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

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

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

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 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 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

A 52-year-old man with hepatocellular carcinoma (single 4.5 cm lesion) within Milan criteria is listed for liver transplantation with MELD exception points. While waiting, alpha-fetoprotein increases from 125 to 850 ng/mL over 3 months despite locoregional therapy. Repeat imaging shows the tumor has grown to 6 cm with possible vascular invasion. He has no extrahepatic disease. His wife offers to be a living donor. Synthesize the clinical data and evaluate the most appropriate management decision.

Remove from transplant list and pursue systemic therapy with sorafenib

Perform surgical resection then relist if recurrence occurs within criteria

Downstage with aggressive locoregional therapy then reassess for transplantation

Proceed with living donor transplantation given no extrahepatic disease

Continue locoregional therapy and maintain listing with exception points

Kidney transplantation for USMLE Step 3: High-Yield Surgery Lessons

Indications & Workup - The Kidney Waitlist

Indication: End-Stage Renal Disease (ESRD) with GFR < 15 mL/min/1.73m² or patient on dialysis.
Core Workup:
- ABO & HLA typing (A, B, DR loci)
- Panel Reactive Antibody (PRA) to assess sensitization
- Infection screen (HIV, HBV, HCV, CMV)
- Cardiovascular & psychosocial evaluation
Key Contraindications:
- Absolute: Active malignancy, uncontrolled infection, severe end-organ damage.
- Relative: Morbid obesity (BMI > 40), active substance abuse, nonadherence.

⭐ High Panel Reactive Antibody (PRA) signifies broad sensitization to donor HLAs, prolonging wait times and increasing rejection risk.

Immunosuppression - Taming the Defenses

Goal: Prevent rejection (hyperacute, acute, chronic) while minimizing drug toxicity & infection risk.
Phases: Induction (at transplant), Maintenance (lifelong), Rejection treatment.

Immunosuppressant Mechanisms in T-Cell Activation

Drug Class	Examples & MOA	Key Side Effects
Calcineurin Inhibitors	Tacrolimus, Cyclosporine - Inhibit IL-2 transcription	Nephrotoxicity, neurotoxicity, hypertension, hyperkalemia.
Antimetabolites	Mycophenolate Mofetil - Inhibits purine synthesis	GI distress (diarrhea), bone marrow suppression, ↑ CMV risk.
mTOR Inhibitors	Sirolimus - Blocks IL-2 signal transduction	Hyperlipidemia, poor wound healing, proteinuria, pneumonitis.
Corticosteroids	Prednisone - Broad anti-inflammatory	Hyperglycemia, osteoporosis, weight gain, mood changes.

Surgical Technique - The Retroperitoneal Tuck

Kidney Transplant: Surgical Anatomy & Ureteral Anastomosis

Placement: The donor kidney is placed in the iliac fossa, remaining outside the peritoneal cavity (extraperitoneal). This protects the graft from potential peritonitis and allows for easier access for biopsy.
Anastomosis Sequence:
- Vascular: Donor renal vein and artery are connected to the recipient's external iliac vein and internal/external iliac artery, respectively.
- Urinary: The donor ureter is implanted into the bladder (ureteroneocystostomy).

⭐ High-Yield: The most common urologic complication is ureteral obstruction, often at the vesicoureteric anastomosis site, leading to hydronephrosis and graft dysfunction.

Post-Op Complications - Rejection & Other Woes

Rejection Types & Timeline
- Hyperacute: Pre-existing recipient antibodies against donor antigens. Gross mottling & cyanosis.
- Acute: Cellular (T-cell) or humoral (antibody) response. Most common type, usually reversible. Presents with ↑ creatinine, fever, graft tenderness.
- Chronic: Slow, progressive graft dysfunction. Dominated by interstitial fibrosis & tubular atrophy.
Other Major Complications
- Thrombosis: Renal artery or vein. Early post-op emergency.
- Urine Leak: Breakdown of ureter-bladder anastomosis.
- Infection: High risk due to immunosuppression. 📌 CMV, BK virus.
- Drug Toxicity: Calcineurin inhibitors (Tacrolimus, Cyclosporine) are nephrotoxic.

⭐ BK virus nephropathy can mimic acute cellular rejection. Both present with a rising creatinine. Diagnosis requires graft biopsy to look for viral inclusions vs. lymphocytic infiltrates.

Kidney transplant rejection mechanisms

High‑Yield Points - ⚡ Biggest Takeaways

Living donor kidneys offer superior graft survival compared to deceased donor organs.

Hyperacute rejection is a type II hypersensitivity due to pre-formed antibodies, causing immediate graft failure.

Acute rejection is most commonly T-cell mediated within the first few months and responds to steroids.

Calcineurin inhibitors (Tacrolimus) are cornerstone immunosuppressants but are nephrotoxic.

Watch for renal artery stenosis as a cause of new-onset hypertension post-transplant.

Prophylaxis for CMV and PCP is crucial in the immediate post-transplant period.

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