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Polyomavirus BK Replication in Adult Polycystic Kidney Disease Post–Renal Transplant Patients and Possible Role of Cellular Permissivity
Polyomavirus BK Replication in Adult Polycystic Kidney Disease Post–Renal Transplant Patients and Possible Role of Cellular Permissivity A.P. Mitterhofer, F. Tinti, V. Pietropaolo, M. Barile, F. Chiarini, A. Meçule, G. Ferretti, L. Poli, P.B. Berloco, and G. Taliani ABSTRACT Cell division and differentiation but not proliferation seem to be necessary for BK virus (BKV) replication and reactivation of persistent infection. Only terminal differentiating cells are permissive to BKV replication. Renal tubular epithelial cells in human adult polycystic kidney disease (ADPKD) are characterized by increased proliferative activity leading to cyst growth with less cellular differentiation. The aim of this study was to evaluate the possibility of different BKV replication patterns in patients with polycystic kidney disease versus non-ADPKD patients. From May 2006 to April 2008, we performed renal transplantations in 47. Eleven patients were affected by ADPKD (Pc group) and 36 patients, non ADPKD (n-Pc group). BKV replication was evaluated by quantitative real-time polymerase chain reactions (PCR) on plasma and urine samples at 12 hours (T0/early) as well as 3 (T3) and 6 (T6) months after transplantation. BKV viremia occurred in 9%, 12.5%, and 20% among the Pc group versus 33.3%, 42.4%, and 50% among the n-Pc group at 12 hours as well as 3 and 6 months posttransplantation, respectively. A higher discordance (BKV-PCR blood ⫺/urine ⫹) was observed in plasma and urine BKV replication among Pc versus n-Pc groups. We hypothesized that the lower number of patients with active BKV plasma replication in the Pc group may be related to a lower cellular permissivity of the renal tubular epithelial cells in ADPKD. RIMARY INFECTION WITH BK VIRUS (BKV) seems to be restricted to a specific, permissive cell type, newborn differentiating nonciliated epithelial cells (Clara cells) of the bronchi and bronchioles. This permissivity to BKV replication decreases in the adult lung due to a reduction among fully functional cell types responsible for BKV replication.1 Primary BKV infection is followed by dissemination to the kidney and urinary tract, in particular to renal proximal tubule epithelial cells, where the virus establishes a lifelong persistent infection.2 Cellular division and differentiation but not proliferation seem necessary for BKV replication and for reactivation of persistent infection; only terminal differentiating cells are indeed permissive to BKV replication.3 BKV infection remains asymptomatic in immunocompetent individuals, as confirmed by no evidence of BKV replication in healthy subjects.4 Polyomavirus-associated nephropathy (PVAN) in kidney transplant patients has an incidence ranging from 1% to 10% with graft loss among 50% of cases.5 BKV
P
viremia detected with polymerase chain reaction (PCR) is a sensitive, specific replication marker developed as a screening method for this infection.6,7 Risk factors for PVAN are related to the features of the recipients, the donors, the grafts and the virus. PVAN seems to show a predilection for renal transplant recipients as compared with the native kidneys of patients with other types of transplantations.8 From the Department of Clinical Medicine, Nephrology and Dialysis Unit (A.P.M., M.B., F.T., A.M.); Department of Science and Public Health (V.P., F.C.); Department of Infectious and Tropical Diseases (G.F., G.T.); and Department of General Surgery, Organ Transplant Unit “Paride Stefanini,” (L.P., P.B.B.); Sapienza University of Rome, Rome, Italy. This study was supported by the Consorzio Interuniversitario per I Trapianti. Address reprint requests to Anna Paola Mitterhofer, Viale dell’Università 37, 00185 Rome, Italy. E-mail: annapaola.mitter@ uniroma1.it
0041-1345/11/$–see front matter doi:10.1016/j.transproceed.2011.02.046
© 2011 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
1048
Transplantation Proceedings, 43, 1048 –1051 (2011)
POLYOMAVIRUS BK REPLICATION
Graft-associated factors related to local cell permissivity to BKV replication include tissue injury from ischemiareperfusion, acute rejection, allosensitization, and human leukocyte antigen HLA mismatch, all conditions associated with reactive cell division and differentiation.2 Posttransplant immunosuppression is considered to be the primary risk factor for the onset of BKV replication, but differential effects of antirejection therapy on cell proliferation may play a role in cellular permissiveness to BKV replication.5 In a study of adult mice with a genetic form of polycystic kidney disease, it was demonstrated that kidney epithelial cells proliferate but do not differentiate into tubular cells, showing low cellular permissivity for BKV replication.9 Renal tubular epithelial cells in human adult polycystic kidney disease (ADPKD) are characterized by increased proliferative activity leading to cyst proliferation with less cellular differentiation.10 In humans with ADPKD, BKV replication has rarely been evaluated. Polycystic kidney disease accounts for 8% to 10% of cases of end-stage renal desease, emerging as the third most common cause for kidney transplantation.11,12 The presence of BKV infection is detectable from the first hours after kidney transplantation.13 BK virus replication has rarely been studied in relation to the underlying renal disease. The aim of our study was to evaluate the possible differential replication of BKV among transplanted patients with ADPKD versus non-ADPKD etiologies.
MATERIALS AND METHODS From May 2006 to April 2008, we enrolled 47 patients including 29 males and 18 females, undergoing renal transplantation. Among this group, 11 subjects were affected by ADKD (Pc group) and 36, non-ADKD (n-Pc group). We evaluated BKV replication by quantitative real-time PCR using plasma and urine samples at 12 hours (T0/early) as well as 3 (T3) and 6 (T6) months after kidney transplantation. All patients were prescribed induction therapy with an interleukin-2 receptor blocker (basiliximab) and potent maintenance immunosuppression with mycophenolate mofetil, tacrolimus/cyclosporine, and steroid. Recipient clinical data considered age and gender, presence of hepatitis C and B, cytomegalovirus infection, diabetes mellitus, months of renal replacement therapy, and retransplantation. Donor characteristics included age, gender, weight, body mass index, cause of death, histological score, and cold ischemia time of the grafts (Table 1). A real-time PCR method quantitated BKV load in plasma and urine samples as previously described.13 Briefly, DNA extraction was performed by the DNeasy Tissue Kit (QIAGEN S.p.A., Milan, Italy) according to the manufacturer’s instructions. The assay was performed using the 7300 Real Time PCR System (AB Applied Biosystems, 850 Lincoln Centre DriveFoster City, Calif, USA). Standard curves to quantitate the viral genome were constructed using serial dilutions of a plasmid containing the target sequences (large T antigen). The results were expressed as copies of viral DNA per milliliter (c/mL) of sample. We followed standard precautions to prevent contamination.
1049 Table 1. Recipient, Donor, and Graft Characteristic in Pc and Non-Pc Patients Patients (n ⫽ 47)
Recipient characteristics Age, y (median ⫾ SD) Weight, kg (median ⫾ SD) BMI (median ⫾ SD) Male, n (%) CMV IgG positivity, n (%) HBV infection HCV infection Diabetes Retransplant RRT months (median ⫾ SD) Transplant type Donor characteristics Age, y (median ⫾ SD) BMI (median ⫾ SD) Gender (M/F) Cause of death, n (%) Subarachnoid hemorrhage Polytrauma Postischemic Graft Score, n (%) 1 2 3 4 Ischemic time, h (median ⫾ SD)
Pc (n ⫽ 11)
Non-Pc (n ⫽ 36)
P
48.9 ⫾ 5.1 68.4 ⫾ 10 23.5 ⫾ 3.7 7 (63.6) 4 (36.3) 1 (9) None None None 31.2 ⫾ 19.5
49.9 ⫾ 10.5 69 ⫾ 13.4 24 ⫾ 3.6 22 (61) 16 (44) None 1 (3) 1 (3) 1/36 52 ⫾ 59.8
NS NS NS NS NS NS NS NS NS NS
LD 0, CAD 11
LD 1, CAD 35
NS
51.4 ⫾ 13.9 24.6 ⫾ 3.2 4/7
51 ⫾ 14.6 25 ⫾ 3.8 21/15
NS
7 (63.6)
25 (80)
NS
4 (36.3) 0 (0)
5 (16) 1 (3)
NS NS
4/11 1 (9) 2 (18) 1 (9) 0 (0) 16.4 ⫾ 2.3
9/36 2 (22) 3 (33) 2 (22) 2 (22) 15.3 ⫾ 2.8
NS
NS NS NS NS NS
BMI: body mass index; CMV: cytomegalovirus; HBV: hepatitis B virus; HCV: hepatitis C virus; RRT: renal replacement therapy; Pc, polycystic group; Non-Pc, nonpolycystic group; SD, standard deviation; IgG, immunoglobulin G; LD, living donor; CAD, cadaveric donor; NS, not significant.
Statistical Analysis All patients entered the analysis. Comparison of values was performed using the chi-square test for categorical variables and by the Mann-Whitney test for continuous variables. Data analysis employed the SPSS statistical package for Windows version 18.0 (SPSS Inc, Chicago, Ill, USA) with a P value of ⬍ .05 considered significant.
RESULTS
In the Pc group, BKV viremia occurred in 1/11 (9%) at 12 hours posttransplantation; 1/8 (12.5%) at three and 1/5 (20%) at 6 months while viruria was present in 8/11 (72%), 3/8 (37.5%), and 3/6 (50%) at the respective times (Fig 1). In the n-Pc group, BK viremia occurred in 12/36 patients (33.3%) at T0; 14/33 (42.4%) at T3; and 16/32 (50%) at T6, with viruria in 21/36 (58.3%) at T0; 18/33 (54.5%) at T3; and 20/32 (62.5%) at T6 (Fig 1). A lower number of patients with active BKV plasma replication was found in Pc versus n-Pc group. This difference was not evidenced in urine replication. We observed a trend to an higher albeit not significant discordance (BKV-PCR blood -/urine ⫹) in
1050
MITTERHOFER, TINTI, PIETROPAOLO ET AL
DISCUSSION
Fig 1. BK virus (BKV) replication in polycystic (Pc) and non-polycystic (n-Pc) groups. (A) Percentage of polymerase chain reaction (PCR) BKV plasma-positive patients. (B) Percentage of PCR BKV urine-positive patients. (C) Percentage of PCR BKV urine-positive/plasma-negative patients (discordant replication patients). T0, 12 hours post– kidney transplant; T3, 3 months post– kidney transplant; T6, 6 months post– kidney transplant.
plasma versus urine BKV replication in the Pc versus n-Pc groups (Fig 1C). The differences between the two groups were not significant for BKV load in plasma and urine (data not shown). Moreover, we did not find any association between BKV plasma and/or urine replication and recipient characteristics (age gender, time of dialysis, etiology of renal failure, or immunosuppressive therapy), donor parameters (age, gender, weight, body mass index, and cause of death), or graft features (score, ischemic time) (data not shown).
Many factors are involved in the development of BKV infection among transplanted patients: immunosuppressive therapy, positive donors/negative recipients, graft ischemiareperfusion injury, and BKV predilection for kidney versus other solid organ transplants. The theory of a differential cell permissivity for polyomavirus replication may account for the most of these risk factors, as showed by experiments in newborn mice as well as in mouse kidneys after ischemic or chemical damage.9 The underlying renal disease may influence BKV replication,3 but few studies are available on this subject in humans. Renal tubular epithelial cells in ADPKD are characterized by a proliferative but nondifferentiated state. In our study, a greater prevalence of plasma viral replication in n-Pc patients was observed compared to the Pc group, early or at 3 and 6 months after transplantation. We hypothesized that this result may reflect reduced cellular permissivity to BKV replication in renal tubular cells of ADPKD patients. The difference in prevalence of viral replication between the two groups was not detectable among urine viral replication tests, confirmed by results on plasma/urine discordance. In our opinion these results would be suggestive for a different origin of plasma and urine replication from native kidney and graft respectively. Moreover, immunosuppressive therapy may have a role in cellular permissiveness. In particular, experimental and observational studies suggest that the mammalian target of rapamycin (m-TOR) pathway plays a critical role in cyst growth14; m-TOR inhibitors suppress cyst growth in animal models. Therefore, the effects of immunosuppressive drugs on cell proliferation may differential affect BKV replication. The main limitation of our study was the small sample size. Our results of our study, if confirmed in a larger series, may yield an interesting contribution to our understand of the renal transplant recipients’ role in BKV infections. REFERENCES 1. Gottlieb KA, Vilarreal LP: Natural biology of polyomavirus middle T antigen. Microbiol Mol Biol Rev 65:288, 2001 2. Jiang M, Abend JR, Tsai B, et al: Early events during BK virus entry and disassembly. J Virol 83:1350, 2009 3. Atencio IA, Villarreal LP: Polyomavirus replicates in differentiating but not in proliferating tubules of adult mouse polycystic kidneys. Virology 201:26, 1994 4. Egli A, Infanti L, Dumoulin A, et al: Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. J Infect Dis 199:837, 2009 5. Hirsch HH, Brennan DC, Drachenberg CB, et al: Polyomavirus associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation 79:1277, 2005 6. Vasudev B, Hariharan S, Hussain SA, et al: BK virus nephritis: risk factors. Timing, and outcome in renal transplant recipients. Kidney Int 68:1834, 2005 7. Kidney disease: improving global outcomes (KDIGO) transplant work group. KDIGO clinical practice guideline for
POLYOMAVIRUS BK REPLICATION the care of kidney transplant recipients. Am J Transplant 9(suppl 3):S1, 2009 8. Puliyanda DP, Amet N, Dhawan A, et al: Isolated heart and liver transplant recipients are at low risk for polyomavirus BKV nephropathy. Clin Transplant 20:289, 2006 9. Atencio IA, Shadan FF, Zhou ND, et al: Adult mouse kidneys become permissive to acute polyomavirus infection and reactivate persistent infections in response to cellular damage and regeneration. J Virol 67:1424, 1993 10. Al-Bhalal L, Akhtar M: Molecular basis of autosomal dominant polycystic kidney disease Adv Anat Pathol 12:126, 2005
1051 11. Gabow PA: Autosomal dominant polycystic kidney disease. N Engl J Med 329:332, 1993 12. Bretagnol A, Büchler M, Boutin J, et al: Renal transplantation in patients with autosomal dominant polycystic kidney disease: pre-transplantation evaluation and follow-up. Nephrol Ther 3:449, 2007 13. Mitterhofer AP, Pietropaolo V, Barile M, et al: Meaning of early polyomavorus-BK replication post kidney transplant. Transplant Proc 42:1142, 2010 14. Tao Y, Kim J, Schrier RW, et al: Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. J Am Soc Nephrol 16:46, 2005
P
viremia detected with polymerase chain reaction (PCR) is a sensitive, specific replication marker developed as a screening method for this infection.6,7 Risk factors for PVAN are related to the features of the recipients, the donors, the grafts and the virus. PVAN seems to show a predilection for renal transplant recipients as compared with the native kidneys of patients with other types of transplantations.8 From the Department of Clinical Medicine, Nephrology and Dialysis Unit (A.P.M., M.B., F.T., A.M.); Department of Science and Public Health (V.P., F.C.); Department of Infectious and Tropical Diseases (G.F., G.T.); and Department of General Surgery, Organ Transplant Unit “Paride Stefanini,” (L.P., P.B.B.); Sapienza University of Rome, Rome, Italy. This study was supported by the Consorzio Interuniversitario per I Trapianti. Address reprint requests to Anna Paola Mitterhofer, Viale dell’Università 37, 00185 Rome, Italy. E-mail: annapaola.mitter@ uniroma1.it
0041-1345/11/$–see front matter doi:10.1016/j.transproceed.2011.02.046
© 2011 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
1048
Transplantation Proceedings, 43, 1048 –1051 (2011)
POLYOMAVIRUS BK REPLICATION
Graft-associated factors related to local cell permissivity to BKV replication include tissue injury from ischemiareperfusion, acute rejection, allosensitization, and human leukocyte antigen HLA mismatch, all conditions associated with reactive cell division and differentiation.2 Posttransplant immunosuppression is considered to be the primary risk factor for the onset of BKV replication, but differential effects of antirejection therapy on cell proliferation may play a role in cellular permissiveness to BKV replication.5 In a study of adult mice with a genetic form of polycystic kidney disease, it was demonstrated that kidney epithelial cells proliferate but do not differentiate into tubular cells, showing low cellular permissivity for BKV replication.9 Renal tubular epithelial cells in human adult polycystic kidney disease (ADPKD) are characterized by increased proliferative activity leading to cyst proliferation with less cellular differentiation.10 In humans with ADPKD, BKV replication has rarely been evaluated. Polycystic kidney disease accounts for 8% to 10% of cases of end-stage renal desease, emerging as the third most common cause for kidney transplantation.11,12 The presence of BKV infection is detectable from the first hours after kidney transplantation.13 BK virus replication has rarely been studied in relation to the underlying renal disease. The aim of our study was to evaluate the possible differential replication of BKV among transplanted patients with ADPKD versus non-ADPKD etiologies.
MATERIALS AND METHODS From May 2006 to April 2008, we enrolled 47 patients including 29 males and 18 females, undergoing renal transplantation. Among this group, 11 subjects were affected by ADKD (Pc group) and 36, non-ADKD (n-Pc group). We evaluated BKV replication by quantitative real-time PCR using plasma and urine samples at 12 hours (T0/early) as well as 3 (T3) and 6 (T6) months after kidney transplantation. All patients were prescribed induction therapy with an interleukin-2 receptor blocker (basiliximab) and potent maintenance immunosuppression with mycophenolate mofetil, tacrolimus/cyclosporine, and steroid. Recipient clinical data considered age and gender, presence of hepatitis C and B, cytomegalovirus infection, diabetes mellitus, months of renal replacement therapy, and retransplantation. Donor characteristics included age, gender, weight, body mass index, cause of death, histological score, and cold ischemia time of the grafts (Table 1). A real-time PCR method quantitated BKV load in plasma and urine samples as previously described.13 Briefly, DNA extraction was performed by the DNeasy Tissue Kit (QIAGEN S.p.A., Milan, Italy) according to the manufacturer’s instructions. The assay was performed using the 7300 Real Time PCR System (AB Applied Biosystems, 850 Lincoln Centre DriveFoster City, Calif, USA). Standard curves to quantitate the viral genome were constructed using serial dilutions of a plasmid containing the target sequences (large T antigen). The results were expressed as copies of viral DNA per milliliter (c/mL) of sample. We followed standard precautions to prevent contamination.
1049 Table 1. Recipient, Donor, and Graft Characteristic in Pc and Non-Pc Patients Patients (n ⫽ 47)
Recipient characteristics Age, y (median ⫾ SD) Weight, kg (median ⫾ SD) BMI (median ⫾ SD) Male, n (%) CMV IgG positivity, n (%) HBV infection HCV infection Diabetes Retransplant RRT months (median ⫾ SD) Transplant type Donor characteristics Age, y (median ⫾ SD) BMI (median ⫾ SD) Gender (M/F) Cause of death, n (%) Subarachnoid hemorrhage Polytrauma Postischemic Graft Score, n (%) 1 2 3 4 Ischemic time, h (median ⫾ SD)
Pc (n ⫽ 11)
Non-Pc (n ⫽ 36)
P
48.9 ⫾ 5.1 68.4 ⫾ 10 23.5 ⫾ 3.7 7 (63.6) 4 (36.3) 1 (9) None None None 31.2 ⫾ 19.5
49.9 ⫾ 10.5 69 ⫾ 13.4 24 ⫾ 3.6 22 (61) 16 (44) None 1 (3) 1 (3) 1/36 52 ⫾ 59.8
NS NS NS NS NS NS NS NS NS NS
LD 0, CAD 11
LD 1, CAD 35
NS
51.4 ⫾ 13.9 24.6 ⫾ 3.2 4/7
51 ⫾ 14.6 25 ⫾ 3.8 21/15
NS
7 (63.6)
25 (80)
NS
4 (36.3) 0 (0)
5 (16) 1 (3)
NS NS
4/11 1 (9) 2 (18) 1 (9) 0 (0) 16.4 ⫾ 2.3
9/36 2 (22) 3 (33) 2 (22) 2 (22) 15.3 ⫾ 2.8
NS
NS NS NS NS NS
BMI: body mass index; CMV: cytomegalovirus; HBV: hepatitis B virus; HCV: hepatitis C virus; RRT: renal replacement therapy; Pc, polycystic group; Non-Pc, nonpolycystic group; SD, standard deviation; IgG, immunoglobulin G; LD, living donor; CAD, cadaveric donor; NS, not significant.
Statistical Analysis All patients entered the analysis. Comparison of values was performed using the chi-square test for categorical variables and by the Mann-Whitney test for continuous variables. Data analysis employed the SPSS statistical package for Windows version 18.0 (SPSS Inc, Chicago, Ill, USA) with a P value of ⬍ .05 considered significant.
RESULTS
In the Pc group, BKV viremia occurred in 1/11 (9%) at 12 hours posttransplantation; 1/8 (12.5%) at three and 1/5 (20%) at 6 months while viruria was present in 8/11 (72%), 3/8 (37.5%), and 3/6 (50%) at the respective times (Fig 1). In the n-Pc group, BK viremia occurred in 12/36 patients (33.3%) at T0; 14/33 (42.4%) at T3; and 16/32 (50%) at T6, with viruria in 21/36 (58.3%) at T0; 18/33 (54.5%) at T3; and 20/32 (62.5%) at T6 (Fig 1). A lower number of patients with active BKV plasma replication was found in Pc versus n-Pc group. This difference was not evidenced in urine replication. We observed a trend to an higher albeit not significant discordance (BKV-PCR blood -/urine ⫹) in
1050
MITTERHOFER, TINTI, PIETROPAOLO ET AL
DISCUSSION
Fig 1. BK virus (BKV) replication in polycystic (Pc) and non-polycystic (n-Pc) groups. (A) Percentage of polymerase chain reaction (PCR) BKV plasma-positive patients. (B) Percentage of PCR BKV urine-positive patients. (C) Percentage of PCR BKV urine-positive/plasma-negative patients (discordant replication patients). T0, 12 hours post– kidney transplant; T3, 3 months post– kidney transplant; T6, 6 months post– kidney transplant.
plasma versus urine BKV replication in the Pc versus n-Pc groups (Fig 1C). The differences between the two groups were not significant for BKV load in plasma and urine (data not shown). Moreover, we did not find any association between BKV plasma and/or urine replication and recipient characteristics (age gender, time of dialysis, etiology of renal failure, or immunosuppressive therapy), donor parameters (age, gender, weight, body mass index, and cause of death), or graft features (score, ischemic time) (data not shown).
Many factors are involved in the development of BKV infection among transplanted patients: immunosuppressive therapy, positive donors/negative recipients, graft ischemiareperfusion injury, and BKV predilection for kidney versus other solid organ transplants. The theory of a differential cell permissivity for polyomavirus replication may account for the most of these risk factors, as showed by experiments in newborn mice as well as in mouse kidneys after ischemic or chemical damage.9 The underlying renal disease may influence BKV replication,3 but few studies are available on this subject in humans. Renal tubular epithelial cells in ADPKD are characterized by a proliferative but nondifferentiated state. In our study, a greater prevalence of plasma viral replication in n-Pc patients was observed compared to the Pc group, early or at 3 and 6 months after transplantation. We hypothesized that this result may reflect reduced cellular permissivity to BKV replication in renal tubular cells of ADPKD patients. The difference in prevalence of viral replication between the two groups was not detectable among urine viral replication tests, confirmed by results on plasma/urine discordance. In our opinion these results would be suggestive for a different origin of plasma and urine replication from native kidney and graft respectively. Moreover, immunosuppressive therapy may have a role in cellular permissiveness. In particular, experimental and observational studies suggest that the mammalian target of rapamycin (m-TOR) pathway plays a critical role in cyst growth14; m-TOR inhibitors suppress cyst growth in animal models. Therefore, the effects of immunosuppressive drugs on cell proliferation may differential affect BKV replication. The main limitation of our study was the small sample size. Our results of our study, if confirmed in a larger series, may yield an interesting contribution to our understand of the renal transplant recipients’ role in BKV infections. REFERENCES 1. Gottlieb KA, Vilarreal LP: Natural biology of polyomavirus middle T antigen. Microbiol Mol Biol Rev 65:288, 2001 2. Jiang M, Abend JR, Tsai B, et al: Early events during BK virus entry and disassembly. J Virol 83:1350, 2009 3. Atencio IA, Villarreal LP: Polyomavirus replicates in differentiating but not in proliferating tubules of adult mouse polycystic kidneys. Virology 201:26, 1994 4. Egli A, Infanti L, Dumoulin A, et al: Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. J Infect Dis 199:837, 2009 5. Hirsch HH, Brennan DC, Drachenberg CB, et al: Polyomavirus associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation 79:1277, 2005 6. Vasudev B, Hariharan S, Hussain SA, et al: BK virus nephritis: risk factors. Timing, and outcome in renal transplant recipients. Kidney Int 68:1834, 2005 7. Kidney disease: improving global outcomes (KDIGO) transplant work group. KDIGO clinical practice guideline for
POLYOMAVIRUS BK REPLICATION the care of kidney transplant recipients. Am J Transplant 9(suppl 3):S1, 2009 8. Puliyanda DP, Amet N, Dhawan A, et al: Isolated heart and liver transplant recipients are at low risk for polyomavirus BKV nephropathy. Clin Transplant 20:289, 2006 9. Atencio IA, Shadan FF, Zhou ND, et al: Adult mouse kidneys become permissive to acute polyomavirus infection and reactivate persistent infections in response to cellular damage and regeneration. J Virol 67:1424, 1993 10. Al-Bhalal L, Akhtar M: Molecular basis of autosomal dominant polycystic kidney disease Adv Anat Pathol 12:126, 2005
1051 11. Gabow PA: Autosomal dominant polycystic kidney disease. N Engl J Med 329:332, 1993 12. Bretagnol A, Büchler M, Boutin J, et al: Renal transplantation in patients with autosomal dominant polycystic kidney disease: pre-transplantation evaluation and follow-up. Nephrol Ther 3:449, 2007 13. Mitterhofer AP, Pietropaolo V, Barile M, et al: Meaning of early polyomavorus-BK replication post kidney transplant. Transplant Proc 42:1142, 2010 14. Tao Y, Kim J, Schrier RW, et al: Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. J Am Soc Nephrol 16:46, 2005