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 50-year-old man presents to a clinic with oliguria. Four weeks ago, he had a kidney transplant. Postoperative follow-up was normal. He is currently on cyclosporine and admits that sometimes he forgets to take his medication. On physical examination, the vital signs include: temperature 37.1°C (98.8°F), blood pressure 165/110 mm Hg, heart rate 80/min, and respiratory rate 16/min. There is mild tenderness on renal palpation. His serum creatinine level is 4 mg/dL, well above his baseline level after the transplant. Which of the following best describes the histological finding if a biopsy is taken from the transplanted kidney?

Lymphocytic infiltration of graft vessels and endothelial damage

Thrombosis and occlusion of vessels

Necrosis with granulation tissue

Thickening of blood vessels, fibrosis of graft vessels, and parenchymal atrophy

A 29-year-old woman comes to the physician because of a 2-day history of intermittent dark urine and mild flank pain. She has also had a cough, sore throat, and runny nose for the past 5 days. She has not had dysuria. She takes no medications. She has no known allergies. Her temperature is 37°C (98.6°F). Examination of the back shows no costovertebral angle tenderness. Laboratory studies show: Hemoglobin 10.4 g/dL Leukocyte count 8,000/mm3 Platelet count 200,000/mm3 Serum Na+ 135 mEq/L K+ 4.9 mEq/L Cl- 101 mEq/L HCO3- 22 mEq/L Urea nitrogen 18 mg/dL Creatinine 1.1 mg/dL Urine Color yellow Blood 3+ Protein 1+ Leukocyte esterase negative An ultrasound of the kidney and bladder shows no abnormalities. Which of the following is the most likely cause of this patient's symptoms?

Interstitial renal inflammation

A 13-year-old boy is brought to the physician because of swelling around his eyes for the past 2 days. His mother also notes that his urine became gradually darker during this time. Three weeks ago, he was treated for bacterial tonsillitis. His temperature is 37.6°C (99.7°F), pulse is 79/min, and blood pressure is 158/87 mm Hg. Examination shows periorbital swelling. Laboratory studies show: Serum Urea nitrogen 9 mg/dL Creatinine 1.7 mg/dL Urine Protein 2+ RBC 12/hpf RBC casts numerous A renal biopsy would most likely show which of the following findings?

Granular deposits of IgG, IgM, and C3 on immunofluorescence

Effacement of podocyte foot processes on electron microscopy

Splitting and alternating thickening and thinning of the glomerular basement membrane on light microscopy

Mesangial IgA deposits on immunofluorescence

"Spike-and-dome" appearance of subepithelial deposits on electron microscopy

A 12-year-old boy comes to the physician for the evaluation of intermittent blood-tinged urine for several months. Four months ago, he had an episode of fever and sore throat that resolved without treatment after 5 days. During the past 2 years, he has also had recurrent episodes of swelling of his face and feet. 5 years ago, he was diagnosed with mild bilateral sensorineural hearing loss. His brother died of a progressive kidney disease at the age of 23. The patient appears pale. His temperature is 37°C (98.6°F), pulse is 70/min, and blood pressure is 145/85 mm Hg. Slit lamp examination shows a conical protrusion of both lenses. Laboratory studies show a hemoglobin concentration of 11 g/dL, urea nitrogen concentration of 40 mg/dL, and creatinine concentration of 2.4 mg/dL. Urinalysis shows: Blood 2+ Protein 1+ RBC 5–7/hpf RBC casts rare Which of the following is the most likely underlying cause of this patient's symptoms?

Autosomal-recessive kidney disease

Type II hypersensitivity reaction

Kidney transplant pathology for USMLE Step 2 CK: High-Yield Pathology Lessons

Rejection Timelines - The Graft's Clock

Hyperacute (Minutes-Hours): Pre-formed anti-donor Abs (Type II HSR) → widespread thrombosis, fibrinoid necrosis.
Acute (<6 months):
- Cellular (Type IV HSR): Lymphocytic infiltrate of tubules & interstitium (tubulitis).
- Humoral (Type II HSR): C4d deposition, neutrophilic glomerulitis, vasculitis.
Chronic (>6 months): Irreversible fibrosis & atrophy.
- Vascular intimal fibrosis, glomerulosclerosis, tubular atrophy.

⭐ Acute cellular rejection is the most common type of rejection and typically responds well to immunosuppressants.

Kidney Transplant Rejection Histopathology

Acute Rejection - The Early Battle

Timeline: Typically occurs <6 months post-transplant.
Presentation: ↑ Serum Creatinine, oliguria, fever, graft pain/swelling.
Two Main Types:
- Acute Cellular Rejection (ACR): T-cell mediated (Type IV HSR).
  - Path: Interstitial inflammation & tubulitis (lymphocytic invasion of tubular epithelium).
  - Grading: Banff classification (t-score, i-score).
- Antibody-Mediated Rejection (AMR): Antibody-driven (Type II HSR).
  - Path: Microvascular inflammation (glomerulitis, capillaritis), C4d deposition in peritubular capillaries.
  - Requires presence of Donor-Specific Antibodies (DSAs).

⭐ C4d staining in peritubular capillaries is a key histological marker for active, antibody-mediated rejection.

Acute kidney rejection: tubulitis and C4d deposition

Chronic Rejection - The Slow Fade

Timeline: Months to years post-transplant; insidious onset.
Pathophysiology: Slow, progressive T-cell and/or antibody-mediated injury, leading to irreversible structural damage.
Hallmark Pathology: Chronic allograft vasculopathy.
- Vessels: Concentric intimal fibrosis & smooth muscle proliferation → arterial occlusion.
- Glomeruli: Chronic transplant glomerulopathy (double contours).
- Tubules/Interstitium: Tubular atrophy and interstitial fibrosis (IF/TA).
Clinical: Gradual ↑ serum creatinine, new or worsening hypertension, proteinuria.
Outcome: Irreversible graft dysfunction leading to eventual graft loss.

Kidney Transplant Pathology: Histological Features

⭐ High-Yield: Chronic antibody-mediated rejection is often associated with the presence of donor-specific antibodies (DSAs), particularly against HLA class II antigens, and C4d deposition in peritubular capillaries.

Other Complications - Rogues' Gallery

Recurrent Glomerulonephritis (GN):
- Primary disease returns to haunt the allograft.
- Most common: IgA Nephropathy, Membranoproliferative GN (MPGN), Focal Segmental Glomerulosclerosis (FSGS).
- FSGS recurrence can be rapid (days to weeks) with massive proteinuria.
De Novo Glomerulonephritis:
- New glomerular disease in the allograft.
- Most common: Membranous nephropathy.
Calcineurin Inhibitor (CNI) Toxicity (e.g., Tacrolimus, Cyclosporine):
- Acute: Toxic acute tubulopathy with isometric vacuolization of proximal tubules.
- Chronic: Arteriolar hyalinosis, striped cortical fibrosis, and tubular atrophy.
Post-Transplant Lymphoproliferative Disorder (PTLD):
- Uncontrolled proliferation of B-lymphocytes, strongly associated with Epstein-Barr Virus (EBV) infection.
- Spectrum: from polyclonal hyperplasia to monoclonal lymphoma.

⭐ Chronic allograft nephropathy is the leading cause of graft loss after the first year, representing the final common pathway of chronic injury (rejection, CNI toxicity, hypertension).

Isometric vacuolization of renal tubules

High‑Yield Points - ⚡ Biggest Takeaways

Hyperacute rejection: Immediate thrombosis & necrosis from pre-formed anti-donor antibodies.

Acute rejection: Weeks to months post-transplant; either cellular (T-cell infiltrate) or humoral (C4d deposition).

Chronic rejection: Months to years; leads to vascular intimal fibrosis, glomerulosclerosis, and interstitial fibrosis.

BK virus nephropathy: Mimics rejection; diagnosed by intranuclear viral inclusions in tubular cells.

Calcineurin inhibitor toxicity: Key cause of non-rejection dysfunction; shows arteriolar hyalinosis.

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