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

A 63-year-old HIV-positive man comes to the physician for a routine health maintenance examination. Four years ago, he was diagnosed with HIV and was started on cART therapy. He tells the physician that he has been having difficulty adhering to his medication regimen. He has been unemployed for the past couple of years and relies on unemployment benefits to cover the costs of daily living. His father died of lymphoma at the age of 60 years. He wants more information about his risk of developing DLBCL. Which of the following is the greatest risk factor for the development of DLBCL in HIV-positive patients?

Positive family history of cancer

A 38-year-old woman comes to the physician for a follow-up examination. Two years ago, she was diagnosed with multiple sclerosis. Three weeks ago, she was admitted and treated for right lower leg weakness with high-dose methylprednisone for 5 days. She has had 4 exacerbations over the past 6 months. Current medications include interferon beta and a multivitamin. Her temperature is 37°C (98.6°F), pulse is 90/min, and blood pressure is 116/74 mm Hg. Examination shows pallor of the right optic disk. Neurologic examination shows no focal findings. She is anxious about the number of exacerbations and repeated hospitalizations. She is counseled about the second-line treatment options available to her. She consents to treatment with natalizumab. However, she has read online about its adverse effects and is concerned. This patient is at increased risk for which of the following complications?

Progressive multifocal leukoencephalopathy

Syndrome of inappropriate antidiuretic hormone

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

Post-transplant immunosuppression protocols for USMLE Step 3: High-Yield Pharmacology Lessons

Immunosuppression Phases - The Game Plan

Induction (Peri-operative): High-potency, short-term lymphocyte depletion to prevent hyperacute/acute rejection. Agents: Basiliximab (IL-2R Ab), Antithymocyte Globulin (ATG).
Maintenance (Lifelong): Lower-dose combination therapy to prevent chronic rejection and minimize toxicity.
Rejection Treatment (Episodic): High-dose pulse therapy for breakthrough rejection (e.g., steroids, ATG).

⭐ Most maintenance regimens use triple therapy: a Calcineurin Inhibitor (Tacrolimus), an Antiproliferative agent (Mycophenolate), and Corticosteroids.

Induction Therapy - The Shock Troops

Goal: Provide intense, short-term immunosuppression immediately post-transplant. Aims to prevent acute rejection by depleting lymphocytes or blocking their activation.
Key Agents:
- Biologics (Antibodies): Cornerstone of induction.
  - IL-2 Receptor Antagonist: Basiliximab. Specifically targets the CD25 receptor on activated T-cells, preventing their proliferation.
  - Polyclonal Antibodies: Antithymocyte Globulin (ATG) (rabbit/equine). Causes broad T-cell depletion.
  - Anti-CD52 Antibody: Alemtuzumab. Depletes a wide range of lymphocytes.
- High-Dose Corticosteroids: e.g., Methylprednisolone, given intraoperatively and for a short period post-op.

⭐ Basiliximab offers targeted therapy against activated T-cells only, sparing resting lymphocytes. This leads to fewer side effects like cytomegalovirus (CMV) infection compared to broadly depleting agents like ATG.

Maintenance Therapy - The Long Patrol

Goal: Prevent acute & chronic rejection while minimizing long-term drug toxicity. This is a lifelong balancing act.
Cornerstone Regimen (Triple Drug Therapy):
- Calcineurin Inhibitor (CNI): Tacrolimus (preferred) or Cyclosporine.
  - Blocks IL-2 synthesis, preventing T-cell activation.
  - ⚠️ Key toxicities: Nephrotoxicity, neurotoxicity, hypertension, hyperglycemia.
- Antiproliferative Agent: Mycophenolate Mofetil (MMF) or Azathioprine.
  - Inhibits lymphocyte proliferation by blocking purine synthesis.
  - ⚠️ Key toxicities: GI intolerance (diarrhea), bone marrow suppression.
- Corticosteroids: Prednisone.
  - Broad anti-inflammatory effects; tapered to the lowest effective dose (e.g., ≤5 mg/day) or discontinued.
CNI-Sparing Alternatives:
- mTOR inhibitors (Sirolimus, Everolimus) may replace CNIs to avoid renal toxicity, but have their own side effects (e.g., poor wound healing, hyperlipidemia).

⭐ Chronic allograft nephropathy is often multifactorial, but long-term CNI-induced nephrotoxicity is a major contributor and can be difficult to distinguish from chronic rejection.

Rejection Treatment - The Firefighters

TCMR Treatment Algorithm

Acute Cellular Rejection: Primarily T-cell mediated. Treated with high-dose corticosteroids.
Antibody-Mediated (Humoral) Rejection: Involves B-cells and antibodies. Requires plasmapheresis, IVIG, and often rituximab.

⭐ Anti-thymocyte globulin (ATG) can induce a "cytokine release syndrome" (fever, chills, hypotension) on first infusion. Pre-medicate with corticosteroids, acetaminophen, and diphenhydramine.

High‑Yield Points - ⚡ Biggest Takeaways

Standard triple therapy combines a calcineurin inhibitor (CNI), an antimetabolite, and corticosteroids.

CNI-induced nephrotoxicity is the most significant long-term complication of tacrolimus and cyclosporine.

Mycophenolate is a potent antimetabolite but is limited by GI intolerance and myelosuppression.

Sirolimus (mTOR inhibitor) is used to spare renal function but can cause hyperlipidemia and impaired wound healing.

Induction therapy (e.g., basiliximab) prevents acute rejection by targeting IL-2 receptors.

Prophylaxis for PJP and CMV is essential in these patients.

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