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Nephrol Dial Transplant (2006) 21: 33643367

doi:10.1093/ndt/gfl404

Advance Access publication 23 September 2006

Current recommendations for diagnosis and managementof polyoma BK virus nephropathy in renal transplant recipients

Katrien Blanckaert and An S. De Vriese

Renal Unit, Department of Internal Medicine, AZ Sint-Jan AV, Brugge, Belgium

Keywords: nephropathy; polyoma BK virus;transplantation

Introduction

Polyoma BK virus (BKV) is a ubiquitous DNA virusfrom the papova virus family [1]. Approximately6090% of the adult population worldwide is seroposi-tive for BKV. Primary infection is usually asympto-matic, but the virus establishes latency within thegenitourinary tract [13]. Reactivation may occur inconditions associated with impaired immunity and iscommon in renal transplant recipients (1068%) [1].Only 110% of patients progress from reactivatedinfection to histologically manifest polyoma BKVnephropathy (BKVN) [1,2,4]. Up to 80% of thepatients with BKVN were reported to lose their graft,

but early reduction of immunosuppression has beenassociated with improved prognosis [2,4,5]. We willdiscuss the available diagnostic tools to identify BKVNand the current practices of adjusting the immunosup-pressive regimen. In addition, we review the availableevidence supporting the use of cidofovir and lefluno-mide in established BKVN. Finally, the approach toacute rejection complicating BKVN, including the useof immunoglobulins, will be highlighted.

Diagnostic evaluation

Clinically silent viruria always precedes BKVN, thusallowing the identification of patients at risk forBKVN and creating a window of opportunity forpre-emptive measures [2,4,6,7]. An inexpensive screen-ing tool is the examination of a Papanicolaou-stainedurine sediment for the presence of decoy cells. Theseare epithelial cells with enlarged nuclei and largebasophilic ground-glass intranuclear viral inclusions

[4,6,7]. Quantification of viruria with a polymerasechain reaction (PCR) for BKV DNA is more sensitivethan urine cytology, but gives little additional informa-tion above repeated urine cytology to justify the extraeffort and expenses [7]. The presence of circulating

virus is associated with active nephropathy, becausevirions enter the circulation through peritubularcapillaries following tubular damage. Detection ofBKV DNA in plasma with quantitive PCR hastherefore been proposed as a surrogate marker forthe diagnosis of BKVN [8]. Progression of BKVN istypically associated with increasing levels of viraemia[2]. Hirsch et al. [2,6] have suggested that a plasmaviral titre >10000 copies/ml is presumptive BKVN,even in the absence of histological evidence of BKVN.A definite diagnosis of BKVN requires the demonstra-tion of viral cytopathic changes in tubular epitheliumon a renal biopsy [1,4,7]. Stages AC have beendefined, with increasing severity and duration of theinvolvement and corresponding adverse effects on graftsurvival [1]. Standardized staging is a valuable tool torender future intervention and outcome studies morecomparable.

Treatment of BKVN

Reduction of immunosuppression

The recent surge in the incidence of BKVN iscommensurate with the widespread use of highlypotent immunosuppressive regimens. Specific drugs

or drug combinations have been associated withBKVN, in particular tacrolimus and the combineduse of tacrolimus and mycophenolate mofetil (MMF)[9,10]. In a prospective study, however, no differencewas found in the incidence of viruria and viraemia inpatients treated with tacrolimus vs ciclosporin orMMF vs azathioprine [2]. In a series of 13 BKVNpatients on various triple immunosuppressant combi-nations, no specific agent could be identified as theculprit [3]. These observations support the contentionthat the overall immunosuppressive load, rather thanindividual immunosuppressive agents, accounts for the

Correspondence and offprint requests to: An S. De Vriese, RenalUnit, Department of Internal Medicine, AZ Sint-Jan AV,Ruddershove, 10, B-8000 Brugge, Belgium.Email: an.devriese@azbrugge.be

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inability of the host to mount a successful antiviralimmune response.

The cornerstone of treatment of BKVN is adecrease in maintenance immunosuppression. Variousinterventions have been pursued, most commonlywithdrawal of MMF or tacrolimus [2,5,10,11], replace-ment of tacrolimus by ciclosporin [6,1113] and overallreduction of the immunosuppressive load [3,5,10,13].

In a retrospective analysis of 67 patients, graft survivalwas similar after reduction vs discontinuation oftacrolimus or MMF [5]. No specific threshold valuesfor drug levels or doses have been identified.

Switch to leflunomide

Leflunomide is an anti-inflammatory drug approvedfor the treatment of rheumatoid arthritis. Leflunomidehas considerable immunosuppressive potency inhuman renal and liver transplant recipients [14]. Itsactive form has substantial antiviral activity againstcytomegalovirus (CMV), herpes and BKV in vitro and

in experimental animals [15]. The rationale for the useof leflunomide in BKVN rests on these combinedimmunosuppressive and antiviral actions. In two largecase series, the same research group reported 26 and17 patients, respectively, who developed BKVN ontriple therapy with tacrolimus, MMF and steroids[15,16]. In all patients, MMF was withdrawn andleflunomide was administered at a loading dose of100 mg daily for 35 days followed by a maintenancedose of 2060 mg daily, aiming at through levels of50100mg/ml. Clearance or a progressive reduction inviral load and a stabilization or improvement of graftfunction was achieved in 84 and 88% of patients,respectively. The patients who deteriorated hadleflunomide plasma levels

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are warranted to define the optimal dose and potentialrole of immunoglobulins as first line treatment inBKVN and/or concomitant rejection.

Pre-emptive treatment of BKV replication

In patients with persistent viraemia and negativebiopsy findings, pre-emptive reduction of immunosup-pression should be considered. In a prospective study,reduction of immunosuppression by withdrawal of theantimetabolite resulted in resolution of viraemia beforethe development of BKVN, without a significant riskfor acute rejection [2].

Recommendations

Screening for decoy cells should be performed in allrenal transplant recipients every 3 months during thefirst 2 years after transplantation and annually for thefollowing 3 years, as well as in those patients whodevelop allograft dysfunction [4,7]. A positive screen-ing result should be followed by a quantitative PCR forBKV DNA in plasma. If this test is positive, a renalbiopsy is indicated [4]. Alternatively, it has beenrecommended to perform a renal biopsy if there ispersistence of decoy cells over a period of 3 months [7].Clearance of BKV after a therapeutic intervention

occurred with a t1/2of 6 h17 days [28], suggesting thatmonitoring viral load every 24 weeks is sufficient.

Confirmed BKVN should lead to prompt reductionof immunosuppression. Only opinion-based recom-

mendations can be forwarded. Hirschet al. [4] suggestedthat during the first year post-transplantation and inpatients at risk for rejection, switching (tacrolimus tociclosporin, MMF to azathioprine) or dose reduction isthe preferred strategy. In other patients, reducing tripleto dual therapy (discontinuation of tacrolimus or MMFor switching to tacrolimus/prednisone) can beattempted. Switching MMF to leflunomide is anattractive alternative strategy, pending confirmation byother research groups. However, widespread off-labeluse of leflunomide may be limited by reimbursementpolicies. Low-dose cidofovir (0.251 mg/kg dependingon renal function, given at 2-week intervals, at least four

times) can be recommended in cases refractory tomodification of maintenance immunosuppression.Whether cidofovir merits a place in the first-linetreatment of BKVN should be the subject of aprospective trial.

In patients with BKV viraema and negative biopsyfindings, pre-emptive reduction of immunosuppressionappears sensible. In patients with concurrent acuterejection, anti-rejection treatment followed by reduc-tion of immunosuppression 2 weeks later should beconsidered. In refractory cases, the use of immuno-globulins can be attempted.

Table 1. Studies using cidofovir in BKVN

Referencena Modification ofImmunosuppression

Cidofovir Outcome

[20] n 1 #CORTb, AZAc!MMFd,#TACe, stop MMF

0.25 mg/kg,then 0.42 mg/kgevery 2 weeks,? doses

1) Stable renal function2) Clearance viraemia3) Control biopsy: NAf

[22] n 4 #TAC/IVIgg

/pulse CORT or#TAC/MMF/CORT orTAC/MMF/CORT or pulseCORT/stop MMF/addrapamycine, then#TAC, stoprapamycine

0.251mg/kgevery 210 weeks,14 doses

1) Stable renal function2) Clearance viraemia3) Control biopsy: NA

[21] n 2 #TAC/MMF 0.25 mg/kgevery 2 weeks,1116 doses

1) Stable renal function2) Clearance viraemia3) Clearance BKV in biopsy

[23] n 1 #TAC/SIRh/CORT, then#TAC/CORT, SIR!MMF

0.25mg/kgevery 2 weeks,8 doses

1) Improved renal function2)Clearance viraemia3) Clearance BKV in biopsy

[18] n 2 #TAC/SIR/CORT, then!CYCi/MMF/CORT or#TAC/MMF/CORT

0.3mg/kg every2 weeks, 7 doses

1) Stable renal function(n 1), graft loss (n1)2) Clearance viraemia3) Clearance BKV in biopsy

[29] n 2 SIR/MMF/CORT!CYC/CORT or#SIR/CORT

0.250.33 mg/kgmonthly or every2 weeks, 26 doses

1) Improved renal function(n 1), graft loss (n1)2) Clearance viraemia (n1)3) Control biopsy: NA

[12] n 21j # Or or stop MMF,#TAC or TAC!CYC orstop TAC

0.51 mg/kg weekly,410 doses

1) Stable renal function.2) Decline viraemia3) Control biopsy: NA

aPatient number; bcorticosteroids; cazathioprine; dmycophenolate mofetil; etacrolimus; fnot available; gintravenous immunoglobulins;hsirolimus; icyclosporin; jof which 8 received cidofovir.

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Despite the importance of BKVN in clinicalpractice, the optimal schedule and targets of reductionof immunosuppression as well as the position ofcidofovir, leflunomide and immunoglobulins are unre-solved issues. Research efforts under the aegis ofscientific societies will hopefully lead to the availabilityof more solid guidelines in the near future.

Conflict of interest statement. None declared.

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Received for publication: 2.4.06Accepted in revised form: 13.6.06

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