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
participants score
intensity and extent
inter-observer variability
organizers score
intensity and extent
SV40
IHC
SV40
IHC
SV40
IHC
SV40
IHC
SV40
IHC
SV40
IHC
inter-laboratory variability
SV40 IHC: inter-observer variability
Substantial agreement (staining intensity and extent of infection)
unpublished data, M. Mengel, Edmonton
SV40 IHC: inter-laboratory variability
Below chance (staining intensity and extent of infection)
Substantial agreement (positive vs. negative cores)
unpublished data, M. Mengel, Edmonton
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
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unpublished data, H. Hopfer, Basel
Summary 1
• High sampling error
< 10’000 c/ml: ~90% negative
≥ 10’000 c/ml: ~40% negative
• YES / NO scoring of SV40 immunohistochemistry
Agenda
• SV40 immunohistochemistry and BK viremia
• PVN treatment: implications for morphology
• PVN and rejection
Guidelines for screening and therapy
Screening
Viruria (Decoy cells)
Viremia
Diagnosis
PVN
•"definite"
•"presumptive"
Therapy
Reduce IS
Monitor viremia
Resolution
Resolved PVN
Hirsch et al., Am J Transplant 9:S136-S146,2009
Therapy
• reduction of immunosuppression
• cidofovir? (nephrotoxicity!)
• leflunomide?
BK-specific cellular immunity
Immunosuppression
↓
↓
↑
Blood
time after transplantation
adapted from Comoli et al., Curr Opin Organ Transplant 13:569-574, 2009
BKV-therapy and course
Definite PVN
Presumptive
PVN
Low BK-viremia
p-level
BKV clearance
92%
88%
100%
0.60
months 1st viremia to
clearance (median)
8.8
4.6
2.9
0.001
clinical rejection after
clearance
8%
7%
12%
0.67
Schaub et al., Am J Transplant 10:2615-2623,2010
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
Resolving PVN (decreasing BKV)
Residual PVN (cleared BKV)
"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
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
Summary 2
BKV-specific cellular immunity
Blood
Kidney
BK-induced tubular damage
BK-induced inflammation
anti-BK inflammation
and IEL
time after transplantation
BK dynamics
PVN
resolving PVN
residual PVN
increasing
decreasing
cleared
PVN and rejection – a matter of faith?
•
•
•
Do you believe in PVN and rejection?
Can you distinguish PVN from rejection?
How do you treat PVN and rejection?
BK-specific, rejection or "innocent"?
• BK-specific lymphocyte?
(anti-BK immune response)
• HLA-specific
lymphocyte? (rejection?)
• "innocent" lymphocyte?
(unspecific infiltrate)
Distinction PVN and ICR?
• SV40 immunohistochemistry?
• Severity and extent of tubulitis and inflammation?
• Cellular composition of infiltrate?
How to treat PVN and rejection?
• Individualize decisions in patients with concurrent vascular or
humoral rejections
• PVN is more important than ICR
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, morphological findings)