BK Polyoma Virus:

1
BK Polyoma Virus

• A Mini Tutorial
• Joel C Reynolds, MD
• Walter Reed Army Medical Center
• Nephrology Service

2
What We Know

• BKV seroprevalence is almost ubiquitous with over
  90 of all people seropositive by age 10.1
• BKV nephropathy is a significant cause of renal
  allograft loss.2
• Urine shedding of BKV is more prevalent than
  viremia.1,2
• Primary infection with seroconversion has been
  documented.1
• To date all studies have shown 100 urine PCR
  positivity when viremia is present by PCR.1,2

3
What We Know

• BKV nephropathy can resemble acute rejection on
  biopsy, usually unresponsive to steroids when
  treated as rejection.3
• Allograft biopsy is currently considered the
  gold standard for diagnosis, but has
  questionable sensitivity.3
• BKV infected renal tubular epithelial (decoy)
  cells appear to deteriorate quickly (within
  minutes), which may limit urine microscopy as a
  screening tool.4

4
What We Know

• Urine BKV DNA load is usually at least 105x
  higher than serum viral DNA load and may be
  present without viremia.5
• No studies to date have identified clear risk
  factors which would help predict those at risk
  for BKV nephropathy, to include tacrolimus,
  mycophenolate, or steroids.2

5
What We Suspect

• Overall immunosuppression levels are too high.
• Prevalence is much higher than previously
  suspected.
• Antiviral drugs (cidofovir) may be effective
  treatment.6
• Failure to detect BKV early leads to irreversible
  nephropathy.4
• Allograft biopsy sensitivity for BKV is suspect
  due to the spotty nature of early infection and
  apparent predeliction of the virus for medullary
  renal tissue.3

6
What We Dont Know

• Is there a reservoir for BKV other than urinary
  tract?
• What are the risk factors for developing BKVN?
• Risk factors for reactivation of harbored BKV?
• Does serology of donor/recipient change risk?
• What level of serum BKV DNA denotes those at
  increased risk of progression to BKVN?
• How does cidofovir (known to inhibit viral DNA
  polymerase) inhibit BKV replication (which has no
  DNA polymerase)?

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What We Dont Know

• What is the most cost effective/sensitive test to
  help predict those at increased risk for
  developing BKVN?
• Serum PCR, very sensitive (4 copies/ml),
  expensive (200), significance of levels?
• Urine PCR, very sensitive, expensive, not
  specific, signficance of levels?
• Urine decoy cell microscopy, inexpensive,
  operator/time dependent, significance of positive
  finding?

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What Is Needed?

• Large, prospective trials including transplant
  recipients not on calcineurin inhibitors, and on
  steroid free protocols, to adequately assess for
  risk factors which would predispose to infection
  by BKV.
• Likely would require multi-center cooperation to
  achieve power to detect factors with significance
  (similar to the studies of CMV status of
  donor/recipient performed in the 70s).

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References

1. Hirsch HH, et.al. Prospective study of
   polyomavirus type BK replication and nephropathy
   in renal-transplant recipients. N Engl J Med.
   2002 Aug 15347(7)488-96.
2. Ramos E, et.al. Clinical course of polyoma virus
   nephropathy in 67 renal transplant patients. J Am
   Soc Nephrol. 2002 Aug13(8)2145-51.
3. Drachenberg RC, et.al. Morphological spectrum of
   polyoma virus disease in renal allografts
   diagnostic accuracy of urine cytology. Am J
   Transplant 2001 Nov1(4)373-81.
4. Personal observations in our clinic (Walter Reed
   AMC).
5. Brennan DC, unpublished data, Washington Univ
   School of Medicine, St. Louis, MO.
6. Vats A, et.al. Quantitative viral load monitoring
   and cidofovir therapy for the management of BK
   virus-associated nephropathy in children and
   adults.Transplantation. 2003 Jan 1575(1)105-12.
7. Nickeleit V, et.al. BK virus infection after
   kidney transplantation. Graft. 2002 Dec S18 (5)
   S46-57.

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A Pictorial Tutorial Unstained Freshly-Voided
Urine with Decoy Cells (Renal Tubular
Epithelial cells with BKV- Associated
Intranuclear Inclusions)
Digital photographs courtesy of Mr. David Oliver
and Mrs. Luana Kiandoli, Nephrology Laboratory,
WRAMC
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Type I An amorphous ground-glass variant
Ground-glass appearance of nucleus
400x (Olympus BH2 microscope)
Reference 7
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Type II granular variant surrounded by a halo
Reference 7
400x (Olympus BH2 microscope)
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Type III a finely granular variant without halo
400x (Olympus BH2 microscope), Enlarged 1.6x in
processing image.
Reference 7
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Type II/III hybrid
Intranuclear vesicles
400x (Olympus BH2 microscope), Enlarged 2x in
processing image.
Reference 7
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Type IV a vesicular variant with clumped,
irregular chromatin
400x (Olympus BH2 microscope), Enlarged 2x in
processing image.
Reference 7