- Email: [email protected]
Monitoring and Treatment for BK Virus After Kidney Transplantation
Monitoring and Treatment for BK Virus After Kidney Transplantation H.H. Moon, T.-S. Kim, S. Lee, S. Song, M. Shin, J.B. Park, J.M. Kim, C.H.D. Kwon, J.-W. Joh, S.-K. Lee, and S.J. Kim ABSTRACT Background. The BK nephropathy (BKN) shows a 10% prevalence among cases of kidney transplantation (KT). We assessed the incidence of BK replication in KT recipients as well as our updated screening strategy and the impact of interventions on BK virus infections. Methods. Since September 2007, our screening protocol for BK virus included examination of urine cytology or BK virus DNA real-time polymerase chain reaction (PCR) detection on postoperative days 1, 5, 9, 16, 24, 36, 48 weeks up to 1 year. IR present, we tested urine BK virus DNA PCR quantitation. We applied the updated screening protocol from August 2010. It urine BK DNA PCR quantification was above 107 copies/ mL, we checked regularly blood the BK virus DNA PCR quantification. In addition, if the blood BK virus DNA load was above 104 copies/mL and the serum creatinine elevated, we was performed an allograft biopsy. Between September 2007 and December 2011, the 58 recipients who showed BK viremia were enrolled in the present study in 2 groups according to the period of screening protocol (era I, era II). Results. The time between kidney transplantation and BK viremia detection of era II was shorter than that of era I (16 vs 29 weeks; P ¼ .001). Viremia clearance rate at 6 months in era II was significant higher than that of era I (82% vs 36.8%; P ¼ .001) as well as at 12 months (100% vs 61.1%, P < .001) after intervention. Interestingly, viremia clearance at 12 months after intervention was 100% in era II. Conclusion. An updated screening protocol for BK virus allowed early detection and accurate diagnosis of BKN. Early detection of BK virus infection enabled early intervention and improved viral clearance rate.
T
HE PRESENCE OF THE BK VIRUS in the allograft parenchyma threatens the transplant.1 The prevalence of BK nephropathy (BKN) has increased to 1% and 10% of kidney transplantations (KT).2,3 Current therapeutic options for BKN are limited.4 There is no established antiviral drug for BK virus infection in controlled trials, but reduction of immunosuppressant dose has been recommended currently.5,6 Therapeutic intervention achieve little effect in cases of late allograft involvement.7 Recently, increased awareness, active screening, and development of diagnostic tools have led to earlier intervention, reducing the incidence of progressive BK virus infection.8 We assessed the incidence of BK virus replication in KT recipients, in the setting of a revised screening protocols, and evaluated the impact of interventions on infections.
PATIENTS AND METHODS Patients Between September 2007 and December 2011, 540 patients underwent KT (living donor, n ¼ 345; deceased donor, n ¼ 195). Of the 540 recipients, 218 (40.3%) displayed BK viruria, including 70 with BK viremia. We excluded 12 patients because their follow-up was shorter than 6 months after detection of BK viruria, leaving
From the Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Address reprint requests to Sung Joo Kim, MD, PhD, Professor, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, #50 Ilwon-Dong, Gangnam-Gu, Seoul, Korea 135-710. E-mail: kmhyj111@skku. edu
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.08.044
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2980
Transplantation Proceedings, 45, 2980e2983 (2013)
MONITORING AND TREATMENT OF BK VIRUS
2981
Fig 1. BK virus screening protocol of Samsung Medical Center. 58 BK viremia recipients available for enrollment in the study. We divided the 58 recipients into 2 groups according to whether data were required before (era I) versus after revision (era II) of our screening protocol to compare their clinical data.
Immunosuppression Induction immunosuppression was performed in all patients: 39 received 2 doses of interleukin-2 receptor antagonist (basiliximab); 11 rabbit anti-thymocyte globulin (rATG; 1.5 mg/kg/d for 3e7 days); 2 anti-CD 52 monoclonal antibody (alemtuzumab); and 6 anti-CD 20 Table 1. Characteristics of the Viremia Recipients According to Era of BK Virus Screening Protocol Era I (n ¼ 19)
Era II (n ¼ 39)
Sex (M:F) 11:8 22:17 50 (20e69) Age 45 (34e64) Living donor/deceased 11:8 24:15 donor 16/1/2/0 22/10/0/6 Induction agent (basiliximan/rATG/ Alem/rituximab þ rATG) Maintenance (FK:CsA) 16:3 36:3 SCr at discharge (mg/dL) 1.21 (0.62e2.32) 1.09 (0.50e3.84) F/U period after 39.3 (5e60) 20.1 (9e34) transplant (mo) 11/3/5/0 26/11/0/1 Steroid pulse therapy before BK viruia detection 0/1/2/3 Interval between KT 29 (11e171) 16 (4e42) and detection of BK viremia (wk)
P value
.571 .666 .505 .485
.382 .875 .000 .181
.001
rATG, rabbit antithymocyte globulin; Alen, alemtuzumab; SCr, serum creatinine; F/U, follow-up; KT, kidney transplantation; CsA, cyclosporme.
antibody (rituximab) with rATG because of ABO-incompatible KT. Tacrolimus, mycophenolate mofetil (MMF)/mycophenolic acid (MPA), and methylprednisolone were the maintenance immunosuppressive regimen. If neutropenia or gastrointestinal problem occurred, we reduced the dose of MMF/MPA. Also, we adjusted the MMF/MPA dose based upon the severity of the BK viral infection. Biopsy-proven acute rejection episodes were treated with intravenous methylprednisolone (500 mg) for 3 consecutive days, those unresponsive to methylprednisolone were treated with rATG.
BK Virus Monitoring Urine and blood BK virus DNA real-time polymerase chain reaction (PCR) assay were introduced in our center in September 2007 (Era I). We routinely checked urine cytology or BK virus DNA PCR at postoperative day 1, 5, 9, 16, 24, 36, 48 weeks up to 1 year. If present, we quantitated urine BK virus DNA by PCR. At that time, there was no rule for applying allograft biopsy or blood BK DNA PCR assay. In August 2010, we revised our protocol if urine BK virus DNA quantification was above 107 copies/mL, blood BKV DNA load was checked regularly; if blood BK virus DNA load was above 104 copies/mL with a serum creatinine (SCr) elevation, we was performed an allograft biopsy. If the BK virus replication in blood disappeared, then we followed urine BK virus DNA (Fig 1).
BKN Diagnosis BKN was diagnosed by allograft biopsy showing histologic involvement by viral cytopathic changes in the renal tubular epithelium, which included mutifocal or diffuse intranuclear viral inclusions, lytic cell death, and tubular necrosis. Also, BKN was confirmed by immunohisochemical staining for SV 40 LT-Ag.
Interventions When BK viremia was detected, we reduced initially the calcineurin inhibitor (CNI) and MMF/MPA doses. Even after reduction of
2982
MOON, KIM, LEE ET AL
Fig 2. BK viruria, viremia, and nephropathy patients according to eras of screening protocol. immunosuppression drugs if SCr or BK DNA load in blood increased, we next changed from a CNI to Rapamune, or MMF to leflunomide. When SCr increased without an increase in BK DNA load, an allograft biopsy was performed to exclude rejection or an other nephropathy.
Statistics Results are presented as mean values standard deviations or medians (ranges). Pearson chi-square test and Mann-Whitney U test was used to analyze the data, as appropriate. A P value of less Table 2. Comparison of Clinical Variables of 2 Eras of BK Virus Screening Protocol
Blood BKV DNA load at detection (log) Blood BKV DNA load at 6 mo after detection (log) Blood BKV DNA load at 12 mo after detection (log) SCr at viremia detection (mg/dL) SCr at 6 mo after intervention (mg/dL) SCr at 12 mo after intervention (mg/dL) Viremia clearance at 6 mo after intervention Viremia clearance at 12 mo after intervention Graft loss
Era I (n ¼ 19)
Era II (n ¼ 39)
P value
4.37 1.31
3.77 1.06
.083
3.92 0.91
3.85 0.37
.728
3.79 1.09
2.75
.380
1.42 0.40
1.48 0.43
.562
1.62 1.37
1.51 0.47
.240
1.36 0.43
1.39 0.37
.914
7/19 (36.8%)
32/39 (82%)
.001
11/18 (61.1%)
32/32 (100%)
<.001
1
0
BKV, BK virus; SCr, serum creatinine.
1
than .05 (2-sided test) was considered statistically significant. SPSS software 17.0 was used for data analysis.
RESULTS
Fifty-eight KT recipients were prospectively followed for a median of 24 months (6e60 ms) after KT. The interval between KT and detection of BK viruria was a median of 12 weeks (2e168 ws). Table 1 shows the characteristics of era I and era II patients. There were no significant differences among sex, age, graft type, induction agent, maintenance CNI drug, SCr at discharge or antirejection treatment before BK viruria dectection. However, the interval between KT and BK viremia detection during era II was shorter than that in era I (16 vs 29 weeks; P ¼ .001). The process of screening for BK virus infection and diagnosis of BKN is illustrated as era of screening protocol in Fig 2. In era II we observes a significant correlation between BK viremia over 104 copies/mL and biopsy-proven BKN (P ¼ .001), suggesting greater diagnostic accuracy BKN during era II versus era I. Table 2 compares the clinical variables in the 2 eras of BK virus screening protocols. There was no significant difference in blood BK virus DNA loads and SCr values at detection of viremia or at 6 and 12 months after intervention. However, viremia clearance rates in era II were significantly greater than that of era I at 6 months (82% vs 36.8%, P ¼ .001) and at l2 months (100% vs 61.1%, P < .001) after intervention. Interestingly, the viremia clearance rate in era II at 12 months after intervention was 100%.
MONITORING AND TREATMENT OF BK VIRUS
2983
Table 3. Viral Clearance According to Interventions Viremia clearance
ACR occurrence At 6 mo At 12 mo after intervention
CNI þ CNI þ CNI þ CNI þ Total
MMF MMF MMF MMF
/ / / /
CNI Y þ MMF Y SRL þ MMF Y SRL þ Leflu CNI Y þ Leflu
28/39 2/2 4/8 5/9 39/58
29/33 0/1 8/8 5/8 43/50
5 1 0 1 7
ACR, acute cellular rejection; SRL, sirolimus; Leflu, leflunomide; CNI, calcinerin inhibitor; MMf, mycophenolate mofetil.
We investigated viral clearance according to the intervention (Table 3). CNI and MMF/MPA doses were reduced in 39/58 recipients. At 12 months after intervention, 29/33 patients achieved viral clearance. But 5 recipients experienced acute cellular rejection (ACR) episodes after CNI and MMF/MPA dose reductions. There were 2 patients who had been treated by changing from CNI to sirolimus with maintaining reduced doses of MMF/MPA, They achieved viremia clearance at 6 months after the intervention. One of 2 experiences ACR episode after treatment. Changing CNI and MMF to sirolimus and leflunomide showed outstanding results; all 8 recipients achieved viremia clearance at 12 months withou an episode of ACR. A switch from MMF to leflunomide associated with reduced CNI doses rendered 5/ 9 recipients clear of virsus. DISCUSSION
BK virus infection does not have typical symptoms or signs. The incidence of BK virus infection among KT recipients has been reported to 10% to 45%.9 BK virus can be produce allograft BKN causing kidney failure among 10% to 50% of patients within 1 year of diagnosis.10 It has been reported that 1% to 10% of KT recipients are diagnosed with BKN.11 Strategies to monitor BKV are evolving.10 The interdisciplinary group has recommended viruria surveillance every 3 months with a biopsy when urine BK DNA >107, capsid protein VP1 mRNA >6.5 105, or blood BK DNA >104. However, some groups have recommended viremia rather than viruria surveillance every 3 months.12 The most recent recommendations from the KDIGO group suggest monthly blood BK PCR during the first 3 to 6 months after transplantation. We adopted those recommendations to revise our screening protocol. Our new screening strategy for BK virus replication provided an earlier diagnosis and intervention. For BK virus, there is no effective antiviral or prophylactic agent or vaccine. Reduction of immunosuppresion drug dosages is the current primary treatment for BK virus.10 An early diagnosis and reduction of immunosuppression may clear viremia preventing progression to BKN.1 In patients who are nonresponsive to reduction of immunosuppression drugs, we consider prescription of antiviral
agents, antibiotics, or intravenous immunoglobulin. In the present study, sirolimus and leflunomide were used for subjects nonresponsive to CNI and MMF reduction. In the present study the combination of sirolimus and leflunomide showed a fairly good effect to suppress BK virus without ACR episodes. Reduction of BK large T-antigen expression by sirolimus and leflunomide may explain the good result of viral clearance. Sirolimus inhibits p70S6K phosphorylation reducing BK virus large T-antigen expression in a dosedependent manner. The tyrosine kinase inhibitor leflunomide decreases PDK1 and Akt phosphorylation to inhibit BK virus genome replication and early gene expression.13 However, the effectiveness of sirolimus against BKN needs more clinical studies. In conclusion our updated screening strategy for BK virus achieved early detection of BK virus infection and accurate diagnosis of BKN, enabling early intervention and improving viral clearance. REFERENCES 1. Wu SW, Chang HR, Hsieh MC, et al. Early diagnosis of polyomavirus type BK infection in tailoring immunosuppression for kidney transplant patients: screening with urine qualitative polymerase chain reaction assay. Transplant Proc. 2008;40(7): 2389e2391. 2. Johnston O, Jaswal D, Gill JS, et al. Treatment of polyomavirus infection in kidney transplant recipients: a systematic review. Transplantation. 2010;89(9):1057e1070. 3. Schold JD, Rehman S, Kayle LK, et al. Treatment for BK virus: incidence, risk factors and outcomes for kidney transplant recipients in the United States. Transpl Int. 2009;22(6):626e634. 4. Hirsch HH, Randhawa P. BK virus in solid organ transplant recipients. Am J Transplant. 2009;9(Suppl 4):S136eS146. 5. Hirsch HH KW, Dickenmann M, et al. Prospective study of polyomavirus type BK replication and nephropathy in renal transplant recipients. N Engl J Med. 2002;347(7):488e496. 6. Vasudev B, HS, Hussain SA, Zhu YR, et al. BK virus nephritis Risk factors, timing, and outcome in renal. Kidney Int. 2005;Oct;68(4):1834e1839. 7. Ramos E. Clinical course of polyoma virus nephropathy in 67 renal transplant patients. J Am Soc Nephrol. 2002;13(8): 2145e2151. 8. Buehrig CK, LD, Stegall MD, Kreps MA, et al. Influence of surveillance renal allograft biopsy on diagnosis. Kidney lnt. 2003;64(2):665e673. 9. Mannon RB. Polyomavirus nephropathy: what have we learned? Transplantation. 2004;77(9):1313e1318. 10. Randhawa P, Brennan DC. BK virus infection in transplant recipients: an overview and update. Am J Transplant. 2006;6(9): 2000e2005. 11. Hirsch HH, Steiger J. Polyomavirus BK. Lancet Infect Dis. 2003;3(10):611e623. 12. Boothpur R, Brennan DC. Human polyoma viruses and disease with emphasis on clinical BK and JC. J Clin Virol. 2010;47(4):306e312. 13. Liacini A, Seamone ME, Muruve DA, Tibbies LA. Anti-BK virus mechanisms of sirolimus and leflunomide alone and in combination: toward a new therapy for BK virus infection. Transplantation. 2010;90(12):1450e1457.
T
HE PRESENCE OF THE BK VIRUS in the allograft parenchyma threatens the transplant.1 The prevalence of BK nephropathy (BKN) has increased to 1% and 10% of kidney transplantations (KT).2,3 Current therapeutic options for BKN are limited.4 There is no established antiviral drug for BK virus infection in controlled trials, but reduction of immunosuppressant dose has been recommended currently.5,6 Therapeutic intervention achieve little effect in cases of late allograft involvement.7 Recently, increased awareness, active screening, and development of diagnostic tools have led to earlier intervention, reducing the incidence of progressive BK virus infection.8 We assessed the incidence of BK virus replication in KT recipients, in the setting of a revised screening protocols, and evaluated the impact of interventions on infections.
PATIENTS AND METHODS Patients Between September 2007 and December 2011, 540 patients underwent KT (living donor, n ¼ 345; deceased donor, n ¼ 195). Of the 540 recipients, 218 (40.3%) displayed BK viruria, including 70 with BK viremia. We excluded 12 patients because their follow-up was shorter than 6 months after detection of BK viruria, leaving
From the Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Address reprint requests to Sung Joo Kim, MD, PhD, Professor, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, #50 Ilwon-Dong, Gangnam-Gu, Seoul, Korea 135-710. E-mail: kmhyj111@skku. edu
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.08.044
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2980
Transplantation Proceedings, 45, 2980e2983 (2013)
MONITORING AND TREATMENT OF BK VIRUS
2981
Fig 1. BK virus screening protocol of Samsung Medical Center. 58 BK viremia recipients available for enrollment in the study. We divided the 58 recipients into 2 groups according to whether data were required before (era I) versus after revision (era II) of our screening protocol to compare their clinical data.
Immunosuppression Induction immunosuppression was performed in all patients: 39 received 2 doses of interleukin-2 receptor antagonist (basiliximab); 11 rabbit anti-thymocyte globulin (rATG; 1.5 mg/kg/d for 3e7 days); 2 anti-CD 52 monoclonal antibody (alemtuzumab); and 6 anti-CD 20 Table 1. Characteristics of the Viremia Recipients According to Era of BK Virus Screening Protocol Era I (n ¼ 19)
Era II (n ¼ 39)
Sex (M:F) 11:8 22:17 50 (20e69) Age 45 (34e64) Living donor/deceased 11:8 24:15 donor 16/1/2/0 22/10/0/6 Induction agent (basiliximan/rATG/ Alem/rituximab þ rATG) Maintenance (FK:CsA) 16:3 36:3 SCr at discharge (mg/dL) 1.21 (0.62e2.32) 1.09 (0.50e3.84) F/U period after 39.3 (5e60) 20.1 (9e34) transplant (mo) 11/3/5/0 26/11/0/1 Steroid pulse therapy before BK viruia detection 0/1/2/3 Interval between KT 29 (11e171) 16 (4e42) and detection of BK viremia (wk)
P value
.571 .666 .505 .485
.382 .875 .000 .181
.001
rATG, rabbit antithymocyte globulin; Alen, alemtuzumab; SCr, serum creatinine; F/U, follow-up; KT, kidney transplantation; CsA, cyclosporme.
antibody (rituximab) with rATG because of ABO-incompatible KT. Tacrolimus, mycophenolate mofetil (MMF)/mycophenolic acid (MPA), and methylprednisolone were the maintenance immunosuppressive regimen. If neutropenia or gastrointestinal problem occurred, we reduced the dose of MMF/MPA. Also, we adjusted the MMF/MPA dose based upon the severity of the BK viral infection. Biopsy-proven acute rejection episodes were treated with intravenous methylprednisolone (500 mg) for 3 consecutive days, those unresponsive to methylprednisolone were treated with rATG.
BK Virus Monitoring Urine and blood BK virus DNA real-time polymerase chain reaction (PCR) assay were introduced in our center in September 2007 (Era I). We routinely checked urine cytology or BK virus DNA PCR at postoperative day 1, 5, 9, 16, 24, 36, 48 weeks up to 1 year. If present, we quantitated urine BK virus DNA by PCR. At that time, there was no rule for applying allograft biopsy or blood BK DNA PCR assay. In August 2010, we revised our protocol if urine BK virus DNA quantification was above 107 copies/mL, blood BKV DNA load was checked regularly; if blood BK virus DNA load was above 104 copies/mL with a serum creatinine (SCr) elevation, we was performed an allograft biopsy. If the BK virus replication in blood disappeared, then we followed urine BK virus DNA (Fig 1).
BKN Diagnosis BKN was diagnosed by allograft biopsy showing histologic involvement by viral cytopathic changes in the renal tubular epithelium, which included mutifocal or diffuse intranuclear viral inclusions, lytic cell death, and tubular necrosis. Also, BKN was confirmed by immunohisochemical staining for SV 40 LT-Ag.
Interventions When BK viremia was detected, we reduced initially the calcineurin inhibitor (CNI) and MMF/MPA doses. Even after reduction of
2982
MOON, KIM, LEE ET AL
Fig 2. BK viruria, viremia, and nephropathy patients according to eras of screening protocol. immunosuppression drugs if SCr or BK DNA load in blood increased, we next changed from a CNI to Rapamune, or MMF to leflunomide. When SCr increased without an increase in BK DNA load, an allograft biopsy was performed to exclude rejection or an other nephropathy.
Statistics Results are presented as mean values standard deviations or medians (ranges). Pearson chi-square test and Mann-Whitney U test was used to analyze the data, as appropriate. A P value of less Table 2. Comparison of Clinical Variables of 2 Eras of BK Virus Screening Protocol
Blood BKV DNA load at detection (log) Blood BKV DNA load at 6 mo after detection (log) Blood BKV DNA load at 12 mo after detection (log) SCr at viremia detection (mg/dL) SCr at 6 mo after intervention (mg/dL) SCr at 12 mo after intervention (mg/dL) Viremia clearance at 6 mo after intervention Viremia clearance at 12 mo after intervention Graft loss
Era I (n ¼ 19)
Era II (n ¼ 39)
P value
4.37 1.31
3.77 1.06
.083
3.92 0.91
3.85 0.37
.728
3.79 1.09
2.75
.380
1.42 0.40
1.48 0.43
.562
1.62 1.37
1.51 0.47
.240
1.36 0.43
1.39 0.37
.914
7/19 (36.8%)
32/39 (82%)
.001
11/18 (61.1%)
32/32 (100%)
<.001
1
0
BKV, BK virus; SCr, serum creatinine.
1
than .05 (2-sided test) was considered statistically significant. SPSS software 17.0 was used for data analysis.
RESULTS
Fifty-eight KT recipients were prospectively followed for a median of 24 months (6e60 ms) after KT. The interval between KT and detection of BK viruria was a median of 12 weeks (2e168 ws). Table 1 shows the characteristics of era I and era II patients. There were no significant differences among sex, age, graft type, induction agent, maintenance CNI drug, SCr at discharge or antirejection treatment before BK viruria dectection. However, the interval between KT and BK viremia detection during era II was shorter than that in era I (16 vs 29 weeks; P ¼ .001). The process of screening for BK virus infection and diagnosis of BKN is illustrated as era of screening protocol in Fig 2. In era II we observes a significant correlation between BK viremia over 104 copies/mL and biopsy-proven BKN (P ¼ .001), suggesting greater diagnostic accuracy BKN during era II versus era I. Table 2 compares the clinical variables in the 2 eras of BK virus screening protocols. There was no significant difference in blood BK virus DNA loads and SCr values at detection of viremia or at 6 and 12 months after intervention. However, viremia clearance rates in era II were significantly greater than that of era I at 6 months (82% vs 36.8%, P ¼ .001) and at l2 months (100% vs 61.1%, P < .001) after intervention. Interestingly, the viremia clearance rate in era II at 12 months after intervention was 100%.
MONITORING AND TREATMENT OF BK VIRUS
2983
Table 3. Viral Clearance According to Interventions Viremia clearance
ACR occurrence At 6 mo At 12 mo after intervention
CNI þ CNI þ CNI þ CNI þ Total
MMF MMF MMF MMF
/ / / /
CNI Y þ MMF Y SRL þ MMF Y SRL þ Leflu CNI Y þ Leflu
28/39 2/2 4/8 5/9 39/58
29/33 0/1 8/8 5/8 43/50
5 1 0 1 7
ACR, acute cellular rejection; SRL, sirolimus; Leflu, leflunomide; CNI, calcinerin inhibitor; MMf, mycophenolate mofetil.
We investigated viral clearance according to the intervention (Table 3). CNI and MMF/MPA doses were reduced in 39/58 recipients. At 12 months after intervention, 29/33 patients achieved viral clearance. But 5 recipients experienced acute cellular rejection (ACR) episodes after CNI and MMF/MPA dose reductions. There were 2 patients who had been treated by changing from CNI to sirolimus with maintaining reduced doses of MMF/MPA, They achieved viremia clearance at 6 months after the intervention. One of 2 experiences ACR episode after treatment. Changing CNI and MMF to sirolimus and leflunomide showed outstanding results; all 8 recipients achieved viremia clearance at 12 months withou an episode of ACR. A switch from MMF to leflunomide associated with reduced CNI doses rendered 5/ 9 recipients clear of virsus. DISCUSSION
BK virus infection does not have typical symptoms or signs. The incidence of BK virus infection among KT recipients has been reported to 10% to 45%.9 BK virus can be produce allograft BKN causing kidney failure among 10% to 50% of patients within 1 year of diagnosis.10 It has been reported that 1% to 10% of KT recipients are diagnosed with BKN.11 Strategies to monitor BKV are evolving.10 The interdisciplinary group has recommended viruria surveillance every 3 months with a biopsy when urine BK DNA >107, capsid protein VP1 mRNA >6.5 105, or blood BK DNA >104. However, some groups have recommended viremia rather than viruria surveillance every 3 months.12 The most recent recommendations from the KDIGO group suggest monthly blood BK PCR during the first 3 to 6 months after transplantation. We adopted those recommendations to revise our screening protocol. Our new screening strategy for BK virus replication provided an earlier diagnosis and intervention. For BK virus, there is no effective antiviral or prophylactic agent or vaccine. Reduction of immunosuppresion drug dosages is the current primary treatment for BK virus.10 An early diagnosis and reduction of immunosuppression may clear viremia preventing progression to BKN.1 In patients who are nonresponsive to reduction of immunosuppression drugs, we consider prescription of antiviral
agents, antibiotics, or intravenous immunoglobulin. In the present study, sirolimus and leflunomide were used for subjects nonresponsive to CNI and MMF reduction. In the present study the combination of sirolimus and leflunomide showed a fairly good effect to suppress BK virus without ACR episodes. Reduction of BK large T-antigen expression by sirolimus and leflunomide may explain the good result of viral clearance. Sirolimus inhibits p70S6K phosphorylation reducing BK virus large T-antigen expression in a dosedependent manner. The tyrosine kinase inhibitor leflunomide decreases PDK1 and Akt phosphorylation to inhibit BK virus genome replication and early gene expression.13 However, the effectiveness of sirolimus against BKN needs more clinical studies. In conclusion our updated screening strategy for BK virus achieved early detection of BK virus infection and accurate diagnosis of BKN, enabling early intervention and improving viral clearance. REFERENCES 1. Wu SW, Chang HR, Hsieh MC, et al. Early diagnosis of polyomavirus type BK infection in tailoring immunosuppression for kidney transplant patients: screening with urine qualitative polymerase chain reaction assay. Transplant Proc. 2008;40(7): 2389e2391. 2. Johnston O, Jaswal D, Gill JS, et al. Treatment of polyomavirus infection in kidney transplant recipients: a systematic review. Transplantation. 2010;89(9):1057e1070. 3. Schold JD, Rehman S, Kayle LK, et al. Treatment for BK virus: incidence, risk factors and outcomes for kidney transplant recipients in the United States. Transpl Int. 2009;22(6):626e634. 4. Hirsch HH, Randhawa P. BK virus in solid organ transplant recipients. Am J Transplant. 2009;9(Suppl 4):S136eS146. 5. Hirsch HH KW, Dickenmann M, et al. Prospective study of polyomavirus type BK replication and nephropathy in renal transplant recipients. N Engl J Med. 2002;347(7):488e496. 6. Vasudev B, HS, Hussain SA, Zhu YR, et al. BK virus nephritis Risk factors, timing, and outcome in renal. Kidney Int. 2005;Oct;68(4):1834e1839. 7. Ramos E. Clinical course of polyoma virus nephropathy in 67 renal transplant patients. J Am Soc Nephrol. 2002;13(8): 2145e2151. 8. Buehrig CK, LD, Stegall MD, Kreps MA, et al. Influence of surveillance renal allograft biopsy on diagnosis. Kidney lnt. 2003;64(2):665e673. 9. Mannon RB. Polyomavirus nephropathy: what have we learned? Transplantation. 2004;77(9):1313e1318. 10. Randhawa P, Brennan DC. BK virus infection in transplant recipients: an overview and update. Am J Transplant. 2006;6(9): 2000e2005. 11. Hirsch HH, Steiger J. Polyomavirus BK. Lancet Infect Dis. 2003;3(10):611e623. 12. Boothpur R, Brennan DC. Human polyoma viruses and disease with emphasis on clinical BK and JC. J Clin Virol. 2010;47(4):306e312. 13. Liacini A, Seamone ME, Muruve DA, Tibbies LA. Anti-BK virus mechanisms of sirolimus and leflunomide alone and in combination: toward a new therapy for BK virus infection. Transplantation. 2010;90(12):1450e1457.