Transcript Development of Quantitative PCR for BK Virus : Role In

POLYOMAVIRUS INFECTION IN RENAL
ALLOGRAFTS: PROGRESS SINCE BANFF 1999
Parmjeet Randhawa
Associate Professor
Division of Transplantation Pathology
Department of Pathology
University of Pittsburgh
SCOPE OF PROGRESS
• BKV infection
• JCV infection
• SV40 infection
MORPHOLOGIC SPECTRUM OF BKVN
•
•
•
•
Silent viral inclusions
Acute tubular necrosis
Viral interstitial nephritis
Basel group believes in concurrent rejection
SIGNIFICANCE OF INTERSTITIAL
INFLAMM & TUBULITIS IN BKVAN
• Morphology can not distinguish response to
viral ags (VIN), from allogeneic ags (ACR)
• Experience with CMV suggests
relationship between viral infection &
rejection is bidirectional
- Therapy of rejection can activate virus
- Reduced immunosuppression after diagnosis
of BKVAN can precipitate rejection
• It is possible to have 2 diagnoses in 1 biopsy
THERAPEUTIC CONSIDERATIONS
IN BKVAN
• Most centers reduce immunosuppression
• Basel group feels steroids indicated in cases with
concurrent rejection but they also reduce immsup
later (n=5)
• Pittsburgh finds worse prognosis if steroids given:
58% graft loss (n=12) vs 10% (n=18)
• Anti-viral drugs are being tried empirically
MONITORING BKV LOAD IN
CLINICAL SPECIMENS
APPLICATIONS
TECHNIQUES
• Early diagnosis before
• Urine cytology
significant graft injury
• Urinary PCR
• Possibility of pre• Blood PCR
emptive Rx
• Titration of dose of
FK506 & duration of
antiviral drugs in cases
of established BKVAN
URINE CYTOLOGY
• Baltimore group finds urinary inclusions to
have 90% predictive value for BKVAN
• Basel finds positive predictive value to be
much lower (30%), but uses it to screen
high risk patients (FK506, MMF, rejection)
• Two samples >5 decoy cells/10hpf trigger
plasma PCR; positive PCR triggers biopsy
UTILITY OF PLASMA PCR IN
DIAGNOSIS OF BKVAN AT BASEL
• Plasma PCR positive in 11/11 BKVAN
• Undetectable after clinical response
• Asymptomatic patients: plasma PCR + in 1/25
without & 1/16 patients with decoy cells in urine
QUANTITATIVE PCR IN URINE
SAMPLES FROM PTS WITH BKVAN
(VATS ET AL, PITTSBURGH)
• 16 patients with BKVAN: urinary viral load
10,000 - 100,000 copies /microgram of
creatinine
• Lowering of immunosuppression produced
variable decrease in viral load
• Antiviral therapy resulted in clearance of
viruria in 5 patients
JCV INFECTION IN RENAL
ALLOGRAFTS
• JCV coinfection in 7/19 (36%) of bx with BKVN
• No JCV found in 19 control biopsies suggesting
JCV replication related to concurrent BKV infection
• JCV viral capsid protein VP-1 found in 1/10 biopsies
confirming active viral transcription
• Exact role in pathogenesis of BKVN uncertain
SV40 INFECTION IN RENAL
ALLOGRAFTS
• SV40 accidentally infected 10-30 million humans
beings who received vaccines produced in monkey
kidney cells (1954-63)
• Recently SV40 sequences have been found by Dr
Butel in allograft biopsies of 3 children born after
1963 (year in which monkey vaccines were
discontinued)
• This raises a concern that continued transmission
of this virus is occurring, & it may be even be an
occasional cause of allograft dysfunction