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• Early diagnosis before

significant graft injury• Possibility of pre-

emptive Rx• Titration of dose of

FK506 & duration of antiviral drugs in cases of established BKVAN

TECHNIQUES

• Urine cytology• Urinary PCR • Blood PCR

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 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

JCV INFECTION IN RENAL ALLOGRAFTS

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