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BK virus nephropathy


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BK virus nephropathy

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