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Nephrol Dial Transplant (2006) 21: 3364–3367

doi:10.1093/ndt/gfl404
Advance Access publication 23 September 2006

Current recommendations for diagnosis and management
of polyoma BK virus nephropathy in renal transplant recipients
Katrien Blanckaert and An S. De Vriese
Renal Unit, Department of Internal Medicine, AZ Sint-Jan AV, Brugge, Belgium

Keywords: nephropathy; polyoma BK virus;
transplantation

Polyoma BK virus (BKV) is a ubiquitous DNA virus
from the papova virus family [1]. Approximately
60–90% of the adult population worldwide is seropositive for BKV. Primary infection is usually asymptomatic, but the virus establishes latency within the
genitourinary tract [1–3]. Reactivation may occur in
conditions associated with impaired immunity and is
common in renal transplant recipients (10–68%) [1].
Only 1–10% of patients progress from reactivated
infection to histologically manifest polyoma BKV
nephropathy (BKVN) [1,2,4]. Up to 80% of the
patients with BKVN were reported to lose their graft,
but early reduction of immunosuppression has been
associated with improved prognosis [2,4,5]. We will
discuss the available diagnostic tools to identify BKVN
and the current practices of adjusting the immunosuppressive regimen. In addition, we review the available
evidence supporting the use of cidofovir and leflunomide in established BKVN. Finally, the approach to
acute rejection complicating BKVN, including the use
of immunoglobulins, will be highlighted.

Treatment of BKVN
Reduction of immunosuppression

Diagnostic evaluation
Clinically silent viruria always precedes BKVN, thus
allowing the identification of patients at risk for
BKVN and creating a window of opportunity for
pre-emptive measures [2,4,6,7]. An inexpensive screening tool is the examination of a Papanicolaou-stained
urine sediment for the presence of decoy cells. These
are epithelial cells with enlarged nuclei and large
basophilic ground-glass intranuclear viral inclusions
Correspondence and offprint requests to: An S. De Vriese, Renal
Unit, Department of Internal Medicine, AZ Sint-Jan AV,
Ruddershove, 10, B-8000 Brugge, Belgium.
Email: an.devriese@azbrugge.be

The recent surge in the incidence of BKVN is
commensurate with the widespread use of highly
potent immunosuppressive regimens. Specific drugs
or drug combinations have been associated with
BKVN, in particular tacrolimus and the combined
use of tacrolimus and mycophenolate mofetil (MMF)
[9,10]. In a prospective study, however, no difference
was found in the incidence of viruria and viraemia in
patients treated with tacrolimus vs ciclosporin or
MMF vs azathioprine [2]. In a series of 13 BKVN
patients on various triple immunosuppressant combinations, no specific agent could be identified as the
culprit [3]. These observations support the contention
that the overall immunosuppressive load, rather than
individual immunosuppressive agents, accounts for the

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Introduction

[4,6,7]. Quantification of viruria with a polymerase
chain reaction (PCR) for BKV DNA is more sensitive
than urine cytology, but gives little additional information above repeated urine cytology to justify the extra
effort and expenses [7]. The presence of circulating
virus is associated with active nephropathy, because
virions enter the circulation through peritubular
capillaries following tubular damage. Detection of
BKV DNA in plasma with quantitive PCR has
therefore been proposed as a surrogate marker for
the diagnosis of BKVN [8]. Progression of BKVN is
typically associated with increasing levels of viraemia
[2]. Hirsch et al. [2,6] have suggested that a plasma
viral titre >10000 copies/ml is ‘presumptive’ BKVN,
even in the absence of histological evidence of BKVN.
A definite diagnosis of BKVN requires the demonstration of viral cytopathic changes in tubular epithelium
on a renal biopsy [1,4,7]. Stages A–C have been
defined, with increasing severity and duration of the
involvement and corresponding adverse effects on graft
survival [1]. Standardized staging is a valuable tool to
render future intervention and outcome studies more
comparable.

Nephrol Dial Transplant (2006) 21: Editorial Comments

inability of the host to mount a successful antiviral
immune response.
The cornerstone of treatment of BKVN is a
decrease in maintenance immunosuppression. Various
interventions have been pursued, most commonly
withdrawal of MMF or tacrolimus [2,5,10,11], replacement of tacrolimus by ciclosporin [6,11–13] and overall
reduction of the immunosuppressive load [3,5,10,13].
In a retrospective analysis of 67 patients, graft survival
was similar after reduction vs discontinuation of
tacrolimus or MMF [5]. No specific threshold values
for drug levels or doses have been identified.
Switch to leflunomide

probenecid to reduce renal clearance. Since high
tissue levels are achieved in the kidney and urinary
tract, lower cidofovir doses suffice for the treatment
of BKVN [12,19–23]. Addition of probenecid appears
non-sequitur for this purpose.
Successful treatment of BKVN by cidofovir has been
reported in several cases and case series (Table 1).
Dosage, duration and timing of administration and
selection of patients were variable. Outcome was
almost uniformly favourable, although the impact of
cidofovir could often not be separated from the effect
of reduced immunosuppression. No nephrotoxicity
was reported [12,19–23]. Further studies are needed
to determine the exact position of cidofovir, as a first
line treatment or after the failure of reduced
immunosuppression.

BKVN and acute rejection
The simultaneous occurrence of acute rejection and
BKVN is a frequent clinical problem. The treatment of
acute rejection with pulse steroids has been associated
with an increased risk of BKVN [6]. In addition,
reduction of immunosuppression to treat BKVN
evidently carries a high risk (25–45%) of acute
rejection [13,24]. Patients with acute rejection episodes
prior to BKVN are at risk for acute rejection after
reduction of immunosuppresion to treat BKVN [24].
A brief increase in immunosuppression followed by
a subsequent decrease has been recommended in these
cases [1,4]. The rationale for this approach is that antirejection treatment is expected to stabilize allograft
function within 5–10 days, whereas clearance of
BKVN takes several weeks [1]. In a study by Howell
et al. [10] however, two of three patients with BKVN
and concomitant rejection treated with pulse steroids
followed by decreased maintenance immunosuppression experienced progressive loss of renal function.

Antiviral agents: cidofovir

Intravenous immunoglobulins

Various antiviral drugs have failed to affect the activity
of BKV, including acyclovir, ganciclovir, foscarnet,
vidarabine and ribavirin [1]. Cidofovir is a phosphonate purine analogue of cytosine that potently inhibits
viral DNA polymerases, and has a broadspectrum
activity against herpesviruses, papillomaviruses and
poxviruses [17]. Cidofovir is approved for the treatment of CMV retinitis in patients with AIDS.
Polyomaviruses, however, do not encode a DNA
polymerase. Therefore, any potential antiviral activity
against polyomaviruses must be achieved by alternative mechanisms that are not fully understood.
Cidofovir is active against non-human polyomaviruses
in vitro [17] and human polyoma JC virus in vivo [18].
Cidofovir is primarily eliminated by the kidneys, but
accumulates in tubular cells. At a dose of 5 mg/kg
substantial nephrotoxicity occurs, but this can be
mitigated by the concomitant administration of

The use of immunoglobulins may be a valuable
treatment option in patients with BKVN and coexisting rejection. Immunoglobulins (500 mg/kg BW daily
for seven consecutive days) were equally effective and
much better tolerated than OKT3 in patients with
steroid-resistant rejection [25]. In addition, transfer of
protective immunity can be expected, since the
majority of adults have antibodies against BKV. The
activity of immunoglobulins against BKV has been
confirmed in vitro [26]. A few anecdotal observations
of successful use in patients with BKVN and rejection
have been reported [2,22,24]. More recently, eight
patients with BKVN, but without concomitant rejection were treated with intravenous immunoglobulins
(2 g/kg BW divided over 2–5 days) following reduction
of maintenance immunosuppression, resulting in clearance of viraemia in four patients [27]. Prospective trials

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Leflunomide is an anti-inflammatory drug approved
for the treatment of rheumatoid arthritis. Leflunomide
has considerable immunosuppressive potency in
human renal and liver transplant recipients [14]. Its
active form has substantial antiviral activity against
cytomegalovirus (CMV), herpes and BKV in vitro and
in experimental animals [15]. The rationale for the use
of leflunomide in BKVN rests on these combined
immunosuppressive and antiviral actions. In two large
case series, the same research group reported 26 and
17 patients, respectively, who developed BKVN on
triple therapy with tacrolimus, MMF and steroids
[15,16]. In all patients, MMF was withdrawn and
leflunomide was administered at a loading dose of
100 mg daily for 3–5 days followed by a maintenance
dose of 20–60 mg daily, aiming at through levels of
50–100 mg/ml. Clearance or a progressive reduction in
viral load and a stabilization or improvement of graft
function was achieved in 84 and 88% of patients,
respectively. The patients who deteriorated had
leflunomide plasma levels <40 mg/ml. Further studies
are warranted to compare the effect of reduction
of immunosuppression alone vs reduction of
immunosuppression with association of leflunomide.

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Nephrol Dial Transplant (2006) 21: Editorial Comments

Table 1. Studies using cidofovir in BKVN
Reference na

Modification of
Immunosuppression

Cidofovir

Outcome

[20] n ¼ 1

#CORTb, AZAc ! MMFd,
#TACe, stop MMF

1) Stable renal function
2) Clearance viraemia
3) Control biopsy: NAf

[22] n ¼ 4

#TAC/IVIgg/pulse CORT or
#TAC/MMF/CORT or
¼TAC/MMF/CORT or pulse
CORT/stop MMF/add
rapamycine, then #TAC, stop
rapamycine
#TAC/MMF

0.25 mg/kg,
then 0.42 mg/kg
every 2 weeks,
? doses
0.25–1 mg/kg
every 2–10 weeks,
1–4 doses

[21] n ¼ 2
[23] n ¼ 1

#TAC/SIRh/CORT, then
#TAC/CORT, SIR!MMF

[18] n ¼ 2

#TAC/SIR/CORT, then
!CYCi/MMF/CORT or
#TAC/MMF/CORT

[29] n ¼ 2

SIR/MMF/CORT
! CYC/CORT or
#SIR/CORT

0.25–0.33 mg/kg
monthly or every
2 weeks, 2–6 doses

[12] n ¼ 21j

# Or ¼ or stop MMF,
#TAC or TAC ! CYC or
stop TAC

0.5–1 mg/kg weekly,
4–10 doses

a

1) Stable renal function
2) Clearance viraemia
3) Clearance BKV in biopsy
1) Improved renal function
2)Clearance viraemia
3) Clearance BKV in biopsy
1) Stable renal function
(n ¼ 1), graft loss (n ¼ 1)
2) Clearance viraemia
3) Clearance BKV in biopsy
1) Improved renal function
(n ¼ 1), graft loss (n ¼ 1)
2) Clearance viraemia (n ¼ 1)
3) Control biopsy: NA
1) Stable renal function.
2) Decline viraemia
3) Control biopsy: NA

Patient number; bcorticosteroids; cazathioprine; dmycophenolate mofetil; etacrolimus; fnot available; gintravenous immunoglobulins;
sirolimus; icyclosporin; jof which 8 received cidofovir.

h

are warranted to define the optimal dose and potential
role of immunoglobulins as first line treatment in
BKVN and/or concomitant rejection.

Pre-emptive treatment of BKV replication
In patients with persistent viraemia and negative
biopsy findings, pre-emptive reduction of immunosuppression should be considered. In a prospective study,
reduction of immunosuppression by withdrawal of the
antimetabolite resulted in resolution of viraemia before
the development of BKVN, without a significant risk
for acute rejection [2].

Recommendations
Screening for decoy cells should be performed in all
renal transplant recipients every 3 months during the
first 2 years after transplantation and annually for the
following 3 years, as well as in those patients who
develop allograft dysfunction [4,7]. A positive screening result should be followed by a quantitative PCR for
BKV DNA in plasma. If this test is positive, a renal
biopsy is indicated [4]. Alternatively, it has been
recommended to perform a renal biopsy if there is
persistence of decoy cells over a period of 3 months [7].
Clearance of BKV after a therapeutic intervention

occurred with a t1/2 of 6 h–17 days [28], suggesting that
monitoring viral load every 2–4 weeks is sufficient.
Confirmed BKVN should lead to prompt reduction
of immunosuppression. Only opinion-based recommendations can be forwarded. Hirsch et al. [4] suggested
that during the first year post-transplantation and in
patients at risk for rejection, switching (tacrolimus to
ciclosporin, MMF to azathioprine) or dose reduction is
the preferred strategy. In other patients, reducing triple
to dual therapy (discontinuation of tacrolimus or MMF
or switching to tacrolimus/prednisone) can be
attempted. Switching MMF to leflunomide is an
attractive alternative strategy, pending confirmation by
other research groups. However, widespread off-label
use of leflunomide may be limited by reimbursement
policies. Low-dose cidofovir (0.25–1 mg/kg depending
on renal function, given at 2-week intervals, at least four
times) can be recommended in cases refractory to
modification of maintenance immunosuppression.
Whether cidofovir merits a place in the first-line
treatment of BKVN should be the subject of a
prospective trial.
In patients with BKV viraema and negative biopsy
findings, pre-emptive reduction of immunosuppression
appears sensible. In patients with concurrent acute
rejection, anti-rejection treatment followed by reduction of immunosuppression 2 weeks later should be
considered. In refractory cases, the use of immunoglobulins can be attempted.

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0.25 mg/kg
every 2 weeks,
11–16 doses
0.25 mg/kg
every 2 weeks,
8 doses
0.3 mg/kg every
2 weeks, 7 doses

1) Stable renal function
2) Clearance viraemia
3) Control biopsy: NA

Nephrol Dial Transplant (2006) 21: Editorial Comments

Despite the importance of BKVN in clinical
practice, the optimal schedule and targets of reduction
of immunosuppression as well as the position of
cidofovir, leflunomide and immunoglobulins are unresolved issues. Research efforts under the aegis of
scientific societies will hopefully lead to the availability
of more solid guidelines in the near future.
Conflict of interest statement. None declared.

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