Question

Difficulty: HardPathology and Biopsy Interpretation

During morning rounds, the nephrology service evaluates a newly admitted patient presenting with severe anasarca and new-onset renal dysfunction. The patient, a 5858-year-old individual with a history of hypertension, reports noticing persistently frothy urine for the past 1212 weeks. Vital signs show a blood pressure of 152/94 mmHg152/94 \text{ mmHg}. Laboratory studies demonstrate a serum creatinine of 1.8 mg/dL1.8 \text{ mg/dL} and a serum albumin level of 2.5 g/dL2.5 \text{ g/dL}. Urinalysis reveals 4+4+ proteinuria with microscopic hematuria, and a 2424-hour urine collection confirms the presence of 5.2 g5.2 \text{ g} of protein. A percutaneous renal biopsy is obtained. Light microscopy reveals prominent mesangial expansion and capillary wall thickening. Congo red staining demonstrates no evidence of apple-green birefringence under polarized light. Electron microscopy reveals dense deposits composed of randomly oriented, non-branching fibrils measuring 18 nm18 \text{ nm} to 22 nm22 \text{ nm} in diameter located within the mesangium and glomerular basement membranes. Immunohistochemical staining of the biopsy tissue shows strong positivity for DNAJB9. Based on these histopathologic and molecular findings, which of the following is the most likely diagnosis?

  1. A
    Primary (AL) amyloidosis
  2. B
    Cryoglobulinemic glomerulonephritis
  3. Fibrillary glomerulonephritisAnswer
  4. D
    Immunotactoid glomerulopathy
  5. E
    Diabetic nephropathy

Answer

Fibrillary glomerulonephritis
The correct answer is fibrillary glomerulonephritis. This diagnosis requires careful interpretation of a renal biopsy to differentiate it from other diseases that deposit structured materials in the glomerulus. The classic triad of findings for fibrillary glomerulonephritis includes: 1) randomly oriented, non-branching fibrils on electron microscopy that measure 10 to 30 nm10 \text{ to } 30 \text{ nm} in diameter (typically around 20 nm20 \text{ nm}); 2) a negative Congo red stain (which distinguishes it from amyloidosis); and 3) positive immunohistochemical staining for DNAJB9 (a highly specific molecular marker for the condition).

Step-by-Step Solution

1
Analyze the patient's clinical presentation and preliminary laboratory findings.
The patient has nephrotic-range proteinuria (5.2 g/day5.2 \text{ g/day}), hypoalbuminemia, severe edema, and renal dysfunction, establishing a nephrotic syndrome with concurrent nephritic features (hematuria, elevated creatinine).
Identifying the clinical syndrome narrows the differential diagnosis to specific glomerular diseases.
2
Evaluate the specific findings on light microscopy and special stains.
Light microscopy shows mesangial expansion. Importantly, the Congo red stain is negative.
A negative Congo red stain effectively rules out amyloidosis, which is a major cause of fibrillary deposits in the kidney.
3
Interpret the electron microscopy and immunohistochemistry details.
Electron microscopy shows non-branching, randomly arranged fibrils that are 18−22 nm18-22 \text{ nm} in diameter. Immunohistochemistry is strongly positive for DNAJB9.
The size and arrangement of the fibrils are pathognomonic. Amyloid fibrils are smaller (8−12 nm8-12 \text{ nm}) and Congo red positive. Immunotactoid deposits are larger (>30 nm>30 \text{ nm}) and highly organized in parallel microtubules. The presence of DNAJB9 is a highly sensitive and specific diagnostic marker for fibrillary glomerulonephritis.

Key Concept

Interpretation of renal biopsy electron microscopy and immunohistochemistry in fibrillary glomerular diseases
Estimated Time:1m 30s
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