Evaluating, scoring and classifying polyomavirus nephropathy (PVN)

1. PVN is defined as an intrarenal PRODUCTIVE polyomavirus infection involving the renal medulla and/or the cortex with light microscopic and/or immunohistochemical or in-situ hybridization evidence of viral replication. PVN has to be separated from non-productive latent polyomavirus infections.
2. A productive infection with polyomaviruses is seen in renal epithelial cells, i.e. tubular and parietal epithelial cells. The earliest sign of a productive infection is intranuclear positivity for SV40 T antigen, i.e. proteins associated with viral replicatio (by immunohistochemistry) or intranuclear in-situ hybridization signals, followed by the development of characteristic intranuclear viral inclusion bodies (by light microscopy) and subsequent host epithelial cell necrosis/lysis with an "ATN" pattern of tubular injury. Generally virally induced changes are focally distributed; very early polyomavirus replication may be limited to the medulla and may not be associated with intranuclear viral inclusion bodies or epithelial cell necrosis.
3. The classification/staging of PVN is primarly based on specific, virally induced tubular epithelial cell lesions, i.e. intranuclear changes, tubular epithelial host cell necrosis/lysis. Secondary changes include the degree of chronicity (presumed secondary to PVN), i.e. fibrosis and tubular atrophy, and inflammation.
4. PVN staging focuses on 3 disease phases: very early, florid acute and chronic - in order to provide some clinical guidance and to provide a basis for comparative data analysis. Additionally, based on the histologic evaluation viral load (vl) levels will be recorded (to be further discussed at Banff – below, i.e. subheader #5, is a suggestion based on the provided feed-back from the group ).
5. Acute and chronic rejection can concur with PVN. Rejection can involve arteries, glomeruli and the interstitium; rejection episodes can be C4d positive or negative. Banff discussions should specifically address guidelines on how to diagnose concurrent Banff type I, C4d negative rejection episodes – below, i.e. subheader#3 is a suggestion based on the provided feed-back from the group ).
6. Since PVN is focal and sometimes limited to the medulla, only biopsies with two cores containing medulla should be considered and reported as diagnostically "adequate" (these expanded ‘Banff’ adequacy criteria would apply to cases with PVN in the list of differential diagnoses).

- Viral replication with intranuclear inclusion bodies and/or positive immunohistochemistry (SV40 T antigen) or in-situ hybridization signals

Stage A 1, 2, 3, 4, 5 (medulla) - Changes limited to medulla

Stage A 1, 2, 3, 4, 5 (cortex) - Changes seen in cortex and possibly also medulla

- Conspicuous viral replication in cortex and/or medulla

- Viral replication in cortex and medulla (minimal to marked)

1 The adequate diagnostic workup for PVN requires 2 biopsy cores including medulla; comment if samples are inadequate

2 Interstitial inflammation varies from Banff scores i0-i3. Inflammation is often most pronounced in PVN stage B. Stage A may lack an inflammatory reaction.

3 PVN and rejection (acute, chronic, cell and/or antibody mediated) can concur and should be diagnosed according to standard criteria. Suggest concurrent Banff type I cellular tubulo-interstitial rejection if inflammation and tubulitis are seen in areas distant from viral replication, i.e. SV40 positive nuclei (by IHC) are more than one 20 x field away from foci with inflammation and tubulitis.

4 Chronicity scores are presumed to be PVN related. If chronic injury can be attributed to other causes, i.e. previous rejection, donor disease etc, comment in diagnosis.

2 3

5 Score and report histologic viral load levels (vl) additionally; vl.1-vl.4 can occur in all PVN stages: