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Difficulty: Very hardPathology and Biopsy Interpretation

A 54-year-old man presents for a routine follow-up 9 months after receiving a deceased-donor renal allograft. His post-transplant course was initially uncomplicated. His current immunosuppressive regimen includes tacrolimus, mycophenolate mofetil, and prednisone. Over the past six weeks, his serum creatinine has steadily increased from a baseline of 1.31.3 mg/dL to 2.72.7 mg/dL. He reports no fever, dysuria, or gross hematuria. Vital signs are within normal limits. Trough tacrolimus level is 7.57.5 ng/mL (target: 5−85-8 ng/mL). Urinalysis shows trace protein and 2−42-4 WBCs/hpf, with no RBCs or casts. A renal allograft biopsy is performed, and the pathology report is as follows:

Microscopic Description:
- Glomeruli: 18 glomeruli present, 1 globally sclerosed. The remaining glomeruli demonstrate normocellular tufts with patent capillary loops. No crescents or transplant glomerulopathy are identified.
- Tubules and Interstitium: Patchy mononuclear inflammatory infiltrates involve approximately 40%40\% of the sampled cortex. Focally, multiple tubular cross-sections show lymphocytes crossing the tubular basement membrane, with up to 6 lymphocytes per tubular cross-section. Scattered tubular epithelial cells exhibit markedly enlarged nuclei containing homogenous, basophilic, ground-glass intranuclear inclusions that compress host chromatin against the nuclear membrane. No intracytoplasmic inclusions are seen. Isometric vacuolization of the proximal tubular cytoplasm is absent.
- Vessels: Small arteries and arterioles demonstrate mild intimal fibroplasia. No significant nodular arteriolar hyalinosis or endothelialitis is observed.
- Immunofluorescence: Staining for IgG, IgA, IgM, C3, and C1q is negative in the glomeruli. Peritubular capillaries are negative for C4d deposition.

Based on the histopathologic interpretation of this biopsy, which of the following is the most likely diagnosis?

  1. Polyomavirus-associated nephropathyAnswer
  2. B
    Acute T-cell-mediated rejection
  3. C
    Cytomegalovirus tubulointerstitial nephritis
  4. D
    Calcineurin inhibitor nephrotoxicity
  5. E
    Active antibody-mediated rejection

Answer

Polyomavirus-associated nephropathy
The biopsy demonstrates the classical features of Polyomavirus-associated nephropathy (PVAN), caused primarily by the BK virus. PVAN commonly presents in renal transplant recipients with an asymptomatic rise in serum creatinine months after transplantation. The hallmark pathologic finding is the presence of enlarged tubular epithelial cells containing basophilic, homogenous, ground-glass intranuclear inclusions that compress the host chromatin to the periphery. Crucially, BK virus nephropathy provokes a dense interstitial mononuclear infiltrate and tubulitis that morphologically mimics acute T-cell-mediated rejection. Identifying the viral cytopathic effect is absolutely essential for accurate diagnosis and management, as the treatment for PVAN involves reducing immunosuppression, whereas treating it as acute rejection (increasing immunosuppression) would lead to catastrophic viral proliferation and graft failure.

Step-by-Step Solution

1
Analyze the clinical presentation.
A renal transplant recipient presenting with a subacute decline in allograft function (rising creatinine) at 9 months post-transplant without systemic signs of infection.
Establishes the differential diagnosis of late graft dysfunction, which prominently includes rejection, calcineurin inhibitor toxicity, and opportunistic viral infections.
2
Evaluate the tubulointerstitial findings on the allograft biopsy.
The biopsy shows interstitial mononuclear inflammation and significant tubulitis (lymphocytes crossing the basement membrane).
Identifies an active inflammatory process that strongly resembles acute cellular rejection, necessitating a careful search for secondary etiologies.
3
Identify the critical distinguishing cytopathic features in the microscopic description.
Observation of enlarged tubular epithelial nuclei with homogenous, basophilic, ground-glass intranuclear inclusions compressing the host chromatin, with no intracytoplasmic inclusions.
Differentiates a specific viral cytopathic effect from pure alloreactivity, ruling out simple acute T-cell-mediated rejection.
4
Correlate the specific viral inclusion morphology with the causative pathogen.
Basophilic, homogenous intranuclear inclusions without cytoplasmic involvement point definitively to BK polyomavirus rather than Cytomegalovirus.
Establishes the definitive diagnosis of Polyomavirus-associated nephropathy, which guides the management strategy (reducing immunosuppression rather than increasing it).

Key Concept

Identifying Polyomavirus-associated nephropathy by distinguishing its basophilic intranuclear inclusions from the morphology of acute cellular rejection and other viral nephropathies.
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Topics

Pathology and Biopsy Interpretation

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