Polyoma virus infections

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POLYOMAVIRUS (BK and JC) INFECTIONS

Background and Clinical Presentation

The polyoma virus infections are acquired early in childhood, and 60-80% of adults in the U.S. test seropositive for these viruses. The majority of infections are subclinical and lead to viral latency within the kidney. Reactivation occurs in transplant recipients as a result of immunosuppressive therapy. Serologic evidence suggests that the donor kidney may act as the vehicle of transmission. BK or JC virus is shed in the urine of 10-60% of patients after renal transplantation, but clinically significant interstitial nephritis is infrequent.

The typical presentation is a rise in the serum creatinine, which cannot be distinguished from rejection or drug toxicity on clinical grounds. A few cases show hydronephrosis on ultrasound examination at the time of allograft biopsy. Ureteric stricture can be present. Hemorrhagic cystitis is described after bone marrow transplantation.

Histopathology

Needle biopsy of the allograft kidney in the earliest stages may show acute tubular injury. However, most cases present as interstitial nephritis and show a mixed interstitial inflammatory infiltrate with focal tubular injury. The tubular epithelium shows marked anisonucleosis, nuclear atypia, and basophilic or amphophilic intranuclear inclusions. Tubulitis is frequently present, and satisfies the Banff criteria for acute rejection. In addition biopsies may show clusters of neutrophils in the tubular lumen suggestive of pyelonephritis. Persistent infecetion can culminate in severe interstitial fibrosis/tubular atrophy (IFTA).

Pathologic Classification

The American Society of Transplantation 2013 Classification categories/histologic patterns can be referenced in Am J Transplant 2013: 13: 179. In essence, Category A includes cases with viral cytopathic effect but little to no inflammation. Category B refers to biopsies with variable degrees of interstitial inflammation graded from B1 to B3. Category C designates presence of interstitial fibrosis and tubular atrophy affecting greater than 50% of the sampled tissue.

In contrast, the more recent Banff Working Group Classification of Definitive Polyomavirus Nephropathy (J Am Soc Nephrol 2018: 29: 680) relies primarily on the extent of polyomavirus replication/load (pvl) and interstitial fibrosis (ci) for prognostication and does not take into account the degree of inflammation:
PVN Class I: pvl1 (1% or less of tubules/ducts with viral replication) and ci score 0-1
PVN Class II: biopsies not falling into class I or III (pvl1/ci2-3 OR pvl2/ci0-3 OR pvl3/ci0-1)
PVN Class III: pvl3 (>10% of tubules/ducts with viral replication) and/or ci score 2-3

(For reference, PVL1 shows involvement (viral inclusions or positivity by immunostain or in situ hybridization) in up to 1% of tubules, PVL2 shows involvement in more than 1% and up to 10% of tubules, and PVL3 shows involvement in >10%; ci0 shows fibrosis in up to 5%, ci1 6-25%, ci2 26-50% and ci3 more than 50%)

Differential Diagnosis

Acute tubular injury due to ischemic or immunologic injury can result in a florid regenerative response with extremely prominent nucleoli, which should not be confused with viral inclusions. Polyomavirus inclusions in biopsy tissue are intranuclear with a homogenous basophilic or amphophilic appearance and may have a halo reminiscent of cytomegalovirus. Herpesvirus and adenovirus inclusions are much less common in the kidney but need to be kept in mind in the differential diagnosis. Definite identification may be done by immunohistochemistry, in-situ hybridization, or PCR. Electron microscopy is also a useful tool in the differential diagnosis. Polyoma virus particles measure 45-55 nm, while adenovirus measures 70-90nm. Herpes simplex and cytomegalovirus are enveloped virions with a size range of 120-160 nm. In formalin fixed tissue viral particles can appear to be smaller than their expected size due to shrinkage artefact.

Treatment

No specific therapy is currently available for polyoma virus infections. Cidofovir, leflunomide, quinolones and human immune globulins are administered by some clinicians, but their efficacy has not been established. Reduction in immunosuppression is helpful and results in a decrease in the viral load in follow-up biopsies. Unfortunately, this strategy results in graft loss due to rejection in 20% of cases. If ureteric stenosis is present, surgical intervention can potentially benefit those patients with significant obstruction. However, the clinical response may be limited in cases with concurrent chronic interstitial fibrosis/tubular atrophy (IFTA).

References

  1. Hirsch HH, Randhawa P, AST Infectious Disease Community of Practice. BK polyomavirus in solid organ transplantation. Am J Transplant 2013 13Suppl4: 179-188.
  2. Nickeleit V, Harsharan KS, Randhawa P. The Banff Working Group classification of definitive polyomavirus nephropathy: morphologic definitions and clinical correlations. JASN 2018 29(2): 680-693.
  3. Pappo O, Demetris AJ, Raikow RB, et al. Human polyoma virus infection of renal allografts: histopathological diagnosis, clinical significance, and literature review. Mod Pathol 1996;9(2):105-109.
  4. Randhawa PS, Finkelstein S, Scantlebury V, et al. Human polyoma virus interstitial nephritis in the allograft kidneyTransplantation 1999;67:103-109.


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Last Modified: Dec 8 2018 10:14 EDT