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Polyomavirus BK nephropathy
Fabrizio Ginevri
Kidney Transplantation Unit, Department of Nephrology, Istituto G. Gaslini, Genova, Italy
• DNA virus that belongs to the polyomaviridae family: Polyomavirus BK Polyomavirus JC SV40 New: Polyomavirus KI, Polyomavirus WU, Polyomavirus MC
BKV infection: the virus
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
• 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: the virus
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 infection after kidney transplantation
BKV nephropathy after kidney Tx: risk factors
Patient determinants
age>50 yrs male gender diabetesnegative recipient serostatus before Tx
Organ determinants
degree of HLA-matchingprior rejection episodesrenal tissue injury positive donor serostatus before Tx
Viral determinants
genome mutation and rearrangements
Immunesuppression
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
Renal injury
+organ BK loadBKV mutations
PVAN
BKV replication
BKV-mediatedtissue damage
Immunosuppression load:triple vs. double therapy
Binet et al. Transplantation 1999 Hirsch et al. Transplantation 2005
Lack of immune memory:BK seronegativity Ginevri et al. Transplantation 2003 Smith et al. Am J Transplant 2004
+
Failure of immune surveillance
BKV nephropathy after kidney Tx: pathogenesis
Analysis of BKV-specific immunity after KTx: parameters correlated with protection from BK viruria
0
75
150
225
300
N U+/U+P+
SF
U/1
05 c
ells
0
75
150
225
300
SF
U/1
05 c
ells
0
12,5
25
37,5
50
% s
pe
cific
lysi
s
0
12,5
25
37,5
50
% s
pe
cific
lysi
s
IFN- secreting cells cytotoxicity
VP1 VP1
LTLT p<0.005 **p<0.05 *
N U+/U+P+
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- secreting cells
SF
U/1
05 c
ells
LT
0
166
333
500
U+_pre U+_peak U+P+_pre U+P+_peakU
p=0.07
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
Ginevri F, Hirsch HH. BK polyomavirus nephropathy. 2008
• The therapeutic mainstay is reduction of maintenance immunosuppression• Antivirals and other pharmacologic approaches have been variably associated
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.
Treatment of “definitive” BKVN: results
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
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36 48 60MONTHS AFTER TRANSPLANTATION
CU
MU
LAT
IVE
IN
CID
EN
CE
(95
% C
I)
Viruria: 64% (53-78)
Viremia: 22% (13-35)
Viruria: N = 62; E = 39Viremia: N = 62; E = 13
Number of patients at risk: 62 42 36 21 11 0
Ginevri et al. Am J Transplant 2007
• 62 pediatric KTx recipients referred between 01/02 and 08/05:
• 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
• Prospective monitoring of BKV DNA, measured by Q-PCR, in urine and plasma.
• +1, +3, +6, +9, +12, +18, +24, >24 months after KTX
Results: effect of IS reduction on viral load and outcome
Ginevri et al. Am J Transplant 2007
0
266
533
800
Pre-BKviremia
BK viremiaincrease
BK viremiadecrease
Post-BK viremia
clearance
Spo
ts/1
05 ce
lls
VP1 LT
Pre-BKviremia
BK viremiaincrease
BK viremiadecrease
Post-BK viremia
clearance
** ** *
Sero+controls
Sero+controls
Sero+KTx-r
no BKV
Sero+KTx-r
no BKV
Reconstitution dynamics of BKV-specific immunity after preemptive treatment
IFN-secreting cells
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
Comoli P, Hirsch HH, Ginevri F. Curr Opin Organ Transplant 2008
Monitoring of specific immunity in patients with BK viremia Modulation of IS reduction according to cellular immunity analysis
0
100
200
300
400
103
104
105
106
1 2 30.5 4 6 9 12
IFN
- S
FU
/105
V
P1
L
T
Plasm
a BK
V lo
ad
Months post-Tx
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 Kidney Tx Program Genova, Italy
Pediatric Nephrology Istituto G. Gaslini
F Ginevri A Parodi E Verrina
M Cioni G Barbano Department of Transplantation
Ospedale S Martino
I Fontana U Valente
Pediatric Hematology/OncologyFondazione Policlinico S. Matteo, Pavia, Italy
P ComoliS BassoA Gurrado
Department of Public HealthUniversità di Firenze, Italy
A Azzi
Department of Transplantation VirologyUniversity of Basel, Switzerland
H H Hirsch
Pediatric Kidney Disease Fund Genova, ItalyR Gusmano
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