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 10-year-old girl with previously diagnosed sickle cell anemia presents to the emergency room with a low-grade fever, malaise, petechiae on her arms, and a rash on her face. She regularly takes hydroxyurea and receives blood transfusions to treat her condition. Her blood tests show a hemoglobin of 4.0 g/dL, MCV of 87 fl, and 2% reticulocyte count. An attempted bone marrow biopsy was a dry, empty tap. What is the most likely diagnosis?

Reaction to the blood transfusions

A 43-year-old woman comes to the office with a 5-day history of a rash. She's had a rash across her neck, shoulders, and the palms of her hands for the past five days. She's also had large-volume watery diarrhea for the same period of time. Past medical history is notable for acute myeloid leukemia, for which she received a stem cell transplant from a donor about two months prior. Physical exam reveals a faint red maculopapular rash across her neck, shoulders, and hands, as well as an enlarged liver and spleen. Labs are notable for a total bilirubin of 10. Which of the following is the mechanism of this patient's pathology?

Graft T cells against host antigens

Host CD8+ T cells against graft antigens

Pre-existing host antibodies against graft antigens

Host antibodies that have developed against graft antigens

A pathologist receives a patient sample for analysis. Cells in the sample are first labeled with fluorescent antibodies and then passed across a laser beam in a single file of particles. The light scatter and fluorescent intensity of the particles are plotted on a graph; this information is used to characterize the sample. This laboratory method would be most useful to establish the diagnosis of a patient with which of the following?

Pancytopenia and deep vein thrombosis with intermittent hemoglobinuria

Ventricular septal defect and facial dysmorphism with low T-lymphocyte count

Painless generalized lymphadenopathy with monomorphic cells and interspersed benign histiocytes on histology

Multiple opportunistic infections with decreased CD4 counts

Vesicular lesions with dermatomal distribution and dendritic corneal ulcers

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 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

An otherwise healthy 47-year-old woman comes to the physician for the evaluation of a 4-month history of worsening fatigue and constipation. She has also noticed that her cheeks appear fuller and her voice has become hoarse. Her temperature is 36.3°C (97.3°F) and pulse is 59/min. Examination of the neck shows a painless, mildly enlarged thyroid gland. Her skin is dry and cool and her nails appear brittle. Serum studies show antibodies against thyroid peroxidase. A biopsy of the thyroid gland is most likely to show which of the following?

Lymphocytic infiltration, Hürthle cells, and germinal centers

Tall follicular cells, scalloped colloid, and vascular congestion

Large, irregular nuclei, nuclear grooves, and Psammoma bodies

Spindle cells, pleomorphic giant cells, and mitotic figures

Multinucleated giant cells, macrophages, and degenerated follicular cells

A 61-year-old woman comes to the physician because of a constant, dull headache and generalized body pains for the past 8 months. She has also had difficulty hearing from her left side, which started a month after the onset of the headaches. Five months ago, she had surgery to correct a fracture of the right femur that occurred without a fall or any significant trauma. Five years ago, she underwent a total thyroidectomy for localized thyroid carcinoma. She takes levothyroxine and calcium supplements, which she started after menopause. Physical examination reveals a prominent forehead and irregular, tender skull surface. Bony tenderness is present over bilateral hip and knee joints, with decreased range of motion of the right hip joint and increased anterior curvature of both tibias. Laboratory studies show a highly elevated level of alkaline phosphatase, with vitamin D, calcium and PTH levels within normal limits. A plain x-ray of the head is most likely to show which of the following findings?

Mixed lytic and sclerotic lesions

Periosteal trabeculations with radiolucent marrow hyperplasia

Generalized dense, sclerotic bone

Multiple, well-defined, punched out lytic lesions

Lytic lesions with no sclerotic margin

Graft-versus-host disease for USMLE Step 3: High-Yield Pathology Lessons

Pathophysiology - Donor's Deadly Attack

Mechanism: Immunocompetent donor T-cells from the graft recognize the recipient's tissues as foreign, as the host is too immunocompromised to reject the graft.
Key Players: Donor CD4+ and CD8+ T-cells react to the host's disparate Major Histocompatibility Complex (MHC) antigens.
Cascade: This triggers a massive inflammatory response, often called a "cytokine storm," leading to widespread tissue damage.

GVHD: Canonical and alternative mechanisms

⭐ Graft-versus-Leukemia (GVL) Effect: A beneficial "side effect" where donor T-cells also eliminate residual host cancer cells, particularly in hematopoietic stem cell transplants for leukemia.

Mnemonic (📌): Major targets are Skin, Liver, GI tract ("Some Lethal Grafts").

Clinical Presentation - Acute vs. Chronic Clash

Feature	Acute GVHD	Chronic GVHD
Onset	Typically < 100 days post-transplant	Typically > 100 days post-transplant
Mechanism	Donor CD8+ T-cells attack host epithelial cells	Donor CD4+ T-cells & B-cells cause autoimmune, fibrotic process
Skin	Maculopapular rash, erythema, bullae (may resemble SJS/TEN)	Poikiloderma, scleroderma-like changes, lichen planus-like lesions
GI Tract	Profuse, watery/bloody diarrhea; nausea, vomiting; abdominal pain	Esophageal webs/strictures, malabsorption, weight loss
Liver	Jaundice, ↑ conjugated bilirubin & alkaline phosphatase	Cholestatic jaundice, potentially progressing to cirrhosis
Other	-	Sicca syndrome (dry eyes/mouth), bronchiolitis obliterans, myositis

⭐ Chronic GVHD is a major cause of late, non-relapse mortality following allogeneic transplant. It can arise de novo without any preceding acute GVHD.

Diagnosis & Prevention - Taming the Treachery

Diagnosis: Primarily clinical (maculopapular rash, diarrhea, ↑LFTs).
- Biopsy is definitive: Shows lymphocytic infiltrate & apoptosis in skin, gut, or liver.
Prevention: The cornerstone of management.
- HLA matching of donor and recipient is paramount.
- Immunosuppressive prophylaxis is standard.
  - Calcineurin inhibitors (Cyclosporine, Tacrolimus)
  - Methotrexate

⭐ Biopsy of affected organs (skin, gut, liver) is the gold standard for diagnosis, revealing lymphocytic infiltration and apoptosis, which confirms the T-cell mediated assault.

High‑Yield Points - ⚡ Biggest Takeaways

In GVHD, transplanted donor T-cells attack recipient tissues, primarily after allogeneic bone marrow transplants.

Key targets are the skin (diffuse maculopapular rash), liver (jaundice, ↑ LFTs), and GI tract (profuse diarrhea).

The mechanism involves donor T-cells recognizing host MHC antigens as foreign.

Acute GVHD develops <100 days post-transplant; chronic GVHD develops >100 days.

Prophylaxis and treatment rely on immunosuppressive drugs like corticosteroids and cyclosporine.

A beneficial graft-versus-leukemia effect may also occur in cancer patients.

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