Polyomaviruses and disease: is there more to know than viremia and viruria?

Abstract

Purpose of review: Polyomavirus nephropathy (PVN) mainly caused by BK virus (BKV) remains the most common productive viral infection of the kidney. Over the past decade, clinical interest often focused on BK viremia and viruria as the diagnostic mainstays of patient management. The purpose of this review is to discuss viral nephropathy in the context of BK viremia and viruria and new strategies to optimize diagnostic accuracy and patient management. The emerging roles of polyomaviruses in oncogenesis, salivary gland disease, and post-bone marrow transplantation as well as novel Polyomavirus strains are highlighted.

Recent findings: Areas of investigation include proposals by the Banff working group on the classification of PVN and studies on PVN progression and resolution, including the role cellular immune responses may play during reconstitution injury. New noninvasive strategies to optimize the diagnosis of PVN, that is, the urinary 'polyomavirus-haufen' test and mRNA expression levels for BKV in the urine, hold great promise to accurately identify patients with viral nephropathy. Tools are now available to separate 'presumptive' from 'definitive' disease in various patient cohorts including individuals post-bone marrow transplantation. Recent observations also point to a currently underrecognized role of polyomaviruses in oncogenesis post-transplantation and salivary gland disease in patients with HIV-AIDS.

Summary: This review summarizes recent studies on PVN and the significance of the BKV strain in disease. Current paradigms for patient management post-(renal) transplantation are discussed in the setting of new observations. Issues that still require clarification and further validation are highlighted.

Box 1

no caption available

FIGURE 1

Histologic polyomavirus nephropathy (PVN) disease grades. (a) and (d) PVN disease grade 1 with mild viral nephropathy. (a) By light microscopy, no characteristic and diagnostic viral inclusion bodies are identified (H&E stain, ×200 magnification). (d) Evidence of viral replication is provided by a positive staining signal for the SV40-T antigen found in rare tubular epithelial cell nuclei (SV40-T antigen immunostain, ×200 magnification). (b) and (e) PVN disease grade 2 with florid viral nephropathy. (b) Severely injured tubules containing many viral inclusion bearing epithelial cells are seen both in an H&E stain (×200 magnification) and (e) in an SV40-T antigen immunostain (×200 magnification). (c) and (f) PVN disease grade 3 with marked sclerosing viral nephropathy [(c) trichrome stain, ×200 magnification; (f) SV40-T antigen immunostain, ×200 magnification].

FIGURE 2

Schematic graph with estimates of BK-virus activation, that is, BK viruria, BK viremia, urinary polyomavirus-haufen shedding and viral nephropathy/PVN postrenal transplantation. Although viruria and viremia are detected in a high percentage of patients, ‘definitive’ PVN develops in only a small subgroup of ‘viral activators’. Note: A positive urinary polyomavirus-haufen test is almost exclusively seen in patients with definitive PVN and can help to render a noninvasive diagnosis in patients clinically presenting with evidence of BK-virus activation. BKV, BK virus; PVN, polyomavirus nephropathy.

FIGURE 3

Cases of ‘definitive’ polyomavirus nephropathy (PVN): severity of intrarenal disease and corresponding titers of urine and plasma markers. Correlation of the degree of marker expression (quantitative screening test results – y-axis) with the severity of PVN –intrarenal polyomavirus replication, that is, the number of SV40-T expressing tubular epithelial cells in a biopsy sample with PVN (x-axis). (a) Urinary polyomavirus-haufen: number of haufen/ml urine; (b) urine PCR for BK virus (BKV): number of BKV copies/ml urine; (c) plasma PCR for BKV: number of BKV copies/ml plasma; and (d) urine decoy cells: number of decoy cells/ThinPrep cytology preparation. Regression lines with corresponding correlation coefficients (σ) and ρ values are depicted. Adapted from [^▪▪].

FIGURE 4

Voided urine sample with polyomavirus-haufen in a patient with ‘definitive’ polyomavirus nephropathy. Negative staining electron microscopy depicting a characteristic polyomavirus-haufen in a voided urine sample. Polyomavirus-haufen are tight cast-like three-dimensional viral aggregates composed of at least six individual virions. Note the large size of this polyomavirus-haufen resembling a tubular cast. The diagnostic viral capsid substructure and uniformity of virions allow for accurate identification by electron microscopy (uranyl acetate stain: ×100 000 magnification).

FIGURE 5

Polyomavirus-haufen in patients with polyomavirus nephropathy. A cartoon image of a bivalved kidney (a) highlighting an area of parenchyma sampled by renal biopsy (square box). An immunostain for the polyomavirus VP1 capsid protein (b) shows strong staining of cast-like intratubular dense polyomavirus aggregates in injured renal tubules. These cast-like viral structures are shed into the urine (c) and can serve as robust ‘structural’ urinary biomarkers for intrarenal disease, that is, they give rise to a positive polyomavirus-haufen test (d) [–32].