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.