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Polyomavirus BK nephropathy
Fabrizio Ginevri
Kidney Transplantation Unit, Department of Nephrology,
Istituto G. Gaslini, Genova, Italy
BKV infection: the virus
• DNA virus that belongs to the polyomaviridae family:




Polyomavirus BK
Polyomavirus JC
SV40
New: Polyomavirus KI, Polyomavirus WU, Polyomavirus MC
Structure:
The BKV genome comprises three
regions:
1. the NCCR
2. the structural region coding for
early T proteins
3. the late structural region encoding
the viral capsid proteins (VP1-3) and
agnoprotein
BKV infection: the virus
• Infects up to 90% of the general population
• Transmitted via aerosol, urinary shedding, allograft
• After primary infection, renal tubular epithelial cells
and the urothelial cell layer represent the principal
sites of viral latency or replication
• BKV disease is rare, and almost invariably
associated with an immunodeficiency status
BKV infection after kidney transplantation
Reactivation/primary infection in KTx recipients:
• asymptomatic infection
• ureteral stenosis
• systemic vasculopathy
• interstitial nephropathy (BKVN):
 increased prevalence of BKVN in the last decade
(from 1% in 1995 to 5-10% in 2001)
 the majority of cases occur within the 1st year after
Tx, but at least 25% of cases are diagnosed later
 10-80% graft loss: but, with increased awareness
and improved diagnostic techniques, the rate of graft
loss has lowered
BKV nephropathy after kidney Tx: risk factors
Patient
determinants
age>50 yrs
male gender
diabetes
negative recipient serostatus before Tx
Organ
determinants
degree of HLA-matching
prior rejection episodes
renal tissue injury
positive donor serostatus before Tx
Viral
determinants
genome mutation and rearrangements
Immune
suppression
major risk factor for BKVN: it is plausible that a
state of “over-immunosuppression”, rather than
a specific agent is responsible for an increased
risk of BKVN development
BKV nephropathy after kidney Tx: pathogenesis
Renal injury
Binet et al. Transplantation 1999
Hirsch et al. Transplantation 2005
+
organ BK load
BKV mutations
 BKV
replication
BKV-mediated
tissue damage
Immunosuppression load:
triple vs. double therapy
+
Lack of immune memory:
BK seronegativity
Ginevri et al. Transplantation 2003
Smith et al. Am J Transplant 2004
PVAN
Failure of immune surveillance
Analysis of BKV-specific immunity after KTx:
parameters correlated with protection from BK viruria
IFN-g secreting cells
cytotoxicity
50
300
VP1
% specific lysis
SFU/105 cells
VP1
225
150
75
25
12,5
0
0
N
U+/U+P+
N
50
300
p<0.05 *
% specific lysis
LT
SFU/105 cells
37,5
225
150
75
LT
U+/U+P+
p<0.005 **
37,5
25
12,5
0
0
N
U+/U+P+
N
U+/U+P+
Ginevri F, Comoli P, et al. manuscript in preparation
Analysis of BKV-specific immunity after KTx:
parameters correlated with protection from BK viremia
IFN-g secreting cells
500
LT
p=0.07
SFU/105 cells
333
166
0
U+_pre
U+_peak
U+P+_pre
U+P+_peakU
Ginevri F, Comoli P, et al. manuscript in preparation
Approach to screening for BKVN diagnosis
Ginevri F, Hirsch HH. BK polyomavirus nephropathy. 2008
BKV nephropathy after KTx: diagnosis
• BKVN has a focal presentation
• as a consequence, negative biopsy results cannot rule out BKVN
with certainty
Histological patterns
A
Viral cytopathic changes only, in near-normal renal parenchyma.
B
Combination of viral cytopathic changes and
focal/multifocal areas of tubular atrophy/interstitial fibrosis/
inflammation
C
Very scarce viral cytopathic changes in diffusely scarred renal tissue.
Extensive tubular atrophy/interstitial fibrosis /inflammation involving
all the tissue core with no residual areas of non atrophic tubules.
Drachenberg et al. Hum Path 2005; 36:1245
Screening for BKVN and therapeutic intervention
Ginevri F, Hirsch HH. BK polyomavirus nephropathy. 2008
Treatment of “definitive” BKVN
•
•
The therapeutic mainstay is reduction of maintenance immunosuppression
Antivirals and other pharmacologic approaches have been variably associated
Ginevri F, Hirsch HH. BK polyomavirus nephropathy. 2008
Treatment of “definitive” BKVN: results
Early diagnosis has allowed a significant amelioration of prognosis
• graft outcome:


no screening: 35-50% of BKVN treated with any protocol  marked graft
dysfunction, with possible progression to graft loss;
screening and early treatment: no graft loss, milder graft dysfunction.
Ginevri F, Hirsch HH. BK polyomavirus nephropathy. 2008
Preemptive treatment of BKVN
On the basis of plasma BKV-DNA analysis
• DNA threshold for treatment: >104 ge/ml
• graft outcome: viremia clearance, no BKVN, no acute rejection
Ginevri F, Hirsch HH. BK polyomavirus nephropathy. 2008
BKVN prospective monitoring and preemptive treatment
after pediatric KTx
• 62
• Group 1: BKV-sero+ patients,
•
•
that did not reactivate after Tx
Group 2: patients with positive
viruria after Tx
Group 3: patients with positive
viruria and viremia after Tx
CUMULATIVE INCIDENCE (95% CI)
pediatric KTx recipients
referred between 01/02 and
08/05:
1.0
Viruria:
Viremia:
0.8
N = 62;
N = 62;
E = 39
E = 13
0.6
Viruria: 64% (53-78)
0.4
0.2
Viremia: 22% (13-35)
0.0
• Prospective monitoring of BKV
0
12
24
36
48
60
MONTHS AFTER TRANSPLANTATION
Number of patients at risk:
62
42
36
21
11
DNA, measured by Q-PCR, in
urine and plasma.
• +1, +3, +6, +9, +12, +18, +24,
>24 months after KTX
Ginevri et al. Am J Transplant 2007
0
Results: effect of IS reduction on viral load and outcome
Ginevri et al. Am J Transplant 2007
Reconstitution dynamics of BKV-specific immunity after
preemptive treatment
IFNg-secreting cells
**
800
*
*
Spots/105 cells
VP1
*
LT
533
266
0
Sero+
controls
Sero+
KTx-r
no BKV
Pre-BK
viremia
BK viremia BK viremia Post-BK
increase decrease viremia
clearance
Sero+
controls
Sero+ Pre-BK
KTx-r
viremia
no BKV
BK viremia BK viremia Post-BK
increase decrease viremia
clearance
Ginevri et al. Am J Transplant 2007
Reconstitution dynamics of BKV-specific T cells and
serology in a patient with BKVN
Comoli, Ginevri, Hirsch. Transplant Infect Dis 2006
Monitoring of specific immunity in patients with BK viremia
Modulation of IS reduction according to cellular immunity analysis
LT
 VP1 
IFN-g SFU/105
106
300
105
200
104
100
103
Plasma BKV load
400
0
0.5
1
2
3
4
6
9
12
Months post-Tx
Comoli P, Hirsch HH, Ginevri F. Curr Opin Organ Transplant 2008
BKVN after KTx: conclusions and open issues
• Outcome of BKVN
 when BKVN is advanced (stages B2-3 and C), outcome is still suboptimal
 early treatment (stages A and B1) yields better results in terms of graft outcome
 preemptive treatment on the basis of BK viremia seems at present the best
option, but screening protocol has to be defined
• Long term outcome of allografts after BKV infection
 data on long-term allograft outcome after successful treatment for BKVN are
scarce. However, preliminary results suggest that BKVN is a risk factor for
progressive chronic allograft dysfunction
 direct virus damage ?
 suboptimal IS ?
 In case of prevalent direct damage, preemptive treatment may allow to reduce
considerably the risk of progressive allograft failure
 In the second instance, tailoring of preemptive treatment on the basis of viremia
and specific immune reconstitution may avoid excess IS reduction, and thus
suboptimal IS
Pediatric Hematology/Oncology
Fondazione Policlinico S. Matteo,
Pavia, Italy
Pediatric Kidney Tx Program
Genova, Italy
 Pediatric Nephrology
P Comoli
S Basso
A Gurrado
Istituto G. Gaslini
F Ginevri
A Parodi
M Cioni
E Verrina
G Barbano
Department of Public Health
Università di Firenze, Italy
A Azzi
 Department of Transplantation
Ospedale S Martino
I Fontana
U Valente
Pediatric Kidney Disease Fund
Genova, Italy
R Gusmano
Department of Transplantation
Virology
University of Basel, Switzerland
H H Hirsch
Retransplantation
•
Retransplantation is a feasible option after graft loss to
PAN : PAN recurrence in 2/13 reported patients (15%)
 In the absence of active BKV infection
 Nephrectomy of the original graft may not be necessary
 Baseline IS: does not need to be specifically adjusted
In case of failure to reduce viral load or when IS reduction is
contraindicated, the administration of antiviral drugs (e.g. cidofovir)
and/or the surgical removal of the alloureter and kidney could be
considered
•
Post-transplant follow-up management
 Monitor: urine/plasma viral load
general/specific immunity
 Therapeutic intervention guided by plasma DNA levels