The Banff Working Group Classification of Definitive Polyomavirus Nephropathy: Morphologic Definitions and Clinical Correlations

Abstract

Polyomavirus nephropathy (PVN) is a common viral infection of renal allografts, with biopsy-proven incidence of approximately 5%. A generally accepted morphologic classification of definitive PVN that groups histologic changes, reflects clinical presentation, and facilitates comparative outcome analyses is lacking. Here, we report a morphologic classification scheme for definitive PVN from the Banff Working Group on Polyomavirus Nephropathy, comprising nine transplant centers in the United States and Europe. This study represents the largest systematic analysis of definitive PVN undertaken thus far. In a retrospective fashion, clinical data were collected from 192 patients and correlated with morphologic findings from index biopsies at the time of initial PVN diagnosis. Histologic features were centrally scored according to Banff guidelines, including additional semiquantitative histologic assessment of intrarenal polyomavirus replication/load levels. In-depth statistical analyses, including mixed effects repeated measures models and logistic regression, revealed two independent histologic variables to be most significantly associated with clinical presentation: intrarenal polyomavirus load levels and Banff interstitial fibrosis ci scores. These two statistically determined histologic variables formed the basis for the definition of three PVN classes that correlated strongest with three clinical parameters: presentation at time of index biopsy, serum creatinine levels/renal function over 24 months of follow-up, and graft failure. The PVN classes 1-3 as described here can easily be recognized in routine renal biopsy specimens. We recommend using this morphologic PVN classification scheme for diagnostic communication, especially at the time of index diagnosis, and in scientific studies to improve comparative data analysis.

Keywords: Interquartile range; Intra renal polyomavirus load/replication level; Polyomavirus Nephropathy; Simian Virus 40 large T antigen; immunohistochemistry; mixed-effects repeated measures model.

Figure 1.

PVN class 1 (pvl 1, Banff ci 0). (A and B) Patient 1. The renal medulla only shows three tubules with polyomavirus replication in an SV40-T stain (arrows in B), representing <1% of all tubules (cortex and medulla) found in a total of two biopsy cores (pvl 1); there are no diagnostic intranuclear viral inclusion bodies, no interstitial fibrosis, and no inflammation. (C–F) Patient 2. The renal cortex shows seven tubules with SV40-T expression (arrows in D), representing <1% of all tubules (cortex and medulla) in a total of two biopsy cores (pvl 1); (C) there are no diagnostic intranuclear viral inclusion bodies, there is no fibrosis (ci 0), and there is only patchy minor inflammation. Note that parenchyma and tubules lacking significant changes by light microscopy (E) show viral replication by IHC (F) with a crisp diagnostic intranuclear staining pattern. (A, C, and E) Hematoxylin and eosin–stained sections and (B, D, and F) IHC on formalin-fixed and paraffin-embedded tissue sections to detect the polyomavirus large T antigen (simian virus large T; mouse mAb, clone 416, DP02; Calbiochem). Original magnification, ×10 (A, B), ×20 (C, D), and ×40(E, F).

Figure 2.

PVN class 2 (pvl 3, Banff ci 0). The cortex shows several areas with polyomavirus replication both by light microscopy (intranuclear viral inclusion bodies; arrows in A, C, and E) and in an SV40-T stain with crisp intranuclear staining (B, D, and F), representing >10% of all tubules (cortex and medulla) found in a total of two biopsy cores (pvl 3); (A) there is only very minimal fibrosis (Banff ci 0) and patchy interstitial inflammation with edema. (A, C, and E) Hematoxylin and eosin–stained sections and (B, D, and F) IHC on formalin-fixed and paraffin-embedded tissue sections to detect the polyomavirus large T antigen (simian virus large T; mouse mAb, clone 416, DP02; Calbiochem). Original magnification, ×10 (A, B), ×20 (C, D), and ×40 (E, F).

Figure 3.

PVN class 3 (pvl 3, Banff ci 3). The cortex shows several areas with polyomavirus replication mainly in an SV40-T stain (with intranuclear staining of different intensities; B, D, and F), representing >10% of all tubules (cortex and medulla) found in a total of two biopsy cores (pvl 3); (A) there is diffuse interstitial fibrosis (Banff ci 3), tubular atrophy, and inflammation. (A) Trichrome-stained section, (C and E) hematoxylin and eosin–stained sections, and (B, D, and F) IHC on formalin-fixed and paraffin-embedded tissue sections to detect the polyomavirus large T antigen (simian virus large T; mouse mAb, clone 416, DP02; Calbiochem). Original magnification, ×10 (A, B), ×20 (C, D), and ×40 (E, F).

Figure 4.

Median change in S-Cr from baseline (y axis) is plotted by visit (x axis) for PVN classes 1–3. A linear MMRM on the ranks, controlling for baseline S-Cr and study center (n=178 study subjects), revealed significantly increasing S-Cr levels with increasing PVN class over time, highlighted here at month 12 (1 versus 2: P<0.001; 1 versus 3: P<0.001; 2 versus 3: P=0.02) and month 24 (1 versus 2: P=0.01; 1 versus 3: P<0.001; 2 versus 3: P=0.02).

Figure 5.

PVN. Flow chart illustrating recommendations for risk assessment and patient management after renal transplantation. The novel morphologic Banff Working Group on Polyomavirus Nephropathy classification of definite PVN with three disease classes (blue box) adds prognostic value and enhances clinical communication. Urinary PV-Haufen Test.^,, *Negative viremia/viruria. Differential diagnosis includes false negative PCR result due to mutant BK virus strain, presence of JC virus, or presence of Simian Virus 40. ^†Other renal diseases can concur with PVN, including calcineurin inhibitor toxicity, recurrent or de novo renal disease, and rejection.