Polyomavirus nephropathy: updated Helmut Hopfer, Basel, Switzerland.

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

inter-observer variability

SV40 IHC

participants scoreintensity and extent

inter-laboratory variability

SV40 IHC

organizers scoreintensity and extent

SV40 IHC

SV40 IHC

SV40 IHC

SV40 IHC

SV40 IHC

SV40 IHC

participantsSV 40 IHC

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unpublished data, M. Mengel, Edmonton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unpublished data, M. Mengel, Edmonton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unpublished data, H. Hopfer, Basel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

Therapy• reduction of immuno-

suppression• cidofovir? (nephrotoxicity!)• leflunomide?

Guidelines for screening and therapy

Hirsch et al., Am J Transplant 9:S136-S146,2009

Viruria (Decoy cells)

Viremia

PVN•"definite"•"presumptive"

Reduce ISMonitor viremia

Resolved PVN

Screening

Diagnosis

Therapy

Resolution

Blood

↓ ↓ ↑

time after transplantation

BK-specific cellular immunity

vire

mia

(c/m

l)

viru

ria (c/

ml)

adapted from Comoli et al., Curr Opin Organ Transplant 13:569-574, 2009

BK-specifi

c im

munity

IFNg S

FU/1

05 PBMC

Immunosuppression

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

decreasing BKVincreasing BKVbefore BKV after BKV

Patients with BKV > 1'000 copies/ml•treated with reduction of maintenance immunosuppression•no rejection therapy•at least 1 surveillance biopsy during 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

time after transplantation

PVN resolving PVN residual PVN

BK dynamics increasing decreasing cleared

viruria

viremiaBK-specific

immunity

BK-induced tubular damage

BK-induced inflammation

anti-BK inflammationand IEL

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, morphologi-cal findings)