# Clinical Cases: Transplant Medicine

## Case 1: Living Donor Kidney Transplant Evaluation

### Patient Presentation
**Demographics:** 42-year-old female accountant

**Chief Complaint:** "My kidneys have failed and I need a transplant — my sister wants to donate"

**History of Present Illness:**
This 42-year-old female accountant with end-stage renal disease (ESRD) secondary to IgA nephropathy presents to the transplant center for living donor kidney transplant evaluation. She was diagnosed with IgA nephropathy by renal biopsy at age 28 after presenting with recurrent episodes of gross hematuria coinciding with upper respiratory infections. Despite treatment with ACE inhibitors and a course of corticosteroids, her kidney function progressively declined over 14 years.

She initiated hemodialysis via a left upper arm arteriovenous fistula 10 months ago when her GFR fell to 8 mL/min/1.73m2. She currently receives in-center hemodialysis three times weekly (Monday/Wednesday/Friday) for 4-hour sessions. She tolerates dialysis reasonably well but reports significant fatigue on dialysis days, limiting her ability to work full-time. She has been listed on the deceased donor kidney transplant waiting list for 6 months with an estimated wait time of 5-7 years in her region.

Her 39-year-old sister has volunteered as a potential living kidney donor. The sister is ABO-compatible (both blood type A+), and preliminary crossmatch is negative. The donor evaluation is being conducted in parallel. The patient has been counseled on the benefits of preemptive or early living donor transplantation, including superior graft survival compared to deceased donor transplantation.

**Past Medical History:**
- ESRD secondary to IgA nephropathy (on hemodialysis for 10 months)
- Hypertension (secondary to CKD)
- Secondary hyperparathyroidism
- Anemia of chronic kidney disease
- Left upper arm AVF (functioning well, adequate flow)
- No prior transplants or pregnancies
- No history of malignancy
- Hepatitis B and C negative, HIV negative

**Medications:**
- Amlodipine 10 mg daily
- Losartan 100 mg daily (held on dialysis days)
- Epoetin alfa 6,000 units IV three times weekly at dialysis
- Iron sucrose 100 mg IV monthly
- Calcitriol 0.25 mcg daily
- Sevelamer 800 mg three times daily with meals
- Cinacalcet 30 mg daily
- Aspirin 81 mg daily
- Atorvastatin 20 mg daily

**Social History:**
- Accountant, currently working part-time due to dialysis schedule
- Non-smoker, never smoked
- No alcohol use
- No illicit drug use
- Single, no children
- Supportive family including potential living donor (sister)
- Excellent health insurance coverage
- Lives independently in a single-story condominium

**Family History:**
- Mother with hypertension and type 2 diabetes
- Father died of myocardial infarction at age 65
- Sister (potential donor) is healthy, age 39
- No family history of kidney disease other than the patient

### Physical Examination
- **Vital Signs:** BP 142/88 mmHg (pre-dialysis), HR 76 bpm, RR 14/min, Temp 36.7°C, SpO2 98% on room air, BMI 23.5, Weight 62 kg (dry weight)
- **General:** Well-appearing female in no acute distress. Appears well-nourished
- **HEENT:** Pale conjunctivae. No oral lesions. Dentition in good repair
- **Neck:** No JVD, no bruits, no lymphadenopathy
- **Cardiac:** Regular rate and rhythm, no murmurs, no friction rub
- **Lungs:** Clear to auscultation bilaterally
- **Abdomen:** Soft, non-tender, non-distended. No hepatosplenomegaly. No surgical scars. Bilateral iliac fossae accessible for transplant placement
- **Vascular Access:** Left upper arm brachiocephalic AVF with palpable thrill and audible bruit. No signs of infection or steal syndrome
- **Extremities:** Trace bilateral pedal edema. No skin lesions. Peripheral pulses 2+ bilaterally
- **Skin:** No rashes, no lesions suspicious for malignancy

### Workup and Results

**Laboratory Studies:**
| Test | Result | Reference Range |
|------|--------|-----------------|
| Creatinine | 9.8 mg/dL | 0.6-1.2 mg/dL |
| BUN | 62 mg/dL | 7-20 mg/dL |
| eGFR | <10 mL/min/1.73m² | >60 mL/min/1.73m² |
| Potassium | 5.2 mEq/L (pre-dialysis) | 3.5-5.0 mEq/L |
| Calcium | 8.8 mg/dL | 8.5-10.5 mg/dL |
| Phosphorus | 5.8 mg/dL | 2.5-4.5 mg/dL |
| Intact PTH | 285 pg/mL | 15-65 pg/mL |
| Albumin | 3.8 g/dL | 3.5-5.0 g/dL |
| Hemoglobin | 10.2 g/dL | 12.0-16.0 g/dL |
| HbA1c | 5.4% | <5.7% |
| PRA (Panel Reactive Antibody) | 0% | -- |
| Blood Type | A positive | -- |
| Crossmatch (with donor) | Negative | Negative |
| CMV IgG | Positive | -- |
| EBV IgG | Positive | -- |
| HIV, Hepatitis B, Hepatitis C | Negative | Negative |
| Urinalysis | Proteinuria 2+, RBC 10-20/hpf | -- |

**Imaging/Additional Studies:**
- Echocardiogram: Normal LV function (LVEF 60%), no significant valvular disease, no LVH. RVSP 28 mmHg (normal)
- Dobutamine stress echocardiogram: No inducible wall motion abnormalities (adequate cardiac risk assessment for transplant surgery)
- CT abdomen/pelvis with contrast (pre-transplant planning): Small bilateral kidneys (8 cm bilaterally). Patent iliac vessels bilaterally suitable for anastomosis. No renal masses. No abdominal aortic aneurysm. Intact urinary bladder
- Voiding cystourethrogram: Normal bladder capacity (400 mL), no vesicoureteral reflux, complete bladder emptying
- Chest X-ray: No active pulmonary disease. Normal cardiac silhouette
- Colonoscopy (age-appropriate screening): Normal, no polyps
- Cervical cancer screening: Pap smear normal, HPV negative
- Mammogram: BI-RADS 1, negative

**Donor Evaluation Summary (Sister, age 39):**
- Blood type A+, crossmatch negative with recipient
- HLA typing: 1-haplotype match (shared one HLA haplotype)
- GFR (iothalamate clearance): 105 mL/min/1.73m²
- 24-hour urine protein: 85 mg (normal <150 mg)
- CT angiography: Single left renal artery, single right renal artery. Left kidney selected for donation (single artery, smaller kidney)
- Medical clearance: No hypertension, no diabetes, BMI 24, non-smoker, normal glucose tolerance test, normal psychosocial evaluation
- Independent donor advocate: Confirmed voluntary donation without coercion

### Clinical Image

![Living donor kidney transplant surgical anatomy diagram](case_01_image.jpg)

*Diagram illustrating the living donor kidney transplant surgical anatomy, showing donor nephrectomy and transplant placement in the recipient's iliac fossa with vascular and ureteral anastomoses. Source: Educational illustration.*

### Diagnosis
**End-Stage Renal Disease Secondary to IgA Nephropathy, Approved for Living Donor Kidney Transplantation**

**Key Diagnostic Criteria:**
- ESRD requiring dialysis (GFR <10 mL/min/1.73m²) with biopsy-proven IgA nephropathy
- Completed recipient evaluation: adequate cardiac function, no active infections, no malignancy, patent iliac vessels, functional bladder, PRA 0%
- Completed donor evaluation: adequate renal function (GFR 105), favorable anatomy (single renal arteries), no medical contraindications, voluntary informed consent with independent donor advocate
- Negative crossmatch and ABO compatibility

### Treatment Plan
1. **Preoperative preparation:**
   - Final crossmatch within 48 hours of transplant
   - Dialysis session the day before surgery to optimize volume and electrolyte status
   - Immunosuppression induction: Basiliximab (anti-IL-2 receptor antibody) 20 mg IV on day 0 and day 4
   - Discontinue ACE inhibitor 48 hours before surgery
   - DVT prophylaxis with sequential compression devices
2. **Surgical procedure:** Living donor laparoscopic left nephrectomy (donor surgery). Recipient surgery: right iliac fossa transplant with renal artery anastomosis to external iliac artery, renal vein to external iliac vein (end-to-side), Lich-Gregoir ureteroneocystostomy with double-J ureteral stent
3. **Immunosuppression protocol:**
   - Induction: Basiliximab (day 0 and day 4)
   - Maintenance: Tacrolimus (target trough 8-12 ng/mL for first 3 months, then 5-8 ng/mL), mycophenolate mofetil 1000 mg twice daily, prednisone taper (starting 500 mg methylprednisolone intraoperatively, taper to prednisone 5 mg daily by 3 months)
4. **Postoperative monitoring:** Hourly urine output (expect immediate graft function with living donor), daily creatinine, tacrolimus trough levels every 2-3 days initially, Doppler ultrasound of graft on postoperative day 1 and if any concern for vascular complications
5. **Infection prophylaxis:** Trimethoprim-sulfamethoxazole (Pneumocystis and UTI prophylaxis for 6-12 months), valganciclovir (CMV prophylaxis for 3-6 months given CMV D-/R+ would be needed if applicable), nystatin oral suspension (candida prophylaxis for 3 months)
6. **Long-term surveillance:** Transplant clinic weekly for first month, biweekly for months 2-3, monthly for months 4-12, then every 3 months. Monitor creatinine, tacrolimus levels, urinalysis, BK virus PCR (months 1-12), CMV PCR, metabolic panel. Protocol surveillance biopsy at 3 and 12 months (center-specific). Screen for post-transplant diabetes, malignancy, and cardiovascular disease
7. **Recurrent IgA nephropathy monitoring:** IgA nephropathy recurs histologically in 30-50% of transplants but causes clinically significant graft loss in <10%; monitor with protocol biopsies and urinalysis for proteinuria/hematuria

### Key Learning Points
- Living donor kidney transplantation provides superior outcomes compared to deceased donor transplantation: better 1-year and 5-year graft survival rates (97% and 90% vs. 93% and 78%), immediate graft function, planned surgery, and avoidance of prolonged dialysis exposure
- A comprehensive recipient evaluation includes cardiac risk assessment, malignancy screening, infection screening, vascular imaging, urologic evaluation, and psychosocial assessment to identify and mitigate perioperative risks
- The donor evaluation must include independent donor advocacy to ensure voluntary, informed consent without coercion, along with thorough medical, surgical, and psychosocial assessment
- Panel Reactive Antibody (PRA) reflects the recipient's degree of HLA sensitization; a PRA of 0% indicates no preformed anti-HLA antibodies and the lowest immunologic risk for transplantation
- IgA nephropathy can recur in the transplant, but clinically significant graft loss from recurrence is uncommon (<10%); it should not preclude transplantation, though patients should be informed and monitored

---

## Case 2: Liver Transplant for Decompensated Cirrhosis

### Patient Presentation
**Demographics:** 51-year-old male former restaurant owner

**Chief Complaint:** "My belly keeps filling with fluid and I turned yellow again"

**History of Present Illness:**
This 51-year-old male with a history of hepatitis C virus (HCV)-related cirrhosis presents with progressive jaundice, worsening ascites, and confusion over the past 2 weeks. He was diagnosed with chronic hepatitis C (genotype 1a) 12 years ago, likely acquired through IV drug use in his twenties. He achieved sustained virologic response (SVR) after a 12-week course of sofosbuvir/velpatasvir 4 years ago, but his cirrhosis had already progressed to a decompensated state by that time.

Over the past year, he has had three hospitalizations for hepatic encephalopathy and four large-volume paracenteses (8-12 liters each). His most recent MELD-Na score has risen from 22 to 28 over the past 3 months. He developed his first episode of spontaneous bacterial peritonitis (SBP) 2 months ago, treated with IV ceftriaxone, and has been on secondary prophylaxis with ciprofloxacin. He has been evaluated and listed for deceased donor liver transplantation. He presents today with worsening symptoms concerning for recurrent encephalopathy and possible recurrent SBP.

His wife reports increasing confusion over the past 5 days. He has been sleeping during the day and awake at night, has difficulty recognizing family members, and had an episode of fecal incontinence yesterday. She also noticed progressive jaundice and increasing abdominal girth despite compliance with diuretics and sodium restriction.

**Past Medical History:**
- HCV-related cirrhosis (Child-Pugh C12, MELD-Na 28), SVR achieved 4 years ago
- Recurrent hepatic encephalopathy (West Haven Grade II-III)
- Refractory ascites
- Prior SBP (2 months ago)
- Esophageal varices (Grade II, banded x2)
- Portal hypertensive gastropathy
- Hepatorenal syndrome type 2 (baseline creatinine 1.8 mg/dL)
- History of IV drug use (heroin, age 18-25), in recovery for 26 years
- Remote history of polysubstance use, no relapse
- Hepatocellular carcinoma screening: No HCC detected

**Medications:**
- Lactulose 30 mL four times daily (titrated to 3-4 bowel movements/day)
- Rifaximin 550 mg twice daily
- Spironolactone 200 mg daily
- Furosemide 80 mg daily
- Ciprofloxacin 500 mg daily (SBP prophylaxis)
- Nadolol 20 mg daily
- Zinc sulfate 220 mg daily
- Midodrine 10 mg three times daily
- Albumin 25 g IV twice weekly

**Social History:**
- Former restaurant owner, now unable to work (on disability)
- Remote history of IV heroin use (ages 18-25), 26 years of sustained recovery
- Attends NA meetings monthly
- No alcohol use for 28 years
- Non-smoker for 20 years (10 pack-years prior)
- Married with two adult children (ages 22 and 24)
- Strong family support system
- Social work and psychiatry clearance for transplant listing completed
- Health care proxy designated to wife

**Family History:**
- Father died of alcoholic cirrhosis at age 58
- Mother alive with type 2 diabetes and hypertension
- No family history of liver cancer

### Physical Examination
- **Vital Signs:** BP 98/56 mmHg, HR 92 bpm, RR 18/min, Temp 38.2°C (100.8°F), SpO2 94% on room air, BMI 26.8 (with ascites), Weight 84 kg
- **General:** Cachectic male with massive ascites and jaundice. Somnolent but arousable. Oriented to person only
- **HEENT:** Deeply icteric sclerae and skin. Fetor hepaticus on breath. Temporal muscle wasting. Dry mucous membranes
- **Neck:** No JVD. No lymphadenopathy
- **Cardiac:** Tachycardic, regular rhythm. Grade II/VI systolic flow murmur. Hyperdynamic circulation
- **Lungs:** Decreased breath sounds at bilateral bases with dullness to percussion (bilateral pleural effusions, right > left). No crackles
- **Abdomen:** Massively distended with tense ascites. Fluid wave positive. Caput medusae. Umbilical hernia with 4 cm defect, reducible. Liver and spleen not palpable due to ascites. Mild diffuse tenderness without rebound
- **Extremities:** 3+ bilateral pitting edema to the thighs. Marked muscle wasting in extremities. Terry's nails. Palmar erythema. Dupuytren's contractures bilaterally
- **Skin:** Jaundice. Multiple spider angiomata (>10) on face, chest, and upper arms. Excoriations from pruritus. Multiple ecchymoses
- **Neurologic:** West Haven Grade III hepatic encephalopathy. Somnolent but arousable. Disoriented to time and place. Asterixis present bilaterally. Hyperreflexia in lower extremities. No focal motor deficits

### Workup and Results

**Laboratory Studies:**
| Test | Result | Reference Range |
|------|--------|-----------------|
| Total Bilirubin | 12.8 mg/dL | 0.1-1.2 mg/dL |
| Direct Bilirubin | 9.4 mg/dL | 0-0.3 mg/dL |
| Albumin | 1.9 g/dL | 3.5-5.0 g/dL |
| INR | 2.4 | 0.8-1.2 |
| Creatinine | 2.4 mg/dL | 0.7-1.3 mg/dL (baseline 1.8) |
| Sodium | 126 mEq/L | 136-145 mEq/L |
| Potassium | 4.8 mEq/L | 3.5-5.0 mEq/L |
| AST | 88 U/L | 10-40 U/L |
| ALT | 52 U/L | 7-56 U/L |
| Alkaline Phosphatase | 142 U/L | 44-147 U/L |
| Ammonia | 128 μmol/L | 15-45 μmol/L |
| WBC | 11,200/μL | 4,500-11,000/μL |
| Hemoglobin | 9.2 g/dL | 13.5-17.5 g/dL |
| Platelets | 42,000/μL | 150,000-400,000/μL |
| Lactate | 2.8 mmol/L | 0.5-2.0 mmol/L |
| AFP | 8.2 ng/mL | <10 ng/mL |
| MELD-Na Score | 34 (calculated) | -- |
| HCV RNA | Undetectable | -- |
| Ascitic Fluid: WBC | 680 cells/μL (82% PMN) | <250 PMN/μL |
| Ascitic Fluid: Albumin | 0.4 g/dL | -- |
| SAAG (Serum-Ascites Albumin Gradient) | 1.5 g/dL | ≥1.1 (portal HTN) |
| Ascitic Fluid: Culture | Pending (later: E. coli) | No growth |

**Imaging/Additional Studies:**
- CT abdomen with contrast (triple phase): Cirrhotic liver with nodular contour, caudate lobe hypertrophy. Massive ascites. Splenomegaly (19 cm). Patent portal vein with hepatopetal flow. No hepatocellular carcinoma (no arterially enhancing lesions). Bilateral pleural effusions
- Doppler ultrasound: Patent portal vein (flow velocity 12 cm/s), patent hepatic artery, patent hepatic veins. No portal vein thrombosis
- Chest X-ray: Moderate bilateral pleural effusions (right > left). No pneumonia
- Echocardiogram: LVEF 65%, no pulmonary hypertension (RVSP 30 mmHg), no significant valvular disease, no diastolic dysfunction — cardiac clearance for transplant
- Right heart catheterization: Mean PAP 18 mmHg, PCWP 10 mmHg, cardiac output 8.2 L/min (hyperdynamic). No portopulmonary hypertension

### Clinical Image

![Liver transplant anatomy and MELD score diagram](case_02_image.jpg)

*Diagram illustrating the MELD score components, comparison of cirrhotic and normal liver, and orthotopic liver transplant surgical anatomy with vascular and biliary anastomoses. Source: Educational illustration.*

### Diagnosis
**Decompensated HCV-Related Cirrhosis (Child-Pugh C12, MELD-Na 34) with Recurrent Spontaneous Bacterial Peritonitis, Grade III Hepatic Encephalopathy, Refractory Ascites, and Hepatorenal Syndrome Type 2 — Awaiting Liver Transplantation**

**Key Diagnostic Criteria:**
- Biopsy-proven HCV cirrhosis with SVR but persistent decompensation
- MELD-Na 34 with rising trend (from 22 to 34 over 3 months)
- Ascitic fluid PMN count >250 cells/μL confirming SBP
- West Haven Grade III encephalopathy with asterixis
- Hepatorenal syndrome evidenced by rising creatinine in the setting of cirrhosis
- Completed transplant evaluation with cardiac and psychosocial clearance

### Treatment Plan
1. **Acute management:**
   - SBP treatment: IV ceftriaxone 2 g daily (change based on culture sensitivities) plus IV albumin 1.5 g/kg on day 1 and 1 g/kg on day 3 (to prevent hepatorenal syndrome progression)
   - Hepatic encephalopathy: Increase lactulose to achieve 4-5 bowel movements/day, continue rifaximin, correct precipitating factors (SBP), check and replace zinc
   - Hepatorenal syndrome: IV albumin infusion, midodrine 15 mg TID and octreotide 200 mcg TID (consider terlipressin if available), hold diuretics
   - ICU admission for close monitoring given Grade III encephalopathy
2. **Transplant status upgrade:** Contact transplant coordinator to update MELD-Na score (now 34) for priority allocation. Apply for MELD exception points if criteria met. Contact UNOS regarding Status 1A consideration if further deterioration
3. **Bridge to transplant:** Optimize nutritional status (nocturnal oral nutritional supplement, high-protein diet unless Grade III-IV encephalopathy, enteral feeding if unable to eat). Continue SBP prophylaxis after treatment completion. Monitor for hepatocellular carcinoma (AFP and ultrasound every 6 months)
4. **Liver transplant surgery (when organ available):** Standard orthotopic liver transplantation with piggyback technique (recipient hepatectomy preserving IVC, donor hepatic veins anastomosed to recipient hepatic vein confluence). Portal vein, hepatic artery, and bile duct anastomoses. Duct-to-duct biliary anastomosis preferred
5. **Post-transplant immunosuppression:** Induction with methylprednisolone, maintenance with tacrolimus (target trough 8-12 ng/mL initially), mycophenolate mofetil, and prednisone taper. Adjust based on renal function (consider delayed tacrolimus introduction if hepatorenal syndrome persists post-transplant)
6. **Post-transplant monitoring:** HCV recurrence is not expected given SVR, but monitor HCV RNA at 3, 6, and 12 months. Screen for de novo or recurrent malignancy. Monitor metabolic complications (new-onset diabetes after transplant, hyperlipidemia, hypertension, obesity)

### Key Learning Points
- The MELD-Na score (incorporating bilirubin, INR, creatinine, and sodium) is the primary allocation tool for deceased donor liver transplantation in the United States; higher scores reflect greater disease severity and shorter predicted survival without transplant
- Spontaneous bacterial peritonitis is diagnosed by ascitic fluid PMN count greater than or equal to 250 cells/μL; IV albumin administration with antibiotics reduces the incidence of hepatorenal syndrome and mortality
- Achieving HCV SVR before transplant eliminates the risk of post-transplant HCV recurrence, which historically was universal and accelerated by immunosuppression, leading to graft loss in 20-30% within 5 years
- Hepatorenal syndrome type 2 is characterized by slowly progressive renal impairment and is associated with refractory ascites; it can progress to type 1 (rapidly progressive) with precipitating events like SBP; liver transplantation is the definitive treatment
- Right heart catheterization is mandatory in the transplant evaluation to exclude portopulmonary hypertension (mean PAP >25 mmHg with PVR >240 dynes) and hepatopulmonary syndrome, which are contraindications or require specific management before transplantation

---

## 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

![Heart transplant acute rejection biopsy and management diagram](case_03_image.jpg)

*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
1. **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)
2. **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
3. **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
4. **Follow-up biopsy:** Repeat endomyocardial biopsy in 1-2 weeks to assess treatment response. Expect improvement from Grade 2R to Grade 0R or 1R
5. **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)
6. **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