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Routine BK Virus Surveillance in Renal Transplantation - A Single Center's Experience
Routine BK Virus Surveillance in Renal Transplantation - A Single Center’s Experience A. Gautam, V. Patel, L. Pelletier, J. Orozco, J. Francis, and M. Nuhn ABSTRACT Background. We started a universal screening of all our kidney transplant recipients for BK virus in 2005. This review of our experience includes patients with ⱖ6 months’ posttransplantation follow-up. Methods. We performed a retrospective chart evaluation of all kidney transplants from January 2005 to February 2010. Urine polymerase chain reaction (PCR) for BK virus was done on all patients starting from 4 weeks after transplantation. If negative, it was repeated monthly for the first 6 months and then every 3– 4 months. If the test was positive, a urine and blood BK virus PCR done on the next visit was repeated every 2– 4 weeks with a slow reduction in immunosuppression. Results. From January 2005 to February 2010 we performed 173 kidney transplantations with 12 graft losses within the first 6 weeks which were excluded from the analysis. Induction immunosuppression consisted of anti–interleukin-2 receptor antibody (n ⫽ 102) or antithymoglobulin (ATG; n ⫽ 59). In 112 patients (70%), the urine BK virus PCR remained negative; 18 (11%) only the urine was positive and among an additional 31 (19%) BK virus PCR was positive in blood. There was no difference in incidence according to induction therapy. Delayed graft function was observed among 39 patients (24%); there was no difference in the incidence of BK virus with versus without DGF. The mean time to first detection was shorter with ATG induction (mean, 199 days; median, 90 days; range, 26 –1198 days) compared with anti–IL-2 (mean, 321 days; median, 195 days; range, 23–1077 days). Urine-only positivity was first detected from 37 to 1198 days (mean, 366 days; median, 227 days) and blood positivity from 23 to 1069 days (mean, 216 days; median, 90 days). Among BK-positive patients, 26 (53%) were detected within the first 6 months and 38 (76%) within the first year. With reduction in immunosuppression, there was gradual reduction or elimination of positive PCR tests in all cases except one, which resulted in graft failure. Conclusions. Routine BK virus surveillance is effective; it tends to detect BK virus replication early, allowing reduction of immunosuppression, which results in good outcomes with renal preservation. he prevalence of BK virus (BKV) after kidney transplantation has increased over the past decade. It has now become an important cause of graft dysfunction and loss.1 Once BKV-associated nephropathy is established, long-term graft outcome is poor.2 Detecting the virus early and then reducing immunosuppression appear to be the best approach to reduce the incidence of BK virus nephropathy, because there is not yet a safe antiviral treatment for BKV.1 We started a universal screening program for all of
T
From the Section of Transplantation, Department of Surgery (A.G., V.P., L.P., J.O., M.N.) and Section of Renal Medicine (J.F.), Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts. Address correspondence to Amitabh Gautam, MD, FRCS, 88 East Newton Street D511, Boston MA 02118, USA. E-mail: [email protected]
0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2010.09.066
© 2010 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
4088
Transplantation Proceedings, 42, 4088 – 4090 (2010)
BK VIRUS IN RENAL TRANSPLANTATION
our kidney transplant recipients, namely, regular BKV polymerase chain reaction (PCR) urine testing in 2005. Herein we reviewed our experience in patients with ⱖ6 months’ follow-up. METHODS Study Design This retrospective chart review of all renal transplant recipients from January 2005 to February 2010 includes patients with ⱖ6 months’ follow-up. Patient data were collected prospectively in an Electronic Medical Record (Logician and Sunrise Clinical Manager) through physician clinical notes, medication lists, and examination and laboratory test reports. Surveillance for BK virus consisted of quantitative PCR testing on urine samples starting at 4 weeks after transplantation. If negative, they were continued every 4 weeks for 6 months and then every 3– 4 months. If the test was positive, urine and blood BK virus PCR was done on the next visit and repeated every 2– 4 weeks as the patient was followed with slow reduction in immunosuppression. The quantitative range of this assay is 2.6 – 8.6 log copies/mL (390 –390,000,000 copies/mL).
Immunosuppression Induction immunosuppression consisted of either 2 doses of interleukin-2 receptor antagonist (IL2RA; basiliximab or zenapax) or rabbit antithymocyte globulin (ATG; total, 4.5–5 mg/kg body weight in 3– 4 divided doses). Maintenance immunosuppression consisted of prednisone (reduced to 5 mg/d by 8 weeks), tacrolimus (Prograf) with a target trough level 9 –12 ng/mL for 0 – 60 days and 4 –7 ng/mL subsequently, and mycophenolate mofetil (MMF; Myfortic or Cellcept). Sirolimus (Rapamune) was substituted for tacrolimus after 3 months in some patients. Since September 2009, we have initiated early steroid cessation by day 7 in selected patients after induction with ATG. Renal biopsy was not done routinely after the diagnosis of BK viremia, only when there was an unexplained deterioration in renal function including a suspicion for allograft rejection.
Statistics Differences in variables among groups were tested with Student t test for continuous variables and chi-square for multiple categoric variables. Analysis of variance for differences in means and Fisher exact test for categoric variables were used for smaller samples. All statistical tests were 2 tailed. Determinations for significance were based on 95% confidence intervals (P ⬍ .05). All tests were calculated using Microsoft Excel.
RESULTS
Between January 2005 and February 2010, we performed 173 kidney transplantations in 170 patients (3 retransplantation patients). There were 12 early graft failures: 6 deaths, including 5 from cardiac complication and 1 from a donorderived lymphocytic choriomeningitis virus infection, and 6 graft losses without death, including 4 from graft thromboses and 2 from infections within 12 weeks of transplantation. These cases were removed from further analysis. Therefore, the study group consisted of 161 subjects. In 112 patients (70%), the surveillance BK virus PCR in the urine was never positive; 18 patients (11%) showed only BK viruria with no viremia, and 31 (19%) showed BK viremia.
4089
Patient and Graft Survival
During the follow-up, 4 patients died, thus yielding a survival rate of 98%. These 4 patients were free of BK virus throughout their courses. Two patients died from cardiac complications; 1 from liver failure, and 1 from respiratory failure. In addition to patient deaths, 4 other late graft losses included 3 patients due to noncompliance with immunosuppressive medications and 1 sustained viremia causing graft loss. The overall graft survival rate was 95%. BK virus was first detected in urine from 37 to 1198 days after transplantation (mean, 366 days; median, 227 days) among patients with only BK viruria and from 23 to 1069 days (mean, 216 days; median, 90 days) among patients with BK viremia as well (P ⫽ .0395). Among all BK-positive patients, 26 (53%) were detected within the first 6 months and 38 (76%) within the first year after transplantation. There were 97 male and 64 female subjects in the study sample. Men exhibited a higher rate of BK viremia (26%) compared with women (9%; P ⫽ .041). The mean maximum urine BKV-PCR level in viremia patients (2.7 ⫻ 108) was significantly greater than that in viruria-only patients (3.8 ⫻ 106; P ⫽ 2.15 ⫻ 10⫺8). The mean maximum BK viremia PCR level was 2.4 ⫻ 105 copies/mL; median, 2.0 ⫻ 104; and range, 7.9 ⫻ 102 to 2.5 ⫻ 106. Effect of Type of Induction Immunosuppression and Delayed Graft Function
Induction immunosuppression consisted of IL2RA in 102 (63%) and ATG in 59 (37%) patients. The type of induction showed no significant effect on the incidence of BK viremia or viruria (Table 1). The mean time to first detection of BK virus was also not significantly different (P ⫽ .1621) between ATG- (mean, 199 days; median, 90 days; range, 26 –1198 days) compared with IL2RA-treated subjects (mean, 321 days; median, 195 days; range, 23–1077 days). Delayed graft function was observed in 39 (24%) patients. Its absence or presence had no significant impact on the incidence of BK viruria or viremia (Table 1). Renal Function
For all patients with a functioning graft, the mean creatinine level was 1.48 ⫾ 1.2 mg/dL (median, 1.33). The mean creatinine levels were higher for patients with BK viremia (1.62 ⫾ 1.5 mg/dL) and BK viruria (1.55 ⫾ 1.7 mg/dL) than Table 1. Incidence of BK Virus with Induction Agent and Presence or Absence of Delayed Graft Function (DGF) No BK BK Viruria Only (%) (n ⫽ 112) (%) (n ⫽ 18)
Induction agent IL-2RA Thymoglobulin P value No DGF DGF P value
73 (72) 39 (66) .468 86 (70) 26 (67) .651
11 (11) 7 (12) .834 12 (10) 6 (15) .338
BK Viremia (%) (n ⫽ 31)
Total (%) (n ⫽ 161)
18 (17) 13 (22) .496 24 (20) 7 (18) .812
102 (100) 59 (100) 122 (100) 39 (100)
4090
for patients with no BK virus (1.43 ⫾ 1.0 mg/dL); however, the difference was not significant (P ⫽ .0983). Sustained viremia or viruria, as defined by BK positivity for a period ⬎3 months, occurred in 15/31 viremia cases and 11/18 viruria cases. Ten viremia patients eventually cleared over time, but 5/31 viremia cases never cleared. Eight of 18 sustained viruria cases never cleared; and 9 cleared viremia cases still exhibited sustained viruria. Two of the viremia cases that never cleared had ongoing reduction of immunosuppression; each patient’s BK viremia had persisted for ⬍8 months. Three chronic viremia patients exhibited viremia for ⱖ30 months. However, the most recent values for chronic BK viremia were 2150, 2550, and 5030 copies/mL. All 3 patients did not show any increase in serum creatinine over this period. The renal function of patients with sustained viremia (mean serum creatinine 1.62 ⫾ 1.1 mg/dL) was not significantly different (P ⫽ .993) from that of patients with transient viremia (serum creatinine 1.61 ⫾ 1.1 mg/dL). Renal Biopsies and Rejection
Renal biopsies were performed as clinically necessary; there were 8 instances of rejection. In 2 patients, BK viremia was detected first; the subsequent reduction in immunosuppression caused an acute rejection episode. Four patients treated for acute rejection with a subsequent increase in maintenance immunosuppression resulted in BK viruria and BK viremia (n ⫽ 2 each). Two patients displayed BK viremia shortly after treatment of antibody–mediated rejection; treatment with leflunomide led to clearance of BK viremia. Immunosuppression Reduction for BK Virus
After detection of BK virus, gradual reduction of immunosuppression was performed in all of the patients. It initially consisted of lowering the MMF and tacrolimus doses with a faster prednisone taper. Since September 2009, 9 patients have been on a steroid-free protocol; 2 of them developed BK viremia. In these patients, decreased MMF and tacrolimus doses resulted in decreasing BK viremia. Among the remaining 47 patients with BK virus during maintenance triple immunosuppression, 1 was weaned off prednisone and 4 had MMF stopped because of sustained viremia. In 7 patients with BK viremia, leflunomide was substituted for MMF, and 1 had leflunomide substituted for tacrolimus. In 6 patients, sirolimus was substituted for tacrolimus owing to chronic allograft nephropathy. Therefore, 28 patients were kept on the the 3-drug regimen of prednisone, tacrolimus, and MMF. Among these 28 patients, 15 showed BK viremia and 13 BK viruria only. Thus, 15/31 viremia patients (48%)
GAUTAM, PATEL, PELLETIER ET AL
remained on 3 medications, whereas 13/18 viruria patients (72%) remained on 3 medications. DISCUSSION
The incidence of BK virus infection after kidney transplantation has been reported to be between 10% and 45%.3 These cases usually present with viruria with about 13% progressing to viremia and 8% to nephropathy.4 It is presumed that the earliest test to detect virus replication in the transplanted kidney is the detection of BK viruria.1,2,4 A screening test to detect this progression would provide a basis for further close monitoring of viral replication and renal function in these patients. The overall incidence of BK virus activation among 30% of our kidney transplant patients was consistent with published series.3,5 Out of this group, 19% progressed to viremia; however, with reduction of immunosuppression there was only 1 case of graft loss due to persistent nephropathy and fibrosis. In about twothirds of the patients with viruria and about one-half of the patients with viremia, this was achieved by gradual reduction of all 3 maintenance immunosuppression medications (tacrolimus, MMF, and prednisone). We did not routinely perform a renal allograft biopsy in patients with BK viremia if the kidney function remained stable and if the viral load improved with reduced immunosuppression. With close monitoring and a gradual reduction in immunosuppression, we had only 2 cases of rejection after immunosuppression reduction. Reactivation of BK virus can occur with increased immunosuppression after rejection treatment1; we had 4 such cases, emphasizing the need to continuously monitor BK virus. Our follow-up was short for some patients, but the strategy of universal screening and preemptive reduction of immunosuppression to halt continuing viral replication appears to be promising.6,7 REFERENCES 1. Hariharan S: BK virus nephritis after renal transplantation. Kidney Int 69:655, 2006 2. Wadei H, Rule A, Lewin M, et al: Kidney transplant function and histological clearance of virus following diagnosis of polyomavirusassociated nephropathy (PVAN). Am J Transplant 6:1025, 2006 3. Mannon R: Polyomavirus nephropathy: what have we learned. Transplantation 77:1313, 2004 4. Hirsch H, Knowles W, Dickenmann M, et al: Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med 347:488, 2002 5. Bohl DJ, Brennan DC: BK virus nephropathy and kidney transplantation. Clin J Am Soc Nephrol 2:S36, 2007 6. Hardinger KL, Koch MJ, Bohl DJ, et al: BK virus and the impact of pre-emptive immunosuppression reduction: 5-year results. Am J Transplant 10:407, 2010 7. Hirsch HH, Brennan DC, Drachenberg CB, et al: Polyomavirusassociated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation 79:1277, 2005
T
From the Section of Transplantation, Department of Surgery (A.G., V.P., L.P., J.O., M.N.) and Section of Renal Medicine (J.F.), Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts. Address correspondence to Amitabh Gautam, MD, FRCS, 88 East Newton Street D511, Boston MA 02118, USA. E-mail: [email protected]
0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2010.09.066
© 2010 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
4088
Transplantation Proceedings, 42, 4088 – 4090 (2010)
BK VIRUS IN RENAL TRANSPLANTATION
our kidney transplant recipients, namely, regular BKV polymerase chain reaction (PCR) urine testing in 2005. Herein we reviewed our experience in patients with ⱖ6 months’ follow-up. METHODS Study Design This retrospective chart review of all renal transplant recipients from January 2005 to February 2010 includes patients with ⱖ6 months’ follow-up. Patient data were collected prospectively in an Electronic Medical Record (Logician and Sunrise Clinical Manager) through physician clinical notes, medication lists, and examination and laboratory test reports. Surveillance for BK virus consisted of quantitative PCR testing on urine samples starting at 4 weeks after transplantation. If negative, they were continued every 4 weeks for 6 months and then every 3– 4 months. If the test was positive, urine and blood BK virus PCR was done on the next visit and repeated every 2– 4 weeks as the patient was followed with slow reduction in immunosuppression. The quantitative range of this assay is 2.6 – 8.6 log copies/mL (390 –390,000,000 copies/mL).
Immunosuppression Induction immunosuppression consisted of either 2 doses of interleukin-2 receptor antagonist (IL2RA; basiliximab or zenapax) or rabbit antithymocyte globulin (ATG; total, 4.5–5 mg/kg body weight in 3– 4 divided doses). Maintenance immunosuppression consisted of prednisone (reduced to 5 mg/d by 8 weeks), tacrolimus (Prograf) with a target trough level 9 –12 ng/mL for 0 – 60 days and 4 –7 ng/mL subsequently, and mycophenolate mofetil (MMF; Myfortic or Cellcept). Sirolimus (Rapamune) was substituted for tacrolimus after 3 months in some patients. Since September 2009, we have initiated early steroid cessation by day 7 in selected patients after induction with ATG. Renal biopsy was not done routinely after the diagnosis of BK viremia, only when there was an unexplained deterioration in renal function including a suspicion for allograft rejection.
Statistics Differences in variables among groups were tested with Student t test for continuous variables and chi-square for multiple categoric variables. Analysis of variance for differences in means and Fisher exact test for categoric variables were used for smaller samples. All statistical tests were 2 tailed. Determinations for significance were based on 95% confidence intervals (P ⬍ .05). All tests were calculated using Microsoft Excel.
RESULTS
Between January 2005 and February 2010, we performed 173 kidney transplantations in 170 patients (3 retransplantation patients). There were 12 early graft failures: 6 deaths, including 5 from cardiac complication and 1 from a donorderived lymphocytic choriomeningitis virus infection, and 6 graft losses without death, including 4 from graft thromboses and 2 from infections within 12 weeks of transplantation. These cases were removed from further analysis. Therefore, the study group consisted of 161 subjects. In 112 patients (70%), the surveillance BK virus PCR in the urine was never positive; 18 patients (11%) showed only BK viruria with no viremia, and 31 (19%) showed BK viremia.
4089
Patient and Graft Survival
During the follow-up, 4 patients died, thus yielding a survival rate of 98%. These 4 patients were free of BK virus throughout their courses. Two patients died from cardiac complications; 1 from liver failure, and 1 from respiratory failure. In addition to patient deaths, 4 other late graft losses included 3 patients due to noncompliance with immunosuppressive medications and 1 sustained viremia causing graft loss. The overall graft survival rate was 95%. BK virus was first detected in urine from 37 to 1198 days after transplantation (mean, 366 days; median, 227 days) among patients with only BK viruria and from 23 to 1069 days (mean, 216 days; median, 90 days) among patients with BK viremia as well (P ⫽ .0395). Among all BK-positive patients, 26 (53%) were detected within the first 6 months and 38 (76%) within the first year after transplantation. There were 97 male and 64 female subjects in the study sample. Men exhibited a higher rate of BK viremia (26%) compared with women (9%; P ⫽ .041). The mean maximum urine BKV-PCR level in viremia patients (2.7 ⫻ 108) was significantly greater than that in viruria-only patients (3.8 ⫻ 106; P ⫽ 2.15 ⫻ 10⫺8). The mean maximum BK viremia PCR level was 2.4 ⫻ 105 copies/mL; median, 2.0 ⫻ 104; and range, 7.9 ⫻ 102 to 2.5 ⫻ 106. Effect of Type of Induction Immunosuppression and Delayed Graft Function
Induction immunosuppression consisted of IL2RA in 102 (63%) and ATG in 59 (37%) patients. The type of induction showed no significant effect on the incidence of BK viremia or viruria (Table 1). The mean time to first detection of BK virus was also not significantly different (P ⫽ .1621) between ATG- (mean, 199 days; median, 90 days; range, 26 –1198 days) compared with IL2RA-treated subjects (mean, 321 days; median, 195 days; range, 23–1077 days). Delayed graft function was observed in 39 (24%) patients. Its absence or presence had no significant impact on the incidence of BK viruria or viremia (Table 1). Renal Function
For all patients with a functioning graft, the mean creatinine level was 1.48 ⫾ 1.2 mg/dL (median, 1.33). The mean creatinine levels were higher for patients with BK viremia (1.62 ⫾ 1.5 mg/dL) and BK viruria (1.55 ⫾ 1.7 mg/dL) than Table 1. Incidence of BK Virus with Induction Agent and Presence or Absence of Delayed Graft Function (DGF) No BK BK Viruria Only (%) (n ⫽ 112) (%) (n ⫽ 18)
Induction agent IL-2RA Thymoglobulin P value No DGF DGF P value
73 (72) 39 (66) .468 86 (70) 26 (67) .651
11 (11) 7 (12) .834 12 (10) 6 (15) .338
BK Viremia (%) (n ⫽ 31)
Total (%) (n ⫽ 161)
18 (17) 13 (22) .496 24 (20) 7 (18) .812
102 (100) 59 (100) 122 (100) 39 (100)
4090
for patients with no BK virus (1.43 ⫾ 1.0 mg/dL); however, the difference was not significant (P ⫽ .0983). Sustained viremia or viruria, as defined by BK positivity for a period ⬎3 months, occurred in 15/31 viremia cases and 11/18 viruria cases. Ten viremia patients eventually cleared over time, but 5/31 viremia cases never cleared. Eight of 18 sustained viruria cases never cleared; and 9 cleared viremia cases still exhibited sustained viruria. Two of the viremia cases that never cleared had ongoing reduction of immunosuppression; each patient’s BK viremia had persisted for ⬍8 months. Three chronic viremia patients exhibited viremia for ⱖ30 months. However, the most recent values for chronic BK viremia were 2150, 2550, and 5030 copies/mL. All 3 patients did not show any increase in serum creatinine over this period. The renal function of patients with sustained viremia (mean serum creatinine 1.62 ⫾ 1.1 mg/dL) was not significantly different (P ⫽ .993) from that of patients with transient viremia (serum creatinine 1.61 ⫾ 1.1 mg/dL). Renal Biopsies and Rejection
Renal biopsies were performed as clinically necessary; there were 8 instances of rejection. In 2 patients, BK viremia was detected first; the subsequent reduction in immunosuppression caused an acute rejection episode. Four patients treated for acute rejection with a subsequent increase in maintenance immunosuppression resulted in BK viruria and BK viremia (n ⫽ 2 each). Two patients displayed BK viremia shortly after treatment of antibody–mediated rejection; treatment with leflunomide led to clearance of BK viremia. Immunosuppression Reduction for BK Virus
After detection of BK virus, gradual reduction of immunosuppression was performed in all of the patients. It initially consisted of lowering the MMF and tacrolimus doses with a faster prednisone taper. Since September 2009, 9 patients have been on a steroid-free protocol; 2 of them developed BK viremia. In these patients, decreased MMF and tacrolimus doses resulted in decreasing BK viremia. Among the remaining 47 patients with BK virus during maintenance triple immunosuppression, 1 was weaned off prednisone and 4 had MMF stopped because of sustained viremia. In 7 patients with BK viremia, leflunomide was substituted for MMF, and 1 had leflunomide substituted for tacrolimus. In 6 patients, sirolimus was substituted for tacrolimus owing to chronic allograft nephropathy. Therefore, 28 patients were kept on the the 3-drug regimen of prednisone, tacrolimus, and MMF. Among these 28 patients, 15 showed BK viremia and 13 BK viruria only. Thus, 15/31 viremia patients (48%)
GAUTAM, PATEL, PELLETIER ET AL
remained on 3 medications, whereas 13/18 viruria patients (72%) remained on 3 medications. DISCUSSION
The incidence of BK virus infection after kidney transplantation has been reported to be between 10% and 45%.3 These cases usually present with viruria with about 13% progressing to viremia and 8% to nephropathy.4 It is presumed that the earliest test to detect virus replication in the transplanted kidney is the detection of BK viruria.1,2,4 A screening test to detect this progression would provide a basis for further close monitoring of viral replication and renal function in these patients. The overall incidence of BK virus activation among 30% of our kidney transplant patients was consistent with published series.3,5 Out of this group, 19% progressed to viremia; however, with reduction of immunosuppression there was only 1 case of graft loss due to persistent nephropathy and fibrosis. In about twothirds of the patients with viruria and about one-half of the patients with viremia, this was achieved by gradual reduction of all 3 maintenance immunosuppression medications (tacrolimus, MMF, and prednisone). We did not routinely perform a renal allograft biopsy in patients with BK viremia if the kidney function remained stable and if the viral load improved with reduced immunosuppression. With close monitoring and a gradual reduction in immunosuppression, we had only 2 cases of rejection after immunosuppression reduction. Reactivation of BK virus can occur with increased immunosuppression after rejection treatment1; we had 4 such cases, emphasizing the need to continuously monitor BK virus. Our follow-up was short for some patients, but the strategy of universal screening and preemptive reduction of immunosuppression to halt continuing viral replication appears to be promising.6,7 REFERENCES 1. Hariharan S: BK virus nephritis after renal transplantation. Kidney Int 69:655, 2006 2. Wadei H, Rule A, Lewin M, et al: Kidney transplant function and histological clearance of virus following diagnosis of polyomavirusassociated nephropathy (PVAN). Am J Transplant 6:1025, 2006 3. Mannon R: Polyomavirus nephropathy: what have we learned. Transplantation 77:1313, 2004 4. Hirsch H, Knowles W, Dickenmann M, et al: Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med 347:488, 2002 5. Bohl DJ, Brennan DC: BK virus nephropathy and kidney transplantation. Clin J Am Soc Nephrol 2:S36, 2007 6. Hardinger KL, Koch MJ, Bohl DJ, et al: BK virus and the impact of pre-emptive immunosuppression reduction: 5-year results. Am J Transplant 10:407, 2010 7. Hirsch HH, Brennan DC, Drachenberg CB, et al: Polyomavirusassociated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation 79:1277, 2005