1) BK virus is a polyomavirus that commonly infects humans and usually causes asymptomatic infection during childhood. However, in immunosuppressed transplant patients it can reactivate and cause polyomavirus-associated nephropathy (PVAN). 2) The primary treatment for PVAN is reduction of immunosuppression to allow the immune system to control viral replication. Additional treatments like cidofovir and leflunomide have not been proven effective. 3) While reduction of immunosuppression can control the virus and prevent graft loss in many cases, PVAN remains a significant problem after transplantation and may contribute to longer term allograft dysfunction. Improved antiviral therapies are still needed.

1. Post renal transplant BK virus
infection
Dr. Sunil Kumar Daksh Parajapati

2. Introduction
 We will discuss today
 Polyoma virus infection, replication, and
disease in renal transplant recipients
 Treatment of PVAN (Polyoma virus
associated nephropathy)

3. Polyoma virus
 Five known human polyoma viruses
 BK & JC virus
 KI virus (KIPyV) & WU viruses (WUPyV)
were identified in 2007 from respiratory
secretions of a RTI pt.
 KI & WU viruses are named after the institutions
 In Jan 2008, Feng et al., identified Merkel cell
polyoma virus (MCPyV) was a/w Merkel cell
carcinoma

4. Transmission
 Occurs mostly through close contact
 Transmission through the feco-oral and
respiratory routes has been suggested
 Other routes include blood transfusion,
transplacentally, through semen, &organ
transplantation

5. BK virus infection
 Named after the first patient in which it was
described by Gardner (Sudanese kidney transplant
patient with ureteric stenosis whose initials were BK)
 Ubiquitous polyomavirus
 Acquired in childhood and becomes latent in
uroepithelial cells
 Reactivation of BK virus occurs in patients in
immunosuppressed states, including
 After transplantation
 HIV
Transplantation Proceedings 2008; 40: S48–51

6. BK virus infection
 Typically occurs during childhood, with
seroprevalence rates of 65% to 90% by the
age of 10 years, and is usually asymptomatic
 Individuals with altered immunity, however,
can experience high-level replication and may
present with urine cytology (“decoy” cells)
Transplantation Reviews 2008;22:241–51

7. Nefrologia 2010;30(6):613-7

8. Polyomavirus (BK)–associated
nephropathy (BKVN)
 Polyomavirus (BK)–associated
nephropathy (BKVN)
 Now recognized as significant problem in
renal transplants that may lead to progressive
allograft dysfunction
 First recognized in 1971 in adult renal
transplant recipients

9. Clinical manifestations
 Risk factors:
 Older, male, White, diabetic recipient
 More HLA mm, ACR, DGF
 Net state of immune suppression
 Seronegativity of the recipient
 lack of HLA-C7
 deceased donor transplantation
 Asymptomatic allograft dysfunction
 Prior tubular injury from rejection or drugs, surgical injury, warm
ischemia & reperfusion injury
 Suspect BK when rejection does not resolve with
usual therapy

10. Polyomavirus infection
 In renal transplant recipients,
 Polyomavirus-associated nephropathy
(PVAN) develops in 5% of patients and leads
to graft loss in approximately 50% of cases
 Pathogenesis of PVAN characterized by
 Persisting high-level polyoma BK virus (BKV)
replication in renal tubular epithelial cells,
inflammation, and progressive organ failure with
tubular atrophy and fibrosis
Transplantation Reviews 2008;22:241–51

11. BK virus Nephropathy
 Polyoma virus: Renal transplant recipients
 Most cases of BKN occur within the first year
after kidney transplantation
 Definitive diagnosis requires histopathological
assessment, notably to exclude acute
rejection
Transplantation Reviews 2008;22:241–51

12. BK virus Nephropathy
 BK viruria: 20% - 40% of renal transplant
patients
 BK viremia: approx. 12% of patients
 Studies have indicated that
 BK viremia greater than 10e4/mL is predictive of
definitive PVAN, and these patients should be
regarded as having “presumptive PVAN,” and
 Reduced immunosuppression should be
considered
Transplantation Reviews 2008;22:241–51

13. BK Nephropathy
 Variable degree of
interstitial inflammation,
fibrosis, atrophy
 Similar in appearance to
cellular rejection
 Immunohistochemistry
useful

14. Nefrologia 2010;30(6):613-7

15. Since it has a patchy distribution affecting
mostly the medulla, two core biopsy
samples including medulla should be
obtained.

16. Polyomavirus infection
 BK nephropathy develops through three stages
 Stage A
 Few viral inclusion bodies and occasional positive
immunohistochemical staining, with an antibody to SV40
large T antigen that cross-reacts with BK large T antigen
 Stage B
 Fulminant nephropathy shows an inflammatory infiltrate with
focal tubulitis, which may mimic acute rejection but includes
prominent intranuclear inclusions and T-antigen staining
 Stage C
 Diffuse interstitial fibrosis and closely resembles chronic
allograft nephropathy

17. Management

18. Nefrologia 2010;30(6):613-7

20. More recently..
 The use of electron microscopy to detect
cast-like, three dimensional polyoma virus
aggregates in urine called “Haufen” has
been found to be sensitive and specific for
BKVN.
 The positive and negative predictive values of
Haufen for BK polyoma virus nephropathy were
97% and 100%, respectively.

21. BK virus infection: Treatment
 The treatment of BKVN is unlikely to be
satisfactory until safe and effective
antiviral drugs are discovered
 Hence, there is a lot of current emphasis on
the prevention of this distressing complication

22. BK virus infection: Treatment
 Antiviral agents used empirically for BKVN
include
 Cidofovir
 Leflunomide,
 Quinolone antibiotics, and
 Intravenous immunoglobulin
 True efficacy of these strategies is unclear
because
 No randomized control trials have been done, and
the
 Value of therapy independent of reduction of
immunosuppression has not been specifically
evaluated Transplantation Reviews 2007;21:77–85

23. BK virus infection: Treatment
 Recent review “Treatment of polyomavirus
infection in kidney transplant recipients”
Conclusions
 There does not seem to be a graft survival
benefit of adding cidofovir or leflunomide to
immunosuppression reduction for the
management of PVAN
 However, the evidence base is poor and
highlights the urgent need for adequately
powered randomized trials to define the
optimal treatment of this important condition
Transplantation. 2010 May 15;89(9):1057-70.

24. BK virus infection: Treatment
 Currently,
 Reduction of immunosuppression remains the
most widely accepted approach to treatment
 It is now assumed that
 Screening all transplant patients with serial
PCR analyses of urine or serum, with
 Prompt reduction of immunosuppression when
patients initially display viruria or viremia, will
 Prevent or reduce the risk for developing BKVN
Transplantation Reviews 2010 ;24: 28–31

28. Reduction in immunosuppresion
 The most robust evidence supports
 Switch
 Tacrolimus to CsA (trough level 100–150 ng/mL)
 CsA/MMF to CsA/ steroids or tacrolimus/steroids
 Decrease
 Tacrolimus trough level to less than 6 ng/mL
 MMF dose to less than or equal to 1g/d
 CsA trough level to 100 to 150 ng/mL
 Conversion from MMF to an mTORinhibitor or
from tacrolimus/MMF to sirolimus/steroids is also
an option, but with fewer supportive data.

29. Two approaches
 Timely screening and adjustment in
immunosuppresion
 Identify patients at risk for BK infection and
use an immunosuppressive regimen from the
time of transplant that could be expected to
minimize risk.

30. BK virus infection: Treatment
 It is a medical and an ethical dilemma
 Whether retransplantation should be done
after a patient loses the renal graft to polyoma
nephropathy
 Should immunosuppressive therapy be
altered?
 Is nephroureterectomy of the failed graft
necessary?
 What is the natural course of the disease after
retransplantation?
Transplantation Reviews 2007;21:77–85

31. BK virus infection: Treatment
 Retransplantation after polyomavirus-
associated nephropathy has been reported in 17
cases
 In these cases, recurrence of nephropathy has
occurred in 2 patients and viremia alone in a
third patient.
 For most of these patients, immunosuppression
after retransplantation was the same as for the
first transplantation
 Allograft nephrectomy was performed in 11 of the 15
patients
Transplantation Reviews 2007;21:77–85

32. BK virus infection: Treatment
 Also, all 15 patients had reconstituted their
BKV-specific immune control, as
demonstrated by negative urine cytology
pretransplant
 Authors conclude that
 Retransplantation in patients without active
replication is generally safe
Transplantation Reviews 2007;21:77–85

33. BK virus infection: Treatment
 Authors conclude that..
 Control of viral replication, allowing enough
time to raise sufficient immune response,
which usually requires more than 12 weeks of
reduced immunosuppression, appears to be a
desirable goal before a second transplant is
contemplated.
 In addition, nephroureterectomy is not
necessary when viral replication is absent
before retransplantation.
Transplantation Reviews 2007;21:77–85

34. Conclusions
 BKV infections remain a significant concern in
kidney transplant patients
 Intensive viral monitoring and preemptive
adjustment of immunosuppression have led to
reduction in the incidence of overt viral
nephropathy
 Nonetheless, approximately 30% of patients in
major transplant programs develop viruria and
need to be carefully monitored for the possible
development of this complication

35. Conclusions
 In those patients who do develop BK Virus
induced allograft injury, we do not have reliable
antiviral drugs available at this time
 Although early diagnosis and prompt therapeutic
intervention have reduced rates of overt graft
loss to approximately 15%, surviving grafts
frequently show progressive decline in graft
function

36. Conclusions
 It is likely that long-term low-grade viruria and
viremia promote the development of chronic
allograft nephropathy
 The magnitude of this problem needs to be
clarified by future clinical studies.

37. THANK YOU