1 / 72

NOVARTIS Symposium

NOVARTIS Symposium. Managing long-term outcomes in renal transplantation. BKV – BKPvVAN: a secret agent responsible for graft loss. Mihai Voiculescu Center of Internal medicine – Nephrology Fundeni Institute. Demand for re- transplants is rising globally. Prevalence of ESRD in USA 1.

bethany-king
Download Presentation

NOVARTIS Symposium

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. NOVARTIS Symposium Managing long-term outcomes in renal transplantation

  2. BKV – BKPvVAN: a secret agent responsible for graft loss Mihai Voiculescu Center of Internal medicine – Nephrology Fundeni Institute

  3. Demand for re-transplants is rising globally Prevalence of ESRD in USA 1 2005 JASN paper: 712, 290 (2015) New projection: 774, 386 (2020) Actual: 527, 282 (2007) 800 • kidney transplant waiting list numbers in Europe have increased from 2,135 in 1981 to 11,010 in 2009 2 • - In the UK, the number of kidney re-transplants rose from 2,067 in 2006 to 2,486 in 2008 3 600 No of patients (1000s) 400 200 0 2008 1984 1988 1992 1996 2000 2004 2012 2016 2020 1980 Year of transplant Number of patients requiring re-transplant is likely to increase Tedesco – Silva Jr H et al Am J Transplant 2010; 42: 1659-66

  4. kidney heart liver Transplanted organs fail over time while the number of patients grows 70000 kidney liver 100 60000 90 50000 40000 80 30000 70 20000 60 10000 50 0 0 1 1992 1995 2 3 4 6 1998 2001 2004 5 Years post Txpl Year The average time on waiting list for a kidney recipient in the US is 963 days. In 2004 more than 3000 people on the waiting list died before they could receive a kidney transplant UNOS - 2005

  5. Cause of graft loss in the 1st year over time 4 quadrants 100 • radiation • prednisone 90 Death with functioning graft 80 Surgical thrombotic • CsA-ME 70 • CsA • tacrolimus 60 • MMF Graft outcome (%) 50 • induction agents 40 • azathioprine Rejection BK-PyVAN • sirolimus 30 20 • everolimus 10 BK-PyVAN ≤10%5 0 1970 1965 1960 1975 1980 1985 1990 1995 2000 2005 2010 Year

  6. Cause of graft loss in the 1st year over time 4 quadrants 100 • radiation • prednisone 90 Death with functioning graft 80 Surgical thrombotic • CsA-ME 70 • CsA • tacrolimus 60 • MMF Graft outcome (%) 50 • induction agents 40 • azathioprine Rejection BK-PyVAN • sirolimus 30 20 • everolimus 10 BK-PyVAN ≤10%5 0 1965 1960 1970 1975 1980 1985 1990 1995 2000 2005 2010 Year

  7. BK-PyVAN is associated with reduced graft survival Retrospective analysis from University of Maryland renal transplant program of 1971 renal transplant patients 1997-2002 100 - BK-PyVAN was significantly associated with reduced graft survival (p<0.0001) - incidence of BK-PyVAN: 5.3% No BK-PyVAN 80 60 Cumulative graft survival (%) 40 BK-PyVAN 20 0 0 10 20 30 40 50 60 70 Follow-up (months) BK-PyVAN, BK polyoma virus-associated nephropathy Ramos E et al Clin Transpl 2002; 143-53

  8. Causes of late kidney allograft loss Causes of late allograft last (>1 yr after transplantation) Chronic renal allograft dysfunction leading to graft failure in 50% of cases Death of a patient with a functioning graft in 50% of cases Chronic allograft nephropathy in 30-40% of cases Other diagnosis in 10-20 % of cases True chronic rejection immunologic injury IF/TA of mixed origin Chronic toxic effects of calcineurin inhibitors Recurrent diseases New diseases Pascual M et al N Engl J Med 2002;346:580-590

  9. Causes of late kidney allograft loss Causes of late allograft last (>1 yr after transplantation) Chronic renal allograft dysfunction leading to graft failure in 50% of cases Death of a patient with a functioning graft in 50% of cases Chronic allograft nephropathy in 30-40% of cases Other diagnosis in 10-20 % of cases True chronic rejection Immunologic injury IF/TA of mixed origin Chronic toxic effects of calcineurin inhibitors Recurrent diseases New diseases BKW nephropathy Chronic AMR Pascual M et al N Engl J Med 2002;346:580-590

  10. Etiologic classification of losses of functioning - subgroup of grafts lost due fibrosis/atrophy -

  11. Contents - background to BKV - risk factors for BKV replication and BK-PyVAN - importance of early detection of BKV replication and BK-PyVAN - interventions for BKV replication and BK-PyVAN BKV, BK virus; BK-PyVAN, BK polyoma virus-associated nephropthy

  12. Contents - background to BKV - risk factors for BKV replication and BK-PyVAN - importance of early detection of BKV replication and BK-PyVAN - interventions for BKV replication and BK-PyVAN BKV, BK virus; BK-PyVAN, BK polyoma virus-associated nephropthy

  13. Contents (1) - background to BKV - risk factors for BKV replication and BK-PyVAN - importance of early detection of BKV replication and BK-PyVAN - interventions for BKV replication and BK-PyVAN BKV, BK virus; BK-PyVAN, BK polyoma virus-associated nephropthy

  14. BKV = ”BK” Virusmmmmmmmmm

  15. BKPvVAN = BK Polyoma virus associated nephropathy

  16. What is BKV? - BKV - DNA viruses; member of the polyoma virus family - detected in 1971 from the urine of a renal transplant patient, initials BK

  17. What is BKV? - BKV - DNA viruses; member of the polyoma virus family - detected in 1971 from the urine of a renal transplant patient, initials BK b - highly prevalent - 80-90 % of the population is infected

  18. What is BKV? - BKV - DNA viruses; member of the polyoma virus family - detected in 1971 from the urine of a renal transplant patient, initials BK - 75% homology with JC virus and 70% with SV403 - highly prevalent - 80-90 % of the population is infected - primary infection: subclinical or unspecific - target tissues: renal tubules, uroepithelium

  19. What is BKV? - BKV - DNA viruses; member of the polyoma virus family - detected in 1971 from the urine of a renal transplant patient, initials BK - 75% homology with JC virus and 70% with SV403 - highly prevalent - 80-90 % of the population is infected - primary infection: subclinical or unspecific - target tissues: renal tubules, uroepithelium3 - latent infection - mainly in the kidney and urogenital tract - can spontaneously reactivate

  20. BKV replication is common in the renal transplant population BK-PyVAN 1-10% 1,2 BK-PyVAN a,3 BK viraemia ~ 10-20% 2 Infected tubular epithelial cells b,3 BK viruria 30-50% 2 BK Seropositive 80-90% 2,3 decoy cells in urine c,3 a anti-large T-antigen staining with mouse monoclonal antibody with 3-amino-9-ethylcarbazole as chromogen and haemotoxylin as counter stain; BKV, BK virus; BK-PyVAN, BK polyoma virus-associated nephropathy 1. Egli A et al J Infect Dis 2009; 199: 837-46 2. Hirsch HH et al N Engl J Med 2009 3. Nickeleit V et al N Engl J Med 2000 342; 1309-15

  21. Contents (2) - background to BKV - risk factors for BKV replication and BK-PyVAN - importance of early detection of BKV replication and BK-PyVAN - interventions for BKV replication and BK-PyVAN BKV, BK virus; BK-PyVAN, BK polyoma virus-associated nephropthy

  22. What are the risk factors for BKV replication? 1. Schold JD et al Transpl Int 2009; 22: 626-34 2. Dharnidharka VR et al Transplantation 2009; 87: 1019-26 3. Hirsch HH et al N Engl J M 2009; 86-96 4. Bohl DL, Brennan DC. Clin J Am Soc Nephrol 2007; 2(Suppl 1): S36-46 5. Brennan DC et al Am J Translant 2005; 5:582-94 CsA, cyclosporine; HLA, human leucocyte antigen MMF; mycophenolate mofetil; BK-PyVAN, BK polyoma virus-associated nephropathy

  23. What are the risk factors for BKV replication? 1. Schold JD et al Transpl Int 2009; 22: 626-34 2. Dharnidharka VR et al Transplantation 2009; 87: 1019-26 3. Hirsch HH et al N Engl J M 2009; 86-96 4. Bohl DL, Brennan DC. Clin J Am Soc Nephrol 2007; 2(Suppl 1): S36-46 5. Brennan DC et al Am J Translant 2005; 5:582-94 CsA, cyclosporine; HLA, human leucocyte antigen MMF; mycophenolate mofetil; BK-PyVAN, BK polyoma virus-associated nephropathy

  24. Intragraft inflammation supports BKVAN Acott P BKV speaker meeting

  25. Immunosuppression is the main risk factor for BKV reactivation 100 Radiation Prednisone 6MP 90 80 CYA ME CYA FK506 70 OKT3 MMF ATG/ALG 60 Percentage (%) DACLIZUMAB BASILOGMAB 50 Azathioprine At Gam THYMOGLOBIN SIROLIMUS 40 FTY720 30 CAMPATH IH EVEROLIMUS 20 BILATACEPT Rejection < 12 month EFALIZUMAB BKV 10 1 year allograft survival 0 1960 1980 1965 1970 1985 1990 1975 2000 2005 1995 2010 Acott P BKV speaker meeting

  26. Tacrolimus-based regimen is a risk factor for BKV treatment Retrospective analysis of scientific registry of transplant recipients data from 34,937 kidney transplant recipients 2004-2006 a As compared to CsA modified as baseline immunosuppression BKV, BK virus; HLA human leukocyte antigen; CsA, cyclosporin 1. Schold JD et al Transpl Int 2009; 22: 626-34

  27. KDIGO guidelines also outline switching to a different immunosuppressive regimen B, moderate evidence to support a recommendation for use; B-III, evidence from opinions of respected authorities based on clinical experience, descriptive studies or reports of expert committee C, poor evidence to support a recommendation; III, evidence from options of respected authorities based on clinical experience, descriptive studies or reports of expert committee KDIGO, kidney disease, improving global outcomes; MMF, mycophenolate mofetil; CsA cyclosporin Transplantation 2005; 79: 1277-86 KDIGO Transplant Work Group Am J Transplant 2009; 9(suppl 3): S44-68

  28. Contents (3) - background to BKV - risk factors for BKV replication and BK-PyVAN - importance of early detection of BKV replication and BK-PyVAN - interventions for BKV replication and BK-PyVAN BKV, BK virus; BK-PyVAN, BK polyoma virus-associated nephropthy

  29. Early screening reduces risk of BK-PyVAN - BKV replication is the single common feature of all renal transplant patients at risk of BK-PyVAN 1 - guidelines recommend screening for BKV replication to identify patients at risk of BK-PyVAN 2,3 - by screening, at least 80-90% of patients at risk of BK-PyVAN can be identified prior to significant histological and functional impairment 2 1. Hirsch HH et al Transplantation 2005; 79: 1277-86

  30. Screening option for BKV • Viruria • allows early • identification of patients • at risk of active BKV • infections 1,2 • cytology is relatively • inexpensive 1 • Viraemia • identification of • Patients at risk for • BKV-PyVAN1-3 • serial quantitative PCR • analysis of blood can • be used to follow • response to treatment 2 • Biopsy • ‘Gold standard” for • diagnosis of BKV • replication and • BK-PyVAN 1-2 Pros PCR can produce false positives 1 • invasive procedure • can produce false • negatives; may miss • focal lesions 1,2 • diagnosis of acute • rejection in the presence • of BK-PyVAN may be • difficult 1,2 Not specific for nephropathy 1,3 Cons BKV, BK virus; PCR, polymerase chain reaction BK-PyVAN, BK polyoma virus-associated nephropthy 1. Hirsch HH et al Transplantation 2005; 79: 1277-86 2. Hirsch HH et al Am J Transplant 2009; 9(Suppl 4): S136-46 3. KDIGO Transplant Work Group Am J Transplant 2009; 9(Suppl 3): S44-58

  31. Possible interventions following BK viraemia and / or BK-PyVAN Switching immunosuppressive regimen Adjunctive therapies Immunosuppression reduction Hirsch HH et al Am J Transplant 2009; 9(Suppl 4): S136-46 KDIGO Transplant Work Group

  32. Early reduction in immunosuppression is associated with resolution of BKV replication and BK-PyVAN prevention BKV, BK virus; BK-PyVAN, BK polyoma virus-associated nephropthy

  33. Reducing immunosuppression in line with KDIGO and AST guidelines B, moderate evidence to support a recommendation for use; B-III, evidence from opinions of respected authorities based on clinical experience, descriptive studies or reports of expert committee KDIGO, kidney disease, improving global outcomes; AST, American Society of Transplant Surgeons; MMF, mycophenolate mofetil; CsA cyclosporin

  34. BKV / polyoma-related AEs with reduced CsA + mTORi vs CsA + MPA A2309: multicentre, randomised trial of 833 de novo renal transplant patients randomised to everolimus + reduced CsA or MPA + standard CsA with basiliximab ± steroids 10 Polyoma virus and/or BKV 8 5.1 6 Incidence at 12 months (%) collected by AE reporting 4 2.5 2 1.1 0 Everolimus 1.5 mg + low CsA Everolimus 3.0 mg + low CsA EC-MPS+ standard CsA BPAR, % 16.2 13.3 17.0 Lowest incidence of BKV / polyoma viral infection seen with low CsA and everolimus CsA through levels (CO), 100-200 ng/mL starting from day 5; 75-150 ng/mL starting from Month 2, 50-100 ng/mL starting from month 4; 25-50 ng/mL starting from month 6 CsA, cyclosporine; ME, microemulsion, MMF; mycophenolate mofetil; BK-PyVAN, BK virus, AE, adverse event Tedesco-Silva Jr H et al Am J Transplant 2010; 10: 1401-13

  35. DIRECT study: lower incidence of BKV replication with CsA vs tacrolimus DIRECT: randomised, open-label study of 682 de novo renal transplant patients randomised to CsA or tacrolimus with MPA, steroids and basiliximab induction BK viraemia BK viruria p=0.0053 p=0.0739 25 25 23 20 20 17 15 15 12 cGFR (mL/min) 10 10 5 5 5 0 0 Tacrolimus (n=256) CsA (n-231) Tacrolimus (n=247) CsA (n-215) BK, BK virus; CsA, cyclosporine, MPA, mycophenolic acid Hirsch HH et al Am J Transplant 2009; 9(suppl2): 337; abs 505

  36. Switching to a different immunosuppressive regimen can prevent graft failure due to BK-PyVAN in kidney transplant patients - retrospective / prospectivea study in 21 renal transplant patients with sustained BK viraemia treated by modification of immunosuppressive regimen - switch from tacrolimus to CsA +/- switch from MMF to AZA - complete therapeutic response b in 10 patients within 4-10 weeks - 11 patients also received low-dose cidofovir - IVIG or leflunomide (n=2) - BK viraemia clearance within 14-48 weeks (n=11) - all 21 patients successfully cleared BKV with this switch strategy a retrospective in 14 patients, prospective in 7 patients b Complete therapeutic response measured by normalisation of BKV load and stabilisation of graft function BK-PyVAN, BK polyoma virus-associated nephropathy; CsA cyclosporin; MMF, mycophenolate mofetil; AZA azathioprine; IVIG, intravenous immunoglobulin, BKV, BK virus Babel N et al Abstract 1889 presented at TTS 2010

  37. In vitro studies show CsA, but not tacrolimus, inhibits primary BKV infection and escape to high-level infection 1.E+10 CsA No CsA 1.E+09 No CsA 1.E+08 1.E+07 1.E+06 *p<0.05 Copies of BKV DNA 1.E+05 1.E+04 1.E+03 CsA 1.E+02 1.E+01 1.E+00 20 0 30 40 50 60 70 80 90 100 Time (days)

  38. In vitro studies show CsA, but not tacrolimus, inhibits primary BKV infection and escape to high-level infection Probability of high BKV replicative stable by 4 weeks culture (>104 BKV DNA copies/mL in supernatant on > 2 consecutive weeks) CsA-treated Verro cells + VJ isolate 8/65 (12%) X2=16.68 p<0.001 CsA (200-3200 ng/mL) Vero cells + VJ isolate 43/102 (42%) Tacrolimus-treated Verro cells + VJ isolate 26/57 (45%) Tacrolimus (4-256 ng/mL) X2=0.18 ns BKV, BK virus; CsA cyclosporin; ns, not significant Acott PD et al Abstract 3070 presented at TTS 2010

  39. Adjunct antiviral therapy is used despite limited data

  40. BK-PyVAN impacts on long-term graft survival Incidence of concomitant viral infections such as BKV increases with sustained or intensive immunosuppression1

  41. BK-PyVAN impacts on long-term graft survival Incidence of concomitant viral infections such as BKV increases with sustained or intensive immunosuppression1 BK-PyVAN is common in the renal transplant population, occurring in 1-10% of patients2-4

  42. BK-PyVAN impacts on long-term graft survival Incidence of concomitant viral infections such as BKV increases with sustained or intensive immunosuppression1 BK-PyVAN is common in the renal transplant population, occurring in 1-10% of patients2-4 BK-PyVAN leads to graft loss in ~ 50% of cases3

  43. BK-PyVAN impacts on long-term graft survival Incidence of concomitant viral infections such as BKV increases with sustained or intensive immunosuppression1 BK-PyVAN is common in the renal transplant population, occurring in 1-10% of patients2-4 BK-PyVAN leads to graft loss in ~ 50% of cases3 Specific individualised immunosuppressive regimens are of increasing importance to avoid the impact of Infections such as BKV5

  44. Conclusions - BKV replication is a major factor leading to graft loss1 - early detection of BKV replication can reduce graft loss2 - routine screening and adjustment of immunosuppressive regimen may help improve early management of BKV replication and optimise graft outcomes3,4 - reduction of immunosuppressant burden is a hallmark of intervention strategy; options include - anti-metabolite5 vs CNI reduction6? - conversion from tacrolimus to CsA3 - reduced-dose CsA with mTORi7 1. Ramos E et al Clin Transpl 2002; 143-53 2. Hirsch HH et al N Engl J Med 2002; 347: 488-96 3. Hirsch HH, Randhawa P Am J transplant 2009; 9(Suppl 4): S136-46 4. KDIGO Transplant Work Group. Am J Transplant 2009; 9(Suppl 3) S44-58 5. Brennan DC et al Am J Transplant 2005; 5:582-94 6. Ginevri F et al Am J Transplant 2007; 7: 2727-35 7. Tedesco-Silva Jr H et al

  45. Unmet needs exist for specific patient subgroups - significant challenges remain in kidney transplantation, posing problems both now and in the future - guidelines have an important role in providing up-to-date evidence-based guidance for physicians - patients subgroups of particular interest are - those with previous MACE, who are at high risk of CV events - those who develop CAN / IFTA - those who receive screening revealing BKV viraemia

  46. Integration of six data types for Prion disease studies in mice (1) - deep brain transcriptome analyses at 10 time points across disease onset in 8 mouse strains - correlate with protein interaction data from known (histopathology) disease-perturbed networks - correlation with dynamical histopathological studies

  47. Integration of six data types for Prion disease studies in mice (2) - correlation with clinical signs - distribution of infectious prion protein in the brains across disease progression - brain-specific blood protein concentration changes

  48. Chr rejection or “chronic allograft nephropathy” If specific causes of graft loss are excluded, alloimmunity remains the most common mechanism leading to graft failure Donor disease – older donors Acute peritransplant injuries Acute rejection Hypertension Recurrent rejection CR/CAN e.g. creatinine: 2.0-4.0 mg/dL urinary protein: 1-3g/day Hyperlipidaemia Non-compliance Alloimmunity glomerular disease Chronic CNI toxicity Pascual M, et al N Engl.J.Med 2002:346;589-90 Nakivell BJ, et al N.Engl J Med 2003:349;2520-33 Wong W, et al. Transplantation 2005: 80;289-96 El-Zoghby et al., Am J Transpl 2009:9; 527-535

  49. What are the specific clinical symptoms of BKVAN? • no any (accidental finding in protocol biopsies) • serum creatinine rise like in acute rejection • histology similar to acute rejection (infiltrates etc) • no response to antirejection therapy Acute rejection and BKVAN similar picture but completely different therapeutic strategies

  50. How to treat BKV associated nephropathy? Analysis of 52898 renal transplants (UNOS) 50951 controls + 2061 treated due to BKV

More Related