BK virus nephropathy is a challenging clinical problem in kidney transplant recipients with wide range of surveillance and management practices, based on individual experience. BK virus reactivation in kidney transplant recipients can result in BK virus nephropathy and graft loss. The most effective strategy for early diagnosis and treatment of BK virus nephropathy is regular monitoring for BK virus, currently achieved by quantification of viral DNA in blood by quantitative polymerase chain reaction. Immunosuppression re­duction remains the mainstay of treatment; however, viral clearance is often followed by acute rejection, likely secondary to a delay between immune reconstitution and viral clearance. Impaired cell-mediated immune response to BK virus has been shown to correlate with progression to BK virus nephropathy, while recon­stitution of this response correlates with resolution of nephropathy. There is recent research to support monitoring BK virus-specific cell-mediated immune response as a predictor of disease progression and resolution. In this article, we review the current concepts and recent developments in understanding BK virus-associated disease in the context of kidney transplant and outline areas for future research.

Key words : BK virus nephropathy, Cell-mediated immune response, Immunosuppression, Transplant

Introduction

BK polyomavirus continues to remain a challenging problem in kidney transplant recipients, with a wide range of surveillance and treatment practices, which are based on individual experience. We review the recent developments in understanding BK virus (BKV)-associated disease in the context of kidney transplant.

The first Polyomavirus (mouse polyomavirus) was identified in 1953 as filterable tumor-causing agent in mice, followed by Simian vacuolating virus (SV40) isolated from rhesus monkey kidney cells that had been used for poliovirus vaccine preparation in 1960. The discovery of the first human polyo­maviruses was in 1971 independently from each other; one was BKV isolated from a urine sample of a renal transplant patient and the other was JC virus isolated from the brain tissue of a patient with progressive multifocal leukoencephalopathy, with both named after the patients’ initials. BK and JC viruses were the only well-known human polyomaviruses for 36 years; however, a dramatic increase in the number of newly identified human polyomaviruses was recorded in the past 8 years due to the use of sophisticated molecular methods and new generation sequencing techno­logies.^1,2

BK virus is a nonenveloped virus with a genome of double-stranded circular DNA. Functionally, the genome consists of an early region that codes for the large and small T antigens involved in viral replication, a late region that codes for viral capsid proteins 1-3 and agnoprotein involved in viral assembly, and a noncoding control region that is required for viral gene expression and replication. BK virus strains are classified into genotypes 1 to 6 based on the polymorphisms in the viral capsid protein 1 region and the noncoding control region.³

Pathogenesis
Primary BK virus infection is acquired during childhood, most likely from person-to-person contact from respiratory secretions or urine; it usually manifests as mild respiratory infection or fever.⁴ The virus multiplies in the respiratory tract and then spreads to other organs through the bloodstream. BK virus remains clinically silent, in the kidneys, in immunocompetent hosts. It is usually reactivated by immunosuppression. Impairment of cell-mediated immune response has been associated with reactivation, which begins with active viral replication in the graft, followed by viral shedding in the urine, and finally viremia. Tubular epithelial cells are common targets, resulting in tubulointerstitial nephritis.⁵ Approximately 80% of the general population has detectable antibody to BKV, which appears early in life and persists throughout life.^6,7 BK virus reactivation in kidney transplant recipients is first evident by viral shedding in urine, which can be seen in 20% to 60% of patients. Incidence of BK viremia in kidney transplant recipients is about 13%, whereas BKV nephropathy is seen in nearly 8% of kidney transplant recipients and can result in allograft loss.^8-10 Data from the United Network for Organ Sharing have shown that graft loss attributable to BK virus-associated nephropathy was 7.5% (70/938) in 2009 and 5.7% (36/632) in 2010.¹¹

Immunosurveillance and Potential Applications
It is likely that humoral immune response alone does not play a significant role in preventing progression to BKV nephropathy, as patients with levels of anti-BKV antibodies similar to those of healthy individuals still develop BKV nephropathy.¹² Furthermore, high levels of antibodies in patients with BKV nephropathy correlate with high levels of viremia and low CD8-positive T-cell responses.¹³ A cellular immune response to BKV was demonstrated in normal individuals by Drummond and associates, who found that the cell-mediated immune response was important in preventing viral reactivation in healthy volunteers.¹⁴ This was further supported by a study of cellular immune response to JC virus in patients with progressive multifocal leuko­encephalopathy, in which Koralnik and associates found that JC virus-specific cytotoxic T lymphocytes were a key factor in containment of progressive multifocal leukoencephalopathy.¹⁵ Low levels of BKV-specific interferon gamma-producing T cells correlate with progression to BKV nephropathy, whereas reconstitution of these cells correlates with resolution of nephropathy.^13,16,17 Batal and associates measured global cell-mediated immune response in kidney transplant recipients with BKV infection using the Cylex ImmuKnow Test (Cylex, Columbia, MD, USA) and found that the mean ± standard deviation amounts of ATP released in recipients with BK viremia was 102.9 ± 58.6 ng/mL, versus 227.2 ± 146.4 ng/mL in those with viruria and 231.8 ± 150.8 ng/mL in those with no viremia or viruria (P = .002, viremia vs all other samples), showing that a decreased immune cell function test result correlates with active viral replication.¹⁸

Impaired BKV-specific cell-mediated immune response is associated with BKV nephropathy, and BKV-specific immune monitoring has been sug­gested as a prognostic tool to identify patients who are at risk of BKV nephropathy.^19-23 Monitoring pretransplant and posttransplant BKV-specific T cells was suggested by Schachtner and associates²⁴ as a sensitive marker to identify kidney transplant recipients at increased risk of BKV reactivation. They studied 24 recipients with BKV replication and compared these patients with a control group of 127 recipients without BKV replication. BK virus-specific and alloreactive T cells were measured using an interferon gamma Elispot assay. The extent of immunosuppression was quantified by lymphocyte subpopulations and interferon gamma levels. Recipients with a loss of BKV-specific T cells directed to large T-antigen from pretransplant to post­transplant were found to be at increased risk of BKV replication (P < .001), whereas recipients with stable or rising BKV-specific T cells were more likely to not develop BKV reactivation (P < .05). Recipients with BKV reactivation showed significantly lower CD3-positive, CD4-positive, and CD8-positive T cells and interferon gamma levels posttransplant, but with significantly higher alloreactive T cell levels (P < .05), thereby making a case for immunosurveillance as a predictor of disease progression and resolution.24 However, this has not been studied in the context of an anti-BKV treatment strategy.

A potentially major breakthrough in the pre­vention and treatment of BKV nephropathy was suggested by a recent longitudinal serologic study of kidney transplant recipients that used sensitive new methodologies to demonstrate that BKV subtype 1 and subtype 4 are serologically distinct.^25,26 In particular, the authors relied on BKV reporter vectors (pseudovirions) to evaluate serotype-specific neutralizing antibodies rather than more traditional recombinant virus-like particle enzyme-linked immunosorbent assays, which crucially detect both neutralizing and nonneutralizing antibodies in the latter case. With these antibody-mediated neutra­lization assays, the studies found that 5% and 49% of kidney transplant recipients were BKV subtypes 1 and 4 naïve before transplant, with 100% of the BKV subtype 1 and 43% of the BKV subtype 4 seronegative patients pretransplant seroconverted in a type-specific manner. A model was presented showing that BKV nephropathy can arise from a de novo infection arising from a BKV subtype 4-infected kidney leading to replication in immuno­compromised patients without prior exposure to this more rare BKV subtype. Interestingly, previous studies have reported higher seroprevalence of BKV subtype 4 in patients with interstitial nephritis.²⁷ Pastrana and associates argued that induction of a neutralizing antibody response to BKV subtype 4, or all subtypes, by vaccination of kidney transplant patients immunologically naïve for certain subtypes before transplant may prevent replication and BKV nephropathy associated with virus present in the transplanted organ.²⁶ In vitro enrichment of BKV-specific T cells and subsequent adoptive T-cell transfer may improve the restoration of immuno­competence in kidney transplant recipients with BKV infection.²⁸ Vaccination of potential transplant recipients with BKV antigens in conjunction with an adjuvant that preferentially induces cell-mediated immune response is a potential area for future research.

Diagnosis
More recently, the emphasis has been on surveillance for earlier diagnosis and treatment. Quantitative estimation of viral DNA in urine by polymerase chain reaction is the most frequently used screening test, but it does not provide any additional information other than the fact that the virus is present in urothelium. Persistently high BKV DNA in plasma > 4 log10 gEq/mL by quantitative polymerase chain reaction for more than 4 weeks in kidney transplant patients defines presumptive BKV nephropathy. BK virus-specific cell-mediated immune response has been a recent area of research. From available literature, BKV-specific immune monitoring has been suggested as a prognostic tool to identify patients who are at risk of BKV nephropathy.^19-23

There has been recent interest in investigating the role of the BKV micro-RNA (miRNA) in regulating virus replication. The function of the BKV miRNA was investigated in archetype BKV, which is the transmissible form of the virus and thought to establish a persistent infection in the host urinary tract. Broekema and associates²⁹ showed that the BKV miRNA targets early mRNAs and that the miRNA plays a significant role in limiting archetype BKV replication in a natural host cell model of infection. This occurs through a balance of regulatory elements located within the noncoding control region that controls early gene expression and miRNA expression before genome replication.²⁹ Li and associates demonstrated that circulating BKV-encoded miRNA (BKV-miRNA-B1) is detectable in the plasma of patients with biopsy-proven BK virus-associated nephropathy and those with significant BKV DNA in the blood. The group also showed that BKV-miRNA-B1-5p levels are highest in patients with biopsy-proven BKV nephropathy, suggesting that circulating virally encoded miRNAs may act as indicators of severity of virus replication.³⁰ Other diagnostic tools include quantitative estimation of polyomavirus-Haufen in voided urine. It has been suggested as a specific biomarker for intrarenal viral disease, with positive and negative predictive values of greater than 90%.³¹

However, allograft biopsy and histology (confirmed by immunohistochemistry or in situ hybridization) still remain the criterion standard for diagnosing BK virus-associated nephropathy.^32,33 Because of the focal nature of the disease and possibility of sampling error, a minimum of 2 c ores are recommended, preferentially containing medullary tissue.^34,35 Typical findings are focal interstitial mononuclear inflammatory cell infiltrates, presence of plasma cells, necrotic tubular epithelium, and presence of homogenous intra­nuclear inclusion bodies. Histologic findings have been classified into types A, B, and C for standardized assessment and reporting.³⁶ The Banff working group on polyoma virus nephropathy classified the disease into 3 grades based on histology to allow comparative analyses and improvement in predicting clinical presentation and outcome.³⁷ Tubular atrophy and interstitial fibrosis remain the most important predictors of poor outcome.³⁸

Risk Factors
In addition to immunosuppression, several risk factors have been proposed for BKV reactivation after kidney transplant. Grafts from BKV-seropositive donors to BKV-seronegative recipients are believed to increase the risk.^39,40 The number of HLA mismatches, ischemic injury, and prior acute rejection are associated with increased risk of BKV reactivation.^32,41,42 Recipient old age, male sex, and prior graft loss due to BKV nephropathy have also been reported to increase the risk.⁴³ Viral capsid serotype and rearrangement of control region are also believed to increase the risk for BKV reactivation.⁴⁴ It is widely agreed that, with more potent immunosuppression, there is a greater likelihood for viral replication.^32,45 However, there are conflicting reports on the effect of individual agents on BKV nephropathy.⁴⁶ It has been reported that induction with thymoglobulin (Genzyme Corporation, Framingham, MA, USA) is associated with a higher incidence of treatment for BKV compared with no induction or induction with interleukin 2 receptor blockers. Alemtuzumab does not increase rates of BK viruria, BK viremia, or BKV nephropathy compared with that shown with non-lymphocyte-depleting therapy.^47-49 Cyclosporine is believed to be associated with a lower incidence of BKV nephropathy than tacrolimus, and myco­phenolate mofetil is associated with a higher incidence of treatment for BKV compared with no antimetabolite therapy or azathioprine.^9,50-52 Whereas data on mammalian target of rapamycin inhibitors, sirolimus and everolimus, are limited, it would be safe to state that they are not associated with an increased risk of BKV nephropathy.50,53-55 It is well established that the combination of tacrolimus and mycophenolate mofetil is associated with a significantly higher risk for BKV nephropathy^56,57 (Table 1).

Treatment
Treatment is indicated for BKV nephropathy, defined by persistently high BKV in plasma > 4 log10 gEq/mL for more than 4 weeks in kidney transplant recipients, even in the absence of elevated serum creatinine levels. BK virus nephropathy usually implies excessive immunosuppression, and immuno­suppression reduction forms the mainstay of treatment. However, acute rejection is frequently observed after virus clearance.⁵⁸ The most effective strategy for early diagnosis and treatment remains regular monitoring for BKV, which is currently achieved by quantification of viral DNA in blood by quantitative polymerase chain reaction. This method of monitoring is suboptimal because there is an apparent delay between immune reconstitution and viral clearance as measured by quantitative polymerase chain reaction, often resulting in acute rejection before resumption of baseline immuno­suppression after viral clearance.

There is no perfect way to approach immuno­suppression reduction, and several strategies have been suggested. A common initial approach is to reduce the calcineurin inhibitor dose by 25% to 50% with target tacrolimus trough levels < 6 ng/mL or cyclosporine levels < 150 ng/mL. This would be followed by dose reduction of the antiproliferative agent (eg, mycophenolate mofetil) by 50% followed by its discontinuation, depending on the response, as monitored with serial quantitative polymerase chain reaction analyses in serum. An alternative approach is to first reduce the dose of the antiproliferative agent and then reduce the calcineurin inhibitor dose. Successful outcomes have also been reported with other strategies, including switching from tacrolimus to cyclosporine, calcineurin inhibitor to sirolimus, or mycophenolate mofetil to leflunomide. The BKV treatment protocol at our center is presented in Figure 1. Acute rejection is frequently observed after immunosuppression reduction to treat BKV nephropathy58 and usually follows virus clearance, further complicating treatment options. Other antiviral treatment options include those detailed below.

Leflunomide
Leflunomide is an anti-inflammatory agent ap­proved for use in rheumatoid arthritis. It has unique antiviral and immunosuppressive properties, making it useful in treatment of BKV nephropathy.^59-61 Mycophenolate mofetil is usually switched to leflunomide. A loading dose of 100 mg daily for 3 to 5 days followed by a maintenance dose of 20 to 60 mg daily with target trough levels of 50 to 100 μg/mL is recommended.⁵⁶ Significant toxic effects have been described, including hepatitis, hemolysis, thrombotic microangiopathy, bone marrow suppression, and fungal pneumonia.

Cidofovir
Cidofovir is a nucleoside analog approved for use in cytomegalovirus retinitis. Its mechanism of action against BKV is poorly understood. It is usually reserved as a last resort for refractory disease. It is primarily excreted by the kidneys but accumulates in tubular epithelial cells with potential for substantial nephrotoxicity. Concomitant administration of probenecid to reduce renal clearance can reduce toxicity. It is usually administered intravenously in doses ranging from 0.25 to 1.0 mg/kg at 1 to 3 weekly intervals. Favorable outcomes have been reported in several cases.^62-64

Brincidofovir (CMX001)
Brincidofovir (CMX001), an experimental prodrug of cidofovir, has shown antiviral efficacy and a better adverse effect profile in isolated reports of kidney transplant and hematopoietic stem cell transplant recipients.^65,66

Intravenous immunoglobulin
Intravenous immunoglobulin preparations have high titers of potent BKV-neutralizing antibodies and act by direct neutralizing activity and indirect immunomodulatory effects, resulting in successful resolution of disease.⁶⁷ It is generally used in doses ranging from 0.2 to 2.0 g/kg.

Fluoroquinolones
Fluoroquinolones exhibit modest antiviral activity by inhibiting the helicase activity of virus-encoded large T antigen, although the selectivity index is low. Ciprofloxacin has demonstrated prophylactic efficacy in both hematopoietic stem cell and kidney transplant recipients.^68,69 However, a recent double-blind, placebo-controlled randomized trial by Knoll and associates failed to demonstrate efficacy of a 3-month course of levofloxacin to prevent BK viruria.⁷⁰

Summary and Future Directions
BK virus continues to remain a challenging clinical problem in kidney transplant with a fairly significant rate of graft loss secondary to BKV nephropathy. Better surveillance with early diagnosis and treatment can prevent potential graft loss.

Recent advances in studies of BKV-related disease in kidney transplant have focused on monitoring BKV-specific cell-mediated immune response and its potential clinical applications, including predicting disease progression and resolution, differentiating between rejection and BKV infection, vaccine development, and providing a guide for treatment. Recently, interest has been directed at investigating the role of BKV miRNA in regulating virus replication and as a marker for disease severity. Newer antiviral drugs like brincidofovir have shown promise in BKV treatment in isolated case reports. Fluoroquinolones, once thought to be effective prophylactic agents, have failed to demonstrate efficacy to prevent BK viruria in a recent randomized controlled trial.

Current treatment recommendations are based on immunosuppression reduction; however, there is no consensus on the perfect strategy, thereby providing an opportunity for a multicenter randomized con­trolled trial of the common treatment strategies.

References:

1. Us D. [New, newer, newest human polyomaviruses: how far?] [Article in Turkish]. Mikrobiyol Bul. 2013;47(2):362-381.
   CrossRef - PubMed
2. Gardner SD, Field AM, Coleman DV, Hulme B. New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet. 1971;1(7712):1253-1257.
   CrossRef - PubMed
3. Chatterjee M, Weyandt TB, Frisque RJ. Identification of archetype and rearranged forms of BK virus in leukocytes from healthy individuals. J Med Virol. 2000;60(3):353-362.
   CrossRef - PubMed
4. Goudsmit J, Wertheim-van Dillen P, van Strien A, van der Noordaa J. The role of BK virus in acute respiratory tract disease and the presence of BKV DNA in tonsils. J Med Virol. 1982;10(2):91-99.
   CrossRef - PubMed
5. Leung AY, Chan M, Tang SC, Liang R, Kwong YL. Real-time quantitative analysis of polyoma BK viremia and viruria in renal allograft recipients. J Virol Meth. 2002;103(1):51-56.
   CrossRef - PubMed
6. Flaegstad T, Ronne K, Filipe AR, Traavik T. Prevalence of anti BK virus antibody in Portugal and Norway. Scan J infectious Dis. 1989;21(2):145-147.
   CrossRef - PubMed
7. Stolt A, Sasnauskas K, Koskela P, Lehtinen M, Dillner J. Seroepidemiology of the human polyomaviruses. J Gen Virol. 2003;84(Pt 6):1499-1504.
   CrossRef - PubMed
8. Hirsch HH, Knowles W, Dickenmann M, et al. Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med. 2002;347(7):488-496.
   CrossRef - PubMed
9. Brennan DC, Agha I, Bohl DL, et al. Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. Am J Transplant. 2005;5(3):582-594.
   CrossRef - PubMed
10. Hirsch HH. BK virus: opportunity makes a pathogen. Clin Infect Dis. 2005;41(3):354-360.
    CrossRef - PubMed
11. Kuypers DR. Management of polyomavirus-associated nephropathy in renal transplant recipients. Nat Rev Nephrol. 2012;8(7):390-402.
    CrossRef - PubMed
12. Hariharan S, Cohen EP, Vasudev B, et al. BK virus-specific antibodies and BKV DNA in renal transplant recipients with BKV nephritis. Am J Transplant. 2005;5(11):2719-2724.
    CrossRef - PubMed
13. Chen Y, Trofe J, Gordon J, et al. Interplay of cellular and humoral immune responses against BK virus in kidney transplant recipients with polyomavirus nephropathy. J Virol. 2006;80(7):3495-3505.
    CrossRef - PubMed
14. Drummond JE, Shah KV, Donnenberg AD. Cell-mediated immune responses to BK virus in normal individuals. J Med Virol. 1985;17(3):237-247.
    CrossRef - PubMed
15. Koralnik IJ, Du Pasquier RA, Letvin NL. JC virus-specific cytotoxic T lymphocytes in individuals with progressive multifocal leukoencephalopathy. J Virol. 2001;75(7):3483-3487.
    CrossRef - PubMed
16. Prosser SE, Orentas RJ, Jurgens L, Cohen EP, Hariharan S. Recovery of BK virus large T-antigen-specific cellular immune response correlates with resolution of bk virus nephritis. Transplantation. 2008;85(2):185-192.
    CrossRef - PubMed
17. Binggeli S, Egli A, Dickenmann M, Binet I, Steiger J, Hirsch HH. BKV replication and cellular immune responses in renal transplant recipients. Am J Transplant. 2006;6(9):2218-2219.
    CrossRef - PubMed
18. Batal I, Zeevi A, Heider A, et al. Measurements of global cell-mediated immunity in renal transplant recipients with BK virus reactivation. Am J Clin Pathol. 2008;129(4):587-591.
    CrossRef - PubMed
19. Comoli P, Azzi A, Maccario R, et al. Polyomavirus BK-specific immunity after kidney transplantation. Transplantation. 2004;78(8):1229-1232.
    CrossRef - PubMed
20. Comoli P, Binggeli S, Ginevri F, Hirsch HH. Polyomavirus-associated nephropathy: update on BK virus-specific immunity. Transpl Infect Dis. 2006;8(2):86-94. d
    CrossRef - PubMed
21. Comoli P, Cioni M, Basso S, et al. Immunity to polyomavirus BK infection: immune monitoring to regulate the balance between risk of BKV nephropathy and induction of alloimmunity. Clin Dev Immunol. 2013;2013:256923.
    CrossRef - PubMed
22. Schachtner T, Muller K, Stein M, et al. BK virus-specific immunity kinetics: a predictor of recovery from polyomavirus BK-associated nephropathy. Am J Transplant. 2011;11(11):2443-2452.
    CrossRef - PubMed
23. Schachtner T, Stein M, Sefrin A, Babel N, Reinke P. Inflammatory activation and recovering BKV-specific immunity correlate with self-limited BKV replication after renal transplantation. Transplant Int. 2014;27(3):290-301.
    CrossRef - PubMed
24. Schachtner T, Stein M, Babel N, Reinke P. The loss of BKV-specific immunity from pretransplantation to posttransplantation identifies kidney transplant recipients at increased risk of BKV replication. Am J Transplant. 2015; 15(8):2159-2169.
    CrossRef - PubMed
25. De Gascun CF, Carr MJ. Human polyomavirus reactivation: disease pathogenesis and treatment approaches. Clin Dev Immunol. 2013;2013:373579.
    CrossRef - PubMed
26. Pastrana DV, Brennan DC, Cuburu N, et al. Neutralization serotyping of BK polyomavirus infection in kidney transplant recipients. PLoS Pathog. 2012;8(4):e1002650.
    CrossRef - PubMed
27. Randhawa PS, Khaleel-Ur-Rehman K, Swalsky PA, et al. DNA sequencing of viral capsid protein VP-1 region in patients with BK virus interstitial nephritis. Transplantation. 2002;73(7):1090-1094.
    CrossRef - PubMed
28. Weist BJ, Schmueck M, Fuehrer H, Sattler A, Reinke P, Babel N. The role of CD4(+) T cells in BKV-specific T cell immunity. Med Microbiol Immunol. 2014;203(6):395-408.
    CrossRef - PubMed
29. Broekema NM, Imperiale MJ. miRNA regulation of BK polyomavirus replication during early infection. Proc Natl Acad Sci U S A. 2013;110(20):8200-8205.
    CrossRef - PubMed
30. Li JY, McNicholas K, Yong TY, et al. BK virus encoded microRNAs are present in blood of renal transplant recipients with BK viral nephropathy. Am J Transplant. 2014;14(5):1183-1190.
    CrossRef - PubMed
31. Nickeleit V, Singh HK. Polyomaviruses and disease: is there more to know than viremia and viruria? Curr Opin Organ Transplant. 2015;20(3):348-358.
    CrossRef - PubMed
32. Hirsch HH, Brennan DC, Drachenberg CB, et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation. 2005;79(10):1277-1286.
    CrossRef - PubMed
33. Hirsch HH, Steiger J. Polyomavirus BK. Lancet Infect Dis. 2003;3(10):611-623.
    CrossRef - PubMed
34. Drachenberg CB, Papadimitriou JC, Hirsch HH, et al. Histological patterns of polyomavirus nephropathy: correlation with graft outcome and viral load. Am J Transplant. 2004;4(12):2082-2092.
    CrossRef - PubMed
35. Hirsch HH, Randhawa P, AST Infectious Diseases Community of Practice. BK virus in solid organ transplant recipients. Am J Transplant. 2009;9 Suppl 4:S136-146.
    CrossRef - PubMed
36. Sar A, Worawichawong S, Benediktsson H, Zhang J, Yilmaz S, Trpkov K. Interobserver agreement for Polyomavirus nephropathy grading in renal allografts using the working proposal from the 10th Banff Conference on Allograft Pathology. Hum Pathol. 2011;42(12):2018-2024.
    CrossRef - PubMed
37. Haas M, Sis B, Racusen LC, et al. Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant. 2014;14(2):272-283.
    CrossRef - PubMed
38. Masutani K, Shapiro R, Basu A, Tan H, Wijkstrom M, Randhawa P. The Banff 2009 Working Proposal for polyomavirus nephropathy: a critical evaluation of its utility as a determinant of clinical outcome. Am J Transplant. 2012;12(4):907-918.
    CrossRef - PubMed
39. Smith JM, McDonald RA, Finn LS, Healey PJ, Davis CL, Limaye AP. Polyomavirus nephropathy in pediatric kidney transplant recipients. Am J Transplant. 2004;4(12):2109-2117.
    CrossRef - PubMed
40. Sood P, Senanayake S, Sujeet K, et al. Donor and recipient BKV-specific IgG antibody and posttransplantation BKV infection: a prospective single-center study. Transplantation. 2013;95(6):896-902.
    CrossRef - PubMed
41. Awadalla Y, Randhawa P, Ruppert K, Zeevi A, Duquesnoy RJ. HLA mismatching increases the risk of BK virus nephropathy in renal transplant recipients. Am J Transplant. 2004;4(10):1691-1696.
    CrossRef - PubMed
42. Prince O, Savic S, Dickenmann M, Steiger J, Bubendorf L, Mihatsch MJ. Risk factors for polyoma virus nephropathy. Nephrol Dial Transplant. 2009;24(3):1024-1033.
    CrossRef - PubMed
43. Ramos E, Drachenberg CB, Portocarrero M, et al. BK virus nephropathy diagnosis and treatment: experience at the University of Maryland Renal Transplant Program. Clin Transplant. 2002:143-153.
    PubMed
44. Randhawa P, Zygmunt D, Shapiro R, et al. Viral regulatory region sequence variations in kidney tissue obtained from patients with BK virus nephropathy. Kidney Int. 2003;64(2):743-747.
    CrossRef - PubMed
45. Hodur DM, Mandelbrot D. Immunosuppression and BKV Nephropathy. N Engl J Med. 2002;347(25):2079-2080; author reply 2079-2080.
    CrossRef - PubMed
46. Suwelack B, Malyar V, Koch M, Sester M, Sommerer C. The influence of immunosuppressive agents on BK virus risk following kidney transplantation, and implications for choice of regimen. Transplant Rev (Orlando). 2012;26(3):201-211.
    CrossRef - PubMed
47. Farney AC, Doares W, Rogers J, et al. A randomized trial of alemtuzumab versus antithymocyte globulin induction in renal and pancreas transplantation. Transplantation. 2009;88(6):810-819.
    CrossRef - PubMed
48. Ison MG, Parker M, Stosor V, Kaufman DB. Development of BK nephropathy in recipients of simultaneous pancreas-kidney transplantation. Transplantation. 2009;87(4):525-530.
    CrossRef - PubMed
49. Theodoropoulos N, Wang E, Penugonda S, et al. BK virus replication and nephropathy after alemtuzumab-induced kidney transplantation. Am J Transplant. 2013;13(1):197-206.
    CrossRef - PubMed
50. Dharnidharka VR, Cherikh WS, Abbott KC. An OPTN analysis of national registry data on treatment of BK virus allograft nephropathy in the United States. Transplantation. 2009;87(7):1019-1026.
    CrossRef - PubMed
51. Schold JD, Rehman S, Kayle LK, Magliocca J, Srinivas TR, Meier-Kriesche HU. Treatment for BK virus: incidence, risk factors and outcomes for kidney transplant recipients in the United States. Transplant Int. 2009;22(6):626-634.
    CrossRef - PubMed
52. Huang G, Chen LZ, Qiu J, et al. Prospective study of polyomavirus BK replication and nephropathy in renal transplant recipients in China: a single-center analysis of incidence, reduction in immunosuppression and clinical course. Clin Transplant. 2010;24(5):599-609.
    CrossRef - PubMed
53. Budde K, Becker T, Arns W, et al. Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet. 2011;377(9768):837-847.
    CrossRef - PubMed
54. Tedesco Silva H Jr, Cibrik D, Johnston T, et al. Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients. Am J Transplant. 2010;10(6):1401-1413.
    CrossRef - PubMed
55. Vincenti F, Friman S, Scheuermann E, et al. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant. 2007;7(6):1506-1514.
    CrossRef - PubMed
56. Hirsch HH, Randhawa P, AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation. Am J Transplant. 2013;13 Suppl 4:179-188.
    CrossRef - PubMed
57. Mengel M, Marwedel M, Radermacher J, et al. Incidence of polyomavirus-nephropathy in renal allografts: influence of modern immunosuppressive drugs. Nephrol Dial Transplant. 2003;18(6):1190-1196.
    CrossRef - PubMed
58. van Aalderen MC, Heutinck KM, Huisman C, ten Berge IJ. BK virus infection in transplant recipients: clinical manifestations, treatment options and the immune response. Neth J Med. 2012;70(4):172-183.
    PubMed
59. Josephson MA, Gillen D, Javaid B, et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation. 2006;81(5):704-710.
    CrossRef - PubMed
60. Williams JW, Javaid B, Kadambi PV, et al. Leflunomide for polyomavirus type BK nephropathy. N Engl J Med. 2005;352(11):1157-1158.
    CrossRef - PubMed
61. Williams JW, Mital D, Chong A, et al. Experiences with leflunomide in solid organ transplantation. Transplantation. 2002;73(3):358-366.
    CrossRef - PubMed
62. Kadambi PV, Josephson MA, Williams J, et al. Treatment of refractory BK virus-associated nephropathy with cidofovir. Am J Transplant. 2003;3(2):186-191.
    CrossRef - PubMed
63. Keller LS, Peh CA, Nolan J, Bannister KM, Clarkson AR, Faull RJ. BK transplant nephropathy successfully treated with cidofovir. Nephrol Dial Transplant. 2003;18(5):1013-1014.
    CrossRef - PubMed
64. Kuypers DR, Vandooren AK, Lerut E, et al. Adjuvant low-dose cidofovir therapy for BK polyomavirus interstitial nephritis in renal transplant recipients. Am J Transplant. 2005;5(8):1997-2004.
    CrossRef - PubMed
65. Papanicolaou GA, Lee YJ, Young JW, et al. Brincidofovir for polyomavirus-associated nephropathy after allogeneic hematopoietic stem cell transplantation. Am J Kidney Dis. 2015;65(5):780-784.
    CrossRef - PubMed
66. Reisman L, Habib S, McClure GB, Latiolais LS, Vanchiere JA. Treatment of BK virus-associated nephropathy with CMX001 after kidney transplantation in a young child. Pediatr Transplant. 2014;18(7):E227-231.
    CrossRef - PubMed
67. Sener A, House AA, Jevnikar AM, et al. Intravenous immunoglobulin as a treatment for BK virus associated nephropathy: one-year follow-up of renal allograft recipients. Transplantation. 2006;81(1):117-120.
    CrossRef - PubMed
68. Gabardi S, Waikar SS, Martin S, et al. Evaluation of fluoroquinolones for the prevention of BK viremia after renal transplantation. Clin J Am Soc Nephrol. 2010;5(7):1298-1304.
    CrossRef - PubMed
69. Sharma BN, Li R, Bernhoff E, Gutteberg TJ, Rinaldo CH. Fluoroquinolones inhibit human polyomavirus BK (BKV) replication in primary human kidney cells. Antiviral Res. 2011;92(1):115-123.
    CrossRef - PubMed
70. Knoll GA, Humar A, Fergusson D, et al. Levofloxacin for BK virus prophylaxis following kidney transplantation: a randomized clinical trial. JAMA. 2014;312(20):2106-2114.
    CrossRef - PubMed