A 55-year-old woman recently underwent kidney transplantation for end-stage renal disease. Her early postoperative period was uneventful, and her serum creatinine is lowered from 4.3 mg/dL (preoperative) to 2.5 mg/dL. She is immediately started on immunosuppressive therapy. On postoperative day 7, she presents to the emergency department (ED) because of nausea, fever, abdominal pain at the transplant site, malaise, and pedal edema. The vital signs include: pulse 106/min, blood pressure 167/96 mm Hg, respirations 26/min, and temperature 40.0°C (104.0°F). The surgical site shows no signs of infection. Her urine output is 250 mL over the past 24 hours. Laboratory studies show: Hematocrit 33% White blood cell (WBC) count 6700/mm3 Blood urea 44 mg/dL Serum creatinine 3.3 mg/dL Serum sodium 136 mEq/L Serum potassium 5.6 mEq/L An ultrasound of the abdomen shows collection of fluid around the transplanted kidney with moderate hydronephrosis. Which of the following initial actions is the most appropriate?

Continue with an ultrasound-guided biopsy of the transplanted kidney

Re-operate and remove the failed kidney transplant

Start on pulse steroid treatment or OKT3

Supportive treatment with IV fluids, antibiotics, and antipyretics

A 62-year-old female with a history of uncontrolled hypertension undergoes kidney transplantation. One month following surgery she has elevated serum blood urea nitrogen and creatinine and the patient complains of fever and arthralgia. Her medications include tacrolimus and prednisone. If the patient were experiencing acute, cell-mediated rejection, which of the following would you most expect to see upon biopsy of the transplanted kidney?

Lymphocytic infiltrate of the tubules and interstitium

Granular immunofluorescence around the glomerular basement membrane

Crescent formation in Bowman’s space

Drug precipitation in the renal tubules

Sloughing of proximal tubular epithelial cells

A 61-year-old-male underwent deceased donor liver transplantation 3 weeks ago. During his follow up visit he complains of nausea and abdominal pain. He has been taking all of his medications as prescribed. He has a history of alcohol abuse and his last drink was one year ago. He does not smoke cigarettes and lives at home with his wife. On physical examination temperature is 98.6°F (37°C), blood pressure is 115/80 mmHg, pulse is 90/min, respirations are 18/min, and pulse oximetry is 99% on room air. He has scleral icterus and a positive fluid wave. Liver function tests are as follows: Alkaline phosphatase: 110 U/L Aspartate aminotransferase (AST, GOT): 100 U/L Alanine aminotransferase (ALT, GPT): 120 U/L Bilirubin total: 2.2 mg/dL Liver biopsy shows mixed dense interstitial lymphocytic infiltrates in the portal triad. What is the mechanism of this reaction?

CD8+ T lymphocytes reacting against donor MHCs

Grafted T lymphocytes reacting against host

CD4+ T lymphocytes reacting against recipient APCs

Pre-existing recipient antibodies

An investigator studying immune-mediated pulmonary damage performs an autopsy on a bilateral lung transplant recipient who died of hypercapnic respiratory failure. The patient underwent lung transplantation for idiopathic pulmonary fibrosis. Microscopic examination of the lung shows diffuse eosinophilic scarring of the terminal and respiratory bronchioles and near-complete luminal obliteration by polypoidal plugs of granulation tissue. Examination of the skin shows no abnormalities. The findings in this patient are most consistent with which of the following conditions?

Transfusion-related acute lung injury

Acute graft-versus-host disease

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

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

Rejection diagnosis and management for USMLE Step 1: High-Yield Surgery Lessons

Rejection Types - Immune System Overdrive

📌 Mnemonic: HACk the graft! (Hyperacute, Acute, Chronic)

Type	Onset	Pathophysiology (HSR Type)	Key Histology/Features
Hyperacute	Minutes-Hours	Pre-formed anti-donor Abs (Type II)	Widespread thrombosis, vessel occlusion, ischemia. Irreversible.
Acute	< 6 months	T-cell mediated cellular infiltrate (Type IV)	Interstitial lymphocytic infiltrate, tubulitis. Usually reversible.
Chronic	> 6 months	Mixed T-cell/Ab-mediated (Type III/IV)	Irreversible fibrosis, atrophy. Graft arteriosclerosis, vanishing bile ducts.

⭐ Acute rejection is the most common type, typically occurring within the first 6 months. It's often reversible with bolstered immunosuppression.

Diagnosis - Spotting the Attack

Clinical Clues: Fever, malaise, and tenderness over the graft site.
Organ-Specific Signs:
- Kidney: ↑ Serum Creatinine (>25% from baseline), ↓ urine output.
- Liver: ↑ LFTs (ALT, AST, GGT), ↑ bilirubin.
- Heart: Symptoms of heart failure (e.g., dyspnea, edema).
Non-Invasive Tests:
- Donor-derived cell-free DNA (dd-cfDNA) levels may rise, indicating graft injury.
- Ultrasound to rule out vascular or surgical complications.
Gold Standard:
- Allograft biopsy is definitive for diagnosis and grading rejection.

Renal Allograft Rejection Mechanisms

⭐ C4d deposition in peritubular capillaries on biopsy is a hallmark of antibody-mediated rejection, indicating complement activation.

Management - Calming the Storm

General Principle: Increase net immunosuppression. Biopsy is key to guide therapy.
Acute Cellular Rejection (ACR):
- 1st Line: High-dose pulse IV corticosteroids (e.g., methylprednisolone).
- Steroid-Refractory: Lymphocyte-depleting agents (e.g., anti-thymocyte globulin [ATG]) or other monoclonal antibodies (Alemtuzumab).
Antibody-Mediated Rejection (AMR):
- Goal: Remove circulating donor-specific antibodies (DSAs) & suppress B-cells.
- Multi-modal approach:
  - Plasmapheresis (PP) or Immunoadsorption (IA) to remove antibodies.
  - IV Immunoglobulin (IVIG) to neutralize antibodies.
  - Targeted therapy: Rituximab (anti-CD20), Bortezomib (proteasome inhibitor).
Chronic Rejection / Chronic Allograft Vasculopathy (CAV):
- Largely irreversible; management is supportive.
- Optimize immunosuppression, manage risk factors (HTN, HLD).
- Eventual re-transplantation is the only definitive treatment.

⭐ The first-line therapy for acute T-cell mediated rejection is a high-dose pulse of corticosteroids. Most rejection episodes are steroid-responsive.

High‑Yield Points - ⚡ Biggest Takeaways

Hyperacute rejection is immediate due to pre-formed recipient antibodies; causes graft thrombosis.

Acute rejection occurs weeks to months later, is T-cell mediated, and usually reversible with immunosuppressants.

Chronic rejection develops over months to years, causing irreversible graft fibrosis and arteriosclerosis.

Graft-versus-host disease (GVHD) occurs when donor T-cells attack host tissues, typically after bone marrow transplant.

Biopsy is the gold standard for diagnosing rejection.

Manage acute rejection with corticosteroids and calcineurin inhibitors.

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