BK VIRUS INFECTION

L.A. Tibbles¹, M. Maric viskovic², C.M. Rodriguez velez³, A. Sar⁴, S. Yilmaz^5
1Medicine And Physiology & Pharmacology, University of Calgary, Calgary/AB/CANADA, ²Medicine, University of Calgary, Calgary/AB/CANADA, ³Altra Transplant Program, Alberta Health Services, Calgary/AB/CANADA, ⁴Pathology, University of Calgary, Calgary/AB/CANADA, ⁵Surgery, Alberta Health Services, Calgary/AB/CANADA

Body: Introduction: BK nephropathy has become the major leading cause of early renal transplant loss. Since the emergence of BK nephropathy occurred during an era of increased immunosuppression, currenttherapy consists of various methods of reduction of immunosuppression, but there are no randomized clinical trials to support this intervention. BK virus activates host intracellular signallingpathways to replicate its DNA and produce its protein coat, so we hypothesized that inhibition of these intracellular pathways would prevent viral replication and be an effective treatment for BKinfection. We chose sirolimus as an mTOR inhibitor, and leflunomide as a tyrosine kinase inhibitor to interfere with BK pathogenesis. Methods: From November 2006 to the present all de novo transplantpatients in the Southern Alberta Transplant Program (ALTRA) were screened monthly for BK DNA in urine by PCR. Positive urine BK PCR was followed by plasma BK PCR measurement. All patients positivefor plasma BK by PCR at any level were treated with a combination of sirolimus (trough level 6-8 ng/ml) and leflunomide (trough level 40-100 micrograms/ml). Results: 17 patients have been followedfor up to 3 years on this treatment regimen. There has been no increase in mean or median serum creatinine over this period of time. All patients have cleared BK virus from their blood (median timeto clearance 78 days). 11 patients have been maintained on sirolimus/leflunomide for greater than one year. Discontinuation of treatment occurred for the following reasons: desire to conceive (1patient), patient death (1 patient; stroke), side effects (1 patient), unrelated illness (2) and drug costs (1). Biopsies were performed at the first indication of BK viremia in all patients. Sevenbiopsies had no evidence of rejection. Four had borderline changes, and six had inflammation that fulfilled criteria for acute rejection (1 Type IA, 3 Type IB, 1 Type IIA and 1 Type III). Repeatbiopsies were performed on 12 patients at one year of follow-up. Compared to the initial biopsy in the same patient, there were no significant differences in any of the Banff scores(g,t,i,v,ah,cg,ct,ci,cv, or the combined score cicvi) showing no increase in fibrosis over this period of time. Cylex ImmuKnow assay measurement of overall immunosuppression demonstrated nodifference between 4 random sirolimus/leflunomide treated patients and 4 random patients without BK viremia treated with protocol tacrolimus and mycophenolate. Conclusions: Kinase inhibition withsirolimus and leflunomide is an effective treatment for BK viremia, which maintains renal function and preserves renal histology without the development of fibrosis over one year, potentially withoutdecreasing immunosuppression. This therapy is currently being compared to reduction of immunosuppression in a multicentre randomized clinical trial (The BK:KIDNI Trial: BK viremia: Kinase Inhibitionto Decrease Nephropathy Intervention Trial; ISRCTN40228609).

Disclosure: All authors have declared no conflicts of interest.