Two weeks after undergoing allogeneic stem cell transplant for multiple myeloma, a 55-year-old man develops a severely pruritic rash, abdominal cramps, and profuse diarrhea. He appears lethargic. Physical examination shows yellow sclerae. There is a generalized maculopapular rash on his face, trunk, and lower extremities, and desquamation of both soles. His serum alanine aminotransferase is 115 U/L, serum aspartate aminotransferase is 97 U/L, and serum total bilirubin is 2.7 mg/dL. Which of the following is the most likely underlying cause of this patient's condition?

Preformed cytotoxic anti-HLA antibodies

Proliferating transplanted B cells

Newly formed anti-HLA antibodies

A 31-year-old female receives a kidney transplant for autosomal dominant polycystic kidney disease (ADPKD). Three weeks later, the patient experiences acute, T-cell mediated rejection of the allograft and is given sirolimus. Which of the following are side effects of this medication?

Hyperlipidemia, thrombocytopenia

Nephrotoxicity, gingival hyperplasia

Cytokine release syndrome, hypersensitivity reaction

Twelve days after undergoing a cadaveric renal transplant for adult polycystic kidney disease, a 23-year-old man has pain in the right lower abdomen and generalized fatigue. During the past 4 days, he has had decreasing urinary output. Creatinine concentration was 2.3 mg/dL on the second postoperative day. Current medications include prednisone, cyclosporine, azathioprine, and enalapril. His temperature is 38°C (100.4°F), pulse is 103/min, and blood pressure is 168/98 mm Hg. Examination reveals tenderness to palpation on the graft site. Creatinine concentration is 4.3 mg/dL. A biopsy of the transplanted kidney shows tubulitis. C4d staining is negative. Which of the following is the most likely cause of this patient's findings?

Allorecognition with T cell activation

Irreversible fibrosis of the glomerular vessels

Preformed cytotoxic antibodies against class I HLA

A 46-year-old man comes to the physician because of a 4-month history of progressively worsening fatigue and loss of appetite. Five years ago, he received a kidney transplant from a living family member. Current medications include sirolimus and mycophenolate. His blood pressure is 150/95 mm Hg. Laboratory studies show normocytic, normochromic anemia and a serum creatinine concentration of 3.1 mg/dL; his vital signs and laboratory studies were normal 6 months ago. Which of the following is the most likely underlying mechanism of this patient’s increase in creatinine concentration?

CD4+ T cell-mediated intimal smooth muscle proliferation

Drug-induced tubular vacuolization

CD8+ T cell-mediated parenchymal cell damage

Donor T cell-mediated epithelial cell damage

Donor endothelial cell damage by preformed host antibodies

Several weeks following a kidney transplantation, a 50-year-old Caucasian female presents for evaluation of the transplanted organ. Biopsy shows inflammation involving the endothelial cells of the kidney vasculature and the presence of mononuclear cells in the interstitium. Which cells are most likely responsible for this presentation?

Deposition of antibody immune complexes

Fourteen days after a laparoscopic cholecystectomy for cholelithiasis, a 45-year-old woman comes to the emergency department because of persistent episodic epigastric pain for 3 days. The pain radiates to her back, occurs randomly throughout the day, and is associated with nausea and vomiting. Each episode lasts 30 minutes to one hour. Antacids do not improve her symptoms. She has hypertension and fibromyalgia. She has smoked 1–2 packs of cigarettes daily for the past 10 years and drinks 4 cans of beer every week. She takes lisinopril and pregabalin. She appears uncomfortable. Her temperature is 37°C (98.6° F), pulse is 84/min, respirations are 14/min, and blood pressure is 127/85 mm Hg. Abdominal examination shows tenderness to palpation in the upper quadrants without rebound or guarding. Bowel sounds are normal. The incisions are clean, dry, and intact. Serum studies show: AST 80 U/L ALT 95 U/L Alkaline phosphatase 213 U/L Bilirubin, total 1.3 mg/dL Direct 0.7 mg/dL Amylase 52 U/L Abdominal ultrasonography shows dilation of the common bile duct and no gallstones. Which of the following is the most appropriate next step in management?

Endoscopic retrograde cholangiopancreatography

Counseling on alcohol cessation

Reassurance and follow-up in 4 weeks

A 38-year-old kidney transplant recipient maintained on tacrolimus presents with a 2-week history of progressive confusion, ataxia, and visual disturbances. MRI shows multifocal white matter lesions without mass effect or enhancement. CSF analysis reveals mild pleocytosis with elevated protein. JC virus DNA is detected in CSF by PCR. Serum tacrolimus level is therapeutic at 8 ng/mL. Apply knowledge of this condition to determine the appropriate management strategy.

Significantly reduce or discontinue immunosuppression and provide supportive care

Switch from tacrolimus to sirolimus to preserve graft while treating infection

Continue current immunosuppression and administer IVIG therapy

Maintain immunosuppression and start cidofovir antiviral therapy

Reduce tacrolimus by 50% and start high-dose corticosteroids

A 41-year-old heart transplant recipient (5 years post-transplant) on cyclosporine, azathioprine, and prednisone develops progressive dyspnea on exertion. Echocardiogram shows preserved ejection fraction but abnormal diastolic dysfunction. Right heart catheterization reveals elevated filling pressures. Endomyocardial biopsy shows interstitial fibrosis without significant cellular infiltration. Coronary angiography shows diffuse, concentric narrowing of distal vessels. Synthesize these findings to determine the underlying pathophysiology and evaluate management options.

Cardiac allograft vasculopathy requiring consideration for retransplantation evaluation

Restrictive cardiomyopathy from previous rejection episodes requiring diuretic therapy

Drug-induced cardiomyopathy from calcineurin inhibitor toxicity requiring switch to mTOR inhibitor

Acute cellular rejection requiring pulse steroids and optimization of immunosuppression

Antibody-mediated rejection requiring plasmapheresis and rituximab therapy

Long-term complications of transplantation for USMLE Step 1: High-Yield Surgery Lessons

Chronic Rejection - The Slow Burn

Timeline: Occurs months to years post-transplant.
Pathogenesis: A slow, progressive, and often irreversible graft dysfunction. It's a mixed T-cell and antibody-mediated process causing chronic inflammation, fibrosis, and eventual atrophy.
Key Organ-Specific Manifestations:
- Kidney: Interstitial fibrosis & tubular atrophy (IF/TA), graft glomerulopathy.
- Lung: Bronchiolitis obliterans (presenting with dry cough, dyspnea).
- Liver: Vanishing bile duct syndrome.
- Heart: Graft arteriosclerosis (accelerated coronary artery disease).
Management: Generally refractory to immunosuppressive therapy; re-transplantation is often the only definitive treatment.

⭐ In lung transplants, chronic rejection manifests as Bronchiolitis Obliterans Syndrome (BOS), an obstructive process seen on PFTs.

Histopathology of Chronic Kidney Transplant Rejection

Infections & Malignancy - Unwanted Guests

Infections: Risk is stratified by time from transplant, reflecting the net state of immunosuppression. See timeline below.
Malignancy: Chronic immunosuppression significantly increases risk.
- Skin Cancers: Most common malignancy. Squamous Cell Carcinoma (SCC) is much more frequent and aggressive than Basal Cell Carcinoma (BCC).
- PTLD (Post-Transplant Lymphoproliferative Disorder): Strongly associated with Epstein-Barr Virus (EBV). Presents as a spectrum from hyperplasia to lymphoma.

⭐ First-line therapy for PTLD is reducing immunosuppression. Rituximab is a subsequent option if this fails.

Histology of Post-transplant Lymphoproliferative Disorder

Cardiovascular & Metabolic - The Price of Pills

Calcineurin Inhibitors (Tacrolimus, Cyclosporine)
- Hypertension (HTN): Common; due to renal vasoconstriction.
- Hyperglycemia: ↓ insulin secretion (Tacrolimus > Cyclosporine).
- Hyperlipidemia: ↑ LDL & triglycerides (Cyclosporine > Tacrolimus).
Corticosteroids (Prednisone)
- Hyperglycemia/Diabetes: Due to insulin resistance.
- Dyslipidemia & Weight Gain: Central obesity, Cushingoid features.
- Hypertension: Mineralocorticoid effects.
mTOR Inhibitors (Sirolimus, Everolimus)
- Profound Hypertriglyceridemia & hypercholesterolemia.
- ⚠️ Can impair wound healing; use with caution early post-transplant.

⭐ Sirolimus is particularly notorious for causing severe hypertriglyceridemia, often requiring lipid-lowering therapy.

Renal & Other Effects - Collateral Damage

CNI Nephrotoxicity:
- Acute: Reversible afferent arteriole vasoconstriction.
- Chronic: Irreversible; leads to hyaline arteriolosclerosis, tubular atrophy, interstitial fibrosis → chronic graft failure.
Hypertension:
- Multifactorial: CNI-induced vasoconstriction, steroid-induced fluid retention, pre-existing disease.
Metabolic Syndrome:
- Hyperlipidemia: mTOR inhibitors (sirolimus), CNIs, steroids.
- New-Onset Diabetes (NODAT): Tacrolimus & steroids are major culprits.
Hyperuricemia & Gout:
- CNIs (esp. Cyclosporine) ↓ renal urate excretion.
Bone Disease:
- Steroid-induced osteoporosis & avascular necrosis.

⭐ CNI-induced afferent arteriole vasoconstriction is a primary driver of both acute and chronic nephrotoxicity, leading to long-term graft loss.

Pathophysiology of Calcineurin Inhibitor Nephrotoxicity

High‑Yield Points - ⚡ Biggest Takeaways

Chronic rejection is the leading cause of long-term allograft failure, characterized by fibrosis and vascular obliteration.

Immunosuppression increases risk for opportunistic infections (CMV, PJP) and malignancies, especially skin cancer and PTLD.

Cardiovascular disease is a major cause of mortality in transplant recipients.

Calcineurin inhibitor nephrotoxicity (cyclosporine, tacrolimus) is a common cause of renal dysfunction.

Monitor for metabolic complications like new-onset diabetes, hypertension, and hyperlipidemia.

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