1. POLYOMAVIRUS INFECTION IN RENAL ALLOGRAFTS: PROGRESS SINCE BANFF 1999 Parmjeet Randhawa Associate Professor Division of Transplantation Pathology Department of Pathology University of Pittsburgh

2. SCOPE OF PROGRESS BKV infection JCV infection SV40 infection

3. MORPHOLOGIC SPECTRUM OF BKVN Silent viral inclusions Acute tubular necrosis Viral interstitial nephritis Basel group believes in concurrent rejection

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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