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Keywords:

  • BK virus;
  • kidney;
  • nephropathy;
  • polyoma;
  • transplantation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of BKV Infection and Replication
  5. Risk Factors of PyVAN
  6. Prevention and Prophylaxis
  7. Diagnosis of PyVAN
  8. Treatment of PyVAN
  9. Acknowledgment
  10. Disclosure
  11. References

The human BK polyomavirus (BKV) is the major cause of polyomavirus-associated nephropathy (PyVAN) putting 1–15% of kidney transplant patients at risk of premature allograft failure, but is less common in other solid organ transplants. Because effective antiviral therapies are lacking, screening kidney transplant patients for BKV replication in urine and blood has become the key recommendation to guide the reduction of immunosuppression in patients with BKV viremia. This intervention allows for expanding BKV-specific cellular immune responses, curtailing of BKV replication in the graft, and clearance of BKV viremia in 70–90% patients. Postintervention rejection episodes occur in 8–12%, most of which are corticosteroid responsive. Late diagnosis is faced with irreversible functional decline, poor treatment response, and graft loss. Adjunct therapies such as cidofovir, leflunomide and intravenous immunoglobulins have been used, but the benefit is not documented in trials. Retransplantation after PyVAN is largely successful, but requires close monitoring for recurrent BKV viremia.


Abbreviations
BKV

BK polyomavirus

HSCT

hematopoietic stem cell transplantation

PyVHC

polyomavirus-associated hemorrhagic cystitis

PyVAN

polyomavirus-associated nephropathy

SOT

solid organ transplantation

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of BKV Infection and Replication
  5. Risk Factors of PyVAN
  6. Prevention and Prophylaxis
  7. Diagnosis of PyVAN
  8. Treatment of PyVAN
  9. Acknowledgment
  10. Disclosure
  11. References

The human BK polyomavirus (BKV) is linked to two major complications in transplant recipients, polyomavirus-associated nephropathy (PyVAN) in 1–10% of kidney transplant patients [1-4] and polyomavirus-associated hemorrhagic cystitis (PyVHC) in 5–15% of allogeneic hematopoietic stem cell transplant (HSCT) patients [5-8]. Both diseases occur only sporadically in patients with nonkidney solid organ transplantation (SOT) or with inherited, acquired or drug-induced immunodeficiency [9, 10]. Besides PyVAN and PyVHC, BKV has been implicated rarely in extrarenal pathologies such as pneumonia, encephalitis, hepatitis, retinitis, capillary-leak syndrome and cancer [9, 11-13]. A potential association of sustained BK viruria with acute T cell mediated rejection has been suggested [14].

Epidemiology of BKV Infection and Replication

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of BKV Infection and Replication
  5. Risk Factors of PyVAN
  6. Prevention and Prophylaxis
  7. Diagnosis of PyVAN
  8. Treatment of PyVAN
  9. Acknowledgment
  10. Disclosure
  11. References

BKV and JC polyomavirus (JCV) infections are widespread in the general population [15-17]. Primary infection with BKV occurs in the first decade of life as evidenced by increases in BKV seroprevalence to 90% and more [15, 16]. Natural BKV transmission is not resolved, but likely occurs via the respiratory or oral route [9]. Subsequently, BKV colonizes the renourinary tract as the principle site of latent infection, most likely via a primary viremia [9, 18]. In healthy BKV seropositive immunocompetent individuals, reactivation and asymptomatic urinary shedding of BKV is detectable in up to 10%, with urine BKV loads of 5 log10 genome equivalents (geq)/mL as the 75th percentile [16]. BKV type I is found in 70–80%, followed by BKV type IV in 10–20% [16]. In individuals with impaired immune functions, particularly after SOT or HSCT, asymptomatic high-level urinary BKV replication is observed with BKV loads of >7 log10 geq/mL, appearance of “decoy cells” in urine cytology and virus particles detectable by direct negative staining electron microscopy [19-21]. High-level BKV viruria only rarely leads to viremia and PyVAN in nonkidney SOT [22-26]. In kidney transplant recipients, however, approximately one third of patients with high-level viruria/decoy cells develop BKV viremia, and in the absence of any intervention, progress to histologically proven PyVAN [3, 27-29]. This progressively affects graft function and increases the risk of graft loss from <10% to more than 90% [28, 30, 31]. Because effective and safe antiviral therapies are lacking, screening for BKV replication has become the key recommendation to initiate and guide a stepwise reduction of immunosuppression. This intervention allows for expanding BKV-specific cellular immune responses, curtailing of BKV replication in the graft and clearance of BKV viremia [32-35].

Risk Factors of PyVAN

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of BKV Infection and Replication
  5. Risk Factors of PyVAN
  6. Prevention and Prophylaxis
  7. Diagnosis of PyVAN
  8. Treatment of PyVAN
  9. Acknowledgment
  10. Disclosure
  11. References

The preferential occurrence of PyVAN in kidney transplants compared to other nonkidney SOT or HSCT is striking and suggests that factors specific to transplanting this organ of BKV latency, are of importance. These include donor (organ) determinants (such as HLA-mismatches, deceased donation, high BKV-specific antibody titers interpreted as a marker of higher recent BKV exposure and possibly graft load, female gender), recipient determinants (such as older age, male gender, low or absent BKV-specific antibody titers) and modulating factors after transplantation (such as ureteric stents, acute rejection and antirejection treatment, steroid exposure, lymphocyte depleting antibodies, higher immunosuppressive drug levels, tacrolimus-mycophenolic acid compared to cyclosporine-mycophenolic acid or to mTOR inhibitor-combinations, and low or absent BKV-specific T cell responses) as well as retransplantation after graft loss due to PyVAN [3, 36-42]. There is a considerable variability of PyVAN incidence rates in different transplant centers as well as discordant results about risk factors, which may reflect differences in the immunosuppressive protocols of the respective programs.

Prevention and Prophylaxis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of BKV Infection and Replication
  5. Risk Factors of PyVAN
  6. Prevention and Prophylaxis
  7. Diagnosis of PyVAN
  8. Treatment of PyVAN
  9. Acknowledgment
  10. Disclosure
  11. References

Kidney transplant recipients should be screened for BKV replication to identify patients at increased risk of PyVAN [II-1]

Screening for BKV replication should be performed at least every 3 months during the first 2 years posttransplant, and then annually until the fifth year posttransplant (Figure 1). Using this strategy, at least 80–90% patients at risk for PyVAN can be identified before significant functional impairment of the renal allograft occurs. More frequent screening will identify additional cases and should be performed according to the center-specific incidence [43]. The following strategies have been used successfully in a larger number of adult and pediatric patients: Biweekly urine cytology for decoy cells for the first 3 months, then monthly until month 6, then every 3 months until 2 years posttransplant followed by plasma testing for BKV viremia if positive [44]; or monthly plasma screening for the first 6 months, then every 3 months until 2 years posttransplant [45-47].

image

Figure 1. Screening and management of kidney transplant patients for BKV replication and polyomavirus-associated nephropathy (PyVAN).

Download figure to PowerPoint

In a simulation model assuming an 80% efficacy to clear PyVAN and a 10% risk of precipitating acute rejection after reduced immunosuppression, screening seemed to be cost-effective for PyVAN incidence rates of more than 2.1% [48]. A cost analysis suggested that preventing PyVAN by screening and reducing immunosuppression may be cost saving after the second year posttransplant [49].

Screening for BKV replication can be done either by testing urine for high-level BKV viruria/decoy cells or by testing plasma for BKV viremia (Table 1).

  • Testing for BKV viruria has the following advantages [3, 22, 50, 51]: (a) a high negative predictive value to rule out BKV nephropathy; (b) a window period of 6–12 weeks before viremia and nephropathy; (c) being noninvasive and (d) lesser costs and instrumentation requirements than PCR in specialized centers with experienced cytopathologists available. Recently, identifying a subgroup of persistent urinary BKV shedders without viremia has been reported to be at risk for recurrent episodes of rejection-like graft dysfunction [14]. The disadvantages of urine BKV testing are: (a) low positive predictive value for PyVAN; (b) the physiological fluctuations of urine BKV loads requiring differences to be greater than 2 log10 in order to be significant and (c) delayed decline of urine BKV loads (and lack of clearance) compared to plasma BKV loads in response to reduced immunosuppression. This may increase the risk of overly reduced immunosuppression and rejection. The positive predictive value for proven PyVAN increases when high-level viruria persists for more than 2 months, but at the same time increases the risk of late diagnosis and irreversible PyVAN.
  • Testing for BKV viremia has a positive predictive value of 30–50% for proven PyVAN with a window period of 2–6 weeks. Because of this shorter window period, monthly plasma screening is preferred in many centers as it detects clinically more significant replication, and provides a widely accepted trigger for therapeutic intervention. The positive predictive value of BKV viremia increases to more than 90% when plasma BKV loads are very high (e.g. 6 log10 copies/mL), renal allograft function is impaired or when rearrangements in the BKV noncoding control region appear in the blood [28, 29, 52-55]. In patients with sustained plasma BKV DNA and loads of >4 log10 cp/mL, a diagnosis of “presumptive PyVAN” should be made in absence of demonstrable BKV replication in biopsies. Increases in serum creatinine from baseline are not required for the diagnosis of presumptive PyVAN.
  • Detection of three-dimensional viral aggregates in urine by electron microscopy has been reported to have high positive and negative predictive values for BKV nephropathy reaching >90% [56]. However, electron microscopy is not widely available and independent prospective studies confirming the utility of this diagnostic tool are warranted.

The caveats of the different strategies reside in suboptimal performance, timing and intra- and interlaboratory variability of all assays including urine cytology, electron microscopy, PCR and graft histology, particularly if performed outside of dedicated expert laboratories with implemented quality assurance [29, 57, 58]. Quantifying BKV DNA in urine and plasma specimens by PCR is key to initiating and monitoring of treatment. However, the results of different assays and laboratories cannot be considered equivalent until an international standard has become available as reference calibrator. In addition, PCR detection may be reduced by rare mutant strains to <1% compared to prototype strains indicating that target sequences and assays must be periodically re-evaluated [59-61]. Similarly, performance and interpretation of PyVAN in biopsies requires quality control regarding the biopsies, the confirmatory assays (immunohistochemistry or in situ hybridization) and histology interpretation [62].

Reducing immunosuppression should be considered for kidney transplant patients with sustained plasma BKV loads [II-1]

The following strategies and their combinations have been reported:

  • Strategy 1. First dose reduction of the calcineurin inhibitor by 25–50% in one or two steps; followed by reducing the antiproliferative drug by 50%; followed by discontinuing the latter [44, 46].
  • Strategy 2. First reducing the antiproliferative drug by 50% followed by reducing calcineurin inhibitors by 25–50% followed by discontinuing the antiproliferative drug [45].

Oral prednisone is typically tapered to 10 mg or less per day. Immunosuppression is further adapted according to the plasma and the course of serum creatinine concentration.

Both protocols appear safe and effective in adult and pediatric patients for preventing PyVAN and clearing BKV viremia with subsequent acute rejections ranging from 8–12% all of which responded to steroid treatment [44-46]. Most centers reduce immunosuppression and monitor serum creatinine in 1–2 week intervals, and the BKV load in 2- to 4-week intervals. Detailed kinetic follow-up data are sparse [51, 63]. In one study, half of the patients with presumptive PyVAN cleared BKV viremia after a one-step intervention, the first ones starting after 4 weeks. The other half required two-step interventions, with overall mean clearance achieved by 4 months [44]. Of note, despite preemptive BKV viremia-guided reduction of immunosuppression, proven PyVAN still occurred in one third of cases [44].

Proven PyVAN was characterized by higher plasma BKV loads, longer median time to clearance of BKV viremia and three steps of reducing immunosuppression in one-third of patients [44].

Diagnosis of PyVAN

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of BKV Infection and Replication
  5. Risk Factors of PyVAN
  6. Prevention and Prophylaxis
  7. Diagnosis of PyVAN
  8. Treatment of PyVAN
  9. Acknowledgment
  10. Disclosure
  11. References

Plasma BKV loads should be determined in all kidney transplant patients undergoing renal allograft biopsy for surveillance or for decline in function [II-3]

The presentation of PyVAN is initially inconspicuous, with no clinical or laboratory signs other than high-level viruria as defined by decoy cell shedding, urine BKV loads >7 log geq/mL, and BKV viremia [3, 50]. Detecting BKV viremia can guide more specific histopathology studies and impact on therapeutic management.

The definitive diagnosis of PyVAN should be sought by demonstrating PyV cytopathic changes in allograft tissue, and confirmed by immunohistochemistry or in situ hybridization (“proven PyVAN”) [II-1]

For immunohistochemistry, most centers use cross-reacting antibodies raised against the large T-antigen of the Simian virus 40 (clone PAb 416, Calbiochem). There is considerable interlaboratory variation in staining intensity and assessment of percentage of infected cells, but the binary classification of biopsies into virus positive and negative is fairly reliable. In one study of 20 biopsies with PyVAN, 50% were plasma cell rich (>15% of infiltrate) with a predominance of IgM positive plasma cells which correlated with high anti-BKV antibody levels [64]. In Pittsburgh, the overall incidence of PyVAN in plasma-cell rich biopsy material is less than 1% (unpublished observations) due to undefined factors such as the immunosuppressive regimen use.

A minimum of two biopsy cores should be taken, preferentially containing medullary tissues [II-2]

Because of the focal nature of PyVAN and the possibility of sampling error in at least 10–36.5% of cases [50], negative biopsy results cannot rule out early focal PyVAN with certainty.

The histological findings PyVAN should be semi-quantitatively assessed [II-3]

Standardized assessment and reporting is important to improve the comparability of case series. Classification of PyVAN into categories PyVAN-A, PyVAN-B and PyVAN-C is reasonably reproducible (kappa = 0.47; Ref. [65]), but may not be sufficient to provide sufficient statistical discriminatory power for clinical studies. Reporting of subgroups B1, B2 and B3 defined by the percentage of biopsy area affected should be considered (Table 2; Ref. 50). Extent of fibrosis and tubular atrophy may be the most important predictor of a poor outcome (Refs. 31,66; Table 2).

Table 1. Screening and intervention for BKV replication and nephropathy
  Diagnosis of PyVAN
Testing PossiblePresumptiveProven
  1. *A, PyVAN histology dominated by cytopathic changes; B1, B2, B3, PyVAN histology dominated by inflammatory infiltrates and tubulitis; C, PyVAN histology dominated by interstial fibrosis and tubular atrophy (see Table 2 for details). , not detectable (testing negative); cp, copies; +, detectable (testing positive); PyVAN, polyomavirus-associated nephropathy.

Urine“High-level viruria”+++
 Decoy cells (check if inflammation and/or casts)   
 BKV DNA load >7 log10 cp/mL   
 BK VP1 mRNA load >6.5 log10 cp/ng RNA   
 PyV particles (check if in clusters)   
Plasma“Viremia”++
 BKV DNA load (check if > 4log10 cp/mL)   
Biopsy“Nephropathy”+
 Viral cytopathic changes  A*
 Inflammatory infiltrates / tubulitis  B1*, B2, B3
 Interstitial fibrosis/tubular atrophy  C*
Therapy NoYesYes
Table 2. Histological patterns of PyVAN modified after [36, 50, 113, 114]
PatternDescriptionExtent of biopsy coreGraft functionRisk of graft loss
  1. Subclassification of PyVAN-B into categories B1, B2 and B3 was initially proposed by Drachenberg using both inflammation and tubular atrophy and biopsies with > 50% involvement were designated B3 [50]. However, tubular atrophy > 50% usually correlates with interstitial fibrosis > 50% which is used to define PyVAN-C. For simplicity, it is suggested that subclassification PyVAN-B be based entirely on inflammation, which is an important and independent predictor of outcome [66, 67]. The degree of viral cytopathic effect has been included in prior staging schema [36, 114], However, biopsies with the same degree of inflammation can vary widely in the frequency of viral inclusions. Moreover, an international quality assurance study indicates that immunohistochemistry techniques available in different laboratories differ substantially in their sensitivity for demonstrating virus infected tubules [62].

PyVAN-A
 Viral cytopathic changesMild≤25%Mostly baseline<10%
 Interstitial inflammationMinimal≤10%  
 Tubular atrophyMinimal≤10%  
 Interstitial fibrosisMinimal≤10%  
PyVAN-B*
 Viral cytopathic changesVariable11 – >50%Mostly impaired50%
 Interstitial inflammationSignificant11 – >50%  
 Tubular atrophyModerate<50%  
 Interstitial fibrosisModerate<50%  
 PyVAN-B1    
  Interstitial inflammationModerate11–25%Slightly above baseline25%
 PyVAN-B2    
  Interstitial inflammationSignificant26–50%Significantly impaired50%
 PyVAN-B3    
  Interstitial inflammationExtensive>50%Significantly impaired75%
PyVAN-C
 Viral cytopathic changesVariableVariableSignificantly impaired>80%
 Interstitial inflammationVariableVariable progressive failure 
 Tubular atrophyExtensive>50%  
 Interstitial fibrosisExtensive>50%  

More recently, the 2009 Banff conference formulated a working proposal in which stage A and B were defined based exclusively on the extent of viral cytopathic effect. Thereby, an identical stage can be assigned to biopsies that differ markedly in the degree of inflammation. This may turn out to problematic, because inflammation may portend an unfavorable prognosis [14, 67].

The diagnosis of acute rejection concurrent with PyVAN is only considered secure if one finds endarteritis, fibrinoid vascular necrosis, glomerulitis, or C4d deposits along peritubular capillaries [II-3]

Determining whether interstitial infiltration and tubulitis is directed against viral or tubular antigens cannot be reliably done by light microscopy. In PyVAN, C4d deposits have been observed in the tubular basement membranes, but not peritubular capillaries [56, 68]. However, one case of PyVAN with intimal arteritis and one with generalized polyomavirus vasculopathy in the skeletal muscle has been reported [69, 70]. MHC class II upregulation by the tubular epithelium has been proposed as a marker of rejection which is absent in PyVAN biopsies with acute viral tubular necrosis, but requires independent studies [71]. Molecular studies attempt to identify markers in biopsies and in urine require further investigation for utility in the routine setting [67, 72, 73].

JCV-mediated PyVAN should be considered in kidney transplant patients with histological signs of PyVAN, declining renal function and absence of BKV in blood, urine and graft tissue [III]

In rare cases, not BKV, but the related JCV has been identified histologically proven PyVAN [28, 74-76]. Although high-level viruria and decoy cell shedding was common, JCV viremia was not a consistent feature of JCV-mediated PyVAN [28]. In most cases, JCV-mediated PyVAN was cleared after reduced immunosuppression. No universal screening for JCV replication and nephropathy can be recommended given the rarity of this condition and the overall better outcome.

Treatment of PyVAN

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of BKV Infection and Replication
  5. Risk Factors of PyVAN
  6. Prevention and Prophylaxis
  7. Diagnosis of PyVAN
  8. Treatment of PyVAN
  9. Acknowledgment
  10. Disclosure
  11. References

Immunosuppression should be reduced in kidney transplant patients with proven PyVAN [II-1]

The mainstay of therapy for PyVAN in kidney transplant patients without concurrent acute rejection is reducing or discontinuing immunosuppressive drugs as outlined above [33, 44, 77, 78]. Although there are no randomized controlled trials, a number of observational studies have reported successful clearance of BKV viremia in >85%. More advanced disease may require more interventional steps, a longer time for recovery and result in a permanent loss of renal function [31, 44, 79-83].

Tacrolimus trough levels are commonly targeted to <6 ng/mL [II-3], cyclosporine trough levels to <150 ng/mL [II-3], sirolimus trough levels of <6 ng/mL [II-3], and mycophenolate mofetil daily dose equivalents of ≤1000 mg [II-3]

Further reduction may be appropriate in individual patients and more advanced disease. Recent studies suggest that lower calcineurin inhibitor levels, i.e. targeting trough levels for tacrolimus of 3 ng/mL and cyclosporine of 100 ng/mL may be appropriate [44, 84].

Additional strategies have been switching from tacrolimus to low-dose cyclosporine, or switching from the calcineurin inhibitor to low-dose sirolimus, or switching from mycophenolic acid to leflunomide or to low-dose sirolimus [III]

Successful outcomes have been reported using each of these different interventions in small case series, but there is to date no randomized controlled trial recommending one over the other strategy.

In patients with sustained high-level plasma BKV load despite adequately reduced immunosuppression, the adjunctive use of antiviral agents may be considered [III]

However, there are no randomized controlled trials providing evidence that adjunctive use of these agents is superior to timely reduction of immunosuppression.

  • Cidofovir, trade name Vistide® (Gilead), is a nucleoside analog, licensed by The Food & Drug Administration for the treatment of cytomegalovirus retinitis. Cidofovir has been administered intravenously for PyVAN in doses from 0.25 to 1.0 mg/kg at 1–3 weekly intervals, without probenecid. The patients should be followed closely by serial measurements of serum creatinine concentration, leukocyte counts, eye symptoms and vision, as well as bi-weekly plasma BKV load. Anterior uveitis was observed in 12–35% cases [85, 86]. Some studies report a stabilization of renal function [87, 88], whereas others report no demonstrable benefit [31, 85, 89-92]. Maximal blood levels of 5 ug/mL were reached [92], which are below the BKV IC-50 or IC-90 of 30–40 ug/mL [93, 94]. Clinical studies are underway in HSCT and kidney transplantation evaluating the in vitro more potent lipid-ester derivative 1-O-hexadecyloxypropyl-cidofovir (CMX001; Refs. [95, 96]).
  • Leflunomide, Trade name Arava® (Aventis) is orally administered as a replacement for discontinued mycophenolic acid with a loading dose of 100 mg for 5 days, followed by an initial maintenance dose of 40 mg. Regular blood counts and liver function tests are advisable once a month for all patients on leflunomide treatment, as well as plasma BKV loads once every two weeks. Significant toxic effects have been described including hepatitis, hemolysis, thrombotic microangiopathy, bone marrow suppression, and fungal pneumonia. Therapeutic response to leflunomide was correlated with blood levels between 40 ug/mL and 100 ug/mL in some studies [89, 97, 98], but not in others [91, 99]. However, in most studies, immunosuppression was also reduced by replacing mycophenolate and/or reducing calcineurin inhibitor dosing.
  • Intravenous immunoglobulin (IVIG) preparations have been administered in doses ranging from 0.2 to 2.0 g/kg in conjunction with reduced immunosuppression [100]. Commercially available IVIG preparations contain high titers of potent BKV neutralizing antibodies [101]. IVIG does not penetrate the intracellular compartment, but its direct neutralizing activity and plethora of indirect immunomodulatory effects could contribute to an improved resolution of active disease.
  • Fluoroquinolones can inhibit BKV replication via an effect on the helicase activity of virus encoded large T antigen but the selectivity index is low [93, 102]. This modest anti-viral effect has been associated with some prophylactic efficacy in both hematopoietic stem cell and kidney transplant recipients in several nonrandomized studies [103-105]. Treatment of well established PyVAN may not be effective [106].

Acute rejection after reduced immunosuppression for presumptive or definitive PyVAN should be treated according to standard protocols [III]

If acute rejection is diagnosed in allograft biopsies, after clearance of plasma BKV DNA and PyVAN by histology, anti-rejection treatment is indicated and a judicious increase in maintenance immunosuppression be considered. Administration of lymphocyte depleting agents should be done after careful evaluation of the competing risks of failure to control rejection and recurrence of PyVAN.

The nature and the pathophysiology of inflammatory infiltrates after clearance of BKV viremia and PyVAN may be diverse and include a response to viral infection termed immune reconstitution inflammatory syndrome (9,13,44,107). In the setting of persistent viruria (without viremia or nephropathy) biopsies with putative episodes of acute rejection that satisfy Banff criteria for diagnosis, do not always respond well to steroids [14].

Retransplantation can be considered for patients after loss of a first kidney allograft due to PyVAN, but frequent screening for BKV replication is recommended [II-2]

Retransplantation after kidney allograft loss due to PyVAN has been successfully performed in at least 118 cases, with a 93% graft survival at 3 years [108]. Therapeutic intervention for recurrent infection is needed in 17.5% of patients [108]. Surgical removal of the primary transplant has been performed in approximately half of all cases, but did not protect against recurrent BKV replication and PyVAN [109]. Safe retransplantation (with or without nephrectomy) requires the expansion of BKV-specific immune effectors that is facilitated by reduced or discontinued immunosuppression [110]. In case of retransplantation of patients with detectable plasma BKV loads, a significant decline of plasma BKV loads indicative of emerging BKV-specific immunity should be achieved and prior graft nephrectomy considered [109, 111, 112]. Induction therapy is not contraindicated after clearance of BKV replication, but extended periods of intense maintenance immunosuppression should be avoided.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of BKV Infection and Replication
  5. Risk Factors of PyVAN
  6. Prevention and Prophylaxis
  7. Diagnosis of PyVAN
  8. Treatment of PyVAN
  9. Acknowledgment
  10. Disclosure
  11. References

This manuscript was modified from a previous guideline written by Hans H. Hirsch and Parmjeet Randhawa published in the American Journal of Transplantation 2009; 9(Suppl 4): S136–S146, and endorsed by American Society of Transplantation/Canadian Society of Transplantation.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of BKV Infection and Replication
  5. Risk Factors of PyVAN
  6. Prevention and Prophylaxis
  7. Diagnosis of PyVAN
  8. Treatment of PyVAN
  9. Acknowledgment
  10. Disclosure
  11. References

The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Dr. Hirsch is on the speaker board or advisory committee for Novartis, Astellas, Pfizer and Chimerix and receives grant support from Chimerix.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of BKV Infection and Replication
  5. Risk Factors of PyVAN
  6. Prevention and Prophylaxis
  7. Diagnosis of PyVAN
  8. Treatment of PyVAN
  9. Acknowledgment
  10. Disclosure
  11. References