# Clinical Cases: Transplantation Immunology

## Case 1: Acute Cellular Rejection in Kidney Transplant

### Patient Demographics
- **Age:** 52 years old
- **Sex:** Male
- **Ethnicity:** African American

### Chief Complaint
Decreased urine output and rising creatinine 3 weeks post-transplant

### History of Present Illness
A 52-year-old man who received a deceased-donor kidney transplant 3 weeks ago presents with decreased urine output over the past 2 days. He had an uncomplicated early post-operative course with excellent initial graft function (creatinine nadired at 1.2 mg/dL by day 5). However, over the past 48 hours, his urine output has decreased from 2L/day to 800mL/day, and routine labs show a rising creatinine. He denies fever, graft site pain, urinary symptoms, diarrhea, or medication non-compliance.

### Transplant Details
- **Donor:** Deceased donor, 45-year-old male
- **HLA matching:** 3/6 antigen mismatch (2 HLA-A, 1 HLA-DR mismatch)
- **Crossmatch:** Negative (CDC and flow cytometric)
- **Induction:** Basiliximab
- **Maintenance immunosuppression:** Tacrolimus, mycophenolate mofetil, prednisone

### Past Medical History
- End-stage renal disease due to hypertensive nephrosclerosis
- Hemodialysis for 4 years prior to transplant
- Hypertension
- Previous blood transfusions (sensitized: cPRA 45%)

### Physical Examination
- **General:** Well-appearing man in no distress
- **Vital Signs:** T 37.4C, HR 78, RR 14, BP 145/88
- **Cardiovascular:** Regular rhythm, no murmurs
- **Lungs:** Clear bilaterally
- **Abdomen:** Soft, non-tender; well-healed incision in right lower quadrant; graft non-tender, no bruit
- **Extremities:** Trace bilateral edema

### Laboratory Workup
| Test | Result (Today) | Result (Day 7) | Reference |
|------|----------------|----------------|-----------|
| **Creatinine** | **2.8 mg/dL** | 1.3 mg/dL | 0.7-1.3 mg/dL |
| BUN | 42 mg/dL | 22 mg/dL | 7-20 mg/dL |
| Potassium | 5.4 mEq/L | 4.2 mEq/L | 3.5-5.0 mEq/L |
| Tacrolimus trough | 8.2 ng/mL | 9.1 ng/mL | Target 8-12 ng/mL |
| WBC | 6,800/uL | 7,200/uL | 4,500-11,000/uL |
| Urinalysis | 1+ protein, no casts | Normal | Normal |
| CMV PCR | Not detected | -- | Not detected |
| BK virus PCR | Not detected | -- | Not detected |
| Donor-specific antibodies | Negative | Negative | Negative |

### Imaging
- **Renal ultrasound:** Normal graft size and echogenicity; good arterial and venous flow; no hydronephrosis; no perinephric fluid collection

### Kidney Biopsy Findings
- **Light microscopy:** Moderate interstitial inflammation with tubulitis (>4 lymphocytes per tubular cross-section); no arteritis
- **Immunofluorescence:** Negative for C4d
- **Histology grading:** Banff 1B acute T cell-mediated rejection

### Clinical Image
![Transplant Pathology](case_01_image.jpg)

*Image illustrating concepts in transplant immunology including allorecognition and rejection mechanisms. The direct pathway involves recipient T cells recognizing intact donor MHC on donor APCs, while the indirect pathway involves processing of donor antigens by recipient APCs. Image source: Course lecture materials.*

### Diagnosis
**Acute T Cell-Mediated Rejection (Banff 1B)** in deceased-donor kidney transplant

### Discussion
Acute cellular rejection is mediated by recipient T cells recognizing donor alloantigens:

**Pathophysiology:**
- **Direct allorecognition:** Recipient T cells recognize intact donor MHC on passenger leukocytes (predominates early)
- **Indirect allorecognition:** Recipient APCs process and present donor antigens to T cells (predominates later)
- Activated T cells infiltrate graft parenchyma
- CD8+ CTLs directly kill tubular epithelial cells
- CD4+ Th1 cells recruit macrophages via IFN-gamma

**Banff classification of acute T cell-mediated rejection:**
| Grade | Histological Findings |
|-------|----------------------|
| 1A | Interstitial inflammation >25%, tubulitis with 1-4 lymphocytes/tubular cross-section |
| 1B | Interstitial inflammation >25%, tubulitis with >4 lymphocytes/tubular cross-section |
| 2A | Mild intimal arteritis (<25% luminal narrowing) |
| 2B | Moderate intimal arteritis (>25% luminal narrowing) |
| 3 | Severe arteritis with fibrinoid necrosis or transmural inflammation |

**Risk factors for rejection in this patient:**
- African American race (higher immunological risk)
- HLA mismatch (3/6)
- Prior sensitization (cPRA 45%)
- Non-depleting induction (basiliximab vs ATG)

**Why wasn't this antibody-mediated rejection?**
- Donor-specific antibodies negative
- C4d staining negative on biopsy
- No microvascular inflammation

### Treatment
1. **Pulse corticosteroids:** Methylprednisolone 500mg IV daily x 3 days
2. **Continue maintenance immunosuppression:** Ensure therapeutic tacrolimus levels
3. **Response assessment:** Check creatinine daily; expect improvement within 3-5 days
4. **If steroid-resistant:** Anti-thymocyte globulin (ATG) for Grade 2A and above or steroid-refractory Grade 1B
5. **Long-term:** May need to intensify maintenance (increase tacrolimus target)
6. **Prognosis:** Grade 1B generally responds well to steroids; however, rejection episodes increase chronic rejection risk

---

## Case 2: Graft-Versus-Host Disease After Stem Cell Transplant

### Patient Demographics
- **Age:** 28 years old
- **Sex:** Female
- **Ethnicity:** Caucasian

### Chief Complaint
Rash, diarrhea, and jaundice 35 days after bone marrow transplant

### History of Present Illness
A 28-year-old woman who underwent allogeneic hematopoietic stem cell transplant (HSCT) 35 days ago for acute myeloid leukemia presents with a progressive rash, profuse watery diarrhea, and yellowing of her skin. The rash began 5 days ago as erythema on her palms and soles, then spread to her trunk and extremities. Over the past 3 days, she has developed watery diarrhea (10-12 episodes daily, approximately 2 liters/day) with crampy abdominal pain. She also notes decreased appetite, nausea, and dark urine.

### Transplant Details
- **Indication:** AML in first complete remission
- **Donor:** Matched unrelated donor (10/10 HLA match)
- **Conditioning:** Myeloablative (busulfan/cyclophosphamide)
- **GVHD prophylaxis:** Tacrolimus and methotrexate
- **Engraftment:** Day +16 (neutrophils), Day +22 (platelets)

### Physical Examination
- **General:** Ill-appearing woman with obvious jaundice
- **Vital Signs:** T 38.2C, HR 105, RR 18, BP 100/65
- **Skin:** Diffuse maculopapular erythematous rash involving >50% BSA; palms and soles affected; no bullae or desquamation
- **HEENT:** Icteric sclerae; dry mucous membranes; no oral lesions
- **Abdomen:** Mildly distended; diffuse tenderness; hyperactive bowel sounds
- **Extremities:** No edema

### Laboratory Workup
| Test | Result | Reference Range |
|------|--------|-----------------|
| WBC | 4,200/uL | 4,500-11,000/uL |
| ANC | 2,100/uL | 1,500-8,000/uL |
| Hemoglobin | 9.8 g/dL | 12-16 g/dL |
| Platelets | 65,000/uL | 150,000-400,000/uL |
| **Total bilirubin** | **8.5 mg/dL** | 0.1-1.2 mg/dL |
| Direct bilirubin | 6.2 mg/dL | 0-0.3 mg/dL |
| AST | 185 U/L | 10-40 U/L |
| ALT | 210 U/L | 7-56 U/L |
| **Alkaline phosphatase** | **520 U/L** | 44-147 U/L |
| Albumin | 2.8 g/dL | 3.5-5.0 g/dL |
| Stool studies | C. diff negative; cultures negative | Negative |

### Skin Biopsy
Interface dermatitis with scattered apoptotic keratinocytes; lymphocytic infiltrate at dermoepidermal junction

### Diagnosis
**Acute Graft-Versus-Host Disease (Grade III)** involving skin, liver, and gastrointestinal tract

### Discussion
GVHD occurs when donor T cells attack recipient tissues. Three requirements (Billingham criteria):

1. Graft contains immunocompetent cells (donor T cells)
2. Recipient expresses antigens foreign to donor (histocompatibility differences)
3. Recipient cannot reject donor cells (immunocompromised)

**Acute GVHD target organs and staging:**
| Stage | Skin | Liver (Bilirubin) | GI (Diarrhea) |
|-------|------|-------------------|---------------|
| 1 | <25% BSA | 2-3 mg/dL | 500-1000 mL/day |
| 2 | 25-50% BSA | 3.1-6 mg/dL | 1000-1500 mL/day |
| 3 | >50% BSA | 6.1-15 mg/dL | >1500 mL/day |
| 4 | Bullae, desquamation | >15 mg/dL | Severe pain, ileus |

**Overall grade:**
| Grade | Staging |
|-------|---------|
| I | Skin 1-2, no liver/GI |
| II | Skin 1-3, liver/GI 1 |
| III | Skin 2-3, liver/GI 2-3 |
| IV | Skin/liver/GI 2-4 with severe organ involvement |

**This patient's staging:**
- Skin: Stage 3 (>50% BSA)
- Liver: Stage 3 (bilirubin 8.5 mg/dL)
- GI: Stage 3 (~2L/day diarrhea)
- **Overall: Grade III acute GVHD**

**Pathology findings:**
- Skin: Interface dermatitis, satellite cell necrosis (apoptotic keratinocytes)
- Liver: Bile duct destruction, cholestasis
- GI: Crypt cell apoptosis, mucosal denudation

### Treatment
1. **First-line:** High-dose corticosteroids (methylprednisolone 2 mg/kg/day)
2. **Supportive care:**
   - IV fluids and electrolyte replacement (for diarrhea)
   - Nutritional support (may need TPN)
   - Ursodiol for cholestasis
   - Infection prophylaxis
3. **If steroid-refractory (no response by day 7):**
   - Ruxolitinib (JAK inhibitor) - FDA approved for steroid-refractory acute GVHD
   - Other options: ATG, extracorporeal photopheresis
4. **Continue tacrolimus prophylaxis**
5. **Monitor for infections:** Severely immunocompromised

**Prognosis:** Grade III acute GVHD has significant mortality (50-70%); early treatment improves outcomes

**Graft-versus-leukemia effect:** Donor T cells also target residual leukemia cells, reducing relapse risk. Complete GVHD suppression may increase leukemia relapse.

---

## Case 3: Chronic Antibody-Mediated Rejection

### Patient Demographics
- **Age:** 48 years old
- **Sex:** Female
- **Ethnicity:** Hispanic

### Chief Complaint
Gradually rising creatinine over 2 years, now with heavy proteinuria

### History of Present Illness
A 48-year-old woman with a kidney transplant from 8 years ago presents for evaluation of progressively worsening graft function. Her creatinine has slowly risen from a baseline of 1.3 mg/dL to 2.5 mg/dL over the past 2 years. Recent urinalysis shows 3+ protein. She reports compliance with her immunosuppressive medications and denies any acute symptoms. She admits to occasionally missing her evening mycophenolate dose.

### Transplant History
- **Original disease:** Polycystic kidney disease
- **Transplant:** Living unrelated donor (spouse), 8 years ago
- **HLA matching:** 3/6 mismatch
- **Initial course:** Excellent function (creatinine 1.0-1.3 mg/dL for first 6 years)
- **Year 6:** Episode of BK nephropathy, treated with immunosuppression reduction
- **Maintenance:** Tacrolimus 3mg BID, mycophenolate 500mg BID, prednisone 5mg daily

### Laboratory Workup
| Test | Result | 2 Years Ago | Reference |
|------|--------|-------------|-----------|
| Creatinine | 2.5 mg/dL | 1.4 mg/dL | 0.7-1.3 mg/dL |
| eGFR | 22 mL/min | 48 mL/min | >90 mL/min |
| Proteinuria | 2.8 g/24hr | 350 mg/24hr | <150 mg/24hr |
| Tacrolimus level | 5.8 ng/mL | -- | Target 5-8 ng/mL |
| **DSA (HLA-DR)** | **MFI 12,500** | Negative | Negative |
| CMV, BK PCR | Negative | -- | Negative |

### Kidney Biopsy Findings
- **Light microscopy:**
  - Glomeruli: Double contours of GBM (transplant glomerulopathy)
  - Interstitium: 40% interstitial fibrosis and tubular atrophy (IFTA)
  - Vessels: Moderate intimal fibrosis
  - Peritubular capillaries: Capillaritis (inflammation)
- **Immunofluorescence:** C4d positive in peritubular capillaries (diffuse, >50%)
- **Electron microscopy:** GBM duplication, subendothelial widening

### Diagnosis
**Chronic Active Antibody-Mediated Rejection** with transplant glomerulopathy

### Discussion
Chronic antibody-mediated rejection (AMR) is a leading cause of late graft loss:

**Pathophysiology:**
- Development of de novo donor-specific antibodies (DSA)
- DSA bind to donor HLA antigens on graft endothelium
- Complement activation (C4d deposition)
- Endothelial injury leads to chronic vascular and glomerular damage
- Results in transplant glomerulopathy and progressive fibrosis

**Diagnostic criteria for chronic active AMR:**
1. Morphological evidence of chronic tissue injury:
   - Transplant glomerulopathy (GBM double contours)
   - Peritubular capillary basement membrane multilayering
2. Evidence of current antibody-graft interaction:
   - C4d deposition or microvascular inflammation
3. Serological evidence:
   - Donor-specific antibodies (DSA) present

**Risk factors in this patient:**
- HLA mismatch (3/6)
- Prior BK nephropathy (reduced immunosuppression)
- Possible non-adherence (missed doses)
- Living unrelated donor (chronic immune stimulation)

**Transplant glomerulopathy:**
- Pathognomonic of chronic AMR
- GBM duplication from recurrent endothelial injury and repair
- Associated with heavy proteinuria
- Poor prognosis once established

### Treatment
1. **Limited options for chronic AMR** - largely irreversible
2. **Optimize immunosuppression:** Ensure adequate tacrolimus levels; improve adherence
3. **Consider:**
   - Plasma exchange + IVIG (limited efficacy in chronic AMR)
   - Rituximab (B cell depletion)
   - Bortezomib (plasma cell depletion) - limited evidence
4. **Supportive measures:**
   - ACE inhibitor/ARB for proteinuria
   - Blood pressure control
   - Cardiovascular risk management
5. **Prepare for graft failure:**
   - Dialysis planning
   - Retransplantation evaluation

**Prognosis:** Poor; most grafts with chronic AMR progress to failure within 3-5 years. Prevention through adherence and DSA monitoring is key.

**Prevention strategies:**
- Medication adherence counseling
- Regular DSA monitoring (every 6-12 months)
- Prompt treatment of acute AMR episodes
- Avoid unnecessary immunosuppression reduction