Transplant Medicine · Supplementary · from Transplant Medicine
Case 3: Heart Transplant with Acute Rejection
Patient Presentation
Demographics: 55-year-old male retired firefighter
Chief Complaint: "I've been feeling short of breath and my legs are swelling again"
History of Present Illness: This 55-year-old male retired firefighter underwent orthotopic heart transplantation 3 months ago for end-stage non-ischemic dilated cardiomyopathy. He had been on left ventricular assist device (LVAD) support as a bridge to transplant for 14 months prior to receiving a donor organ from a 32-year-old male who died of a traumatic brain injury. The transplant surgery was uncomplicated with a cold ischemia time of 3 hours and 20 minutes. The postoperative course was unremarkable, and he was discharged on postoperative day 14 on standard triple immunosuppression.
He has been doing well with improving exercise tolerance and functional status. He completed cardiac rehabilitation and had been walking 2 miles daily without symptoms. His two previous surveillance endomyocardial biopsies (at 1 month and 2 months post-transplant) showed no rejection (Grade 0R).
Over the past 5 days, he has noticed progressive dyspnea on exertion. He can now only walk one block before becoming short of breath (previously walking 2 miles without difficulty). He reports bilateral leg swelling, a 4 kg weight gain over 1 week, and a new sensation of heart racing and palpitations. He denies chest pain, fever, cough, or orthopnea. He admits to missing several doses of his tacrolimus over the past 2 weeks due to running out of medication before his pharmacy refill.
Past Medical History:
- Orthotopic heart transplantation 3 months ago for non-ischemic dilated cardiomyopathy
- Prior LVAD support (HeartMate 3) for 14 months pre-transplant
- Non-ischemic dilated cardiomyopathy (diagnosed 6 years ago, progressive decline despite guideline-directed medical therapy)
- Chronic kidney disease stage 3 (multifactorial: cardiorenal syndrome, calcineurin inhibitor nephrotoxicity)
- Hypertension (post-transplant, calcineurin inhibitor-related)
- New-onset diabetes after transplant (NODAT)
- LVAD driveline infection (MRSA, treated, resolved pre-transplant)
- ICD removed at time of transplant
Medications:
- Tacrolimus 3 mg twice daily (self-reported missed doses over past 2 weeks)
- Mycophenolate mofetil 1000 mg twice daily
- Prednisone 5 mg daily
- Valganciclovir 900 mg daily (CMV prophylaxis, D+/R-)
- Trimethoprim-sulfamethoxazole DS three times weekly (PJP prophylaxis)
- Amlodipine 10 mg daily
- Metformin 500 mg twice daily
- Insulin glargine 12 units at bedtime
- Atorvastatin 40 mg daily (cardiac allograft vasculopathy prevention)
- Aspirin 81 mg daily
- Magnesium oxide 400 mg twice daily
Social History:
- Retired firefighter (25 years of service, retired on disability 4 years ago)
- Married for 28 years
- Two adult children
- Non-smoker, non-drinker
- Lives in a single-story home
- Completed cardiac rehabilitation
- Excellent social support
- Admitted to medication non-compliance due to pharmacy logistics
Family History:
- Father had dilated cardiomyopathy, died at age 62
- Mother alive with hypertension
- No siblings
Physical Examination
- Vital Signs: BP 102/68 mmHg (baseline 128/78), HR 110 bpm (baseline 85-90), RR 22/min, Temp 37.2°C, SpO2 92% on room air (baseline 98%), Weight 88 kg (baseline 84 kg)
- General: Anxious-appearing male in mild respiratory distress. Sitting upright. Using accessory muscles of respiration
- HEENT: No JVD visible (difficult to assess with neck body habitus). Moist mucous membranes
- Neck: Elevated JVP to 14 cm H₂O
- Cardiac: Tachycardic, regular rhythm. New S3 gallop. No murmurs. Diminished heart sounds compared to prior visits
- Lungs: Bilateral basilar crackles extending to mid-lung fields. No wheezing
- Abdomen: Soft, mildly distended. Hepatomegaly with liver palpable 4 cm below right costal margin (tender). No ascites
- Extremities: 3+ bilateral pitting edema to the mid-shins (previously no edema at last visit). Cool extremities
- Skin: Well-healed median sternotomy scar. Healed LVAD driveline exit site. No rashes
Workup and Results
Laboratory Studies:
| Test | Result | Reference Range |
|---|---|---|
| Tacrolimus trough level | 3.2 ng/mL | Target: 8-12 ng/mL |
| BNP | 1,842 pg/mL | <100 pg/mL (baseline post-transplant: 120) |
| Troponin I | 0.82 ng/mL | <0.04 ng/mL |
| Creatinine | 2.1 mg/dL | 0.7-1.3 mg/dL (baseline 1.6) |
| BUN | 38 mg/dL | 7-20 mg/dL |
| Sodium | 132 mEq/L | 136-145 mEq/L |
| Potassium | 4.6 mEq/L | 3.5-5.0 mEq/L |
| AST | 52 U/L | 10-40 U/L |
| ALT | 48 U/L | 7-56 U/L |
| LDH | 380 U/L | 120-246 U/L |
| WBC | 9,800/μL | 4,500-11,000/μL |
| Hemoglobin | 11.8 g/dL | 13.5-17.5 g/dL |
| CMV PCR | Undetectable | -- |
| Donor-Specific Antibodies | Negative | -- |
| CRP | 28 mg/L | <10 mg/L |
| HbA1c | 7.4% | <7.0% |
Imaging/Additional Studies:
- Echocardiogram: LVEF 35% (prior LVEF 60% at 2-month visit). New global hypokinesis. Moderate mitral regurgitation (new). Mild pericardial effusion. Dilated RV with reduced function (TAPSE 12 mm, prior 20 mm). Elevated estimated RAP 15 mmHg
- ECG: Sinus tachycardia 110 bpm. Low voltage QRS complexes (new). No ST-T wave changes. No arrhythmias
- Chest X-ray: Cardiomegaly (increased from prior). Bilateral pleural effusions. Pulmonary vascular congestion. Kerley B lines
- Right heart catheterization: RA pressure 18 mmHg (elevated), PA pressure 48/24 mmHg (mean 32 mmHg, elevated), PCWP 26 mmHg (elevated), cardiac index 1.8 L/min/m² (low), SVR elevated
- Endomyocardial Biopsy: ISHLT Grade 2R (moderate) acute cellular rejection — multifocal inflammatory infiltrate with associated myocyte damage. No evidence of antibody-mediated rejection (negative C4d staining). No Quilty effect
Clinical Image
Diagram illustrating the endomyocardial biopsy technique and histopathology findings of ISHLT Grade 2R acute cellular rejection, showing lymphocytic infiltrate with myocyte damage. Source: Educational illustration.
Diagnosis
ISHLT Grade 2R (Moderate) Acute Cellular Rejection of Cardiac Allograft, with Hemodynamic Compromise, 3 Months Post-Heart Transplant — Precipitated by Medication Non-Compliance
Key Diagnostic Criteria:
- Endomyocardial biopsy demonstrating ISHLT Grade 2R: multifocal aggressive infiltration with myocyte damage
- Hemodynamic compromise: LVEF decline from 60% to 35%, elevated filling pressures, reduced cardiac index
- Clinical heart failure: dyspnea, edema, weight gain, elevated BNP and troponin
- Subtherapeutic tacrolimus level (3.2 ng/mL, target 8-12) due to medication non-compliance
- Negative donor-specific antibodies excluding antibody-mediated rejection
Treatment Plan
- Acute rejection treatment (hemodynamically significant Grade 2R):
- IV methylprednisolone pulse: 1000 mg IV daily for 3 consecutive days
- Followed by oral prednisone 100 mg daily with rapid taper to 20 mg over 2 weeks, then slow taper to maintenance dose of 5 mg
- Consider addition of anti-thymocyte globulin (ATG) 1.5 mg/kg/day for 3-5 days if no response to steroid pulse within 48-72 hours (reserve for steroid-resistant rejection)
- Immunosuppression optimization:
- Increase tacrolimus dose to achieve target trough of 10-12 ng/mL (reload with supplemental doses, then adjust maintenance)
- Continue mycophenolate mofetil 1000 mg twice daily
- Pharmacy coordination: arrange 90-day supply, automatic refills, and medication delivery to prevent future non-compliance
- Medication adherence counseling with transplant pharmacist and social worker
- Heart failure management:
- IV furosemide 80 mg twice daily (diuresis targeting net negative 1-2 L/day)
- Daily weights, strict I&O monitoring
- If hemodynamics do not improve with rejection treatment: consider temporary inotropic support (milrinone)
- Telemetry monitoring for arrhythmias
- Follow-up biopsy: Repeat endomyocardial biopsy in 1-2 weeks to assess treatment response. Expect improvement from Grade 2R to Grade 0R or 1R
- Surveillance intensification: Increase biopsy frequency to every 2 weeks for the next 2 months, then monthly for 3 months, then per standard protocol. Add donor-specific antibody monitoring monthly. More frequent echocardiography (weekly until LVEF recovery)
- Psychosocial support: Address barriers to medication compliance. Social work consultation for pharmacy assistance programs. Psychological support for adjustment to chronic illness and medication regimen. Pill organizer and smartphone medication reminders
Key Learning Points
- The ISHLT grading system for cardiac allograft rejection includes: 0R (no rejection), 1R (mild — interstitial or perivascular infiltrate without myocyte damage), 2R (moderate — multifocal infiltrate with myocyte damage), and 3R (severe — diffuse infiltrate with myocyte necrosis, edema, hemorrhage, and vasculitis)
- Hemodynamically significant acute cellular rejection (Grade 2R or 3R with graft dysfunction) requires aggressive treatment with high-dose IV corticosteroids; steroid-resistant rejection is treated with anti-thymocyte globulin (ATG) or OKT3
- Subtherapeutic calcineurin inhibitor levels are the most common precipitant of acute rejection; medication non-compliance is the leading cause of late acute rejection and graft loss after heart transplantation
- Endomyocardial biopsy remains the gold standard for diagnosing cardiac allograft rejection; non-invasive monitoring with gene expression profiling (AlloMap) can reduce biopsy frequency in low-risk patients beyond 6 months post-transplant
- Cardiac allograft vasculopathy (CAV) is the leading cause of long-term graft loss and death beyond the first year; it is a diffuse, concentric intimal proliferation of coronary arteries that is distinct from typical atherosclerosis and is detected by annual coronary angiography or intravascular ultrasound