Article. Leflunomide Efficacy and Pharmacodynamics for the Treatment of BK Viral Infection

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1 Article Leflunomide Efficacy and Pharmacodynamics for the Treatment of BK Viral Infection Jill C. Krisl,* David J. Taber,* Nicole Pilch,* Kenneth Chavin, Charles Bratton, Beje Thomas, John McGillicuddy, and Prabhakar Baliga Summary Background and objectives BK virus is an infection in kidney transplantation patients jeopardizing graft survival. Unfortunately, there is no consensus on treatment of BK viremia and nephropathy. Leflunomide has been studied for the treatment of BK viremia and nephropathy, but there are limited data on the utility of leflunomide therapeutic drug monitoring. This study aimed to determine if a pharmacodynamic relationship exists between BK viral load reduction and leflunomide metabolite, A , serum concentrations. Design, setting, participants, & measurements This study was a retrospective, single-center, longitudinal analysis of patients identified with BK viremia with or without nephropathy. Patients were grouped according to whether they received leflunomide. All BK viral PCR and A concentrations were analyzed to determine pharmacodynamics, and were correlated with clinical outcomes. Results Of 76 patients identified, 52 received leflunomide therapy and 24 did not. Patients who received leflunomide were further analyzed according to A concentrations and BK clearance; there was no difference in BK clearance. There was a lack of correlation between A concentrations and log change in BK viral PCR concentration. Multivariate analysis demonstrated that mycophenolate mofetil discontinuation, BK viremia without nephropathy, and mean BK viral load were significantly associated with BK viral clearance; leflunomide use lacked this association. *Department of Pharmacy Services and Divisions of Transplant Surgery and Transplant Nephrology, Medical University of South Carolina, Charleston, South Carolina Correspondence: Dr.JillC.Krisl, Department of Pharmacy Services, Medical University of South Carolina, 43 Sabin Street, QE213, PO Box , Charleston, SC krisl@musc.edu Conclusions Pharmacodynamic analysis revealed no association between A concentrations and BK viral PCR reductions. Multivariate analysis demonstrated that leflunomide therapy was not associated with BK viral clearance. Randomized studies are needed to determine the utility of leflunomide for BK viremia and nephropathy. Clin J Am Soc Nephrol 7: , doi: /CJN Introduction Polyoma BK virus is a progressively destructive infection endangering allograft survival in kidney transplant patients. Up to 90% of the general adult population (1 3) is seropositive for BK virus, the virus remaining latent in the genitourinary tract. Reactivation of the virus often occurs in patients receiving immunosuppression, and the recent use of more potent immunosuppressive agents may be responsible for emergence of BK virus infections (4 6). The prevalence of BK nephropathy in kidney transplantation recipients is 1% 10%; and the risk of graft failure secondary to BK nephropathy is up to 65% (7 9). To date, there is no established consensus on the treatment of BK viremia and nephropathy. However, reduction in immunosuppression is fundamental to clearance of the virus (1,2,5,10). Alternative treatment options include cidofovir, intravenous Ig, fluoroquinolones, and leflunomide (1,5,11). Leflunomide is an immunosuppressant approved for use in rheumatoid arthritis. It is a prodrug, rapidly metabolized to its active metabolite, teriflunomide, A Leflunomide inhibits dihydro-orotate dehydrogenase and inhibits signaling involved in T and B cell proliferation (2,4,7,12 16). In vitro, leflunomide has exhibited antipolyomavirus activity, but the mechanism is not clear (7,12,17). There are limited clinical data on the utility of leflunomide therapeutic drug monitoring in the treatment of BK viral infection. Suggested target concentrations are based on in vitro IC 50 concentrations, and limited previous studies (7,13,17). The proposed therapeutic goal of A serum concentrations is.40 mg/ml (7,18 20). Potentially serious adverse effects associated with leflunomide therapy include hepatotoxicity, thrombocytopenia, leukopenia, and hemolytic anemia (18). The data available regarding monitoring of A concentrations are inconsistent, and a clear relationship between BK viral clearance and A concentration has not been identified. The primary objective of this study was to determine if a pharmacodynamic relationship exists between A concentrations and reduction in BK viral PCR. Vol 7 June, 2012 Copyright 2012 by the American Society of Nephrology 1003

2 1004 Clinical Journal of the American Society of Nephrology Materials and Methods This was a retrospective, single-center analysis of kidney transplant recipients with diagnosed BK viremia or nephropathy transplanted from June 2001 to December 2009 at our center. The institution transplant database was used to identify kidney transplantation patients with diagnosed BK viremia with or without nephropathy. BK infection was defined as detectable plasma BK viral PCR or biopsyproven nephropathy. Exclusion criteria included pediatric patients and multiorgan transplantations. Patients were separated and analyzed according to those who received leflunomide therapy and those who did not. In addition, subgroup analysis was conducted within the group that received leflunomide therapeutic drug monitoring. The Institutional Review Board at the Medical University of South Carolina approved this study. All data were collected from electronic and printed medical records. Baseline patient data collection included the following: age, sex, race, living or deceased donor, if patients were re-transplanted, peak plasma renin activity, number of HLA mismatches, cold and warm ischemic times, and delayed graft function. For baseline analysis and comparison, day zero was defined as the date of first detectable BK viral PCR or the date of diagnostic kidney biopsy. Patient data collected included the following: immunosuppressant regimen doses and blood concentrations, complete blood count, and serum chemistries. These data were collected at baseline (days 27 to 0), weeks 1 4, months 1 6 and 9, and yearly thereafter for up to 3 years postdiagnosis. Initial immunosuppressant regimens consisted of a calcineurin inhibitor (CNI) (e.g., cyclosporine or tacrolimus), prednisone, and mycophenolate mofetil (MMF) or mycophenolic acid. All doses and therapy discontinuation were documented at each of the designated follow-up dates. Available CNI whole blood concentrations were collected. Baseline immunosuppressant regimens were compared with final data collection points to determine rate of discontinuation or dose reduction. Primary clinical outcome measurements were BK viral clearance and graft failure. Two consecutive nondetectable BK viral PCRs were used to define BK clearance, without re-emergence of the virus at a later date. Secondary outcomes were immunosuppressant regimen modifications, adverse effects associated with leflunomide therapy, and the economical effect of leflunomide therapeutic drug monitoring. Multivariate analysis was conducted to determine the independent effects of variables on graft loss and BK viral clearance. Leflunomide and BK Data All BK viral PCR concentrations were collected; viral PCR concentrations,500 copies/ml were considered negative. Renal biopsy characteristics were analyzed, including the Banff grade, chronic changes (mild, moderate, and severe), presence of arteriolar hyalinosis, and BK staining results. Additional data were collected within the group that received leflunomide for subgroup analysis. All plasma BK viral PCR concentrations were collected along with any corresponding leflunomide doses and A concentrations. The log difference between corresponding BK viral PCR concentrations was calculated for each A drug concentration. Specifically, the BK viral PCR concentration drawn on the same day as the A concentration was analyzed and compared with the most recent BK viral PCR concentration available before that date. The log difference was analyzed as the reduction in BK viral PCR for the corresponding A concentration. In addition, the cost of each PCR and teriflunomide concentration was analyzed. For each data collection point, patients on leflunomide therapy were analyzed for predefined adverse effects. Thrombocytopenia was defined as platelet drop,100,000 cells/mm 3,anemiawasahemoglobindecreaseto,8 mg/dl, leukopenia was a white blood cell count,3000 cells/mm 3, and hepatotoxicity was aspartate aminotransferase or alanine aminotransferase.3 times the upper limit of normal. Durations of laboratory value abnormality and interventions were noted. The current protocol at our center involves monitoring BK viral PCR at months 1, 2, 3, 6, 9, 12, 18, 24, 36, 48, and 60 posttransplant, and obtaining renal biopsy if PCR.10,000 copies/ml or if graft dysfunction is present. For BK nephropathy without rejection, the protocol recommends discontinuing MMF, reducing CNIs, initiating leflunomide, and monitoring. If no BK nephropathy is present, the algorithm recommends reducing the CNI dose, decreasing or discontinuing MMF, and considering leflunomide. The decision to initiate leflunomide is by physician discretion and clinical scenario. Intravenous cidofovir is considered for patients with inadequate response to immunosuppressant reduction and those intolerant or refractory to leflunomide. This protocol was instituted in December of 2006; before this date, monitoring was by physician discretion and usually occurred if graft dysfunction was present. Statistical Analyses All values were reported as mean 6 SD or median (interquartile range [IQR]) for ordinal or continuous data and percentages for categorical data. Data were analyzed using the t test for continuous data and the Chi-squared test for categorical data. Cox proportional hazard regression with multivariate analysis was used to identify patient factors associated with BK viral clearance. P,0.05 was statistically significant. The pharmacodynamic relationship was determined by plotting A concentration in relationship to log change in BK viral PCR. A correlation curve was applied to these data to obtain the R 2 value and to determine linear dependence between the variables. Results From June 2001 to December 2009, there were 1291 kidney transplantation patients identified; 1215 patients were excluded (pediatric, multiorgan transplants, or no diagnosis of BK infection). There were 82 patients identified with BK viremia and/or nephropathy; 6 patients were excluded for multiorgan transplantations or lack of sufficient information. The remaining 76 patients were included in the analysis. Patients were divided into two groups based on whether leflunomide therapy was initiated; 52 received leflunomide and 24 did not. Within the leflunomide group, 48 patients had therapeutic drug monitoring. To note, the

3 Clin J Am Soc Nephrol 7: , June, 2012 Leflunomide and BK Viral Infection, Krisl et al institution BK monitoring protocol was initiated in 2006; only eight (10%) patients identified during the 8-year study period were before protocol implementation. Demographic and transplant characteristics are listed in Table 1. There were no significant differences in demographic characteristics between the two groups. At baseline, 100% of patients were receiving prednisone, and 90% and 80% of patients were receiving MMF or mycophenolic acid in the leflunomide and no leflunomide groups, respectively (Table 2). CNI use was consistent between groups, and the majority of patients received tacrolimus. There was no difference in baseline laboratory values between the two groups (Table 2). Graft failure occurred in 15% of patients in the leflunomide group and 7% of patients in the group that did not receive leflunomide (P=0.32). Acute rejection after diagnosis of BK infection occurred in 19% and 9% of patients, respectively (P=0.32). Modifications to prednisone dose and CNI concentrations were assessed for the first year after diagnosis and compared with baseline mean values. There was no significant difference in reduction of either medication between the groups. The mean percentage reduction in CNI concentrations was 18% in patients who received leflunomide and 12% in patients who did not (P=0.42). Each patient was analyzed according to the following: MMF discontinued anytime after diagnosis, MMF therapy continued with dose reduction, or no MMF therapy before diagnosis. Within the leflunomide group, 77% of patients had MMF discontinued, 13% did not have MMF discontinued, and 10% were not receiving MMF before diagnosis. In the group not taking leflunomide, 17% had MMF discontinued, 63% did not have MMF discontinued, and the remaining patients were not taking MMF before diagnosis. The mean reduction in dose for those patients who continued to receive MMF therapy was 70%. The rate of BK viral clearance was 30.8% in the leflunomide group and 60.9% in the group that did not receive leflunomide (P=0.02). There were 32 patients in the leflunomide group with BK nephropathy and 20 patients with BK viremia versus 1 and 23 patients, respectively, in the group that did not receive leflunomide. The median times to clearance were 529 days in the leflunomide group and 124 days in the group that did not receive leflunomide (P=0.02). The median follow-up times were 1.4 (IQR, 0.99, 2.58) and 1.16 (IQR, 0.67, 1.9) years (P=0.35). Separate analysis of outcomes was performed in patients with BK viremia without nephropathy (Table 3). There was no difference in BK clearance between those who did or did not receive leflunomide (P=0.19). According to Cox proportional multivariate analysis, discontinuation of MMF, BK viremia without nephropathy, and mean BK viral load were independently associated with BK viral clearance (Table 4). Table 1. Demographic and transplant characteristics Characteristic Leflunomide (n=52) No Leflunomide (n=24) P Value Age, yr Sex, male Race African American Caucasian other 2 4 Re-transplant, yes Body mass index, median (interquartile range) 26 (21, 30) 26 (23, 30) 0.66 Years on dialysis Living donor, yes Donor sex, male Donor race African American Caucasian other Mean peak panel reactive antibody HLA mismatches Cold ischemic time, min Warm ischemic time, min Induction therapy alemtuzumab IL-2 receptor antagonist antithymocyte globulin none 0 4 BK nephropathy, yes 32 1,0.001 Time from transplant to diagnosis (d), median (min, max) 235 (54, 1175) 415 (65, 1977) 0.86 Data are presented as mean 6 SD or percentage, unless otherwise specified.

4 1006 Clinical Journal of the American Society of Nephrology Subgroup Analyses of Patients Who Received Leflunomide A total of 527 teriflunomide (A ) concentrations were analyzed in the 48 patients with leflunomide therapeutic drug monitoring. The mean A concentrations were mg/ml and mg/ml (P=0.75) in the patients who did and did not achieve BK viral clearance, respectively (Table 5). Maximum concentrations were mg/ml and mg/ml (P=0.34). The mean dose of leflunomide was 40 mg daily. Among the nine patients who received cidofovir, five achieved BK viral clearance and four did not (P=0.47). When patients were grouped based on those with A mean concentrations.40 mg/ml versus concentrations,40 mg/ml, there was no difference in BK clearance. Within the group that achieved BK clearance, 50% of patients had A mean concentrations.40 mg/ml and 50% had concentrations,40 mg/ml (P=0.76). Each A concentration was plotted with the corresponding log change in BK viral PCR. There was no correlation between the two variables (R 2,0.0001) (Figure 1). Within the leflunomide group, 12 patients had at least one of the prespecified adverse effects. Thrombocytopenia was the most common adverse effect, occurring in 15.4% of patients receiving leflunomide. Leukopenia, anemia, and hepatotoxicity occurred in 9.6%, 3.8%, and 5.8% of patients, respectively. Adverse effects were managed with dose reduction and/or therapy discontinuation. Institution costs of BK viral PCR are $311 USD for BK viral PCR and $345 USD for A concentration. There were 527 A concentrations among the 48 patients Table 2. Baseline immunosuppression regimens Drug Leflunomide (n=52) No Leflunomide (n=24) P Value Prednisone, yes MMF or MPA, yes CNI, yes tacrolimus cyclosporine 8 25 SCr, mg/dl WBC, 1000 cells/mm Hemoglobin, g/dl Hematocrit Platelets, 1000 cells/mm Data are presented as mean 6 SD or percentage. MMF, mycophenolic mofetil; MPA, mycophenolic acid; CNI, calcineurin inhibitor; SCr, serum creatinine; WBC, white blood cell. Table 3. Outcomes among patients with BK viremia without nephropathy Outcome Leflunomide (n=20) No Leflunomide (n=23) P Value BK viral clearance Rejection after BK diagnosis Mean BK PCR during time of 152, , follow-up, copies/ml Discontinuation of MMF within 1 mo 84 14,0.001 Death or graft failure Table 4. Multivariate analysis for BK viral clearance Variable Odds Ratio 95% Confidence Interval P Value Use of leflunomide Decrease in prednisone dose Discontinue mycophenolate Decrease in calcineurin inhibitor concentration BK viremia without nephropathy Acute rejection after BK viremia diagnosis Mean BK viral load, copies/ml

5 Clin J Am Soc Nephrol 7: , June, 2012 Leflunomide and BK Viral Infection, Krisl et al Table 5. Serum Concentration BK clearance and A serum concentrations BK Clearance (n=14) BK Viremia (n=34) P Value A , mean 6 SD A , max 6 SD A ,40 mg/ml mg/ml with therapeutic drug monitoring, resulting in a total cost of $342,000 USD or roughly $6600 USD per patient. Discussion Pharmacodynamic analysis from our experience with leflunomide suggests that there is no correlation between leflunomide metabolite, A , concentrations, and reduction in BK viral PCR or viral clearance. In addition, both univariate and multivariate analysis suggests that the use of leflunomide is not associated with BK viral clearance. The lack of correlation identified in this study differs from findings of several other studies. Results from Josephson et al. (7) suggest that patients with A concentrations.40 mg/ml had BK clearance or significant reduction in BK viral load. This was a small study of 26 patients and variation of leflunomide metabolite concentrations was observed suggesting wide interpatient and intrapatient variability. Williams et al. (20) also suggested that patients with A concentrations.40 mg/ml had BK clearance or BK viral load reductions in blood and urine. In both studies, all patients had MMF discontinued after diagnosis; discontinuation of MMF is known to be associated with BK viral clearance but the effect of MMF discontinuation without leflunomide therapy was not analyzed. Data collected in this study suggest there was no difference in A concentrations between patients who did or did not achieve BK clearance; concentrations.40 mg/ml and,40 mg/ml had similar rates of BK clearance. There was no correlation between A concentration and log change in BK viral PCR (R 2,0.001). Faguer et al. (18) also did not find a correlation between leflunomide dose and A concentrations. In their study, median trough concentrations were 35 mg/ml (R 2 =0.04; P=0.76) and 42% of patients achieved BK clearance. The anti-bk activity of leflunomide remains to be fully understood. The anticytomegalovirus effect is thought to be from activity on the viral envelope, but BK virus is not an enveloped virus (13,17). Therapeutic goals of A concentrations from 40 to 100 mg/ml were established after extrapolation of in vitro IC 50 concentrations for cytomegalovirus viral replication (7,13). In addition, a lack of correlation between leflunomide dose and A concentration (18), and wide interpatient variability have been noted (21). In the study from Faguer et al. (18), there was no correlation between daily dose and trough concentrations. The results of the study from Faguer et al. aswellas this study confirm the wide patient variability in A Figure 1. Correlation curve for BK viral PCR reduction and A serum concentrations.

6 1008 Clinical Journal of the American Society of Nephrology concentrations in response to a given dose of leflunomide. Leflunomide is most commonly dosed at 100 mg daily for 3 days and then 20- to 60-mg/d with dose adjustments as necessary (1,2). The mean daily dose of leflunomide in this study was 40 mg. Derived from an active metabolite of leflunomide, FK 778, is an investigational immunosuppressant that has been studied in the treatment of BK nephropathy. Unfortunately, no benefit offk778hasbeen identified (22). Leflunomide is also an immunosuppressant and inhibits dihydro-orotate dehydrogenase and tyrosine kinases, resulting in inhibition of T and B lymphocytes (16,23). Leflunomide decreases TNF-dependent activation of NFkB (24), which would suggest that leflunomide could minimize the risk of rejection in patients with BK nephropathy (25). In this study, graft failure and rejection rates were similar between the two groups. To note, in vitro data suggest that A concentrations lower than those needed for antiviral effects may provide immunosuppressive effects (12,24). A fundamental approach to facilitating BK clearance is reduction in immunosuppression (1,2,5,10,26). Schold et al. (27) identified risk factors for the development of BK nephropathy, which included donors aged.65 years, male recipients, female donors, patients with HLA mismatched transplants, and recipients given antithymocyte globulin and tacrolimus as baseline immunosuppression. A discontinuation of MMF, replacement of tacrolimus with cyclosporine, and/or overall reduction in immunosuppression are initiated to facilitate BK viral clearance. Discontinuation of MMF has consistently been shown to correlate with BK clearance and is a therapy mainstay (1). Multivariate analysis in this study suggested that discontinuation of MMF had the strongest association with BK clearance. There is no consensus on the clinical utility of leflunomide therapeutic drug monitoring. Several studies recommend monitoring due to concern for adverse effects at higher A concentrations (18,20). With a lack of correlation between A concentrations and BK viral PCR reduction seen in this study, the utility and cost of frequent monitoring should be considered. The 527 serum concentrations evaluated in this trial had a total cost of $342,000 USD or $6600 USD per patient. Adverse effects from leflunomide therapy have been a concern in prior studies (7,18). Identified side effects include hepatotoxicity, leukopenia, anemia, and thrombocytopenia (12). There were only 12 patients who experienced an adverse effect. Each adverse effect was managed with dose reduction initially and discontinuation if necessary; four patients had leflunomide discontinued. Several occurrences of adverse effects were associated with elevated A concentrations (.80 mg/ml). A limitation of this study is the retrospective nature of the data. All BK viral PCR, leflunomide doses, and A concentrations were obtained from electronic and printed medical records. In addition, we were not able to account for physician discretion in use of leflunomide therapy and reductions in other immunosuppressants. Patients with BK viremia and BK nephropathy were included and evaluated similarly. All but one of the patients with BK nephropathy received leflunomide versus 20 patients with BK viremia. This presents a selection bias that was beyond the control of these retrospective data, but is recognized as a limitation. Because BK nephropathy may suggest a more progressive infection, these patients may not be comparable with those with viremia without nephropathy. The time to clearance was significantly shorter in the group that did not receive leflunomide. This may be attributed to more patients with nephropathy that received leflunomide, which may take longer to clear. The rate of BK viral clearance was statistically higher in the group that did not receive leflunomide, but this was likely due to the differences in the percentage of patients with BK viremia without nephropathy. The multivariate analysis confirmed that BK viremia without nephropathy was associated with BK viral clearance. The multivariate analysis included more variables than some consider statistically acceptable; however, this was conducted to insure that important variables identified in the univariate analysis were included. The multivariate analysis served solely to confirm that the important predictor of BK clearance (MMF reduction or discontinuation) held true after controlling for other variables. Our sample size was small but one of the largest compared with other studies that have evaluated the safety, efficacy, and monitoring of patients receiving leflunomide for the treatment of BK viremia or nephropathy. These data suggest that leflunomide was not efficacious in the treatment of posttransplant BK viral infections. In conclusion, pharmacodynamic analysis demonstrates a lack of correlation between leflunomide and BK viral PCR reduction or clearance. Reduction in MMF remains an important factor for BK clearance. The use of leflunomide may not be associated with improved clinical outcomes. A prospective clinical trial is needed to determine the true utility of leflunomide therapy and monitoring in BK viremia or nephropathy. Acknowledgments Information in this manuscript was presented in abstract form at the 2011American Transplant Congress, April 30 May 4, 2011, Philadelphia, Pennsylvania. Disclosures None. References 1. Blanckaert K, De Vriese AS: Current recommendations for diagnosis and management of polyoma BK virus nephropathy in renal transplant recipients. Nephrol Dial Transplant 21: , Wu JK, Harris MT: Use of leflunomide in the treatment of polyomavirus BK-associated nephropathy. 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