clinical/echo changes - Lymphocytic infiltration with myocyte damage **Antibody-Mediated Rejection (AMR) Grading:** - pAMR 0: Negative - pAMR 1: Suspicious (C4d or histology alone) - pAMR 2: Pathologic AMR (C4d + histology + DSA) **Additional Biopsy Information:** - Can have mixed (cellular + antibody-mediated) - Gene expression profiling (AlloMap) used in adults; less validated in pediatrics - Biopsy remains gold standard despite risks

Question 3

If biopsy shows Grade 2R rejection, what is the treatment approach?

Answer **Treatment of Grade 2R Acute Cellular Rejection:** **First-Line: Pulse Corticosteroids** - Methylprednisolone 10-15 mg/kg IV daily x 3 days - Or oral prednisone burst if hemodynamically stable **Augmented Immunosuppression:** - Increase tacrolimus target (e.g., 10-12 ng/mL) - Verify mycophenolate dosing adequate - May increase maintenance prednisone temporarily **Follow-Up:** - Repeat biopsy in 1-2 weeks to confirm resolution - Echo to document functional recovery - BNP trending **If Grade 3R or Hemodynamic Compromise:** - IV methylprednisolone - Consider antithymocyte globulin (ATG) if severe or steroid-resistant - Monitor for hemodynamic instability - May need inotropic support **If Recurrent/Refractory:** - ATG or OKT3 (rarely used now) - Total lymphoid irradiation - Adjust maintenance regimen - Consider alternative agents (everolimus, azathioprine) **Prognosis:** - Grade 2R usually responds well to pulse steroids - Recurrent rejection worsens long-term outcomes - Each episode may contribute to CAV development

Question 4

What are the differences between acute cellular rejection (ACR) and antibody-mediated rejection (AMR)?

Answer **Comparison:** | Feature | ACR | AMR | |---------|-----|-----| | **Mechanism** | T-cell mediated | Antibody (B-cell) mediated | | **Timing** | More common early | Can be early or late | | **DSA** | Usually negative | Usually positive | | **C4d staining** | Negative | Positive in capillaries | | **Histology** | Lymphocytic infiltrate | Capillaritis, edema | | **Response to steroids** | Usually good | Often poor | | **Prognosis** | Better | Worse (higher CAV, graft loss) | **Treatment of AMR:** 1. **Plasmapheresis** - Remove circulating antibodies 2. **IVIG** - Immunomodulation 3. **Rituximab** - B-cell depletion 4. **Bortezomib** - Plasma cell depletion 5. **Complement inhibitor** (eculizumab) in severe cases **Why AMR is Worse:** - Often refractory to standard treatment - Strong association with cardiac allograft vasculopathy - Can cause rapid graft failure - Sensitization limits retransplant options **Prevention:** - Avoid sensitization (blood transfusions, VADs) - Desensitization protocols if highly sensitized - Monitor for de novo DSA development

Question 5

What is cardiac allograft vasculopathy (CAV) and how is it monitored?

Answer **Cardiac Allograft Vasculopathy (CAV):** **Definition:** Diffuse, progressive narrowing of the coronary arteries in the transplanted heart. Different from typical atherosclerosis. **Pathophysiology:** - Chronic immune-mediated injury to endothelium - Intimal smooth muscle proliferation - Diffuse, concentric narrowing (not focal plaques) - Affects entire coronary tree including distal vessels **Risk Factors:** - Recurrent rejection episodes - CMV infection - Hyperlipidemia - Hypertension - Older donor - Prolonged ischemic time **Surveillance:** | Modality | Frequency | Notes | |----------|-----------|-------| | **Coronary angiography** | Annual (most centers) | Gold standard but misses early disease | | **IVUS** | If available | More sensitive for intimal thickening | | **Stress testing** | Variable | Limited by denervation | | **CT angiography** | Some centers | Non-invasive option | **ISHLT CAV Grading:** - CAV0: No stenosis - CAV1: Mild (<50% stenosis) - CAV2: Moderate (50-70% stenosis or branch narrowing) - CAV3: Severe (>70% stenosis or graft dysfunction) **Treatment:** - Statins (all transplant patients) - Risk factor modification - mTOR inhibitors (everolimus/sirolimus) may slow progression - Revascularization limited (diffuse disease) - Retransplant for severe CAV **Prognosis:** - Present in ~50% by 10 years post-transplant - Leading cause of late graft failure and death - Once severe, options are limited

Question 6

What are the key components of long-term post-transplant surveillance?

Answer **Comprehensive Surveillance Protocol:** **Regular Monitoring:** | Parameter | Frequency | Purpose | |-----------|-----------|---------| | **Clinical visit** | Every 1-3 months | Symptoms, exam, vitals | | **Labs** (tacrolimus, Cr, LFTs) | Every visit | Drug levels, toxicity | | **Echo** | Every 3-6 months | Function, effusion | | **Biopsy** | Protocol varies | Rejection surveillance | | **Coronary angiography** | Annual | CAV surveillance | | **DSA** | Every 3-12 months | AMR risk | **Infection Monitoring:** - CMV PCR monthly (especially first year) - EBV PCR (PTLD risk) - Respiratory viral testing if symptomatic - Pneumocystis prophylaxis (TMP-SMX lifelong) **Malignancy Surveillance:** - Skin exams (sun protection education) - PTLD monitoring (EBV) - Age-appropriate cancer screening **Drug Levels and Toxicity:** - Tacrolimus level: 5-15 ng/mL (varies by time post-transplant) - Monitor creatinine (calcineurin inhibitor nephrotoxicity) - Monitor glucose (steroids, tacrolimus) - Blood pressure monitoring **Growth and Development:** - Growth curves - School performance - Developmental milestones - Steroid effects **Quality of Life:** - Activity level - Psychosocial support - Transition planning (adolescents) - Medication adherence (especially teens)

Hospital Course

Endomyocardial biopsy showed Grade 2R acute cellular rejection with no evidence of AMR. She received 3 days of IV methylprednisolone (10 mg/kg/day) with resolution of symptoms. Tacrolimus target was increased to 10-12 ng/mL. Repeat biopsy 2 weeks later showed Grade 0R. EF recovered to 60%. She was counseled about the importance of medication adherence.

Key Teaching Points

  1. Subtle symptoms + objective changes = rejection until proven otherwise in transplant patients
  2. BNP is a sensitive marker for rejection; trending is valuable
  3. The denervated transplant heart compensates with tachycardia, not angina
  4. Grade 2R ACR usually responds to pulse steroids
  5. AMR is more difficult to treat and has worse prognosis than ACR
  6. Cardiac allograft vasculopathy is the leading cause of late graft failure
  7. Lifelong surveillance required: biopsies, angiography, labs, echo
  8. Medication adherence is critical - especially challenging in adolescents

References

  • ISHLT Guidelines for Heart Transplantation. J Heart Lung Transplant. 2023
  • Pediatric Heart Transplant Society Guidelines