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Polyomavirus nephropathy: updated

Polyomavirus nephropathy: updated. Helmut Hopfer, Basel, Switzerland. Agenda. SV40 immunohistochemistry and BK viremia PVN treatment: implications for morphology PVN and rejection. How to diagnose PVN?. BK-BIFQUIT: trial design. participants SV 40 IHC. SV40 IHC. SV40 IHC. SV40 IHC.

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Polyomavirus nephropathy: updated

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  1. Polyomavirus nephropathy: updated Helmut Hopfer, Basel, Switzerland

  2. Agenda • SV40 immunohistochemistry and BK viremia • PVN treatment: implications for morphology • PVN and rejection

  3. How to diagnose PVN?

  4. BK-BIFQUIT: trial design participants SV 40 IHC SV40 IHC SV40 IHC SV40 IHC SV40 IHC SV40 IHC SV40 IHC SV40 IHC SV40 IHC participants score intensity and extent inter-observer variability organizers score intensity and extent inter-laboratory variability

  5. SV40 IHC: inter-observer variability Substantial agreement (staining intensity and extent of infection) unpublished data, M. Mengel, Edmonton

  6. SV40 IHC: inter-laboratory variability Below chance (staining intensity and extent of infection) Substantial agreement (positive vs. negative cores) unpublished data, M. Mengel, Edmonton

  7. BK-BIFQUIT: summary • BK "best practice": automated stainer, heat induced epitope retrieval (>30 minutes), either citrate or EDTA buffer, monoclonal antibody (PAB416) <1:100 for 25-35 minutes, polymer detection system • Scoring of staining intensity and percentage tubules infected is not reproducible Binary categorization of cases as positive/ negative gives acceptable inter-laboratory and inter-observer reproducibility

  8. SV40 IHC and BK viremia • Number of tubules with SV40+ cells per mm biopsy length significantly correlates with number of BK copies in the blood • High number of SV40 negative biopsies: <10'000 copies/ml ~90% of cases, >10'000 copies/ml ~ unpublished data, H. Hopfer, Basel

  9. Summary 1 • High sampling error < 10’000 c/ml: ~90% negative ≥ 10’000 c/ml: ~40% negative • YES / NO scoring of SV40 immunohistochemistry

  10. Agenda • SV40 immunohistochemistry and BK viremia • PVN treatment: implications for morphology • PVN and rejection

  11. Guidelines for screening and therapy Screening Diagnosis Therapy Resolution • Viruria (Decoy cells) • Viremia • PVN • "definite" • "presumptive" • Reduce IS • Monitor viremia • Resolved PVN Hirsch et al., Am J Transplant 9:S136-S146,2009 Therapy • reduction of immuno-suppression • cidofovir? (nephrotoxicity!) • leflunomide?

  12. BK-specific cellular immunity Immunosuppression BK-specific immunity IFNg SFU/105 PBMC viruria (c/ml) viremia (c/ml) adapted from Comoli et al., Curr Opin Organ Transplant 13:569-574, 2009

  13. BKV-therapy and course Schaub et al., Am J Transplant 10:2615-2623,2010

  14. BKV therapy and morphology • Patients with BKV > 1'000 copies/ml • treated with reduction of maintenance immunosuppression • no rejection therapy • at least 1 surveillance biopsy during BKV before BKV increasing BKV decreasing BKV after BKV Morphological assessment, statistical analysis and correlation with clinical data unpublished data, H. Hopfer, Basel

  15. Resolving PVN (decreasing BKV) Residual PVN (cleared BKV)

  16. "Tubulitis " and inflammation • During decreasing viremia there was a significant increase in the Banff tubulitis score (t) as well as the extent of interstitial inflammatory infiltrate. • Persistence of intraepithelial lymphocytes and interstitial inflammation after viral clearance. unpublished data, H. Hopfer, Basel

  17. Creatinine course • Serum creatinine values overall remained stable (baseline - 1st replication - peak replication - clearance - last follow up) • Increase of serum creatinine ≥40 umol/l during decreasing viremia in ~40% of patients, which returned to baseline without additional treatment unpublished data, H. Hopfer, Basel

  18. Summary 2 BK-specific immunity viruria viremia BK-induced tubular damage BK-induced inflammation anti-BK inflammation and IEL

  19. Do you believe in PVN and rejection? Can you distinguish PVN from rejection? How do you treat PVN and rejection? PVN and rejection – a matter of faith?

  20. BK-specific, rejection or "innocent"? • BK-specific lymphocyte? (anti-BK immune response) • HLA-specific lymphocyte? (rejection?) • "innocent" lymphocyte? (unspecific infiltrate)

  21. Distinction PVN and ICR? • SV40 immunohistochemistry? • Severity and extent of tubulitis and inflammation? • Cellular composition of infiltrate?

  22. How to treat PVN and rejection? • Individualize decisions in patients with concurrent vascular or humoral rejections • PVN is more important than ICR

  23. Take-home messages • PVN is focal, high number of falsly negative cases • Resolving PVN is an anti-viral acute interstitial nephritis • Give BK-specific immunity a chance • Clinicopathological correlation is key to the correct diagnosis (clinical history, viral dynamics, creatinine course, morphologi-cal findings)

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