5/30/2013 Management of Polyomavirus (BK Virus) Infection in Kidney Transplant Patients GDCN Meeting March 10, 2013 • Using modern surveillance protocols most diagnoses in first year • Diagnoses after 2 years uncommon • Rates of graft loss have improved considerably Diagnosis of BKVAN (Single Center Studies) < 1 year 1‐2 years > 2 years Hirsch. Transplantation 79:1277,2005 Pang. J. Clin Microbiol 45: 3568, 2007 Viscout. Transplantation 84:340, 2007 Babel. Transplantation 88:89, 2009 Singh. H. J Am Soc Neph 20:210, 2009 1 5/30/2013 PVN absent: Reduce IS Kidney Biopsy and EM Urinary Screen for Haufen Early Biopsy Directed Approach Viremia Detected Any Level Viremia Negative Biopsy Transplant Biopsy Urine EM for Haufen Viremia Viremia Viremia BKVAN Haufen BK Nephropathy No Rejection No Biopsy (Technical) Rejection 2 5/30/2013 Immunosuppression Reduction: The Cornerstone of Therapy Antimetablolites Calcineurin Inhibitors Corticosteroids • Reduce dose • Discontinuation • Replace with leflunomide • Reduce dose (Tacrolimus level 4‐6 ng/ml) • Discontinuation • Initiate in steroid free patients • Taper in steroid treated patients Antiviral Options Treatment of BK Virus Infection Leflunomide Cidofovir IVIG Fluoroquinolones • Anti‐inflammatory properties, inhibits BKV replication • Drug level dependent • Hepatotoxicity • Thrombocytopenia, hemolytic anemia (TMA), leukopenia • In vitro activity against BKV • Nephrotoxic • Anti‐BKV neutralizing antibodies • Immunomodulatory effect may be advantageous • Serum sickness, fluid overload, expensive • In vitro activity • Prophylaxis studies only • Long term therapy = tendon rupture, AIN risk 3 5/30/2013 Johnston et al, Transplantation 89:1057‐1070, 2010 Johnston et al, Transplantation 89:1057‐1070, 2010 4 5/30/2013 Cumulative Results for Treatment of BK Virus Infection (State of the Literature) • Graft survival – highly variable • Rejection – highly variable, rates up to 30% • Clearance of Viremia – 90% of cases, median 8 months • Ureteric involvement, obstruction rare • Hemorrhagic cystitis, uncommon except in stem cell transplants • Drug toxicities ‐ variable Johnston et al, Transplantation 89:1057‐1070, 2010 Biopsy Directed Therapy (UNC Approach) Viremia Only No BKVAN No Rejection Viremia Viremia BKVAN Haufen (no Biopsy) Viremia Rejection BKVAN Pulse Solumedrol Reduce MMF/MPS 50% Stop MMF/MPS Tacrolimus Level Target 4‐6 ng/ml Tacrolimus Target 4‐6 ng/ml Stop MMF/MPS Consider Starting Prednisone Consider Starting Leflunomide and/or Prednisone Add Leflunomide and Prednisone Same as BKVAN Rarely Thymoglobulin Refractory or advanced cases consider IVIG, fluoroquinolones 5 5/30/2013 Prevention Strategies Surveillance Screening • Monthly for 3 to 6 months then q 2 to 3 months until 2 years • Recommend urinary screening or plasma PCR • Beyond 2 years screen yearly or for allograft dysfunction Tailored Immunosuppression • Viruria, viremia induced treatment strategy • Risk assessment analysis – rejection vs. infection • Measures of immunocompetence Antiviral Prophylaxis • Fluoroquinoles 6 5/30/2013 Preemptive Immunosuppression Reduction • Discontinuation of antimetabolite upon detection of viremia resulted in clearance of BK viremia 95%, no graft losses to BKVAN • BK viral clearance accomplished in 90% in other studies • 8.6‐36.3% rejection rates following BKVAN, no apparent effect on graft outcome Brennan, D. Am J Transpl 5: 582‐594, 2005 Hardinger, K. Am J Transpl 10:407‐415, 2010 Bennett, W. Am J Nephrol 32:10‐12, 2010 Almeras, C. Transpl 85:1099‐1104, 2008 Schaub, S. Am J Transpl 10:2615‐2623, 2010 BK Virus Nephropathy Risk Factors Age >65 years Male recipient Deceased donor Higher HLA mismatch Recipient BK antibody seronegative • Reduced dendritic cell numbers • Urinary Stents • • • • • • Early Rejection • Cumulative prednisone dose • Rabbit Anti‐thymocyte globulin induction • Tacrolimus/MMF maintenance regimen • Viral co‐infection 7 5/30/2013 Fluoroquinolone Effect Gyrase Ciprofloxacin Prophylaxis Group 1: no Cipro (n = 106) Group 2: 30 days Cipro prophylaxis (n=130) 8 5/30/2013 Thank You 9