Renal Pathology, Pathology, USMLE Step 1 - Full Vignette with Extended Explanations

Описание: A 45-year-old man presents with sudden onset shortness of breath, hemoptysis, and evidence of both kidney dysfunction and anemia following a week of worsening fatigue and tea-colored urine. With a complex medical history including atopic dermatitis, long QT syndrome, and previous systemic workups, what unifying process could link his acute respiratory and renal symptoms in this emergent scenario? How can lab and imaging findings guide your differential?

VIDEO INFO
Category: Renal Pathology, Pathology, USMLE Step 1
Difficulty: Moderate - Intermediate level - Requires solid foundational knowledge
Question Type: Mechanism
Case Type: Critical Condition

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QUESTION
A 45-year-old man is brought to the emergency department with acute shortness of breath and coughing up bright red blood that began overnight. Over the past week he has felt increasingly fatigued and noticed tea-colored urine and decreased urine output. He has a history of atopic dermatitis, long QT syndrome, prior giardiasis, remote Ebola virus disease exposure during humanitarian work (no active illness now), hearing loss, and Peyronie s disease....

OPTIONS
A. Autoantibodies target the noncollagenous (NC1) domain of the alpha-3 chain of type IV collagen in glomerular and alveolar basement membranes.
B. Autoantibodies target the alpha-5 chain of type IV collagen in the glomerular basement membrane, a hereditary defect classically seen in Alport syndrome with hearing loss.
C. Autoantibodies target desmoglein-3 in epithelial desmosomes, causing mucocutaneous blistering.
D. Autoantibodies target type II collagen in articular cartilage, producing inflammatory arthritis.

CORRECT ANSWER
A. Autoantibodies target the noncollagenous (NC1) domain of the alpha-3 chain of type IV collagen in glomerular and alveolar basement membranes.

EXPLANATION
Massive hemoptysis with diffuse alveolar hemorrhage plus rapidly progressive glomerulonephritis defines a pulmonary-renal syndrome. The most likely unifying mechanism here is anti-glomerular basement membrane disease (Goodpasture disease), in which autoantibodies bind the noncollagenous (NC1) domain of the alpha-3 chain of type IV collagen shared by glomerular and alveolar basement membranes. KDIGO 2021 and foundational studies identify the alpha-3(IV) NC1 domain as the antigenic target.

Alport syndrome involves hereditary defects of the alpha-5(IV) chain (COL4A5) and presents with hematuria, progressive renal failure, and sensorineural hearing loss-not an acute pulmonary-renal vasculitic-type syndrome mediated by circulating anti-GBM antibodies. Desmoglein-3 autoantibodies cause pemphigus vulgaris with mucocutaneous blistering, not alveolar hemorrhage or crescentic GN. Antibodies to type II collagen relate to joint disease and do not produce diffuse alveolar hemorrhage with glomerulonephritis.

In summary, the correct answer is autoantibodies to the NC1 domain of the alpha-3 chain of type IV collagen, the defining target in anti-GBM (Goodpasture) disease.

Primary teaching point: Anti-GBM disease targets alpha-3(IV) NC1 in GBM and alveolar basement membrane, causing pulmonary hemorrhage and rapidly progressive GN.

Secondary teaching point: Alport syndrome (alpha-5[IV] defects) is hereditary and lacks circulating anti-GBM antibodies; do not confuse structural collagen disorders with autoimmune anti-GBM disease.


Further reading:

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