Kidney nontumor

Infection

BK virus / polyomavirus



Last author update: 28 October 2022
Last staff update: 28 October 2022

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PubMed Search: BK virus / polyomavirus

Arzu Sağlam, M.D.
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Cite this page: Sağlam A. BK virus / polyomavirus. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/kidneybkvirus.html. Accessed December 2nd, 2022.
Definition / general
  • Interstitial nephritis caused by invasion of the renal parenchyma by BK polyomavirus; most commonly seen in the posttransplant setting
  • Resulting disease is referred to as polyomavirus nephropathy
Essential features
  • Polyomavirus nephropathy is caused by a ubiquitous, opportunistic, nonenveloped double stranded DNA virus belonging to the Polyomaviridae, with a very high seroprevalence rate in adults
  • It is characterized by interstitial nephritis and tubular injury and is most commonly encountered in the setting of immunodeficiency, especially in posttransplant patients, where the reactivated dormant virus in the uroepithelium escapes immunosurveillance
  • Most common histomorphologic changes encompass patchy interstitial inflammation and cytopathic changes in the tubular epithelial cells
  • Minimal and early stages of polyomavirus nephropathy may present with normal renal function and may not show intranuclear viral inclusion bodies, tubular injury or significant renal injury; this is why screening and routine staining of renal allograft biopsies (including surveillance biopsies) with SV40 immunohistochemistry is recommended: unchecked infection leads to renal scarring and allograft loss (BMC Nephrol 2021;22:226, Transplantation 2008;85:1008)
  • Reduction of immunosuppression is mainstay therapy
Terminology
  • BK polyomavirus nephropathy
  • BK virus associated nephropathy
  • Polyomavirus nephropathy
  • Definitive BK polyomavirus nephropathy: patients with biopsy proven viral nephropathy
  • Presumptive BK polyomavirus nephropathy: patients with high viremia titers but no histologic confirmation of renal disease
ICD coding
  • ICD-10: B33.8 - other specified viral diseases
Epidemiology
  • Encountered in the immunosuppressive settings, most commonly posttransplant and especially in those with overimmunosuppression
  • Has become more prevalent with the introduction of new potent immunosuppressive medication
  • More common in male patients, Afro-Caribbean ethnicity, pediatric patients and the elderly
  • In kidney transplant recipients the incidence of BK polyomavirus viruria is ~30 - 40%, that of viremia is ~13% and that of BK virus nephropathy is ~8% (N Engl J Med 2002;347:488)
Sites
  • Renal disease
Pathophysiology
  • Virus is acquired by direct person to person contact, through contaminated surfaces, food and water
  • Infection, which is most often subclinical, is usually encountered in childhood, where after the virus remains latent in the urothelial and renal tubular epithelial cells lifelong and is kept in check predominantly by T cells
  • With immunosuppression (suppression especially of T cell immune surveillance) the virus, either the dormant one in the host or donor derived (in a portion of transplant cases), reactivates and causes viremia by crossing into the peritubular capillaries (J Med Virol 2019;91:1136)
  • Lytic replication of the reactivated virus results in lysis of renal tubular epithelial cells, release of daughter virions into tubular lumens, infection of adjacent cells, basement membrane denudation, viruria, influx of inflammatory cells, and eventually leads to renal fibrosis and graft failure if left untreated
  • Viremia seldom causes infection of glomerular endothelial and mesangial cells, podocytes and Bowman capsular epithelial cells, potentially resulting in glomerular damage (J Clin Med 2019;8:1477)
  • BK virus genome, encodes 2 viral oncoproteins: the large T antigen (TAg) and the small t antigen (tAg), which have been shown to target p63 and pRb, and can potentially modify the normal cell cycle, leading to cell immortalization and neoplastic transformation (Am J Transplant 2016;16:398)
  • References: Transplantation 2016;100:2276, Nephrol Dial Transplant 2021;36:587
Etiology
Diagrams / tables

Images hosted on other servers:

Pathogenesis

Risk factors

Sources of infection

Clinical features
Diagnosis
Laboratory
Prognostic factors
Case reports
  • 39 year old woman with heart transplant who developed BK virus nephropathy (J Bras Nefrol 2021;43:434)
  • 41 year old woman with type I diabetes and pancreas / kidney transplant diagnosed with BK virus associated metastatic renal allograft carcinoma (Transplantation 2021;105:423)
  • 58 year old woman with chronic lymphocytic leukemia who developed hematuria due to concurrent BK polyomavirus, adenovirus and cytomegalovirus (BMJ Case Rep 2021;14:e235981)
  • 60 year old woman, a liver transplant patient with BK virus nephropathy of the native kidney (Kidney Int Rep 2021;6:1743)
Treatment
  • Screening and reduction of immunosuppression is mainstay therapy but carries the risk of rejection and development of de novo donor specific antibodies
  • mTOR inhibitor based regimen may be beneficial
  • Novel therapies: on trial
    • Immunotherapy: intravenous immunoglobulin, cellular therapy (virus specific T cells)
    • Vaccine
  • No effective antiviral medication present
  • No effective prophylaxis treatment
  • Regular screening between 1 - 24 months posttransplant is recommended
  • Reference: Viruses 2021;13:487
Microscopic (histologic) description
  • Findings are composed of interstitial nephritis and tubular injury; these findings are focal
  • Involvement is more prominent in the distal nephron, therefore evaluation of medulla is important, especially in early stage infection; it is recommended that 2 core biopsies be provided, at least 1 where the medulla is sampled (Clin J Am Soc Nephrol 2020;15:1015)
  • Interstitial edema and inflammation, composed predominantly of mononuclear cells, accompanied by plasma cells and less frequently eosinophils and neutrophils; these changes may be absent in early stages of infection (Ren Fail 2019;41:855)
  • Inflammation is patchy and associated with infected tubules, usually well demarcated from surrounding
  • Tubulitis and tubular cell injury; cell necrosis / dropout, desquamation / sloughing, flattening
  • Tubular epithelial cell cytopathy; maybe absent in early stages of infection
    • Cell enlargement
    • Nuclear hyperchromasia and anisonucleosis
    • Intranuclear inclusions: basophilic granules, ground glass appearance or clearing, no halo; chromatin changes: smudging, clumping or peripheral margination
    • Urine cytology: decoy cells (resemble cells in uroepithelial cancer); BK virus infected tubular epithelial cells that have been shed into the urine
      • Rounded basophilic nuclei larger than the average transitional and tubular epithelial cells
      • Nuclei have viral inclusions appearing as dense granular basophilia and no halo
      • Dirty background: transitional, tubular and inflammatory cells and clumps of amorphous basophilic material (harder to appreciate in slides prepared with thin layer methods)
      • Graded as rare, up to 4 per cytospin and > 10 per cytospin; when rare cells are present with lack of inflammation, chances of positive infection in biopsy sample is low
  • Cytopathic changes of the glomeruli (Bowman capsular epithelial cells, podocytes, mesangial cells) and crescent formation may also be seen (J Clin Med 2019;8:1477)
  • In early stage infection, morphological findings are only present in scattered cells, mostly in the medulla and may even be characterized by only a handful of SV40 positive cells without discernable cytopathy
  • Interstitial fibrosis and tubular atrophy: late stage disease
  • Histologic classification system: consisting of polyomavirus replication load / level (pvl) score and Banff score for interstitial fibrosis (ci) (J Am Soc Nephrol 2018;29:680)
    • PVN class 1: pvl 1; ci ≤ 1
    • PVN class 2:
      • pvl 1; ci ≥ 2
      • pvl 2; any ci score
      • pvl 3; ci ≤ 1
    • PVN class 3: pvl 3; ci ≥ 2
  • Scoring of polyomavirus replication load / level (pvl): percentage of positive tubules / ducts by morphologic assessment of cytopathy or SV40 immunohistochemistry in the entire biopsy (cortex and medulla)
    • pvl 1: 1%
    • pvl 2: 1 - 10%
    • pvl 3: > 10%
  • References: Yonsei Med J 2004;45:1065, Nephrol Dial Transplant 2021;36:587
Microscopic (histologic) images

Contributed by Arzu Sağlam, M.D.
Well demarcated inflammation

Well demarcated inflammation

Tubulitis and intranuclear inclusions

Tubulitis and intranuclear inclusions

Polyomavirus score - pvl3

Polyomavirus score: pvl 3

Luminal casts and cytopathic changes Luminal casts and cytopathic changes

Luminal casts and cytopathic changes


Cytopathic changes

Cytopathic changes

Intranuclear basophilic granules

Intranuclear basophilic granules

Glomerular cytopathy

Glomerular cytopathy

Anti-SV40 antibody, immunohistochemistry

Anti-SV40 antibody, IHC

Cytology images

Contributed by Çisel Aydιn Meriçöz, M.D.
Decoy cells in urine cytology

Decoy cells in urine cytology

Immunofluorescence description
  • No immunoglobulin or only nonspecific scarce staining
  • Immune deposits (most commonly IgG and C3) may be present along tubular basement membranes (Am J Transplant 2007;7:1552)
  • Peritubular C4d negative (positivity indicates accompanying antibody mediated rejection)
Immunofluorescence images

Contributed by Arzu Sağlam, M.D.
IgG deposition

IgG deposition

C3 deposition

C3 deposition

Positive stains
  • Anti-SV40 antibody, immunohistochemistry, is positive (part of the routine panel used in transplant biopsy assessment)
    • Large T antigen (LTAg), one of the proteins encoded by the BK polyomavirus genome shares sequence homology with the LTAg of the simian virus (SV40)
    • Anti-SV40 antibody directed against the SV40 T antigen, hence crossreacts with the BK polyomavirus LTAg and is used to identify BK polyomavirus
    • This antibody also crossreacts with the JC polyomavirus
  • In situ hybridization for BK virus DNA
  • Anti-BK polyomavirus VP1 recombinant antibody, immunohistochemistry: a novel monoclonal antibody directed against the viral VP1 capsid protein (Am J Transplant 2007;7:1552)
Negative stains
  • C4d immunohistochemistry, routinely used to assess transplant biopsies: peritubular and glomerular capillary wall staining is negative unless accompanying antibody mediated rejection is present
Electron microscopy description
  • Urine cytology: Haufen - icosahedral aggregates of polyomavirus particles and Tamm-Horsfall protein visualized using negative staining electron microscopy (Ultrastruct Pathol 2009;33:222)
    • These are viral particles that form in virally injured tubular epithelial cells and excreted in the urine and hence represent evidence of active disease
  • Presence of BK virions, 30 - 50 nm in diameter nonenveloped particles arranged in paracrystalline arrays, in tubular epithelial cells
    • This finding is not diagnostic of BK polyoma nephropathy / interstitial nephritis since dormant virions can persist in the tubular epithelial cells (Ultrastruct Pathol 2005;29:469)
    • Presence of necrotic tubular cells, prominent lysosomal inclusions and luminal protein and cellular cylinders should also be sought
  • Tubular basement membrane immune deposits: finely granular electron dense deposit with no substructure along the tubular basement membrane (Am J Transplant 2007;7:1552)
Electron microscopy images

Contributed by Jonathan E. Zuckerman, M.D., Ph.D.
IgG deposition

Viral particles

IgG deposition IgG deposition

Nuclear viral particles



Images hosted on other servers:

Polyomavirus Haufen

Polyomavirus Haufen and CISH staining

Tubular basement membrane deposits

Genetics
  • Presence of certain HLA alleles may predispose to (lack of HLA-C7) or protect against BK virus nephropathy
  • Killer cell immunoglobulin receptor genes of NK cells are also correlated with risk of infection; genotyping of recipients in the pretransplant or early posttransplant period is being envisioned
  • Genotype of the virus and single nucleotide polymorphisms in the genes coding for the major viral capsid protein VP1 and the noncoding control region affects pathogenicity of the virus
  • References: Viruses 2020;12:1417, Kidney Int 2013;84:359, Viruses 2021;13:1502
Videos

Histomorphological characteristics of BK virus associated nephropathy in a transplant patient
by Dr. Arzu Sağlam

Sample pathology report
  • Kidney, allograft biopsy:
    • BK virus associated nephropathy (see comment)
    • No significant deposition on immunofluorescence microscopy. No evidence of T cell or antibody mediated rejection. Interstitial fibrosis / tubular atrophy absent. Arterial intimal fibrosis (mild) arteriolar hyalinosis (ah2).
    • Microscopic description: Serial sectioning shows 120 glomeruli, 5 of which are globally sclerotic. Glomeruli appear close to normal by light microscopy. Endocapillary or extracapillary proliferation, necrosis, intracapillary inflammatory cells (g0), intracapillary thrombi or double contouring of the capillary walls are absent (cg0). Interstitium shows patchy multifocal edema and inflammatory infiltrate with predominance of lymphomononuclear cells and plasma cells. Tubular epithelial cells in these areas display features of cytopathic changes characterized by nuclear enlargement, coarse granular chromatin and nuclear clearing with peripherally condensed chromatin. Some of the tubuli contain granular casts with sloughed epithelial cells, others show simplification with flattened epithelial cells and dilated lumina. Immunohistochemical staining for SV40 shows positivity affecting 5 - 10% of tubuli represented in the biopsy sample (pvl 2). Narrow foci of IFTA can be identified, comprising less than 10% of the cortical parenchyma with scattered mononuclear cells (i-IFTA0, ci0, ct0). Immunohistochemical staining for C4d is negative. Arteries display mild intimal fibrosis (cv1). Intimal arteritis is not identified (v0).
    • Immunofluorescence microscopy: 3 glomeruli observed
      • Anti-IgG Ab: no deposits
      • Anti-IgA Ab: no deposits
      • Anti-IgM Ab: no deposits
      • Anti-C3 Ab: no deposits
      • Anti-C1q Ab: no deposits
      • Anti-kappa Ab: no glomerular deposits, 2+ staining of tubular casts
      • Anti-lambda Ab: no glomerular deposits, 2+ staining of tubular casts
    • Comment: Biopsy findings are consistent with BK virus associated nephropathy. Tubulitis is restricted to areas of viral cytopathy. There is no evidence of accompanying T cell or antibody mediated rejection or significant chronic tubulointerstitial damage.
Differential diagnosis
  • JC virus nephropathy:
    • Should be considered in patients with BK viremia loads inconsistent with strong SV40 staining in renal biopsy samples
  • High grade urothelial carcinoma:
    • Causes confusion especially in urine cytology, presence of Haufen in urine cytology and SV40 immunohistochemistry is diagnostic; other helpful morphologic findings are as follows:

      BK virus: High grade urothelial carcinoma:
      • Hyperchromasia less pronounced
      • Smudgy chromatin
      • Homogeneous, opaque nucleus
      • Absence of cell clusters
      • Hyperchromasia more prominent
      • Coarse chromatin
      • Eccentrically located nucleus
      • Presence of cell clusters

  • Acute T cell mediated rejection:
    • SV40 immunohistochemistry is diagnostic (does not resolve diagnostic dilemma in cases with concurrent infection and rejection); other helpful morphologic findings are as follows:

      BK virus: Acute T cell mediated rejection:
      • Cytopathic changes
      • Tubulitis less prominent
      • Inflammation patchy, well demarcated, more B cells
        (Transplantation 2001;71:896)
      • No edema
      • No vasculitis
      • Neutrophils may be present
      • Cytopathic changes absent but degenerative
        regenerative changes may be confused with cytopathy
      • Tubulitis more prominent
      • Inflammation less demarcated, more T cells
        (Transplantation 2001;71:896)
      • Edema positive
      • Vasculitis may be present
      • Neutrophils rarer

  • Acute tubular injury:
    • Nuclear degenerative / regenerative changes that accompany acute tubular injury may resemble viral cytopathy; the nuclear changes, however, are usually not as exaggerated, are composed of nucleolar enlargement and hyperchromasia and less often show chromatin changes that resemble intranuclear inclusions
    • Moreover, inflammatory infiltration is not prominent, as that which accompanies viral infection
    • SV40 immunohistochemistry also aids diagnosis
  • Other viruses may have similar cytopathic changes, such as cytomegalovirus (presence of both intranuclear and intracytoplasmic inclusions and perinuclear halo may aid histologic diagnosis), adenovirus and human herpes simplex virus (presence of both intranuclear and intracytoplasmic inclusions may aid histologic diagnosis):
    • Immunohistochemistry is diagnostic
    • It should be kept in mind that concurrent infection with multiple viruses can be present in the immunosuppressed (BMJ Case Rep 2021;14:e235981)
  • References: Yonsei Med J 2004;45:1065, Nephrol Dial Transplant 2021;36:587
Board review style question #1

A 36 year old kidney transplant patient presents with hematuria and laboratory tests show increased serum creatinine. Biopsy of the renal allograft reveals findings demonstrated in the photomicrograph above. Which of the entities below should be first on the differential diagnostic list?

  1. Acute tubular injury
  2. Antibody mediated rejection
  3. BK polyomavirus nephropathy
  4. High grade urothelial carcinoma
  5. T cell mediated rejection
Board review style answer #1
C. BK polyomavirus nephropathy

Comment Here

Reference: BK virus / polyomavirus
Board review style question #2
Below are the pathological examination findings of a bone marrow transplant patient:

  • Intranuclear inclusions in tubular epithelial cells in renal biopsy
  • Nuclear staining of tubular epithelial cells with SV40 immunohistochemistry in renal biopsy
  • Inflammatory infiltrate composed predominantly of lymphomononuclear cells in renal biopsy
  • Urinary Haufen in electron microscopic evaluation of urine cytology

What is your diagnosis?

  1. Acute hypersensitivity type tubulointerstitial nephritis
  2. Acute tubular injury
  3. BK virus associated nephropathy
  4. Graft versus host disease
  5. Pyelonephritis
Board review style answer #2
C. BK virus associated nephropathy

Comment Here

Reference: BK virus / polyomavirus
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