Screening and Treatment Strategies for BK Virus in Kidney Transplant Recipients David Wojciechowski UCSF Kidney Transplant Service Discovery of Human Polyomaviruses *SV40: simian virus introduced to the population through contaminated polio and adenovirus vaccines Risk Factors Dall et al. BK virus nephritis after renal transplantation. Clin J Am Soc Nephrol 2008; 3: S68-S75. Pathogenesis Diminished immune response Uroepithelial injury Ischemia Ureteral stent Rejection Donor BKV* Lysis of tubular cells releases BKV into tubules with bare basement membranes. Virus particles can leak into the interstitium; the virus gains access to capillaries: viremia results. BKV Natural History 78 renal tx recipients prospectively followed 30% 16Wks 13% 23Wks 8% 28Wks Hirsch et al. Prospective study of polyomavirus type BK replication and nephropathy in renal transplant recipients. N Engl J Med 2002; 347: 488:96. Screening: KDIGO Guidelines Treatment of BKV Treatment of BK Viremia Reduction of immunosuppression! Treatment of BK Viremia Prospective study of 200 new renal transplant recipients 23 developed BK viremia Anti-metabolite was stopped If viremia failed to clear after 4 weeks CNI dose was reduced (CSA trough of 100-200 ng/ml; TAC trough of 3-5 ng/ml) Brennan et al. Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. AJT 5: 582-594, 2005. Treatment of BK Viremia 22/23 (95%) cleared viremia by 1 year post-transplant Mean time to clearance was 54 days 1 patient developed acute rejection related to immunosuppression reduction No patients developed BK nephropathy Brennan et al. Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. AJT 5: 582-594, 2005. Treatment of BK Viremia No BK nephropathy identified on cause biopsies No new BK viremia after month-12 Only checked on patients undergoing a cause biopsy Hardinger et al. BK-Virus and the Impact of Pre-Emptive Immunosuppression Reduction: 5-Year Results. AJT 2010; 10: 407-415. BK Nephropathy Treatment First-step: Immunosuppression Reduction Second-step: Active therapy Anti-Viral Agents • Leflunomide • Cidofovir • Fluoroquinolones IVIG Leflunomide Leflunomide Metabolized to A77 1726 Inhibits dihydroorotic acid dehydrogenase (necessary for de novo pyrimidine synthesis) and tyrosine kinases involved in T and B cell signaling cascades MOA against BK unclear May inhibit viral assembly Leflunomide 26 patients with biopsy proven BKVAN (mean time to diagnosis 15.4 months post-transplant) MMF stopped TAC trough target 4-6 ng/ml Prednisone 5-10 mg/day Leflunomide started with a loading dose of 100 mg/day for 5 days Leflunomide maintenance dose: 40 mg/day (target trough 50-100 µg/ml) *Cidofovir could be added at the discretion of the treating physician Josephson et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation 2006; 81: 704-710. In Vitro Data Josephson et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation 2006; 81: 704710. Leflunomide Josephson et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation 2006; 81: 704-710. Leflunomide Repeat biopsies in 16 patients ≥4 weeks after initial biopsy 4 had no evidence of SV40 staining 8 had significantly reduced SV40 staining 2 had persistent or worse staining (neither pt had A77 1726 blood level >35 at time of repeat bx) Follow-up of 6-40 months graft loss 4/26 (15%) Josephson et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation 2006; 81: 704-710. Cidofovir Nucleotide analogue of cytosine active against a wide array of DNA viruses Use limited by renal toxicity (accumulates in RTC causing apoptosis and ARF) Given at 10-20% of that needed for the treatment of CMV (0.25-1 mg/kg) Cidofovir Prospective, non-randomized trial, biopsy proven BKVAN Cidofovir dosed at 1 mg/kg for a maximun duration of 10 weeks Immunosuppression reduction also employed No significant difference in BK viremia between groups 5/41 experienced acute rejection 4/26 (15.4%) cidofovir; 1/15 (6.7%) no cidofovir Kuypers et al. A single-centre study of adjuvant cidofovir therapy for BK virus interstitial nephritis in renal allograft recipients. J Antimicrob Chemother 2009; 63: 417-419. Fluoroquinolones Inhibit bacterial DNA replication by targeting the enzymes gyrase and topoisomerase IV Inhibit helicase activity of SV40 T-antigen in vitro1 Two conflicting studies: 1) 10 day course of gatifloxacin in 10 patients with active BKV replication2 • 70% had reduction in viremia by >80% or disappearance of detectable urinary decoy cells 1Ali 2) No improvement in viral clearance in 4 patients after a 10 day course of ciprofloxacin3 SH et al. Inhibition of Simian virus 40 large T antigen helicase activity by fluoroquinolones. Antivir Ther 2007; 12:1. 2Chandraker A, et al. Use of fluoroquinolones to treat BK infection in renal transplant recipients [Abstract]. AJT 2004; 4:587. 3Thamboo TP et al. Urine cytology screening for polyoma virus infection following renal transplantation: The Oxford experience. J Clin Pathol 2007; 60: 927-930. Fluoroquinolones Gabardi et al. Evaluation of Fluroquinolones for the Prevention of BK Viremia after Renal Transplantation. CJASN 2010. Fluoroquinolones Recipient Age, years (SD) Recipient gender, male, n (%) Recipient race, n (%) Caucasian African American Others ESRD, n (%) Diabetes Hypertension GN PCKD Other Donor Type, n (%) Deceased Living Ureteral stent at time of transplant, n (%) HLA mismatches, mean (SD) PRA, mean (SD) Group 1 (n=106) 53.1 (12.4) Group 2 (n=130) 50.4 (13.8) P-value 0.33 64 (60.4) 81 (62.3) 0.76 Month 3 0.16 38 (35.8) 11 (10.4) 57 (53.8) 39 (30.0) 25 (19.2) 66 (50.8) Viremia Viruria Group 1 Group 2 Estimated Estimated Risk Risk Risk Difference 95% CI P-value 0.161 0.303 0.065 0.146 0.096 0.157 0.007-0.184 0.043-0.271 0.0378 0.0067 0.238 0.361 0.161 0.230 0.077 0.131 -0.039-0.192 0.002-0.261 0.1982 0.0549 0.263 0.395 0.217 0.323 0.046 0.072 -0.082-0.175 -0.069-0.214 0.4782 0.3470 0.297 0.437 0.261 0.389 0.036 0.048 -0.101-0.174 -0.099-0.197 0.6061 0.5363 Month 6 0.14 Viremia Viruria 33 (31.1) 20 (18.9) 18 (17.0) 10 (9.4) 25 (23.6) 34 (26.2) 27 (20.8) 39 (30.0) 10 (7.7) 15 (11.5) 64 (60.4) 42 (39.6) 77 (59.2) 53 (40.8) 10 (9.4) 4.2 (1.7) 13 (10) 3.9 (1.9) 0.89 0.21 10.5 (26) 17.4 (30.7) 0.07 Month 9 0.86 Viremia Viruria Month 12 Viremia Viruria Wojciechowski et al. Ciprofloxacin prophylaxis in kidney transplant recipients reduces BK virus infection at 3 months but not at 1 year. Transplantation 2012 (In Press). Figure 1: Kaplan‐Meier plot of proportion of patients with BK viremia and viruria during the first 12‐months post‐transplantation. P= 0.4058 % Wojciechowski et al. Ciprofloxacin prophylaxis in kidney transplant recipients reduces BK virus infection at 3 months but not at 1 year. Transplantation 2012 (In Press). Treatment: IVIG Contains polyomavirus-reactive antibodies Retrospective study of 8/216 renal transplant recipients who developed biopsy proven BKVAN and BK viremia All underwent reduction of immunosuppression by 50% IVIG given at 2g/kg divided over 2-5 days Sener A, et al. Intravenous immunoglobulin as a treatment for BK virus associated nephropathy: one-year follow-up of renal allograft recipients. Transplantation 2006; 81:117-120. Treatment: IVIG 5/8 patients cleared viremia One graft loss Sener A, et al. Intravenous immunoglobulin as a treatment for BK virus associated nephropathy: one-year follow-up of renal allograft recipients. Transplantation 2006; 81:117-120. Anti-Viral Summary Hilton R and Tong CYW. Antiviral therapy for polyomavirus-associated nephropathy after renal transplantation. Journal of Antimicrobial Chemotherapy 2008; 62: 855-859. Future Directions Sirolimus + Leflunomide In vitro reduced large T antigen expression and BK DNA replication Liacini et al. Anti-BK Virus Mechanisms of Sirolimus and Leflunomide Alone and in Combination: Toward a New Therapy for BK Virus Infection. Transplantation 2010; 90: 1450-1457. Screening/Treatment Summary Thank You! Questions???
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