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Polyomavirus BK nephropathy Fabrizio Ginevri Kidney Transplantation Unit, Department of Nephrology, Istituto G. Gaslini, Genova, Italy

BK virus nephropathy

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Page 1: BK virus nephropathy

Polyomavirus BK nephropathy

Fabrizio Ginevri

Kidney Transplantation Unit, Department of Nephrology, Istituto G. Gaslini, Genova, Italy

Page 2: BK virus nephropathy

• 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

Page 3: BK virus nephropathy

• 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

Page 4: BK virus nephropathy

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

Page 5: BK virus nephropathy

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

Page 6: BK virus nephropathy

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

Page 7: BK virus nephropathy

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

Page 8: BK virus nephropathy

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

Page 9: BK virus nephropathy

Approach to screening for BKVN diagnosis

Ginevri F, Hirsch HH. BK polyomavirus nephropathy. 2008

Page 10: BK virus nephropathy

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

Page 11: BK virus nephropathy

Screening for BKVN and therapeutic intervention

Ginevri F, Hirsch HH. BK polyomavirus nephropathy. 2008

Page 12: BK virus nephropathy

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

Page 13: BK virus nephropathy

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

Page 14: BK virus nephropathy

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

Page 15: BK virus nephropathy

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

Page 16: BK virus nephropathy

Results: effect of IS reduction on viral load and outcome

Ginevri et al. Am J Transplant 2007

Page 17: BK virus nephropathy

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

Page 18: BK virus nephropathy

Reconstitution dynamics of BKV-specific T cells and serology in a patient with BKVN

Comoli, Ginevri, Hirsch. Transplant Infect Dis 2006

Page 19: BK virus nephropathy

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

Page 20: BK virus nephropathy

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

Page 21: BK virus nephropathy

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

Page 22: BK virus nephropathy

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