Nathan Roberts, MD
Patrick J. Shenot, MD, FACS
BASICS
DESCRIPTION
• JC and BK viruses are 2 of 10 different human polyoma viruses
– Small DNA viruses in the papovaridae family
– JC and BK viruses named after 1st patients the viruses were isolated from in 1971
– These viruses typically manifest clinical sequelae only in immunocompromised hosts
– BK virus has a tropism for genitourinary epithelium
Clinical manifestations: Hemorrhagic cystitis (HC), ureteral stenosis, nephropathy, and rare GU-associated malignancies
EPIDEMIOLOGY
Incidence
N/A
Prevalence
• BK virus has an 82–99% seroprevalence in adults of the United States, Italy, and Australia
– 50% @ 2 yr of age; 90% @ 10 yr of age
• JC virus has a 39–81% seroprevalence in same regions
– Clinically manifest only in immunocompromised subjects
• Ureteral stenosis due to BK virus infection among allograft recipients is approximately 3%
• BK-induced nephropathy:1–10% of transplants
• Hemorrhagic cystitis
– Reported to cause hemorrhagic cystitis in 5.7–7.7% of bone marrow transplant recipients
RISK FACTORS
• Immunocompromised host
– Degree of immunosupression
– Transplant recipients
Solid organ (especially kidney), stem cell transplants
– HIV/AIDS
Predilection toward hemorrhagic cystitis
– Autoimmune disorders requiring immunosuppression
– Multiple sclerosis
– Systemic lupus erythematous
Genetics
• Small nonenveloped icosahedral particles of 40–45-nm diameter, with a nonenveloped, circular double-stranded DNA genome
• Polyoma viruses encode 6 proteins
• 3 structural capsid proteins
• 3 noncapsid regulatory proteins
– Large and small T antigen (cell immortalization and latency), and agnoprotein (assembly of viral particles)
Proteins interact with cellular target proteins and impair pathways involved with cell cycle and DNA repair
PATHOPHYSIOLOGY
• Route of transmission is unknown but seems to occur early in life most likely oral/respiratory exposure (1,2)
• Hypothesized that subclinical infection leads to viremia that seeds the kidneys
• Pathology is postulated to occur from reactivation of latent infection and not reinfection
• Immuno-reconstitution inflammatory syndrome
– Dominant inflammatory response to abundant polyoma virus antigen followed by brisk recovery of the cellular immune response
Seen in BKV-associated hemorrhagic cystitis after allogeneic stem cell transplantation
• Cytopathic-inflammatory polyomavirus pathology
– High-level virus replication and a significant inflammatory response due to cytopathic lysis, necrosis, with infiltration of granulocytes and lymphocytes. Dominant inflammatory response to abundant polyoma virus antigen followed by brisk recovery of the cellular immune response
Seen in BKV-associated nephropathy in kidney allografts
• Oncogenic polyoma virus pathology
– Early viral gene expression activating host cells but without sufficient late gene expression to cause rapid host cell lysis
Seen in rare BKV-associated urothelial and renal tubular cancers
There is conflicting evidence of BK virus involvement in these tumors
• Hemorrhagic cystitis
– Another theory suggests 3 phases
Conditioning regimen for stem cell transplant damages the bladder mucosa providing environment for virus replication
Viral replication unchecked in the absence of functional immunity
Further damage to the bladder mucosa with immune reconstitution and return of anti-BK immunity
ASSOCIATED CONDITIONS
• BK virus has a tropism for genitourinary epithelium
– Kidney transplant recipients
Tubulointerstitial nephritis
Ureteral stenosis
– Stem cell transplant recipients
Hemorrhagic cystitis
• JC virus has a tropism for neural tissue
– Causes progressive multifocal leukoencephalopathy
– Not as common, but JC can also be related to genitourinary manifestations like BK virus and vice versa
GENERAL PREVENTION
• Route of transmission is unknown so difficult to prevent
• Competent immune system will prevent clinical sequelae
DIAGNOSIS
HISTORY
• Hemorrhagic cystitis
– From pink colored urine to clot retention
– Pt can also have bladder pain
– Pt may have LUTS
• BK virus nephropathy
– Typically occurs 10–13 mo after transplant
– Often asymptomatic
– May have hematuria
– May have decreased urine output
• Transplanted ureteral stenosis (3)
– Typically occurs 2–4 mo after transplant
– Often asymptomatic
– May have decreased urine output
PHYSICAL EXAM
• Hemorrhagic cystitis
– May present with palpable bladder if in clot retention
• BK virus nephropathy
– No significant findings on exam
• Ureteral stenosis of kidney transplant
– May have no significant findings
– Pelvic mass bulge from transplant hydronephrosis
– Due to denervation of transplanted kidney, patient may not present with pain
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Virus culture mostly used in research setting
– Takes weeks to months to grow
• Urine cytology
– Detects virus shedding
– Characteristic finding is an enlarged nucleus with a single large basophilic intranuclear inclusion (“decoy cells”)
Does not distinguish between various types of polyoma virus
• Urine quantitative PCR
– Correlates with BK virus associated nephropathy
– Can be positive in normal controls, elderly patients and HIV-infected patients without clinical manifestations
Difficult to assess clinical significance
• Plasma quantitative PCR
• Hemorrhagic cystitis
– Urinalysis positive for blood/RBCs
• BK virus nephropathy
– Elevated creatinine
– Urinalysis
Pyuria, hematuria, and/or cellular casts of renal tubular cells and inflammatory cells
• Transplanted ureteral stenosis
– Can have elevated creatinine
Imaging
• Hemorrhagic cystitis
– Ultrasound or CT can show bladder thickening and possibly clot if present
• Transplanted ureteral stenosis
– Hydronephrosis seen on renal ultrasound, CT or MRI
– Obstruction seen on renogram
Diagnostic Procedures/Surgery
• Hemorrhagic cystitis
– Cystoscopy can show evidence of clots/active bleeding
• BK virus Nephropathy
– Renal Biopsy
Most often percutaneous approach
Histopathology results listed below
Can also use Immunohistologic or in situ hybridization evidence of virally infected cells to make diagnosis
Strongly positive using an SV40 immunohistochemical stain
Pathologic Findings
• BK Virus nephropathy
– Usually infects tubular epithelial cells
– Anisonucleosis, hyperchrmoasia, and chromatin clumping of infected cells
– Interstitial mononuclear or polymorphonuclear cell infiltrates in the areas of tubular damage
– Tubular injury with tubular cell apoptosis
– Intranuclear basophilic viral inclusions with a surrounding halo
– Not pathognomonic for BK virus
CMV has cytoplasmic inclusion
HHSV has both intranuclear and cytoplasmic inclusions
DIFFERENTIAL DIAGNOSIS
• Hemorrhagic cystitis
– Medication related (high-dose cyclophosphamide)
Often occurs within 72 hr
– Adenovirus related
– Radiation induced
– Infectious source
– Trauma
Possibly from urethral catheter placement
– BPH related
• BK virus nephropathy
– Cellular rejection
• Transplanted ureteral stenosis
– Surgical technique; ischemia of distal ureter
– Typically occurs in 7–10 days
TREATMENT
GENERAL MEASURES
• Reduction of immunosuppression if possible (4)
– Often most effective strategy
MEDICATION
First Line
• Quinolone antibiotic (ciprofloxacin, etc.)
– Suggested for prophylactic role
• Intravenous immunoglobulin
– Can be used in hypogammaglobulinemic patients
– Leflunomide: Antiviral activity
• Hemorrhagic cystitis
– Increased hydration
– Catheter placement with clot evacuation
– Continuous bladder irrigation (CBI)
Second Line
• Intravesical vs. intravenous cidofovir
– Nucleotide analog of cytosine
– Active against DNA viruses
– Anecdotal evidence for use against polyoma viruses
– Highly nephrotoxic
• Hemorrhagic cystitis
– Cystoscopic fulguration (electro cautery or laser)
– Conjugated estrogens: Act by stabilization of microvasculature
– Intravesical instillation of alum
An astringent precipitates protein over bleeding surface
1% Alum solution in CBI
Can be used in presence of VUR
– Intravesical instillation of silver nitrate
Chemical coagulation and eschar at bleeding sites
0.5–1% instilled for 10–20 min
VUR may lead to renal failure due to precipitation and obstruction of upper tracts
– E-aminocaproic acid
Inhibits fibrinolysis preventing activation of plasminogen to plasmin
Given orally, parenterally, or intravesically
Patients can form hard clots that are difficult to flush from the bladder
– Intravesical instillation of prostaglandin
PGE2: May encourage platelet aggregation and induce vasoconstriction
PGE2: 0.75 mg in 200 mL of normal saline and left indwelling
May cause bladder spasms
– Intravesical instillation of formalin (40% formaldehyde)
Hydrolyzes proteins and coagulates tissue on superficial level
Painful and needs to be done with general anesthesia
Should not be done with VUR. Can fibrose the ureters, cause obstruction, hydronephrosis and also papillary necrosis
Can result in small contracted bladder
SURGERY/OTHER PROCEDURES
• Hemorrhagic cystitis (5)
– Cystectomy if refractory life-threatening cases
– Selective embolization
Vesical or internal iliac artery
• BK virus Nephropathy
– Kidney re-transplant
Limited information for outcomes
Recommend patients have absence of BK replication prior to re-transplantation
• Transplant ureteral stenosis
– Decompression of the transplanted kidney
Percutaneous nephrostomy tube
Ureteral stent placement
– Surgical excision of stenotic segment
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
• Hemorrhagic cystitis
– Hyperbaric oxygen: Promotes healing of hypoxic tissues and aid in angiogenesis
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Hemorrhagic cystitis: Dramatic in presentation but usually resolves spontaneously within 2 wk with supportive care
• BK virus nephropathy: Graft failure in 15–50%
FOLLOW-UP
Patient Monitoring
BK virus nephropathy: After transplant some recommend periodic monitoring for viremia
Patient Resources
N/A
REFERENCES
1. Dalianis T, Hirsch HH. Human polyomaviruses in disease and cancer. Virology. 2013;437(2):63–72.
2. Hirsch HH, Randhawa P. BK polyomavirus in solid organ transplantation. Am J Transplant. 2013;13 suppl 4:179–188.
3. Thomas A, Dropulic LK, Rahman MH, et al. Ureteral stents: A novel risk factor for polyomavirus nephropathy. Transplantation. 2007;84(3):433–436.
4. van Aalderen MC, Heutinck KM, Huisman C, et al. BK virus infection in transplant recipients: Clinical manifestations, treatment options and the immune response. Neth J Med. 2012;70(4):172–183.
5. Manikandan R, Kumar S, Dorairajan LN. Hemorrhagic cystitis: A challenge to the urologist. Indian J Urol. 2010;26:159–166.
ADDITIONAL READING
Kazory A, Ducloux D. BK virus-associated urologic complications. Pediatr Transplant. 2007;11(7):821–822.
See Also (Topic, Algorithm, Media)
• Cystitis, Hemorrhagic (Infectious, Noninfectious, Radiation)
• Immunocompromised Patients, Urologic Considerations
• Polyoma Virus (BK, JC), Urologic Considerations Image 
CODES
ICD9
• 079.89 Other specified viral infection
• 593.3 Stricture or kinking of ureter
• 595.9 Cystitis, unspecified
ICD10
• B33.8 Other specified viral diseases
• N13.5 Crossing vessel and stricture of ureter w/o hydronephrosis
• N30.90 Cystitis, unspecified without hematuria
CLINICAL/SURGICAL PEARLS
Polyoma virus will only have clinical sequelae in immunocompromised patients.