Transcript Document
BK virus infection post renal
transplant
Dr.
Introduction
We shall discuss today regarding
Polyomavirus infection, replication, and
disease in renal transplant recipients
Polyomavirus infection
Polyomavirus 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
Nefrologia 2010;30(6):613-7
Polyomavirus infection
BK virus
Named after the first patient in which it was
described
Ubiquitous polyomavirus
Acquired in childhood and becomes latent in
uroepithelial cells
Reactivation of BK virus occurs in patients in
immunosuppressed states, including
After transplantation
Transplantation Proceedings 2008; 40: S48–51
Polyomavirus infection
Polyomavirus (BK)–associated
nephropathy (BKVN)
Now recognized as significant problem in
renal transplants that may lead to progressive
allograft dysfunction
First recognized in 1999 in adult renal
transplant recipients
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
Polyomavirus infection
Polyoma virus: Renal transplant recipients
Definitive diagnosis requires histopathological
assessment, notably to exclude acute
rejection
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
Transplantation Reviews
2008;22:241–51
Nefrologia 2010;30(6):613-7
Polyomavirus infection
Screening patients and donors for BKspecific immunoglobulin G antibodies has
the potential for clinical relevancy but is
not currently recommended until more
extensive data are available
Transplantation Reviews 2010 ;24: 28–31
Polyomavirus infection
Patients with 107 viral copies/mL of serum
can be treated as having “presumptive” BK
nephropathy
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
Polyomavirus infection
BK nephropathy
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
Nefrologia 2010;30(6):613-7
Lancet Infect Dis 2003; 3: 611–23
Polyomavirus infection
A variety of factors related to the
Recipient, donor, transplant, or viruses have
been proposed as risk factors for PVAN after
renal transplantation, including
Use of intense immunosuppression
(often, but not exclusively, comprising triple therapy with
tacrolimus-MMF-prednisolone)
Seems likely that both
Potency of immunosuppression and
Agent specific influences may contribute to
the risk of BK reactivation and PVAN
Transplantation Reviews 2008;22:241–51
Polyomavirus infection
Consistent with the role of T cells to
control BK infection,
he use of antithymocyte globulins has been
associated with higher risk
Clin J Am Soc Nephrol 2007;2:1037, Transplantation 2007;84:83,
Nephrol Dial Transplant 2007;22(suppl 8):viii66,
Nefrologia 2010;30(6):613-7
BK viral nephropathy
recommendations for
prevention and early
diagnosis
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
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
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
Transplantation Reviews 2007;21:77–85
evaluated
BK virus infection: Treatment
Recent review “Treatment of polyomavirus
infection in kidney transplant recipients”
data
Pooled results found a death- censored graft
loss rate of
8/100 patient-years for immunosuppression
reduction alone and
8 and 13/100 patient-years for the addition of
cidofovir or leflunomide, respectively
Transplantation. 2010 May 15;89(9):1057-70.
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.
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
BK virus infection: Treatment
Retransplantation after polyomavirusassociated 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
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
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
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
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
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.